COURSE

GUIDE

PHS810
PHARMACOLOGY AND THERAPEUTICS IN PUBLIC
HEALTH

Course Team Dr Peter U. Bassi (University of Abuja) &

Professor Karniyus S. Gamaniel (NIPRD)-Course
Developers/Writers)
Assoc. Prof. Modupe I. Builders (Course Editor)-
Bingham University, Karu
Professor Grace Okoli (Faculty Coordinator)-
NOUN

NATIONAL OPEN UNIVERSITY OF NIGERIA

PHS810 COURSE GUIDE

© 2021by NOUN Press

National Open University of Nigeria
Headquarters
University Village
Plot 91, Cadastral Zone NnamdiAzikiwe Expressway
Jabi, Abuja

Lagos Office
14/16 Ahmadu Bello Way
Victoria Island, Lagos

e-mail: [email protected]
URL: www.nou.edu.ng

Printed 2021

ISBN: 978-978-058-307-1

All rights reserved. No part of this book may be reproduced, in any form
or by any means, without permission in writing from the publisher.

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PHS810 COURSE GUIDE

CONTENTS PAGE

Introduction and scope of Pharmacology iv

What You Will Learn in this Course iv
Course Aims vi
Course Objectives vi
Working through this Course v
Course Materials v
Study Units vi
Further Reading/Textbooks and References vi
Assessment Files viii
Tutor- Marked Assignment viii
Final Examination and grading xiii
Presentation Schedule ix
Course Marking Scheme ix
Course Overview ix
How to Get the Most from this Guide x
Facilitators/ Tutors and Tutorials x
Summary xiii

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PHS810 COURSE GUIDE

INTRODUCTION

Pharmacology in Public Health

PHS 810: Pharmacology and Therapeutics in Public is a biomedical

science that is concerned with the study of drugs and their actions on
biological systems (living cells, tissues, organs, whole animals) including
the human body. This is the science that deals with all experiments,
researches and preparations before pills, syrups, ointments and other
pharmaceutical dosage forms come in retail to the drugstores. The
importance of this science can hardly be exaggerated, since it is referred
to the human health and person’s well-being. Drugs can treat different
illnesses and improve general physical and mental state of a person, but at
the same time their wrong usage, mistaken dosage or at least minimally
incorrect calculations can lead to unacceptable health outcome. A number
of medical and disease conditions are attributed to improper use of drugs
and chemical substances. In order to deal with such health situations
professionally, the public health practitioner needs to be armed with the
basic principles of pharmacology and a good understanding of the
characteristics and dynamics of drug actions in man.

Understanding the population perspective of the availability and use of

drugs and medicines have been referred to as public health pharmacology.
The study is aimed at informing society about the required pharmaco-
therapeutic resources and their best use for the common therapeutic good
of the whole population and to fulfil the universal human right to adequate
health care.

WHAT YOU WILLLEARN IN THIS COURSE

The course will bring to you the knowledge of pharmacokinetics,

pharmacodynamics, metabolomics and Pharmacogenetic into focus as
important phenomenon in drug actions and effects. Furthermore,
therapeutic and adverse drug effects shall be studied in details to acquaint
you understand the issues of drug compliance, substance abuse, drug
interactions and toxicology needed by public health professional.
Emerging public health issues related to pharmaceuticals and
phytochemicals would be discussed under evidence-based pharmaco-
therapeutics. The Courses consist of units and course guides. The course
guides describe briefly the course and its specific objectives and also helps
you to know how to go about your Tutor- Marked Assignment (TMT)
which will form part of your overall assessment at the end of the course.
Also, there will be regular tutorial classes that are related to this course,
where you can interact with your facilitator and other students. Please, I
encourage you to attend these tutorial classes.

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COURSE AIMS

The course aims to you understanding ability to apply

Pharmacokinetic/Pharmacodynamic principles in solving Public Health
problems.

COURSE OBJECTIVES

To achieve the aims set out, the course has a set of objectives. Each unit
has specific objectives which are included at the beginning of the unit.
You should read these objectives before you study the unit. You may wish
to refer to them during your study to check on your progress. You should
always look at the unit objectives after completion of each unit. By doing
this, you would have followed the instructions in the unit.
The comprehensive objectives of the Course are given below. By the end
of the course/after going through this course, you will be able to:

 define the terms in Pharmacology

 identify the basic principles of Pharmacokinetics and
Pharmacodynamics
 analyse mechanisms of drug action of drug used in various diseases
 explain therapeutics and adverse effects of drugs sufficient enough
for a public health office to deal with situations involve in;
 describe drug compliance
 discuss substance abuse
 describe drug interaction and Toxicology
 manage emerging public health problems related to
Pharmaceuticals and phytomedicines such as evidence medicine

WORKING THROUGH THE COURSES

To complete each course, students are required to read each course unit,
read the recommended textbooks and other materials which may be
provided by the National Open University of Nigeria.

Each course unit contains self-assessment exercises and at certain points

in the course students would be required to submit assignments for
assessment purposes. At the end of the course, there is a final examination.
A course should take about a total of 20 weeks to complete. Below, you
will find listed, all the components of the course, what you have to do and
how you should allocate your time to each unit in order to complete the
course on time and successfully.

This course entails that you spend a lot of time to read and holding group
discussions. I would advise that you avail yourself the opportunity of

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attending the tutorial sessions where you have the opportunity of

comparing your knowledge with that of other people.

THE COURSE MATERIALS

i. The main components of a given course are:

ii. The Study Guide
iii. Study Units
iv. References/Further Reading
v. Assignments
vi. Presentation Schedule

STUDY UNITS

The course has 9 study units arranged in 3 modules as given below.

MODULE 1 BASIC PRINCIPLESOF PHARMACOLOGY

Unit 1 Basic Principles and Pharmacokinetics

Unit 2 Toxicology and Adverse Drug Reaction
Unit 3 Drug Discovery/Development/Toxicity
/Phytomedicine

MODULE 2 APPLIED PHARMACOLOGY IN PUBLIC

HEAL TH

Unit 1 Principles of Drug Action and Effects

(Pharmacodynamics)
Unit 2 Mode of Action of Antimicrobial and
Chemotherapeutic Drugs
Unit 3 Mode of Drug Action in Diseases

MODULE 3 PHARMACOTHERAPEUTICS IN PUBLIC

HEALTH

Unit 1 Taking Drug History and Evidence Based

Medicine
Unit 2 Pharmacovigilance/Pharmacovigilance in Public
Health Programmes
Unit 3 Rational Use of Medicines/Drug Dependence and
Substance Abuse

Module -1: This unit focuses on the basic principles of pharmacology and
consists of three broad units. Unit 1, focuses on the nature and sources of
drugs. Unit one is centred on pharmacokinetic processes which are

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concerned with drug administration, absorption and bioavailability,

distribution and elimination (by metabolism and excretion). The students
will learn some basic description of pharmacokinetic characteristics of
drug can provide a great deal of information of relevance therapeutically
and/or toxicological effects. Consequences of metabolism
(biotransformation), drug interaction, concept of renal clearance,
pharmacokinetics changes in pregnancy and lactation, placental transfer
of drugs, pharmacokinetics in children and the elderly and geriatric. Unit
2, focusses on toxicology and adverse drug reactions. The definition of
terms in toxicology, purpose of toxicology, historical perspective of
toxicology, toxicology sub-discipline, routes drug toxicity, mechanisms of
drug toxicity, classification of toxic agents, and poisons that can heal.
Adverse drug reactions are centred on adverse drug reaction classification,
types and causes of adverse drug reactions, risk factors of adverse drug
reactions and factors masking adverse drug reactions. In unit 3 of this
module, the student will learn drug development and phytomedicine that
deals with preclinical drug discovery, clinical drug development, (phases
of development, ethics in clinical trials, clinical trial design, phases of
clinical trials,) and how to appraise a clinical trial. Also, phytomedicine,
its introduction and historical background, characteristics of
phytomedicines, uses of herbal preparations, preparations of herbal
medicines, standardized phytomedicines, routes administration of herbal
medicines, safety issues in the use of phytomedicines, challenges of
phytomedicine and the future of herbal medicine.

Module 2, Brings the understanding of the principles of drug action

(pharmacodynamics), in man, types (mechanism) of drug action, receptor
families, the basis of affinity and efficacy, graded drug dose response,
potency and efficacy, therapeutic window, factors modifying drug effects
in man, assaying receptor affinity and binding, and monitoring drug
therapy. Basic mode of action of antimicrobial drugs, definition of terms
in antimicrobials, types of antimicrobials, features of antimicrobial drugs,
anti-infective drugs, anti-bacterial, antifungal, antiviral, cancer
chemotherapy, general introduction and goals of cancer chemotherapy,
cell cycle (cell proliferation), classifications and mechanisms of action of
antineoplastic drugs, principles of cancer chemotherapy, factors that
determine cancer drug response, resistance of cancer cells to
chemotherapy. Adverse effects of antineoplastic drugs. Also,
antiprotozoal and anthelminthic. Mode of action of drug acting on specific
diseases, such as drug acting on the uterus (uterotonics and tocolytics),
uterine relaxants, hypertensive disorders in pregnancy, anticonvulsants,
contraception and pregnancy, anti-diabetes, drug acting on the heart,
cardiac failure, antihypertension, drug acting on pain, drug action on
pregnancy and lactation, drug therapy in young, drug therapy in elderly
and geriatric.

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Module 3, enables the student to learn pharmacotherapeutics issues

relating to public health. unit 1 focusses on taking drug history &evidence-
basedmedicine. This includes objectives obtaining medication history,
taking drug history, information sources, challenges with difficult clients,
questions to ask, tips for performing medication history, client education,
tools, reconciliation and documentation. The other aspect of unit 1
introduces the students to the concepts of evidence-based medicine (EBM)
as it relates to modern therapy, sources of Information for EBM general
concepts of evidence-based medicine, theories and method, steps of emb
model, some cases and examples of how to practice EBM, benefits, -why
evidence-based medicine and limitations of EBM. unit.2:
pharmacovigilance/pharmacovigilance in public health programmes.
Pharmacovigilance as science of ADR reporting, origins of
pharmacovigilance (era of safety monitoring, detection of adverse drug
reactions, causality assessment, uses and limitation of causality
assessment. Pharmacovigilance in public health programmes. unit+ 3,
deals with rational use of medicines/drug dependence and substance
abuse, example of over the counter (OTC) drugs, common inappropriate
prescribing practices, irrational drug combinations, obstacles/reasons
irrational use , factors underlying irrational use of drugs, impact of
inappropriate use of drugs, the role of hcps in promoting rational drug use,
objectives, changing a drug use problem: an overview of the process,
strategies to improve use of drugs and, prescriber and dispenser. This unit
drug dependence and substance abuse, the burden of substance abuse,
classification of drug dependence/substance abuse, diagnosis of drug
dependence / substance abuse, management of substance
abuse/dependence.

FURTHER READING/ TEXTBOOKS/REFERENCES

Further reading links have been provided at the end of each module. This
will help you in your exercises and forms part of your course materials
where your assessment and final examination questions shall be derived.
Ensure you download and read them.

ASSESSMENT

There are three aspects of the Assessment of the course. First is made of
self- assessment exercise, second consists of the tutor marked Assignment
(continuous assessment) and third is the final examination at the end of
the course. You are advised to do the exercises and go through the further
reading links provided at the end of each module. In tackling the
assignments, you are expected to apply information, knowledge and
techniques you gathered during the course. The assignments must be
submitted to your facilitator for formal assessment in accordance with the
assignment file. The work you will submit to your tutor for assessment

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will count for 30% of your total course work. At the end of the course, you
will need to sit for a final or end of course examination of about three-hour
duration. The examination will count for 70% of your total course mark.

TUTOR MARKED ASSIGNMENTS (TMAs)

The TMA is a continuous assessment component of your course. It

accounts for 30% of the total score. You will be given four (3) TMAs to
answer. Three of them must be answered before you are allowed to sit for
the end of course examination. The TMAs would be given to you by your
facilitator and returned after you have done the assignment. Assignment
questions for the units in this course are contained in the assignment file.
You will be able to complete assignment from the information and the
material contained in your reading, references and study units. However,
it is desirable in all degree level of Education to demonstrate that you have
read and researched more into your references, which will give you a
wider view point and may provide you with a deeper understanding of the
subject.

Make sure that each assignment reaches your facilitator on or before the
dead- line given in the presentation schedule and assignment file. If for
any reason, you cannot complete your work on time, contact your
facilitator before the assignment is due to discuss the possibility of an
extension. Extension will not be granted after the due date unless there are
exceptional circumstances.

FINAL EXAMINATION AND GRADING

The end of course examination for Public Health Pharmacology will be

for about two(2) hours and or has a value of 70% of the total course work.

The examination will consist of questions, which will reflect the type of
self-testing, practice exercise and tutor marked assignment problems you
have previously encountered. All areas of the course will be assessed.

Use the time between finishing the last unit and sitting for the examination
to revise the whole course. You might find it useful to revise yourself test,
TMAs and comments on them before the examination. The end of course
examination covers information from all parts of the course.

PRESENTATION SCHEDULE

There is a time-table prepared for the early and timely completion and
submission of your TMAs as well as attending the tutorial classes. There
are three modules and three units in each, followed by TMA. The course
is of 15 weeks duration and you are expected to spend 3 hours per week

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in your study and preparation (see table 2). You are required to submit all
your assignments at the stipulated time and date. Avoid falling behind the
schedule time. The presentation schedule included in this course guide
provides you with important dates for completion of each e-tutor marked
assignment (e-TMAs). You should therefore try to meet the deadlines.

TABLE 1: COURSE MARKING SCHEME

Assignment Marks
Tutor Marked Three Tutor Marked Assignments, three
Assignment – 3 marks of 10%each, 30% of the course marks
End of course 70% of overall course marks
Examination
Total 100% of course materials

Table 2: COURSE OVERVIEW

Unit Title of Work Weeks Assignment

Activity (End of
Units)
Course Guide Week
1 Basic Principles of Pharmacokinetics Week -1 Assignment1
2 Toxicology &Adverse Drug Reaction Week -2 Assignment2
3 Drug Week -3 Assignment3
Development/Toxicity/Phytomedicine
1 Principles of Drug Action Week -4 Assignment4
(Pharmacodynamics)
2 Mode of Action of Antimicrobial & Week-5 Assignment5
Chemotherapeutic Drugs
3 Mode of Drug Action in Diseases Week -6 Assignment6
1 Taking Drug History & Evidence Week -7 Assignment7
Based Medicine
2 Pharmacovigilance/Pharmaco. in Week -8 Assignment8
Public Health Programmes
3 Rational Use of Medicines/Drug Week -9 Assignment9
Dependence and Substance Abuse

HOW TO GET THE MOST OUT OF THIS COURSE

In distance learning, the study units replace the university lecturer. This is
one of the huge advantages of distance learning mode; you can read and
work through specially designed study materials at your own pace and at
a time and place that suit you best. Think of it as reading from the teacher,
the study guide tells you what to read, when to read and the relevant texts
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to consult. You are provided exercises at appropriate points, just as a

lecturer might give you an in-class exercise. Each of the study units
follows a common format. The first item is an introduction to the subject
matter of the unit and how a particular unit is integrated with the other
units and the course as a whole. Next to this is a set of learning objectives.
These learning objectives are meant to guide your studies. The moment a
unit is finished, you must go back and check whether you have achieved
the objectives. If this is made a habit, then you will significantly improve
your chances of passing the course. The main body of the units also guides
you through the required readings from other sources. This will usually be
either from a text- book or from other sources. Self-assessment exercises
are provided throughout the unit, to aid personal studies and answers are
provided at the end of the unit. Working through these self-tests will help
you to achieve the objectives of the unit and also prepare you for tutor
marked assignments and examinations. You should attempt each self-test
as you encounter them in the units.

The following are practical strategies for working through this course

i. Read the Course Guide thoroughly.

ii. Organize a study schedule. Refer to the course overview for more
details. Note the time you are expected to spend on each unit and
how the assignment relates to the units. Important details, e.g.
details of your tutorials and the date of the first day of the semester
are available. You need to gather together all this information in
one place such as a diary, a wall chart calendar or an organizer.
Whatever method you choose, you should decide on and write in
your own dates for working on each unit.
iii. Once you have created your own study schedule, do everything you
can to stick to it. The major reason that students fail is that they get
behind with their course works. If you get into difficulties with your
schedule, please let your tutor know before it is too late for help.
iv. Turn to Unit 1 and read the introduction and the objectives for the
unit.
v. Assemble the study materials. Information about what you need for
a unit is given in the table of contents at the beginning of each unit.
You will almost always need both the study unit you are working
on and one of the materials recommended for further readings, on
your desk at the same time.
vi. Work through the unit, the content of the unit itself has been
arranged to provide a sequence for you to follow. As you work
through the unit, you will be encouraged to read from your text
books.
vii. Keep in mind that you will learn a lot by doing all your assignments
carefully. They have been designed to help you meet the objectives
of the course and will help you pass the examination.

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viii. Review the objectives of each study unit to confirm that you have
achieved them. If you are not certain about any of the objectives,
review the study material and consult your tutor.
ix. When you are confident that you have achieved a unit’s objectives,
you can start on the next unit. Proceed unit by unit through the
course and try to pace your study so that you can keep yourself on
schedule.
x. When you have submitted an assignment to your tutor for marking,
do not wait for its return before starting on the next unit. Keep to
your schedule. When the assignment is returned, pay particular
attention to your tutor’s comments, both on the tutor- marked
assignment form and also that written on the assignment. Consult
you tutor as soon as possible if you have any questions or problems.
xi. After completing the last unit, review the course and prepare
yourself for the final examination. Check that you have achieved
the unit objectives (listed at the beginning of each unit) and the
course objectives (listed in this course guide).

FACILITATORS / TUTORS AND TUTORIALS

These are 20 hours of tutorials provided in support of this course you will
be notified of the dates, times and location of these tutorials as well as the
name and phone number of your facilitator, as soon as you are allocated a
tutorial group. Your facilitator will Mark and comment on your
assignments, keep a close watch on your progress and any difficulties you
might face and assistance will be provided to you during the course. You
are expected to mail your Tut or Marked Assignment to your facilitator
before the schedule date (at least two marking days are required). They
will be marked by your tutor and return to you as soon as possible. Do not
delay to contact your facilitator by telephone or e-mail if you need
assistance.

The following might be circumstances in which you will find assistance

necessary, hence you will have to contact your facilitator if:

 You do not understand any part of the study or the assigned

readings.
 You have difficulty with the self –tests.
 You have a question or problem with an assignment or with the
grading of an assignment.

You should endeavour to attend the tutorials. This is the only chance to
have face to face contact with your course facilitator and to ask questions
which are answered instantly. You can raise any problem encountered in
the course of your study. To gain much benefit from course tutorials,

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prepare a question list before attending them. You will learn a lot from
participating actively in discussions.

SUMMARY

You should endeavour to attend the tutorials. This will afford you an
opportunity to have face to face contact with your course facilitators and
to ask questions which are answered instantly. You can raise any problem
encountered in the course of your study.

This course is a study unit of clinical skills. But tutorials and practical
clinical skills – will be covered only by a practical attachment in hospital.
To gain more benefits from the course tutorials, please prepare a list of
questions before attending them. You will learn a lot from participating
actively in discussions. I wish you success in the course and I hope that
you will find it both interesting and useful.

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COURSE

CONTENTS PAGE

Module 1 Basic Principles of Pharmacology 1

Unit 1 Basic Principles and Pharmacokinetics..……. 1

Unit 2 Toxicology and Adverse Drug Reaction……. 55
Unit 3 Drug Discovery/Development/Toxicity
/Phytomedicine……………………..……….. 86

Module 2 Applied Pharmacology in Public Health…. 115

Unit1 Principles of Drug Action and Effects

(Pharmacodynamics)………………………… 115
Unit2 Mode of Action of Antimicrobial and
Chemotherapeutic Drugs…………………… 145
Unit3 Mode of Drug Action in Diseases…………… 196

Module 3 Pharmacotherapeutics in public Health…… 252

Unit 1 Taking Drug History and Evidence Based

Medicine…………………………………….. 252
Unit2 Pharmacovigilance/Pharmacovigilance in
Public Health Programmes…………………… 279
Unit 3 Rational Use of Medicines/Drug Dependence
and Substance Abuse…………………………. 308
PHS 810 MODULE 1

MODULE 1 BASIC PRINCIPLESOF

PHARMACOLOGY

Unit 1 Basic Principles and Pharmacokinetics

Unit 2 Toxicology and Adverse Drug Reaction
Unit 3 Drug Discovery/Development/Toxicity/Phytomedicine

UNIT 1 BASIC PRINCIPLES OF PHARMACOKINETICS

CONTENTS

1.0 Introduction
2.0 Objectives
3.0 Main Content
3.1 Definition of Terms
3.2 The Nature and Sources of Drugs
3.3 Pharmacokinetics Processes
3.4 Drug absorption
3.4.1 Routes of Drug Absorption
3.4.2 The advantages and disadvantages of oral Absorption
3.4.3 Parenteral administrations
3.4.4 The advantages and disadvantages of Parenteral
route
3.4.5 Mechanisms of Transport (Absorption)
3.4.6 Barriers to absorption:
3.5 Bioavailability (F)
3.6 Eliminations Half-Life
3.6.1 Therapeutic Window
3.6.2 Steady-State Concentrations
3.7 Drug distribution
3.7.1The factors determining the pattern of distribution
3.8. Drug Metabolism
3.8.1 Introductions
3.8.2 Sites of metabolism
3.8.3 First-pass elimination
3.8.4 Cytochrome P450 (Classification, Role of sub-
families, Structure)
3.8.5 Stages of metabolism
3.8.6 Mechanisms of drug metabolism
3.9 Drug interaction
3.9.1 Types of drug interactions
3. 9 .2 Patterns of Drug-Drug interactions:
3.9.3 Clinically significant interactions
3.9.4 Minimising interactions
3.10 Renal Drug Clearance (Excretion)
3.10.1 Routes of Drug Elimination

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PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

3.10.2 Processes of Renal Drug Excretion

3.10.3Concept of Renal Clearance
3.11 Pharmacokinetic Changes in Pregnancy and Lactation
3.11.1 Introduction
3.11.2 Absorption
3.11.3 Distribution
3.11.4 Metabolism
3.11.5 Elimination:
3.11.6 Placental Transfer of Drugs
3.11.7 Factors affecting placental drug transfer & fetal tissue
4.0 Conclusion
5.0 Summary
6.0 Tutor- Marked Assignment (TMA)
7.0 References/Further Reading

1.0 INTRODUCTION TO PHARMACOKINETICS

Pharmacokinetics principles and processes are concerned with the

absorption, distribution, and elimination (by metabolism and excretion) of
drugs. In pharmacokinetics we try to answer the following questions; 1. Is
the drug getting into body (through serum/plasma concentration
estimate)? 2. Is the drug getting to the site of action and at what rate/extent
(bioavailability, steady state concentrations)? 3. How long does it stay
before the body gets rid of it (half-life, metabolism and excretion)? and 4.
Are the pharmacological activities being translated into therapeutic effects
(therapeutic process)?

Thus, proper mathematical description of pharmacokinetic characteristics

of a drug can provide a great deal of information of relevance to both the
pharmacological and the therapeutically or toxic effects. By the study of
pharmacokinetic process individual and inter-individual variability in
absorption, distribution, metabolism and excretion of drugs can be
defined. Such studies have contributed much to our understanding of the
variability of response to drug.

2.0 OBJECTIVES

By the end of this unit, you will be able to:

 identify basic concepts and scientific underpinnings of the

pharmacological sciences
 list various terminologies used in Pharmacokinetics and
Pharmacodynamics
 describe both the theoretical and applied aspects of
pharmacokinetics like bioavailability, bioequivalence, half-life,
order of kinetics, steady state plasma concentration.

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 explain how the total clearance of a drug determines its steady

state plasma concentration through continuous administration
 state theoretical and clinical significance of drug
metabolism, clearance, drug - drug interactions and
Pharmacokinetic changes in Pregnancy.

3.0 MAIN CONTENT

3.1 Definition of Terms

i. Drug: (There is no single satisfying definition) but can be defined

as chemical agents that interact with specific target molecules,
thereby producing a biological effect.
WHO 1996 Define drug as any substance or product that is used or
intended to be used to modify or explore physiological system or
pathological states for the benefit of the recipients.
Dutch word “droog” means dry, used for treatment of disease, for
the prevention of illness of pathologic states and for diagnosing
disease condition.

ii. Pharmacology: Pharmacology is defined as (from the Greek

word; pharmakon = “drugs” (áµaƘ0) i.e. drug and the word
logos (λό‫צ‬Ģ), study, explore or science)Is the scientific study of
the origin, nature, chemistry, effects, and uses of drugs. It deals
with how drugs interact within biological systems to effect
function. A branch of knowledge that has to do with the chemicals
that have biological effects.

Pharmacology Simply: the science of drug actions and uses.

Pharmacologists work to identify drug targets in order to learn how

drugs work. Pharmacologists also study the ways in which drugs
are modified within organisms. A fundamental knowledge of the
underlying biological processes is required to achieve these
objectives and to identify new targets for future therapeutic
intervention. Thus, pharmacologists study many basic aspects of
cellular and molecular biology. Pharmacy: often confused with
pharmacology, is a wholly separate profession concerned with the
preparation, dispensing and use of medications. Whereas pharmacy
can be viewed as a profession that is part of health care delivery
and information systems, pharmacology is a basic biomedical
scientific discipline.

In recent years, there has been a dramatic increase in the rate at

which novel drugs are discovered and marketed. As a consequence,

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PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

it is essential to train a new generation of pharmacologists who will

meet the challenges this opportunity presents.
iii. Clinical pharmacology: is the division which deals with the
pharmacological effects of drugs in man. It provides information
about the usefulness, potency, and toxicity of new drugs in humans.
It is of great importance for the effective and safe use of drugs in
man.

iv. Medicine: Is a chemical preparation, which usually but not

necessarily contains one or more drugs, administered with the
intention of producing a therapeutic effect, (Medicine usually
contain other substances (excipients, stabilisers, solvents etc.)

Note: To count as drug the substance must be administered as such, rather

than released by physiological mechanism.

Toxicology (Greek toxikon means poison) Toxicology is the science of

poisons, their sources, chemical composition, action, tests for
detection and antidotes. It forms a major part of forensic and
environmental medicine. All drugs are potential poisons when
given in high doses.

v. Clinical toxicology deals with the detection, diagnosis and

treatment of poisoning.

vi. Toxicodynamic: describes the harmful effects that the poison

produces on the body. Toxicokinetic: encompasses the absorption,
distribution, biotransformation and elimination of the poison.

vii. Pharmacogenetics: is a relatively new field, which deals with the

study of genetically determined variation in drug response.

viii. Pharmacokinetics: Literally, movement of the drug within the

body (“what the body does to the drug”).

ix. Pharmacodynamics: Is study of the biochemical and

physiological effects of drugs as well as their mechanism of action.
Simply. The study of what the drug does to the body – The
mechanism of drug actions in living tissues, Mechanisms of action
(“what the drug does to the body”).

x. Therapeutics: Use of drugs for intended clinical benefits – cure of

a disease, relief of symptoms etc.

xi. Pharmacotherapeutics. – study of how drug may be used in the

treatment of disease – which among the drugs would be most

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effective or appropriate for a specific disorder or what dose would

be required. – Use of drugs and clinical indications of drugs to
prevent and treat disease.

xii. Pharmacogenetics. – The study of genetically-determined

reactions of drugs in the human body.

xiii. Absorption: is how the drug enters the blood

xiv. Distribution: how the drug travels in the blood and how it goes
into and out of other areas of the body.

xv. Metabolism: how the body changes a drug usually in intestine and
liver.

xvi. Drug Elimination: how the body gets the drug out via kidneys
through urine or via liver though stool.

3.2 The Nature and Sources of Drugs

3.2.1. Sources of Drugs Include

1. Plant sources: Plants Important source of chemicals developed

into drugs e.g. Digitalis, morphine, atropine, Quinine and some
vitamins
2. Animal sources e.g., Animals Products e.g. Insulin =Cow and pig
pancreas tissue, Thyroid drugs (thyroxine),& growth hormones =
animal thyroid/hypothalamus tissues

3. Mineral sources: Mineral/Inorganic Products Elements with

therapeutic effects in human body e.g. lithium, Liquid paraffin,
magnesium sulfate, Aluminium, Fluoride etc.

4. Microorganisms e.g. penicillin’s cephalosporins & other

antibiotics

5. Synthetic e.g. Aspirin, Sulfonamides, benzodiazepines,

phenothiazines, some vitamins

6. Bioengineered (recombinant DNA technology) e.g. human

insulin, human growth hormone.

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3.3 Pharmacokinetics (Pk) Processes

The term ‘pharmacokinetics’ refers to the rate and manner in which a drug
is absorbed, distributed, metabolised and eliminated within and from the
body. It is a tool for describing the movement of drug through the body
over time, and deals with the processes of absorption from the site of
administration, distribution throughout the body, metabolism or
conjugation of the drug and elimination from the body. Study of the
relationship between dose, amount of drug in the body and therapeutic
or toxic effects of a drug

The study of drug therapy encompasses four main processes;

Pharmaceutical process, Pharmacokinetic process, Pharmacodynamic
process and Therapeutic process

i. Pharmaceutical Process: i.e. is the drug getting into the patient?

Drug in dosage form, GIT, Hepatic Metabolism
ii. Pharmacokinetic Process: Is the drug getting to the site of action?
Extracellular fluid (protein bound), tissue site of action,
iii. Pharmacodynamic Process: Is the drug producing the required
Pharmacological effects?
iv. Therapeutic Process: Is the pharmacological Effect being
translated into a Therapeutic effect?

3.3.1 Why study pharmacokinetic?

You administer drugs (dose) because you seek a certain effect (response).
A complex chain of events links the administered dose to the observed
response. Pharmacokinetics determine the blood concentration from a
prescribed dosing regimen. More often the plasma concentration for
analytical purposes. Pharmacokinetic data help us understand: dose and
schedule (once a day vs. twice a day, etc.), dose adjustments due to drug
interactions and other issues. Pharmacokinetics is essential for
determining dosing regimens.

An understanding of pharmacokinetics should therefore help the clinician

to:

i. Appreciate how dosage regimen are devised

ii. Tailor a dosage regimen to the individual requirements of the
patient (e.g. in renal failure)
iii. Determine what may be wrong when a patient fails to response to
treatment
iv. Determine why a drug has caused toxicity
v. Elucidate the mechanism of drug interactions.

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3.3.2 Why study Pharmacokinetic?

Pharmacokinetic study enables the clinician ask, am I getting the dose,

right?

Achievement of the correct dose for individual patients is fundamental to

clinical practice. Below a certain threshold concentration, the drug is
inactive and above a certain concentration, side effects appear. Therefore,
the dose should be aimed to be within the therapeutic window. Fig. (1)
The therapeutic dose can vary between patients depending on a number of
factors.

Figure 1: Therapeutic Range of a right dose. (Mathijssen (2014)

3.3.3 Importance of drug concentration

i. Ideally, drug concentration should be measured at the receptor.

ii. Blood or plasma level is used as a measure to reflect the
concentration.
iii. You need to identify the ideal concentration-time profile.
iv. Knowledge of individual pharmacokinetic parameters allows you
to manipulate dosage regimens.
v. You need to understand the pharmacokinetic characteristics of the
drug and the physiological processes that are going on.
vi. Pharmacokinetics is based on the analysis of drug concentrations.
In the graphic, after one or more doses, the drug concentration in
the desired matrix is measured.

3.4 Absorption

Drug Absorption is the process by which drug proceeds from the site of
administration to the site of measurement (blood stream) within the body.

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Irreversible transfer processes, which a drug from its site of administration

to the systemic circulation.

Absorption is the movement of unchanged drug from the site of

administration into the blood. Drug absorption is nnecessary for the
production of a therapeutic effect. The movement of drug through
membranes is an essential step in absorption and is influenced by the

i. Routes of administration
ii. Physicochemical properties of the drug
iii. The nature of the membrane
iv. The perfusion of the absorption site and the local pH.
v. Formulation, for example, tablets, capsules or solutions

For most drugs, there are a direct relationship between pharmacological

response and concentration at the receptor; thus, to be biologically active,
drug must gain access to the systemic circulation. Plasma drug
concentration depends on both drug kinetics and the design of the drug
delivery system.

Table 1: Routes of drug absorption

Oral Sublingual: drug dissolved under the tongue and Transdermal
absorbed through mucous membranes into
bloodstream
Rectal Inhalational Intestinal Parenteral: intravenous,
intramuscular and subcutaneous

3.4.1 Oral administration

The most commonly used delivery systems involve absorption of drug

from the gastrointestinal tract following buccal, sublingual, rectal or most
often, oral administration. Commonly encountered oral drug forms
include: includes Solution, Suspension, Capsules, Tablets, Coated tablets
and Modified-release tablets.

i. Coated tablets – it is possible to alter the delivery and apparent

kinetic of a drug by changing the dissolution characteristics of the
tablet. Thus, a table may be enteric-coated to prevent breakdown in
the stomach, ensuring that it remains intact until it reaches the small
bowel. This approach is commonly used to protect drugs that are
destroyed by gastric acid (e.g. omeprazole).
ii. Modified-release tablets– the excipients of a tablet may be
modified to improve drug delivery by controlling the rate, amount
and duration of drug release over a 24-hour period. This approach
is used for drugs with a short t1/2 which required frequent dosing to

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 PHS 810 MODULE 1

maintain therapeutic level (e.g. theophylline, verapamil,

nifedipine).
iii. Prodrugs– a similar effect may be achieved by using a prodrug.
Prodrugs are inactive compounds which are activated by biological
fluids or metabolising enzymes following administration (e.g.
enalapril is converted to its active form enalaprilat).

For drugs administered orally, absorption may begin in the mouth and
stomach. However, most drugs are usually absorbed from the small
intestine. The drug passes through the intestinal wall and travels to the
liver before being transported via the bloodstream to its target site. The
intestinal wall and liver chemically alter (metabolise) many drugs,
decreasing the amount of drug reaching the bloodstream. Consequently,
these drugs are often given in smaller doses when injected intravenously
to produce the same effect

3.4.2 The advantages and disadvantages of oral Absorption

Oral absorption has the following advantages:

i. Convenience and accuracy of dose.

ii. Administration does not require special skills
iii. No aseptic preparations are necessary
iv. In case of drug poisoning or adverse reactions, reversal with
antidotes are possible.
v. It is non invasive
vi. Buccal and sublingual modes of administration have added
advantage of avoiding first-pass effects and circumvention of the
exposure of the acidic digestive fluids.
vii. The disadvantages of oral administration include:
viii. Slow onset of action –at least 15-30mins onset time
ix. First –pass effect
x. Gastric irritation- hence nausea, anorexia and vomiting and
diarrhoea

3.4.3 Parenteral administrations

These includes intravenous, intramuscular, subcutaneous, intrathecal,

inhalational, intranasal and sublingual/buccal/rectal. Drugs given
intravenously (iv) enter the systemic circulation directly. However, drugs
injected intramuscular (i.m) or subcutaneous (sc) must cross one or more
biologic membranes to reach the systemic circulation. If protein drugs
with a molecular mass > 20,000 g/mol are injected i.m or SC, movement
across capillary membranes is so slow that most absorption occurs via the
lymphatic system. In such cases, drug delivery to systemic circulation is
slow and often incomplete because of first-pass metabolism (metabolism

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of a drug before it reaches systemic circulation) by proteolytic enzymes in

the lymphatics.

Perfusion (blood flow/gram of tissue) greatly affects capillary absorption

of small molecules injected im or sc. Thus, injection site can affect
absorption rate. Absorption after i.m or sc injection may be delayed or
erratic for salts of poorly soluble bases and acids (e.g., parenteral form of
phenytoin) and in patients with poor peripheral perfusion (e.g., during
hypotension or shock).

Controlled-Release Forms; Controlled-release forms are designed to

reduce dosing frequency for drugs with a short elimination half-life and
duration of effect. These forms also limit fluctuation in plasma drug
concentration, providing a more uniform therapeutic effect while
minimising adverse effects. Absorption rate is slowed by coating drug
particles with wax or other water-insoluble material, by embedding the
drug in a matrix that releases it slowly during transit through the GI tract,
or by complexing the drug with ion-exchange resins. Most absorption of
these forms occurs in the large intestine. Crushing or otherwise disturbing
a controlled-release tablet or capsule can often be dangerous.
Transdermal controlled-release forms are designed to release the drug for
extended periods, sometimes for several days. Drugs for transdermal
delivery must have suitable skin penetration characteristics and high
potency because the penetration rate and area of application are limited.
Many non-iv parenteral forms are designed to sustain plasma drug
concentrations. Absorption of antimicrobials can be extended by using
their relatively insoluble salt form (e.g., penicillin Gbenzathine) injected
im. For other drugs, suspensions or solutions in non-aqueous vehicles
(e.g., crystalline suspensions for insulin) are designed to delay absorption.

Intravenous administration is most commonly used when a rapid onset of

action and careful control of plasma levels are required.
The drug may be given as a bolus injection, slow infusion or continuous
infusion

Slow infusion is used when excessively high transient plasma levels are
undesirable (e.g. phenytoin). Continuous infusion is used when the drug
has a short t1/2 or when its therapeutic index is narrow and sustained
controlled blood levels are required.

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3.4.4 Advantages and Disadvanges Intravenous administration

Advantages Intravenous administration

Advantages intravenous administration includes

i. 100% bioavailability
ii. allow for easy measurement of plasma drug concentration at any
time “t”
iii. Modes of actions is faster
iv. First-pass effects is avoided

Disadvanges include

i. require special skills to administer

ii. in case of emergency reversal of effects is almost impossible
iii. completed dosing regimen with fatal outcome
iv. sepsis, embolism may be complications
v. require aseptic procedure for administration

Other modes drug administration includes;

Topical, inhalational and ophthalmic etc.

3.4.5 Mechanisms of Transport (Absorption)

i. Transport and the Cell Membrane Transport?

Transport is any process in which movement of matter and / or

energy occurs from one part of a system to another. If a substance
can cross a membrane, the membrane is said to be permeable to
that substance, if a substance is unable to pass, the membrane is
impermeable to it. The plasma (cell) membrane is selectively
permeable in that it permits some particles to pass through while
excluding others. Across the cell membrane without any assistance,
substances can pass through if they are lipid soluble and if they are
of small particle size.
The small intestine is where the majority of drug absorption takes place.
The small intestine has:
2 2
A much larger surface area: small intestine = 200 m , stomach = 1 m
A much better blood flow (for perfusion rate-limited absorption) small
intestine = 1000 mL/min through intestinal capillaries, stomach =
150 mL/min
Better permeability: intestinal membrane>stomach
The small intestine, which is more basic in pH, favours absorption of
weakly basic drugs:

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GI transit: Transit time in the small intestine is slower than in the

stomach. Rate of gastric emptying is a controlling step for rapid
absorption

i. Transport across Cell Membrane

Following movement into the small intestine, the drug must cross the
intestinal epithelial membrane to reach the systemic circulation. Drugs can
cross cell membranes by: Passive diffusion, Facilitated passive
diffusion and Active transport.

Figure2: Schematic Representation of the cell membrane showing the

Phospholipid bilayer and embedded Protein (@open source 2019).

ii. Passive diffusion

Drugs diffuse across a cell membrane from a region of high concentration

(e.g., GI fluids) to one of low concentration (e.g., blood) until equilibrium
is reached. Diffusion rate is directly proportional to the gradient but also
depends on the molecule's lipid solubility, size, degree of ionization, and
the area of absorptive surface. Because the cell membrane is lipoid, lipid-
soluble drugs diffuse most rapidly.

It also depends on physicochemical properties of the molecule including:

Lipophilicity: Lipid-soluble drugs diffuse most rapidly.

Size: Small molecules tend to penetrate membranes more rapidly than

larger ones.

Degree of ionisation

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The area of absorptive surface

Figure 3: Schematic Representation of the cell membrane showing

Drugs diffuse across a cell membrane from a region of high
concentration(https://en.wikipedia.org/)

Most drugs are weak organic acids or bases, existing in un-ionized and
ionized forms in an aqueous environment. The un-ionized form is usually
lipid soluble (lipophilic) and diffuses readily across cell membranes. The
ionized form has low lipid solubility (but high-water solubility i.e.,
hydrophilic) and high electrical resistance and thus cannot penetrate cell
membranes easily. The proportion of the un-ionized form present (and
thus the drug's ability to cross a membrane) is determined by the
environmental pH and the drug's pKa (acid dissociation constant). The pKa
is the pH at which concentrations of ionized and un-ionized forms are
equal. When the pH is lower than the pKa, the un-ionized form of a weak
acid predominates, but the ionized form of a weak base predominates.
Thus, in plasma (pH 7.4), the ratio of un-ionized to ionized forms for a
weak acid (e.g., with a pKa of 4.4) is 1:1000; in gastric fluid (pH 1.4), the
ratio is reversed (1000:1). Therefore, when a weak acid is given orally,
most of the drug in the stomach is un-ionized, favouring diffusion through
the gastric mucosa. For a weak base with a pKa of 4.4, the outcome is
reversed; most of the drug in the stomach is ionized. Theoretically, weakly
acidic drugs (e.g., aspirin) are more readily absorbed from an acid medium
(stomach) than are weakly basic drugs (e.g., quinidine). However, whether
a drug is acidic or basic, most absorption occurs in the small intestine
because the surface area is larger and membranes are more permeable.

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Table 2: Passive diffusion efficiency

Efficient Inefficient
Lipids Ionized molecules
Hydrocarbons Carbohydrates
Anaesthetics drugs Proteins
Alcohol Ethanol
Most drugs Aspirin and Quinidine

iii. Facilitated passive diffusion: Facilitated passive diffusion

requires binding between the drug or molecule with a specific
membrane- embedded channel or carrier proteins. It allows the
entry of specific groups of molecules while excluding others. It is
a passive process: Molecules move down their concentration
gradient. Molecules cannot be transported against their
concentration gradient. It is a saturable process. The availability
of carriers limits the process.

Figure4: Schematic Representation of the cell membrane facilitated

passive diffuse across a cell membrane (@open source 2019).

vi. Active Transport: Active transport is a selective process. It

requires a structurally specific transporter to transport drugs of a
certain conformation.
 It requires energy expenditure.
 It can move molecules across the membrane against their
concentration gradient. From a low concentration to a high
concentration
 It is also a saturable process.

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Figure 5: Schematic Representation of the cell membrane showing

active across a cell membrane against concentration gradient (@open
source 2019)

Exposure to transporters

Figure 6: showing three types of active transport – Protein pump,

Endocytosis and Exocytosis (@open source 2019)

3.4.6 Barriers to absorption: An orally administered drug must survive

additional encounters in the systemic circulation. First-pass effect through
the liver and hepatic portal system,

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3.5 Bioavailability (F)

Bioavailability (F) describe the rate and concentration (the extent) at

which the. administered drug reaches the circulation intact. It is the
proportion of administered drug available to produce a
pharmacological response.

The drug, its route of administration and its galenic formulation determine
the amount of administered dose absorbed into the circulation. Patient
dependant factors also influence bioavailability.
When the drug is administered orally the bioavailability depends on
several factors:

i. Physicochemical properties of the drug and its excipients that

determine its dissolution in the intestinal lumen and its absorption
across the intestinal wall.
ii. Decomposition of the drug in the lumen.
iii. pH and perfusion of the small intestine.
iv. Surface and time available for absorption.
v. Competing reactions in the lumen (for example of the drug
with food).
vi. Hepatic first-pass effect: Orally administered drugs are absorbed
from the GItract and reach the liver via the portal circulation. In
the liver they undergo first pass metabolism before they
enter systemic circulation, which decreases the bioavailability of
the drug. Rectal and sublingual by pass the first past effects and
the drug is absorbed directly through the blood stream.

Bioavailability can also be determined for other extravascular routes of

administration such as intramuscular, subcutaneous, rectal, mucosal,
sublingual, transdermal etc. Sublingual and rectal routes are often used to
bypass hepatic first-pass effect. Bioavailability of most small molecular
weight drugs administered i.m or S.C. are perfusion rate-limited. Large
molecules administered i.m or S.C. enter the blood in part via the
lymphatic pathway.

3.5.1 Clinical implications

When changing the route of administration or the formulation of a drug,

the dose must be adapted with regard to the respective bioavailability of
each route. Bioavailability of a drug administered intravenously is by
definition 100%. Bioavailability is less or equal to 100% for any other
route of administration.

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PHS 810 MODULE 1

3.5.2 Absolute and relative F

The term absolute bioavailability is used when the fraction

of absorbed drug is related to its I.V. bioavailability. A drug given by the
intravenous route will have an absolute bioavailability of 1 (F=1 or 100%
bioavailable). The term relative bioavailability is used to compare two
different extravascular routes of drug administration.Drugs given by other
routes usually have an absolute bioavailability of less than one.

Figure7: absolute bioavailability is the area under curve (AUC) non-

intravenous divided by AUC intravenous (Roy SK @ Novartis 2004)

3.5.3 Bioavailability (assessment) Pharmacokinetic study

Bioavailability is proportional to the total area under the plasma

concentration- time curve (AUC). To determine the bioavailability of a
drug, you must carry out a pharmacokinetic (PK) study to obtain a
blood/plasma concentration versus time plot for the drug in question.
The relative bioavailability of drug 1 compared to drug 2 can be calculated
using the following equation:

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Figure 8: Area under the plasma concentration curve (AUC)

• Cmax = The peak plasma concentration of a drug after
administration
• Tmax = The time to reach Cmax

C max
Plasma Con.

AUC

Time

Figure 9: Theoretical Plasma concentration over time. (Roy SK @

Novartis 2004

Cmax = the peak plasma concentration which is the function of speed and
extent absorption, tmax = the time taken to reach the peak which is a
function of the speed of absorption, AUC = the total area under the plasma
curve – a function of absorption

3.5.4 Causes of Low Bioavailability

A number of other factors may affect the absorption and bioavailability

of a drug taken by mouth. Physiological characteristics include, how long
the stomach takes to empty, what the acidity (pH) of the stomach is and
how quickly the drug is moved through the digestive tract. Other factors
include a person's age, sex, level of physical activity, and level of stress.

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Food, other drugs, and digestive disorders can affect drug absorption and
bioavailability. For example, high-fibre foods and calcium supplements
may bind with a drug and prevent it from being absorbed. Laxatives and
diarrhoea, which speed up the passage of substances through the
digestive tract, may reduce drug absorption. Surgical removal of parts of
the digestive tract (such as the stomach or colon) may also affect drug
absorption.

3.5.5 Bioequivalence: Two proprietary (galenic formulations)

preparations of a drug are said to be bioequivalent if they exhibit the
same bioavailability when administered in equal doses. Bioequivalence
indicates that the drug products, when given to the same patient in the
same dosage regimen, result in equivalent concentrations of drug in
plasma and tissues. Therapeutic equivalence indicates that drug
products, when given to the same patient in the same dosage regimen, have
the same therapeutic and adverse effects. Bioequivalent products are
expected to be therapeutically equivalent. Therapeutic non-equivalence
(e.g. more adverse effects, less efficacy) is usually discovered during long-
term treatment when patients who are stabilised on one formulation are
given a non-equivalent substitute. Bioequivalence;

i. It can provide useful information about the:

ii. Dosage or dosage regimen of a given drug
iii. Performance of a drug formulation compared to other
formulations
iv. It is quoted as a percentage (43%) or a decimal (0.43) and has no
units.
v. Intravenous (IV) administration equals 100% bioavailability.
vi. For a non-IV dose, F ranges from 0 to 100%.

Table3: Variation of drug Bioavailability

Drug Foral (5)
Gentamycin <5
Verapamil 22
Lignocaine 35
Digoxin 75
Phenytoin 98
Valproate 100

3.6 Elimination Half-Life

The half-life (t1/2) of a drug is the time taken for the circulating
concentrations of the drug to fall by 50%. By definition, the plasma
concentration of a drug is halved after one elimination half-life. Therefore,
in each succeeding half-life, less drug is eliminated. After one half-life the
amount of drug remaining in the body is 50% after two half-lives 25%,

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etc. After 4 half-lives the amount of drug (6.25%) is considered to be

negligible regarding its therapeutic effects.

A concentration-time curve (figure… below) can be constructed by

administering the drug intravenously and removing blood for assay at
frequent intervals. With most drugs, the curve is a strength line when the
concentration (vertical axis) is expressed on a logarithmic scale, enabling
11/2 to be determined easily Complete drug elimination occurs in 4-5 half
lives. After that drug will reach steady state concentration in the plasma.
(Drug administered=drug eliminated)

Figure10: Time to elimination half life (Roy SK @ Novartis 2004

= 1-50 %
= 2-75% (50+25)
= 3-87.5% (50+25+12.5)
= 4-3.75% (50+25+12.5+6.25)

The half-life can be calculated with the following formula: t 1/2 =

0,693•Vd/CL

Where Vd is the volume of distribution at the steady-state, and CL is the

clearance.

Importance:

i. it denotes how quickly a drug is removed from the plasma by

biotransformation or excretion.
ii. Since drug requires a minimum concentration in the plasma to
produce pharmacological action, a drug which is eliminated
quickly requires more frequent dosing than a drug with a long
half-life.

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PHS 810 MODULE 1

iii. It thus indicates the duration of action of drug and therefore it

determines the frequency of administration of dose of the drug for
therapeutic effectiveness.
iv. The half-life of a drug depends on its clearance and volume of
distribution. The elimination half-life is considered to be
independent of the amount of drug in the body.

3.6.1 Therapeutic window

Therapeutic Window: Therapeutic window is a range of doses that

produces therapeutic response without causing any significant adverse
effect in patients.

Generally therapeutic window is a ratio between minimum effective

concentrations (MEC) to the minimum toxic concentration (MTC). The
levels of drug should always be between MEC and MTC in order to
provide risk free therapeutic effects. If any drug crosses MTC then it will
surely elicit toxic effects and if drug is unable to surpass MEC then it will
cause therapeutic failure. MEC is also called as minimum inhibitory
concentration (MIC).

Figure 11: Therapeutic window (@ medimoon.com 2018)

Therapeutic Index
Therapeutic index (TI) describes a relationship between the doses of a
drug that causes lethal or toxic effects with the dose that causes therapeutic
effects. It is also called as therapeutic ratio.

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Figure 12: Showing Therapeutic index (TI) (@ medimoon.com 2018)

Therapeutic Index = TD50 or LD50

ED50
Where

LD50 is the minimum amount of drug that causes adverse effects in 50%
of the population. LD50 could also be replaced with Toxic dose (TD50)
ED50 is the quantity of a drug that can produce desired therapeutic effects
in 50% of the population. Such types of studies are usually conducted in
animal models.

The higher the TI the better the drug. TI’s vary from 1.0 (some cancer
drugs) to: >1000 (penicillin). Drugs acting on the same receptor or enzyme
system often have the same TI: (e.g. 50 mg of hydrochlorothiazide about
the same as 2.5 mg of indapamide)

Ideally any drug that requires more amount to produce toxic or adverse
effects in 50% of population will have wider therapeutic index and vice
versa. Drugs having wider therapeutic index are safer in comparison to
those having low therapeutic index because minor modification in the dose
of such drugs (aspirin, acetaminophen) will not produce toxic effects.

For examples NSAIDs have wider therapeutic index and warfarin has
narrow therapeutic index as it has therapeutic index less than two. Some
common potent drugs having low therapeutic index; Digoxin, Lithium,
Warfarin, Theophylline, Phenytoin, Gentamicin, Amphotericin B and 5-
fluorouracil etc.

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3.6.2 Steady-State Concentrations

Steady-state concentration: Steady-state concentration (Css) is defined

as the time during which the concentration remains stable or consistent
when the drug is given repeatedly or continuously (IV infusion). The time
to reach steady-state is a function of T½ and is achieved when the rate of
the drug entering the systemic circulation equals the rate of elimination.
For most drugs, the Css is reached in approximately five half-lives. The
time to reach steady-state is independent of dose size, dosing interval, and
number of doses.

In case of multiple dosing, when a drug is administered in a fixed dose at

fixed intervals, the plasma concentration increases exponentially to a
plateau or steady-state with a half time of increase that is equal to the T½ of
the drug. As indicated previously, 50% of the steady-state level is achieved
in one T½, 75% (50+25) is achieved in two, 87.5% is achieved in three,
and more than 99% is achieved in seven half-lives. In practice, a useful
estimate of time to reach a steady-state is obtained by the following
equation: ½Time to 95% steady-state = 4.3×t½

Figure 13: Steady state giving after every half-life. (Linear PK

Example.png 2014)

Therefore, the shorter the half-life, the more rapidly the steady-state is
reached, and vice versa. Steady-state occurs after a drug has been given
for approximately five elimination half-lives. At steady-state the rate of
drug administration equals the rate of elimination and plasma
concentration - time curves found after each dose should be approximately
superimposable.

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Steady state pharmacokinetics are important for chronically administered

drug products. Understanding the basic concept that a drug reaches steady
state once the rate of drug input and elimination are equivalent helps
simplify the concept of steady state.

3.7 Drug Distribution

Drug distribution describes the reversible transfer of a drug from one

location to another within the body. After a drug enters the systemic
circulation, it is distributed to the body's tissues.

3.7.1 The factors determining the pattern of distribution:

Distribution is generally uneven because of differences. The factors

determining the pattern of distribution are the

i. tissular delivery of drug by blood,

ii. the ability of the drug to cross membranes,
iii. the binding of drug with blood and tissues components (e.g.,
because of lipid content),
iv. its partitioning between water and fat, and
v. Its ability to undergo active transport through cell-membrane
carriers (e.g. P-glycoprotein).

After the drug reaches the bloodstream, it is initially distributed in the most
vascularised organs.

The entry rate of a drug into a tissue depends on the rate of blood flow to
the tissue, tissue mass, and partition characteristics between blood and
tissue. Distribution equilibrium (when entry and exit rates are the same)
between blood and tissue is reached more rapidly in richly vascularised
areas, unless diffusion across cell membranes is the rate-limiting step.
After equilibrium, drug concentrations in tissues and in extracellular fluids
are reflected by the plasma concentration. Metabolism and excretion occur
simultaneously with distribution, making the process dynamic and
complex

Table 4: Blood flow to tissues: Good blood supply is vital for efficient
drug delivery.

Organ Blood flow Organ Blood flow

ml/min mass/kg ml/min
Cardiac output 5,600 - -
Myocardium 250 0.5 833 Highly
Liver 1,700 2.5 680 Perfused
Kidney 1,200 0.3 4,000

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CNS 800 1.3 615

Fat 250 10 25 Slowly
Other (Muscle, 1,400 55 25 perfused
etc.)
Total 69.4

i. Plasma protein binding: A drug's efficiency can be affected by the

degree to which it binds to the proteins in the blood. The drug binds to
specific sites on plasma proteins, which results in sequestering of the drug,
making it unavailable to its site of action. Competition for plasma protein
binding sites can sometimes occur when another drug is given in
combination with your drug of interest, resulting in displacement of the
drug and increasing its unbound concentration in the blood plasma. Such
competition can be very significant clinically

Figure 14: demonstrating competitive Plasma protein binding (Roy SK

@ Novartis 2004

Consider the anticoagulant Warfarin as an example. It is approximately

98% protein-bound. So, for each 5 mg dose, only 0.1 mg of the drug is
free. The patient takes a normal dose of aspirin at the same time, which
occupies 50% of binding sites; the aspirin displaces some of the Warfarin.
If 96% of the Warfarin dose is protein-bound, 0.2 mg of Warfarin is now
free. The dose has been effectively doubled.

Common blood proteins: Common blood proteins that drugs bind to are:

Human serum albumin: Most concentrated protein in blood plasma:

Acidic drugs

-α1 – acid glycoprotein: Basic drugs

α, β‚ and γ globulins: Steroid hormones

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 PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

Drug binding to plasma proteins is generally reversible and rapid. •The

extent of binding is determined by quantifying the free drug fraction (fu).
The extent of binding can vary widely among drugs. Plasma albumin:
This table shows examples of the extent of plasma albumin binding to
various drugs. The unbound fraction of some drugs is dependent on the
concentration of plasma proteins and can be altered in disease states that
produce hypoalbuminemia. An example of this type of drug is phenytoin

Table5: Showing examples of the extent of plasma albumin binding to

various drugs

Acidic Drugs % Bound Basic Drugs

Ibuprofen 100% Diazepam
Warfarin Methadone
Aspirin Erythromycin
phenobarbitone Pethidine

Ampicillin < 50% Theophylline

i. Volume of Distribution

The volume of distribution (Vd), or apparent volume of distribution, is: A

theoretical volume that the total amount of drug administered would need
to occupy to provide the same concentration as in blood plasma. It is not
a physical volume, nevertheless, the volume of distribution of a drug gives
information on its distribution in the body.

The Vd is calculated as the ratio of the dose present in the body and its
plasma concentration, when the distribution of the drug between the
tissues and the plasma is at equilibrium.

An equilibrium concept that relates the amount of drug in the body (A) to
either the plasma or blood concentration (C): Vd = D/C

Example: A patient is administered an intravenous analgesic at a dose of

75 mg. A few minutes later, a blood sample is taken and the concentration
of the analgesic in the blood is 0.65 μg/mg. What is the volume of
distribution (in litres) of the analgesic?

Vd = D/C = 75mg / 0.65 μg/mg = 75,000 μg / 0.65 μg/mg = 115,385 ml =

115.4 litres

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 PHS 810 MODULE 1

Accordingly, a drug that accumulates in tissues as e.g. fat tissue, will have
a relatively low plasma concentration with regard to the administered
dose, and consequently, the calculated Vd will be high.
Volume of distribution provides little information about the specific
pattern of distribution. Some drugs cannot enter cells because of their low
lipid solubility. Interstitial fluids of most tissues, drug distribution rate is
determined primarily by perfusion. For poorly perfused tissues (e.g.,
muscle, fat), distribution is very slow Vd (12-20 L), especially if the tissue
has a high affinity for the drug

Drugs with a very small Vd (<10 L) are mainly confined to the

intravascular fluid, thus the blood, corresponding to roughly twice the
plasma volume. This may occur for two reason 1. The molecule is too
large to leave this compartment and 2. The molecule binds preferably to
plasma proteins (e.g. to albumin) and much less to tissue proteins.
Competition for plasma protein binding sites can occur between such
drugs or with endogenous substances.

Drugs that accumulate in organs either by active transport or by specific

binding to tissue molecules have a high volume of distribution, which can
exceed several times the anatomical body volume. Therefore, Vd should
not be identified too closely with a particular anatomical compartment.
Lipid-soluble drugs are stored in fat. Bone is a reservoir for drugs such as
tetracycline and heavy metals.

Distribution coefficient: measure of hydrophobicity/hydrophobicity of a

drug C (drug concentration in the organic solvent)/ C (drug concentration
in water.

Table6: Showing each drug is uniquely distributed in the body

Volume of distribution
High Low
High lipid solubility (non – polar) Polar
Low rates of ionization More highly ionised
Low plasma binding capabilities High plasma binding

Volume of distribution can be: Increased by renal failure or liver failure,

Decreased in dehydration.

ii. Real water distribution: The body is composed of 'real'

compartments that contain 'real' volumes of fluid:

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Table 7: Distribution of Water in the Body for a 70kg Person

Compartment Volume (V) Percentage (%)
Total body water (TBW) 42 60
Intracellular Fluids (ICF) 28 40
Extracellular Fluids (ICF) 14 20
Interstitial 10 15
Plasma 4 0

Examples

Heparin: High molecular weight drug binds to plasma proteins

extensively, and volume of distribution of about 4 litres. This correlates
very well with the plasma volume. Such volume of distribution for this
drug is considered a 'real' volume. The volume occupies 'real space ‘in the
plasma volume. Heparin unable to transport out of the vascular system.

Atracuronium: Neuromuscular blocking agent of low molecular weight

drug but is hydrophilic. Its volume of distribution of about 11 litres. This
is equivalent to the volume in the extracellular compartment of the body.
A very polar compound, Atracuronium is unable to transport across cell
membranes and therefore remains in the extracellular fluids.

The majority of drugs, which bind strongly to tissues, have volumes of

distribution higher than total body water. A minority of drugs that diffuse
to intracellular fluid have a volume of distribution equivalent to TBW
volume.

Table8: Example of drug variation in drug Vd

Compound Volume/Litres
Ethanol 38
Caffeine 36
Alfentanyl 56
Fentanyl (Anaesthetics) 280
Propofol (Anaesthetics) 560
Digoxin (Cardiac drugs) 365
Drug Volume Location
Aspirin 9.8 Located mainly in
Amoxycillin 14 plasma, little in tissues
Theophylline 35 Similar concentration in
Diazepam 105 plasma and tissues
Digoxin 490 Mainly located in tissue,
Haloperidol 1,750 very little in plasma
Values in litres for an average 70kf adult

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PHS 810 MODULE 1

Clinical usefulness of drug distribution

i. The volume of distribution reflects the size of the distribution

space, thereby giving you an idea of the localisation of the drug in
the target organ.
ii. With a large volume of distribution, you will need a higher dose to
load.
iii. With a low volume of distribution, you will need a lower dose to
load.
iv. The volume of distribution is useful in estimating the dose required
to achieve a given plasma concentration as A = C ·Vd, with A =
amount of drug in the body (≈ dose, shortly after administration)
and C = plasma concentration.
v. Gives us idea of variation of the peak plasma concentration of the
drug. This is important when peak plasma concentration is essential
for the therapeutic effect (e.g. hypnotics). Drug dosage must be
adapted to the Vd for such drugs.
vi. Vd varies with individual height and weight. The most important
causes of variation of Vd are accumulation of fat (for lipid-soluble
drugs) such as for obese patients, or accumulation of fluids (for
water-soluble drugs) such as ascites, oedema or pleural effusion.
As the proportion of each body compartment varies with age, so
does the Vd for most drugs.

3.8 Drug Metabolism (Biotransformation)

3.8.1 Introduction

Metabolism (biotransformation) is a process by which drugs are converted

into more polar forms through a series of enzymatic reactions. This serves
to increase the renal elimination of the substance, this usually, but not
always, results in a less toxic form of the substance. The metabolites might
still have potent biological activity (or might have toxic properties). An
inactive or weakly active substance that has an active metabolite is called
a prodrug. Is the main mechanism of drug elimination involving the
enzymatic conversion of one chemical entity to another within the body?
Occurs predominantly in the liver. Results in metabolites that are more
polar than the parent drug and that can be excreted by the kidneys

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Example of Metabolism
Barbital: It is water soluble and after metabolism, is excreted unchanged.
Theoretical and measured half-life of 55-75 hours

Figure 15: Metabolism of Barbital to Hexobarbital

Hexobarbital: A Lipophilic drug is metabolised. Its theoretical half-life

of 2-5 months, while measured half-life of 5-6 hours.

3.8.2 Sites of metabolism: Metabolic enzymes are located in many

different tissues and usually reflect tissues with a high exposure to
xenobiotic. These include tissues of the Liver, Lungs, Nasal mucosa, Eye
and - Gastrointestinal tract (GIT). The main site of biotransformation is
the liver because of its size and concentration of enzymes.

3.8.3 First-pass elimination: Many xenobiotics are absorbed from the

GIT by the liver and metabolised then. This is designed to prevent high
levels of orally ingested xenobiotic reaching circulation. However, this
first-pass metabolism can limit the bioavailability of some drugs.
Alternative routes of administration avoid the first-pass effect. Notable
drugs that experience a first-pass effect include imipramine, morphine,
diazepam, demerol, cimetidine and lidocaine.

3.8.4 Cytochrome P450 Classification

Cytochrome P450: Cytochrome P450 (CYP) is a haemoprotein that plays

a key role in the metabolism of drugs and other xenobiotics.
Understanding the CYP system is essential for advanced practitioners
(APs), as the consequences of drug-drug interactions can be profound.

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PHS 810 MODULE 1

Cytochrome P450s are classified by amino acid homology of the genes.

Cytochrome P450 pathways are classified by similar gene sequences; they

are assigned a family number (e.g., CYP1, CYP2) and a subfamily letter
(e.g., CYP1A, CYP2D) and are then differentiated by a number for the
isoform or individual enzyme (e.g., CYP1A1, CYP2D6). Those with <
40% homology are put into separate families, with numbers as identifiers.
Those with 40–55% homology have different sub-families and are given
letter names. Those with > 55% homology are members of a different sub-
family. These are given numbers as identifiers.

Drugs that share a common pathway have the potential for drug-drug
interactions. The classification of CYP proteins will be the APs first hint
of the potential for drug interactions. Not all drugs have CYP activity.
However, drugs with CYP activity may be inhibitors, inducers, or
substrates for a specific CYP enzymatic pathway, thus altering the
metabolism of concurrently administered agents. Drugs that inhibit an
enzymatic pathway of CYP may cause increased concentrations of other
drugs metabolised by the same pathway, resulting in drug toxicity.
Likewise, drugs that induce an enzymatic pathway of CYP may reduce
concentrations of drugs metabolised by the same pathway, leading to sub
therapeutic drug levels or treatment failure.

Role of sub-families: There are 74 families but only 17 families in

humans and there are approximately 57 CYP genes. The important sub-
families involved in drug metabolism are: CYP1A and CYP1B, CYP2A–
D. CYP3A.

Found in every class of organism, including Archaea. For example, CYP1,

CYP2 and CYP3 are found in the microsome and are involved in drug
metabolism and CYP4 is found in the microsome but is involved in fatty
acid metabolism. The p450 superfamily is believed to have originated
from ancestral gene that existed over 3 billion years ago. In humans, they
play central role in Phase 1 drug metabolism, significant problems in
clinical pharmacology, drug -drug interactions, Inter-individual variation
in drug metabolism and Genetic polymorphism resulting in marked
metabolic activity e.g. CYP2D6

CYP structure: Cytochrome P450s are haem-containing proteins. They

usually require a second enzyme for catalytic activity – something that
provides electrons. In the endoplasmic reticulum (ER), or primary
metabolic enzymes, this is NADPH-cytochrome P450 reductase. In
mitochondria, the second enzyme is ferredoxin and ferredoxin reductase.

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Figure 16: CYP structure (Roy SK @ Novartis 2004

The most common reaction catalysed by cytochromes P450 is a

monooxygenase reaction, e.g., insertion of one atom of oxygen into the
aliphatic position of an organic substrate (RH) while the other oxygen
atom is reduced to water:

• RH + O2 + NADPH + H+ ROH + H2O + NADP+

3.8.5 Stages in Metabolism

i. Phase I

Introduces or exposes a functional group. – OH, - NH2, - SH and -

COOH.

Only slightly increases polarity

There are three types of Phase I reaction: Hydrolysis, Oxidation and

Reduction

Many Phase I products are not efficiently eliminated and may require a
second conjugation reaction by Phase II enzymes to form a highly polar
conjugate that can then be excreted in the urine.

CYP oxidation reactions involve;

i. Hydroxylation (aliphatic or aromatic carbon)

ii. Epoxidation of double bond
iii. Heteroatom (S-, N- and I-) oxygenation

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PHS 810 MODULE 1

iv. Heteroatom (O-, S-, N-, Si-) dealkylation

v. Oxidative group transfer
vi. Cleavage of esters
vii. Dehydrogenation

ii. Phase II metabolism

Phase II drug metabolising reactions are synthetic, anabolic reactions that

involve conjugation whereby another molecule is added to the drug such
as Glucuronidation, Sulfation, Acetylation, Methylation, Glutathione
conjugation and Amino acid conjugation. These are primarily cytosolic
reactions, and are much faster than Phase - I reactions.

i. Glucuronidation: Glucuronidation is the most common Phase II

reaction. It is mediated by UDP-glycotransferases. Requires
uridine diphosphate-glucuronic acid as a co-factor.
ii. Substrates include: Aliphatic alcohols and phenols Carboxylic
Acids Secondary aromatic and aliphatic amines
iii. Glucuronides: The resulting glucuronide conjugates of drugs are
secreted in bile or urine depending on their molecular weight.
Those of low molecular weight are excreted in urine whereas those
molecules of high molecular weight are excreted in bile. It is a very
important reaction, particularly for drugs such as: Acetaminophen,
Morphine, Propranolol, Diclofenac and Lamotrigine
iv. Sulfation: Sulfation is described as a higher affinity but lower
capacity reaction than glucuronidation. It has similar substrates to
glucuronidation and is catalysed by sulfotransferases. The reaction
requires the co-factor, 3’-phosphoadenosine-5’-phosphosulfate
(PAP), which is the reason for the low capacity of this reaction, that
is, the limitation of PAP.
v. Sulfate: The sulphate conjugates are excreted in the urine or bile.
Sulfation can activate some carcinogens, such as safrole. Many
drugs are sulphated: Acetaminophen, Chloramphenicol, Dopamine
and Ethanol.
vi. Methylation: Methylation is a relatively minor reaction that often
decreases water solubility. It is mediated by methyltransferases,
with the best-known being Catechol-O-methyltransferases. The co-
factor is S-adenosylmethionine. Methylated drugs include:
Catecholamines, Captopril, and Azathioprine.
vii. N-acetylation: N-acetylation is another major conjugation
reaction, particularly for: Aromatic amines, Hydrazine. It is
mediated by N-acetyltransferases (NAT). The co-factor is acetyl-
coenzyme A. This can also decrease water solubility. There are two
enzymes involved, NAT1 and NAT2.

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Table 9: Major Enzymes involved in Acetylation

N-acetyltransferases (NAT)
NAT1 preferentially conjugates NAT2 preferentially acetylates
p-Aminosalicylic acid Isoniazid
Sulfamethoxazole Dapsone

Slow acetylation: NAT2 contains a number of polymorphisms that can

decrease the rate of acetylation. Individuals who express this phenotype
are known as slow acetylators. ~70% incidence in Middle East, 50%
incidence in Caucasians, and <25% in Asians. Slow acetylators have an
enhanced response to hydralazine (anti-hypertensive). Its increased nerve
damage from isoniazid and dapsone

Xenobiotic activation: Cytochrome P450s biotransformation can lead to

activation of some toxins and carcinogens. In some cases, the activation is
desirable because it produces the active agent from a pro-drug.

Other CYP reactions: CYP450 enzymes can be induced or inhibited by

many drugs and substances, resulting in drug interactions in which one
drug enhances the toxicity or reduces the therapeutic effect of another
drug.

3.8.6 Mechanisms of enzymatic Processes Drug Metabolism

The mechanisms are brought about by enzymatic Processes

i. Enzyme inhibition
ii. Enzyme induction
iii. Auto Induction

It should be noted that p450 Induction is not limited to drugs as other

substrates such as, grapefruit juice can inhibit CYP3A4 mediated
metabolism. Alcohol, chronic cigarette smoking, and even charbroiled
meats can induce hepatic CYP450 enzymes

i. Inhibition of CYP: Inhibitors of CYP450s include: Cimetidine,

Ciprofloxacin, Erythromycin, Fluoxetine etc. Inhibition can lead to
adverse drug reactions due to altered metabolism. However,
inhibition is typically reversible depending on the half-life of the
drug and can be used to increase bioavailability of a drug, for
example: Ritonavir inhibits CYP3A enzymes, Saquinavir is
metabolised by CYP3A. A combination of ritonavir and Saquinavir
is synergistic in HIV. Inhibition can be due to a number of factors
including:

Competition for a CYP between two substrates

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PHS 810 MODULE 1

i. Competition with a non-substrate inhibitor e.g. Omeprazole and

diazepam compete for CYP2C19, CYP2D6 metabolises
dextromethorphan and is inhibited by quinine, Celecoxib inhibits
CYP2D6, and Grapefruit juice inhibits CYP3A enzymes.
ii. Substrates that can also be converted to a suicide inhibitor e.g.
Erythromycin inhibits CYP3A4, Furafylline inhibits CYP1A2, and
Trienoic acid inhibits CYP2C9.
iii. Terfenadine is a non-sedating H1 antagonist.It is metabolised to an
active agent by CYP3A4. This active metabolite does not cross the
blood-brain barrier (BBB). Azole antifungals and macrolide
antibiotics inhibit CYP3A4.This results in increased plasma levels
of terfenadine. Terfenadine blocks cardiac K+ channels. This can
result in torsade de pointes and even ventricular arrhythmias.

Table10: Examples of Common Drug-Drug Interactions Involving the

Cytochrome P450 Enzyme System (@Lynch, T.et al 2007)

CYP Drug substrate Inhibitor Inducer

1A2 Paracetamol Furafylline Smoking,

(Acetaminophens) charred foods
caffeine,
odansetron,
Phenacetin
tacrine, tamoxifen,
Theophylline
2A6 Coumarin, Dicarb sodium
Caffeine (Diethyldithiocarbamate)
2C9 Diclofenac. Sulfapenazole Barbiturate,
Flurbiprofen, rifampicin
losartan, (rifampin)
phenytoin,
Piroxicam, acid,
Tolbutamide
2C19 Diazepam, (S) –
Mephenytoin,
omeprazole,
entamidine,
Propranolol (R) –
Warfarin
26D Defuralol, Quinidine
codeine,
debrisoquine,
haloperidol,
nortriptyline

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2E1 Paracetamol, Dicarb Sodium Alcohol,

enflurane, (ethanol)
caffeine, isoniazid
chlorzoxazone,
theophylline
3A4 Clarithromycin, Gastrodne ketoconazole, Barbiturate,
dapsone, itraconazole Rifampicin,
Indinavir, codeine, dexamethasone,
midazolam, carbamazepine
cyclosporine,
erythromycin,
Nifedipine
Felodipine,
diazepam, Commented [U1]:
verapamil,
Loxatan, quinidine

ii. Induction of CYP: Some drugs can enhance the expression of

some CYP enzymes. This can be beneficial because induction
increases the pool of enzyme available to catalyse specific drug
metabolising reactions. However, other drugs can be metabolised
much more rapidly than would be anticipated. This does not cause
a toxic effect but results in sub-therapeutic levels of drugs, such as
oral contraceptives.

Mechanism of induction is cytosolic receptor mediated: CYP1A and

AhR (dioxin), - CYP2B and CARβ (phenobarbital), CYP3A and PXR
(rifampin), CYP4A and PPARα (clofibric acid) and Activation of the
receptors leads to gene induction and increased mRNA production.

iii. Autoinduction: Polymorphisms: Polymorphisms in the CYP

family are considered to have the most impact on the fate of
therapeutic drugs.

Functions

i. To function within phase, I Liver Detoxification

ii. To detoxify xenobiotic sources of toxicity, chemicals, alcohols
and carcinogens, converting them into water and oxygen
iii. To assist endogenous sources of waste such as Bilirubin
iv. To assist in the synthesis of Vitamin D

For hormone synthesis: To effectively convert cholesterol into

pregnenolone which then gets converted into other hormones like
oestrogen, testosterone, cortisol and DHEA.

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PHS 810 MODULE 1

For the synthesis of bile and bile acids, which are necessary for the
assimilation of fat-soluble vitamins. Bile also contains many of the toxins
conjugated in the liver, which then get dumped into the bowels for proper
elimination.

3.8.9 Consequences of Metabolism (biotransformation)

The end product can involve

Active drug to Inactive metabolite: Pentobarbitone, Morphine,
Chloramphenicol

Active drug to Active metabolite: Phenacetin

Inactive drug to active metabolite: Levodopa
Prodrugs: Inactive drug is converted to active metabolite

Advantages:

i. Increased absorption
ii. Elimination of an unpleasant taste
iii. Decreased toxicity
iv. Decreased metabolic inactivation
v. Increased chemical stability
vi. Prolonged or shortened action

3.9 Rug – Drug Interactions

A drug interaction occurs when a drug interferes in a negative way with

another drug or medical condition. These interactions can occur between
two drugs, by combining medications with particular foods or drinks, or
by a drug interfering with another medical condition. It does not only
happen with prescription drugs, it can happen with over the counter
medications, vitamins and supplements, and illegal substances.

The objectives of a drug interaction study are to

i. Explore if a new agent significantly affects the metabolic

elimination of approved drugs and vice versa
ii. Determine if any interactions are clinically significant to
necessitate dose adjustment, warning or contraindication.
iii. Understand dose adjustments or how to avoid interaction, may
allow marketing for drug that otherwise been associated with
unacceptable level of toxicity.

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3.9.1 Types of Drug Interactions

Two types of drug interactions

Pharmacokinetic (ADME) interactions: A drug usually alters

absorption, distribution, protein binding, metabolism, or excretion of
another drug.

Pharmacodynamic drug interactions: Pharmacodynamic drug

interactions occur when one drug alters the sensitivity or responsiveness
of tissues to another drug by:

i. Having the same effect (agonistic)

ii. Blocking effect (antagonistic)

For example, if fluoxetine is given with tramadol serotonin syndrome can

result. This is a pharmacodynamic drug interaction. Fluoxetine and
tramadol both increase availability of serotonin leading to the possibility
of “serotonin overload” This happens without a change in the
concentration of either drug)

These effects usually occur at the receptor level but may also occur
intracellularly and can occur in one or 6 ways.

3.9.2 Pattern of Drug-Drug interactions: 6 patterns

i. Pattern1: An inhibitor is added to a substrate e.g. Paroxetine is

added to nortriptyline, leading to an increase in the nortriptyline
blood level.
ii. Pattern 2: A substrate is added to an inhibitor Nortriptyline is added
to paroxetine, leading to a higher than expected blood level of
nortriptyline at a given dose
iii. Pattern 3: An inducer is added to a substrate Carbamazepine is
added to be haloperidol, leading to a decrease in the haloperidol
blood level.
iv. Pattern 4: A substrate is added to an inducer Haloperidol is added
to carbamazepine, leading to a lower than, expected blood level of
haloperidol at a given dose
v. Pattern 5: Reversal of inhibition. An inhibitor and a substrate have
been stably co-administered and then the inhibitor is discontinued.
E.g. Cimetidine is discontinued in the presence of nortriptyline,
leading to a decrease in the nortriptyline blood level
vi. Pattern 6: Reversal of induction. An inducer and a substrate have
been stably co-administered and then the inducer is discontinued.
E.g. a patient on clozapine abruptly discontinues smoking, leading
to an increase in the clozapine blood level

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PHS 810 MODULE 1

3.9.3 Clinically significant interactions

Clinically significant interactions are often predictable and usually

undesired.

Therapeutic effects

i. Co-administration of the two anti-retroviral drugs, lopinavir and

ritonavir, to patients with HIV infection results in altered
metabolism of lopinavir and increased serum lopinavir
concentrations and effectiveness.
ii. Lopinavir/Ritonavir is now marketed as a fixed dose combination
drug for the treatment of HIV infection, combining lopinavir with
a sub-therapeutic dose of ritonavir. Kaletra (high-income countries)
and Aluvia (low-income countries)

Table 11: Showing detail description and effects of drug interaction

(@Lynch, T.et al 2007)

Interacting Drug Findings and Recommendations/Com

Mechanism of ments
Interaction
Amiodarone Increased risk for Do not exceed 40 mg
myopathy/rhabdomy lovastatin or 20 mg
olysis due to
simvastatin.
decreased metabolism Consider limiting
of atorvastatin,
atorvastatin dose.
lovastatin, andFluvastatin is primarily
simvastatin. metabolised by CYP2C9.
Amiodarone is a Amiodarone can
CYP3A4 andpotentially decrease its
CYP2C9 (moderate) metabolism.
inhibitor Consider using
pitavastatin, pravastatin,
or rosuvastatin
Azole Antifungals Posaconazole, Hold lovastatin and
Fluconazole, Voriconazole. simvastatin during the
Itraconazole Decreased course of itraconazole,
Ketoconazole, metabolism of ketoconazole, or
Nizoral, atorvastatin, Posaconazole treatment.
fluvastatin, lovastatin, Consider reducing
and simvastatin. lovastatin or simvastatin
Itraconazole, dose when used with
ketoconazole, are Voriconazole. Hold
atorvastatin during the

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PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

strong CYP3A4 course of itraconazole

inhibitors. treatment.
Fluconazole is a Consider reduced
moderate CYP3A4 atorvastatin dose if used
and CYP2C9 with ketoconazole, or
inhibitor Voriconazole. Use
caution when co-
administering fluconazole
with atorvastatin,
lovastatin, simvastatin, or
fluvastatin. Limit
fluvastatin dose to 20 mg
twice daily. Consider
fluvastatin, rosuvastatin,
or pravastatin rather than
lovastatin, simvastatin, or
atorvastatin with
itraconazole or
ketoconazole
Cimetidine Decrease in TG- If atorvastatin TG
lowering effect of lowering effect not
atorvastatin from satisfactory, use another
34% to 26%. H2-antagonist.
No data for rosuvastatin
Colchicine Increased risk of Use combination with
myopathy/rhabdomy caution/clinical
olysis with monitoring
atorvastatin,
lovastatin, and
simvastatin.
Colchicine is a P-
glycoprotein
inhibitor.
Glyburide Increased glyburide Monitor response to
levels due to glyburide with fluvastatin
fluvastatin inhibition 80 mg
of CYP2C9.
Increased levels of
fluvastatin due to
competition for
CYP2C9
Grapefruit/Grape Increased risk for Experts suggest avoiding
fruit Juice myopathy/ grapefruit with
rhabdomyolysis due atorvastatin, simvastatin,
to decreased and lovastatin.
metabolism of

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PHS 810 MODULE 1

atorvastatin, Consider using

lovastatin, and pravastatin, rosuvastatin,
simvastatin. or Fluvastatin
Grapefruit juice
inhibits CYP3A4 and
P-glycoprotein
Macrolide Increased risk for Lovastatin and
Antibiotics myopathy/rhabdomy simvastatin should be held
Clarithromycin olysis due to during treatment with
(e.g., Biaxin, decreased metabolism these macrolides.
generics) of atorvastatin, Do not exceed atorvastatin
Erythromycin lovastatin, and 20 mg with
simvastatin. clarithromycin. Also
consider cautious dosing
with erythromycin. Use
azithromycin if treatment
with a macrolide
antibiotic is unavoidable
(considered less likely to
interact).
Nefazodone Increased risk for Hold lovastatin and
(U.S. only, myopathy/rhabdomy simvastatin during
generics) olysis due to nefazodone use.
decreased metabolism Atorvastatin dose
of atorvastatin, reduction recommended.
lovastatin, and Consider fluvastatin,
simvastatin. pravastatin, or
Nefazodone is strong rosuvastatin
CYP3A4 inhibitor
Phenytoin Increased phenytoin Monitor phenytoin levels
(Dilantin, generics) levels due to with fluvastatin initiation
fluvastatin inhibition or dosage
of CYP2C9. change.Fluvastatin dose
Increased levels of adjustment not necessary.
fluvastatin due to
competition for
CYP2C9.
Protease Increased risk for Do not use protease
Inhibitors myopathy/rhabdomy inhibitors with lovastatin
Darunavir olysis due to or simvastatin.
Fosamprenavi, decreased metabolism Do not exceed atorvastatin
Indinavir of atorvastatin, 20 mg with
Lopinavir/Ritonavi lovastatin, and saquinavir/ritonavir,
r, simvastatin. darunavir/ritonavir,
Ritonavir fosamprenavir/ritonavir,
or boceprevir.

41
PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

Saquinavir These antivirals are Do not exceed 40 mg

strong CYP3A4 atorvastatin with
inhibitors. nelfinavir.
Use lowest necessary dose
of atorvastatin with
atazanavir, indinavir,
lopinavir/ritonavir, and
ritonavir.
Rifampin Dual mechanism: Give rifampin and
rifampin induces atorvastatin
CYP450 enzymes but simultaneously.
inhibits some non- Limit pitavastatin dose to
CYP450 elimination 2 mg with rifampin
pathways.
Simultaneous
rifampin/atorvastatin
administration
increases
Warfarin Potential increase in Monitor INR closely
INR due to decreased when initiating, stopping,
warfarin metabolism or changing the statin
and displacement of dose.
warfarin from protein Atorvastatin may be less
binding sites likely to interact
Project Leader in preparation of this PL Detail-Document: Melanie
Cupp, Pharm.D. BCPS Pharmacist's Letter 2012; 28(6):280606

3.9.4 Minimising Interactions

Clinicians should know all of their patients' current drugs. The fewest
drugs in the lowest doses for the shortest possible time should be
prescribed. Patients should be observed and monitored for adverse effects,
particularly after a change in treatment.

Effects that are influenced by enzyme induction may take more than one
week to appear. Drug interactions should be considered as a possible cause
of any unexpected problems.

Prescribers should determine serum concentrations of selected drugs being

taken, consult the literature or an expert in drug interactions and adjust the
dosage until the desired effect is produced.

If dosage adjustment is ineffective, the drug should be replaced by one that

does not interact with other drugs being taken.
3.10 Drug Clearance (Excretion)

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 PHS 810 MODULE 1

3.10.1 Routes of Drug Elimination

i. Renal Clearance (excretion): Consists of elimination of

chemically unchanged drug or its metabolites from the body.
Occurs in the kidney most drugs leave the body in urine, either
unchanged or as polar metabolites. Also occurs at other sites such
as the liver, the lungs, stool and skin. This is not always for example
while drugs like Amiloride, Frusemide etc. can be metabolized and
excreted 100%, 80% Amphetamine, 85% Digoxin, 50%
Ampicillin, metronidazole, trimethoprim, 60% Flucloxacillin.
Because some drugs remain unchanged in the body, excretion is
important for the termination of the drug’s effect. Other major
routes of elimination include biliary, pulmonary, skin and two
minor but significant forms of excretion are mammary and salivary.
ii. Biliary excretion: Excretion in the bile is similar to excretion in
the kidney and occurs by active secretory transport. When plasma
drug concentrations are high, secretory transport may approach an
upper limit. Substances with similar physicochemical properties
may compete for excretion. Drugs with a molecular weight of >
300 g/mol and with both polar and lipophilic groups are more likely
to be excreted in bile. Smaller molecules are generally excreted
only in negligible amounts. The molecular weight of most drugs is
too low for efficient biliary excretion. Conjugation to glucuronic
acid often increases molecular weight sufficiently for biliary
excretion. Conjugation to acetate or glycine is generally too small.
Bile is a significant route of excretion for: Glucuronide conjugates
(morphine) and a limited number of ionised drugs with very high
molecular weight (cromoglycate)
iii. Pulmonary excretion: Pulmonary excretion refers to excretion
through the lungs and breath. This is a significant route of excretion
for some volatile molecules, especially anaesthetics.
iv. Excretion through the skin: sweat - Drugs can be excreted
through the skin. Drugs are secreted into sweat by passive
diffusion. – This depends on the plasma/sweat partition coefficient
(sweat pH: 4–6.8). There are also some active secretion
mechanisms by which drugs can be excreted into sweat.
v. Mammary: milk - Mammary excretion is a minor route but can be
clinically important. There is no active excretion, just passive
diffusion. Concentration in milk reflects free concentration in
blood. As milk is slightly acidic (with a pH of 7 compared to blood
with a pH of 7.4), the ionisation of the drug may differ slightly
between the milk and the blood — thus affecting its partitioning.
Erythromycin in milk has pH of breast milk: 7.0 and pH of blood:
7.4.
vi. Drugs in milk: clinical significance

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 PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

The clinical relevance of the effect of a drug is evident when

considering breastfeeding a baby, for example; Tetracyclines are
incorporated into teeth, which become weakened and 'mottled'.
Chloramphenicol can result in bone marrow toxicity and 'grey
baby' syndrome, where babies cannot metabolise the drug
effectively.
vii. Saliva: Excretion through saliva is a minor route but can be
significant because of possible use in drug monitoring.
Pharmacokinetic experiments often need a number of blood
samples (10 or more) so there are doubts about ethical approval.
Saliva sampling is non-invasive. For neutral molecules, salivary
concentrations will reflect free concentrations in plasma. Ionised
drugs are a problem. Saliva pH is variable so, in this case, there is
a variable degree of ion trapping.

3.10.2 Processes of Renal Drug Excretion

Three renal processes account for renal drug excretion:

i. Glomerular filtration
ii. Active tubular secretion
iii. Passive diffusion across the tubular epithelium

Table12: Transmembrane passage

Principles of transmembrane passage govern renal handling of

drugs
Drugs bound Unbound Un-ionised forms of drugs and their
to plasma drugs are metabolites tend to be reabsorbed from
proteins contained in tubular fluids
remain in the the glomerular
circulation filtrate
Urine pH affects drug reabsorbed and excretion because it determines
the ionisation of a weak acid or base
Acidification Alkalinisation
• Increased reabsorption • Has opposite effects
• Decreased excretion of • Enhanced excretion of
weak acids acetylsalicylic acid for example
• Decreased reabsorption
of weak basis
Drug elimination rate changes from urinary pH on the:
• Contribution of the Polarity of the Polarity of the
renal route to total unionised form unionised form
elimination
• Polarity of the unionised
form

44
 PHS 810 MODULE 1

i. Filtration: Filtration is a passive process driven by pressure

difference. Approximately 20% of plasma volume is filtered in one
flow through the kidney. Small molecules with a molecular weight
of less than 20,000 are readily filtered, including most drugs.
Plasma albumin (Mwt: 68,000) cannot cross the membrane.
Therefore, most proteins are not filtered nor are drugs that are
extensively protein bound.
ii. Active secretion: Active secretion is energy dependent and
transports substances from the plasma into the tubular urine. It can
generate positive concentration gradients.

Aside from specific transport systems, there are two relatively

unspecific mechanisms, one for anions and one for cations (acids
and bases). This process is saturable. Therefore, there are some
possible interactions.

As blood passes through the kidney, the blood is cleared of some

of the drug. If renal clearance is greater than the glomerular
filtration rate (GFR), there must be active secretion.

Table13: Actively secreted drugs

Acids Bases
• Cephaloridine • Dopamine
• Frusemide • Morphine
• Indomethacin • Pethidine
• Penicillins • Quinine
• Probenecid • Quaternary
• Thiazide diuretics • Ammonium salts

Probenecid and penicillins share the same mechanism for acid secretion.
Probenecid competes with penicillins – penicillin clearance is reduced.

Tubular reabsorption

99% of water is reabsorbed. There are specific transport systems but the
majority of reabsorption is by passive diffusion through the distal tubular
epithelium.

Lipid-soluble drugs are reabsorbed along with water. Only very water-
soluble molecules can be efficiently excreted by the kidneys.

Acidic urine – Basic drug ionisation – Reabsorption – excretion.

Renal clearance

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PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

As blood passes through the kidney, the blood is cleared of some of the
drug. The maximum possible renal clearance is approximately 660 ml/min
– all plasma is cleared. If renal clearance is greater than the glomerular
filtration rate (GFR), there must be active secretion.

Not filtered OR extensively reabsorbed

The maximum possible renal clearance is approximately 660 ml/min – all

plasma is cleared. If the clearance is much less than the GFR, the drug is
not filtered or is extensively reabsorbed

3.11 Concept of Clearance

Clearance is: Used to evaluate efficiency of drug removal from the body.
A pharmacokinetic measurement of the renal excretion ability. Clearance
is almost synonymous with renal clearance or renal plasma clearance. –
Each drug has a specific clearance that depends on its filtration
characteristics in the kidney. Clearance is the proportionality constant that
makes the average steady state drug level equal to the rate of drug
administration.

Clearance = Rate of elimination / plasma concentration

Clearance only represents the theoretical volume of blood that is totally

cleared of drug per unit time. – It is not an indicator of how much drug is
being removed. The amount of drug removed depends on the
concentration. Clearance expresses the rate or efficiency of drug removal.
Units of flow (mg/h)/ (mg/l) = l/h

Example: Clearance = 1 l/hr. Concentration = 0.5 mg/l

Rate of elimination = Clearance × concentration = 0.5 mg/hr.

Clearance is the apparent volume of plasma completely cleared of drug

per unit time.
The rate of elimination is always the same. The value of clearance will
differ depending on where you measure the drug:
Rate of elimination = CL × C = CLb × Cb = CLu × Cu
Plasma blood plasma water
If you want to measure the volume based on plasma and you want to relate
that to clearance, clearance has to be measured with respect to plasma.

3.11.3 Rate of elimination

Volume of reservoir (V) = 1,000 ml

Dose = 10 mg Initial concentration = 10 mg/l
Removal rate (flow rate) (Q) = 100 ml/min

46
PHS 810 MODULE 1

Clearance = Q = 100 ml/min

Fractional rate of removal (K) = 100 ml/min = 0.1 or 10%/min
1,000 ml
The relationship between the amount of drug in the body (A) and the
plasma concentration (C) is defined by the volume of distribution (V).

A=V×C

The fractional elimination rate constant (k) is the rate of elimination

divided by the total amount of drug in the body
Example: k = Rate of elimination = CL × C = CL
Amount V× C V
CL = k × V

Elimination rate constant

The elimination rate constant can also be expressed as a half-life: t1/2 =

ln (2) = K
0.693 V
CL
Table14: Terminal Half-life versus Plasma Clearance (Dog Data)
Benzyl Gentamicin Oxytetracycline Tylosin
Penicillin
Cl (plasma) 3.5 3.1 4 22
(ml/kg/min)
t1/2 (min) 30 75 360 54

Half-life changes as a result of changes in elimination

3.11.2Extraction Ratio

Extraction ratio: Rate of elimination = Rate in – Rate out = (Q × CA) –

(Q × CV)

Extraction

Extraction ratio (E) = Rate of elimination Rate in = Q × (CA – CV) Q × CA

CA – CV CA
= Extraction ratio (E) =Rate of elimination = Q × (CA – CV) =
CA – CV
Rate in Q × CA× (
Extraction ratio and clearance
Rate in Q × CA Rate out Q × (1 – E) × CA

Rate of elimination = Q × (E × CA)

CL = Rate of elimination = Q (CA – CV) = Q × E

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PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

Entering concentration CA

Clearance depends on blood flow and extraction ratio

Low and high extraction: The extraction ratio must be between 0 and 1.
E = Q (CA – CV) CA

Table 15: Renal extraction Ratio

Low extraction drug High extraction drug

 The eliminating organ is not  The drug is efficiently
very efficient at removing the drug. eliminated from the organ.
 Clearance is low.  Clearance is high.
Low clearance drug: E 0 High clearance drug: E 1

Table 16: Hepatic extraction ratio

Low extraction Medium extraction High extraction
Diazepam Quinidine Alpranolol
Warfarin Codeine Propranolol
Tolbutamide Morphine Pentazocine
Phenytoin Lidocaine

3.11.3 Additivity of clearance: Some drugs can be eliminated by more

than one organ, for example, hepatic metabolism (liver) and renal
excretion (kidneys), such that clearance is additive. In such cases, total
clearance is the sum of the component organ clearances.
Rate of elimination (CL X C) = Rate of excretion (CLR X C) + Rate of
hepatic metabolism (CLH XC)

CL = CLR + CLH

3.12 Pharmacokinetics Changes in Pregnancy and Lactation

3.12.1 Introduction: Physiological Changes in Pregnancy

Immediate Physiological Changes; As the fetus and placenta grow and

place increasing demand on the mother, phenomenal alterations in
metabolism occur. The most obvious physical changes are weight gain and
altered body shape. Weight gain is due to increase in breast tissue, blood
and water volume in the form of extra vascular and extra cellular fluid.

Deposition of fat and protein and increased cellular water are added to
maternal stores. The average weight gain during pregnancy is 12.5 kg
while during normal average increase in non- pregnant women is about 1
kg weight gain is due to protein. Also, plasma albumin levels are
decreased and fibrinogen levels are increased. Total body fat increases

48
PHS 810 MODULE 1

during pregnancy. During second half of pregnancy plasma lipids increase

but triglycerides, cholesterol and lipoproteins decrease soon after delivery.
The ratio of LDL to HDL increases during pregnancy

3.12.2 Absorption: Gastric emptying/small intestine motility are reduced

in pregnancy due to elevation of progesterone particularly in the third
trimester thus delaying the appearance in the plasma of orally
administered drugs & onset of effect of the drug, especially during labor.
Absorption from an intramuscular site is likely to be efficient because
tissue perfusion is increased due to vasodilatation.

Inhalational drugs may be enhanced due to increased cardiac output and

tidal volume, increasing alveolar uptake. For example, dose requirements
for volatile anaesthetic agents, such as halothane, are reduced in
pregnancy

3.12.3 Distribution: During Pregnancy. a woman's plasma volume

increases by 30-50% (up to 8litre of water) and cardiac output and
glomerular filtration rate also increase in similar proportion. These factors
contribute to lower circulating concentration of some drugs (especially
those excreted by kidney) in a pregnant woman and possibly to sub-
therapeutic drug levels. Also, there is increase in body fat during
pregnancy; which increases the volume of distribution of fat-soluble drugs
as a result of haemodilution, plasma albumin (normal 33-55 g/1) declines
by some 10 g/1. Thus, there is scope for increased free concentration of
drugs that bind to plasma proteins (albumin). e.g. anticonvulsants.
Unbound drug is free to distribute, metabolised and excreted out more
rapidly by the kidney and liver; and this offset the effect of increased
volume of distribution; e.g. the free (and pharmacologically active)
concentration of phenytoin is unaltered, although the total plasma
concentration is reduced.

3. 12.4 Metabolism: Concurrent use of other common medications during

pregnancy such as antacids, iron and vitamins could also bind and
inactivate some drugs

3.12.5 Hepatic metabolism increases, but not the blood flow to liver.
oestrogen/progesterone induces some enzymes of P-450 system, resulting
in a higher rate of metabolism (and hence elimination) of drugs, like
Phenytoin. Other isoenzymes are competitively inhibited by progesterone
and oestradiol, leading to impaired elimination, for example, theophylline.
Drugs that are so rapidly metabolised that their elimination rate depends
on their delivery to the liver, i.e. on hepatic blood flow, have unaltered
clearance, e.g. pethidine.

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PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

3.12.6 Elimination: Renal plasma flow almost doubles: RBF is increased

by 60±80% during pregnancy, and GFR rises by 50%, leading to enhanced
elimination of drugs that are normally excreted unchanged ± for e.g.
penicillin and digoxin. So, there is rapid loss of drugs that are excreted by
kidney e.g. amoxycillin, dose of which should be doubled for systemic
infections

3.12.7 Placental Transfer of Drugs: The placenta is not a perfect barrier

to drugs and chemicals administered to mother.
Thalidomide tragedy, showed that placenta was capable of transferring
drugs ingested by mother to fetus, with potential for great harm. On other
hand, placental transfer of drugs administered to mother has been used to
treat fetal arrhythmias, congestive heart failure, & other conditions.

3.12.-8 Factors affecting placental drug transfer & fetal tissue

The rate of transfer (Rate at which drug crosses placenta & amount of drug
reaching the fetus) depends on the chemical properties of the drug such as

i. Duration of exposure to drug

ii. Protein binding: Only free unbound drug crosses the placenta,
during pregnancy maternal plasma albumin decreases while fetal
albumin increases. As a result, the concentration of free drug
increases which crosses the placenta to reach the fetus
iii. pH difference: Fetal pH is slightly more acidic than maternal pH
and so weak bases are more likely to cross the placenta.,
iv. Lipid solubility: Moderately lipid soluble drugs can easily diffuse
across the placental membrane
v. Molecular weight of the drug: Drugs with low molecular weight
(<500 g/mol) diffuse freely across the placenta. Drugs with a higher
molecular weight (between 500-1000 g/mol) cross the placenta less
easily, while a few drugs with a high molecular weight (>1000
g/mol) do not cross the placental membrane
vi. Physicochemical properties of drug
vii. Distribution characteristics in different fetal tissues
viii. Stage of placental & fetal development at time of exposure to
the drug: Transplacental: transfer of drugs increases in the third
trimester due to increased maternal and placental blood flow,
decreased thickness and increased surface area of the placenta
ix. Effects of drugs used in combination: steroid and placental
hormones displace drugs from their protein-binding sites.

50
PHS 810 MODULE 1

SELF ASSESSED EXERCISES

i. What is the importance of drug concentration?

ii. What are the advantages and disadvantages of oral drug
administration?
iii. Explain the terms “Therapeutic window” and “Therapeutic
index”.

4.0 CONCLUSION

In this unit, you learnt about definition terms in pharmacology, and

sources of drugs. You have been exposed to one of the major topics in
pharmacology; pharmacokinetics (routes of drug administration, kinetics
of drug absorption, distribution. Blood-brain-barrier, placental barrier,
biotransformation and elimination etc.) and also pharmacokinetic changes
in pregnancy and lactations necessary for a public health professional.

5.0 SUMMARY

Basic principles of pharmacology have been discussed. These include

Pharmacokinetics, which literally means "What the body does to the
drug". It describes the movement of drug as it passes through the body
through absorption, distribution, metabolism and excretion. Drug may
enter the body in a variety of ways: as an oral liquid, pill, or capsule; as
an inhaled vapour or aerosol; absorbed through intact skin or a mucous
membrane; injected into muscle, subcutaneous tissue, spinal fluid, or
directly into the bloodstream. Pharmacokinetics determine the blood
concentration from a prescribed dosing regimen. More often the plasma
concentration for analytical purposes. Pharmacokinetic data help us
understand: dose and schedule (once a day vs. twice a day, etc.), dose
adjustments due to drug interactions and other issues. Many factors affect
drug absorption such as particles size, physicochemical properties of the
drug, surface area of absorption, pH, and blood supply etc. ort.

Once the drug is in the bloodstream a portion of it may exist as free drug,
dissolved in plasma water. Some drugs will be reversibly taken up by red
cells and some will be reversibly bound to plasma proteins. For many
drugs, the bound forms can account for 95-98% of the total. This is
important because it is the free drug which traverses cell membranes and
produces the effect. It is also important because protein-bound drug can
act as a reservoir which releases drug slowly and thus prolongs its action.

This total volume of distribution determines the equilibrium

concentration of drug after a specified dose. The liver metabolises most
drugs into inactive or less active compounds which are more readily
excreted. These metabolites and some of the parent compounds may be

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PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

excreted in the bile and eventually may pass out of the body in the faces.
Parent drug and metabolites in the bloodstream may then be excreted:
most are filtered by the kidney, where a portion undergoes reabsorption,
and the remainder is excreted in the urine. Some drugs are actively
secreted into the renal tubule. Another route of excretion is the lung:
Drugs like alcohol and the anaesthetic gases are eliminated by this route.
Smaller amounts of drugs are eliminated in the sweat, tears and breast
milk. Biotransformation may sometimes produce metabolites with a
great deal of activity. Occasionally, we administer a parent drug which
is inactive (a pro-drug) and only the metabolite has activity.

6.0 TUTOR- MARKED ASSIGNMENT

1) What are different routes of drug administration and write about

advantages and disadvantages of parenteral route of
administration.
2) Define bio-availability and describe the factors affecting drug
absorption.
3) Define the following:
a) Half-life of a drug
b) Steady state plasma concentration
c) Drug - drug interactions

7.0 REFERENCES/FURTHER READING

Craig, C. & Stitzel, R.E.(2003). Modern Pharmacology with Clinical

Applications (6th ed.). LWW.

Malcolm, R. & Tozer T.N. (1995). Clinical Pharmacokinetics: Concepts

and Application(3rd ed.).

Michigan, Williams and Wilkins.

Rajaram, L., Roy, S. & Skerjanec, A. (2004). Bioavailability and

Bioequivalencetrials: Statistics and Pharmacokinetics principles.
Studies in health technology and informatics,103 (1159-
79).https://doi.org10.3233/978-1-60750-946-2-159.

David. W. A. B. (2012). PHAR 7633 Chapter 4 Pp1 -

34.http://www.boomer.org/c/p4/c04/c0414.html. (Accessed may
2020).

DiPiro, J.T. (ASHP, 2010) Concepts in Clinical Pharmacokinetics:

introduction to Pharmacokinetics and Pharmacodynamics. Pp1
113. Retrieved

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from.https://books.google.com.ng/books/about/Concepts_in_Clinical_Ph
armacokinetics.html?id=vMI_cPtEqdQC&source=kp_book_descr
iption&redir_esc=y[access 10 April 2020).

Mathijssen, R. H. J., Sparreboom, A. & Verweij, J. (2014). Determining

the optimal dose in the development of anticancer Agents. Nat. Rev.
Clin. Oncol11(5), 272-281.https://doi:10.1038/nclinonc.2014.40.

PHAR 7633 Online Resources (Chapter 11 29th April 2010) Physiological

Factors Affecting Oral Absorption. Retrieved
fromhttps://www.boomer.org/c/p4/c01/manual.pdf.

Robin J. Heyden. Anatomy and Physiology the cell membrane.Rice

University “open source”
https://opentextbc.ca/anatomyandphysiology/chapter/the-cell-
membrane.

Tarek, A.A. (2015). Pharmacokinetics of Drugs Following IV Bolus, IV

Infusion, and Oral Administration. Reviewed: September 21st
2015 Published: November 18th 2015 DOI: 10.5772/61573

Bioavailability. From Wikipedia, the free encyclopaedia.

en.wikipedia.org/wiki/Bioavailability.

Melanie, C. (2012). Project Leader in preparation of this PL Detail-

Document.Pharmacist's Letter 28(6):280606.

Assessment of bioequivalence studies [3rd March 2020]. Experience from

WHO Prequalification Programme. Retrieved from
http://apps.who.int/prequel/.

Katzung, B.,Masters, S., &Anthony, T.(2009).Basic and Clinical

Pharmacology. (11th ed). McGraw Hill Medical.

Thierry, B., Marie, N., Stephan, K., Kenji, M. Myriam, G., AUC Graph:
“Swiss virtual Campus" project, in close collaboration with the
CENTEF of the University of Lausanne. Coordinated by the
eLearning coordinator of the Faculty of Biology and Medicine,
University of Lausanne. Authors contributed to the content.

Teferra A., Srinivasa A.R., Amare M., Solomomon W., Eshetu Le. &
Musie A. (2004). Pharmacology LECTURE NOTES for Health
Science Students. Dawit University of Gondar in collaboration with
the Ethiopia Public Health Training Initiative, The Carter Centre,
the Ethiopia Ministry of Health, and the Ethiopia Ministry of
Education.

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David, E.G., Armen, H.T., Ehrin, J.A., &April W.A., (4th Eds). (2016).
Principles of Pharmacology:The Pathophysiologic Basis of Drug
Therapy. US:Wolters Kluwer Health.

The Pharmacology Education Project (PEP) developed by The

International Union of Basic and Clinical Pharmacology
(IUPHAR), with support from sponsors, as a service to the
international pharmacology community. January 2019 issue.
https://doi.org/10.1002/cpt.1278 PMID:30588614. (cited April 13
2020)

Coleman, M.D. (2010). Human Drug Metabolism: An Introduction. (2nd

ed.). John Wiley & Sons, Ltd.

Gupta, P.K. (2016).Fundamentals of Toxicology: Essential Concepts and

Applications. (1st ed.). Academic Press.

McDonnell, A.M. & Dang, C.H. (2013). Basic review of cytochrome P450
system. JAdv Pract Oncol,4(4): 263–
268. https://doi: 10.6004/jadpro.2013.4.4.7.

Bourne D. D. First Course in Pharmacokinetics and

Biopharmaceutics.https://www.boomer.org/c/p4 (Access march
2020).

Kimberly, S., Swan, T., (2010) HIV Research Catalyst Forum; Treatment
Action Group. http://www.wisegeek.com/what-is-a-drug-
interaction.htm.

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UNIT 2 TOXICOLOGY AND ADVERSE DRUG REACTIONS

CONTENTS

1.0 Introductions
2.0 Objectives
3.0 Main Contents
3.1 Definition of Terms
3.2 Purpose of Toxicology
3.3 The goal of toxicology
3.4 History of Toxicology
3.5 Toxicology Sub-Discipline
3.5.1 Environmental Toxicology
3.5.2 Occupational (Industrial) Toxicology
3.5.3 Regulatory Toxicology
3.5.4 Food Toxicology
3.5.5 Clinical Toxicology
3.5.6 Descriptive Toxicology
3. 5.7 Forensic Toxicology
3.5.8 Analytical Toxicology
3.5.9 Mechanistic Toxicology
3.6 Routes of Drug Toxicity
3.7 Mechanisms of drug toxicity
3.7.1 On -Target toxicity
3.7.2 Hypersensitivity and immunological Toxicity
3.7.3 Off target Toxicity
3.7.4 Bio activation
3.7.5 Idiosyncratic Reactions
3.8 Classification of Toxic Agents
3.8.1 Heavy Metals
3.8.2 Solvents and Vapours
3.8.3 Radiation and Radioactive Materials
3.8.4 Dioxin/Furans
3.8.5 Pesticides
3.8.6 Plant Toxins
3.8.7 Animal Toxins
3.9 Poisons that can heal
3. 9.1Adverse drug reactions
3.9.2 Adverse Drug Reaction Classification
3.9.3 Types of Adverse Drug Reactions
3.9.4 Causes of Adverse Drug Reactions
3.9.5 Impact of genetics
3.9.6 Risk Factors of Adverse Drug Reactions
3.9.7 Factors Masking Adverse Drug Reactions:
4.0 Conclusion
5.0 Summary

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PHS 810 PHARMACOLOGY AND THERAPEUTICS PUBLIC HEALTH

6.0 Tutor- Marked assignment

7.0 References/Further reading

1.0 INTRODUCTION

Traditionally, the study of poisons was centred around the inherent

capacity of a chemical or compound to produce injury. Today, toxicology
is more safety driven and modern toxicology uses chemicals as tools to
understand molecular/cellular biology. One basic function of toxicology
is to assess the likelihood of occurrence of adverse effects (qualitative): Is
a chemical or compound safe? This is hazard identification. Also,
toxicology studies the nature and mode of action of adverse effects
(quantitative). At what concentration is it safe? This is known as dose-
response assessment or hazard characterisation

2.0 OBJECTIVES

By the end of this unit, you will are to

 define toxicology, drug interactions and adverse drugs commonly

associated terms
 describe the classifications of toxic agents and poisons that can heal
 distinguish adverse drug reactions (ADRs) from adverse drug
events
 devise methods for ADR detection, and classify an ADR when it
presents
 detect populations most at risk of ADRs.

3.0 MAIN CONTENT

3.1 Definition of Terms

i. Toxicity: The word “toxicity” describes the degree to which a

substance is poisonous or can cause injury. The toxicity depends
on a variety of factors: dose, duration and route of exposure, shape
and structure of the chemical itself, and individual human factors.
ii. Toxic: This term relates to poisonous or deadly effects on the body
by inhalation (breathing), ingestion (eating), or absorption, or by
direct contact with a chemical.
iii. Toxicant: A toxicant is any chemical that can injure or kill humans,
animals, or plants; a poison. The term “toxicant” is used when
talking about toxic substances that are produced by or are a by-
product of human-made activities. For example, dioxin (2, 3-7, 8-
tetrachlorodibenzop-dioxin {TCDD}), produced as a by-product of
certain chlorinated chemicals, is a toxicant. On the other hand,

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arsenic, a toxic metal, may occur as a natural contaminant of

groundwater or may contaminate groundwater as a by-product of
industrial activities. If the second case is true, such toxic substances
are referred to as toxicants, rather than toxins.
iv. Toxin: The term “toxin” usually is used when talking about toxic
substances produced naturally. A toxin is any poisonous substance
of microbial (bacteria or other tiny plants or animals), vegetable, or
synthetic chemical origin that reacts with specific cellular
components to kill cells, alter growth or development, or kill the
organism.
v. Poisoning: Definition of a Poison? The study of the adverse effects
of a toxicant on living organisms. Any agent capable of producing
a deleterious response in a biological system. Living organism: a
sachet of water with target sites, storage depots and enzymes. All
substances are poisons; there is none that is not a poison. The right
dose differentiates a poison and a remedy. -Paracelsus (1493-
1541)
vi. Adverse drug reaction (ADR): WHO definesas an adverse drug
reaction is “a response to a drug which is noxious and unintended
and which occurs at doses normally used in man for prophylaxis,
diagnosis, or therapy of disease or for the modification of
physiologic function.” (WHO definition, 2005). This excludes
therapeutic failures, overdose, drug abuse, noncompliance, and
medication errors
vii. An adverse drug reaction (ADR) is an injury caused by
taking medication. ADRs may occur following a single dose or
prolonged administration of a drug or result from the combination
of two or more drugs.
viii. An adverse drug event is “any untoward medical occurrence
that may present during treatment with a pharmaceutical product
but which does not necessarily have a causal relationship with
this treatment” (WHO definition, 2005). In other words,
the reaction is where the drug does something nasty, and
an event is something nasty which potentially happens randomly
and might be totally unrelated to the drug. The basic requirements
for an ADR are that: The reaction is directly related to the drug; the
drug was being used correctly and appropriately and the reaction is
harmful. Thus, prescribing errors and intentional overdoses do not
fall under the definition of an adverse drug reaction.
ix. Side Effects: Is define as An unintended effect of a drug
occurring at the normal dose related to the pharmacological
properties of the drug.
x. Drug overdose: Toxic reactions linked to excess dose or impaired
excretion, or to both.
xi. Drug interaction: Action of a drug on the effectiveness or toxicity
of another drug. Reactions that occur only in susceptible subjects

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xii. Drug intolerance: A low threshold to the normal pharmacological

action of a drug
xiii. Drug idiosyncrasy: A genetically determined, qualitatively
abnormal reaction to a drug related to a metabolic or enzyme
deficiency
xiv. Drug allergy: An immunologically mediated reaction,
characterised by specificity, transferability by antibodies or
lymphocytes, and recurrence on re-exposure
xv. Pseudo allergic reaction: A reaction with the same clinical
manifestations as an allergic reaction (e.g., as a result of histamine
release) but lacking immunological specificity
xvi. Expected Reaction: The process of assessing the likelihood that
the reported adverse reaction is actually due to the suspected
medicine using pre-determined criteria such as the WHO causality
assessment criteria.
xvii. Expected Reaction: A reaction that is consistent with the
applicable product information or characteristics of the drug. The
reaction can be explained from the mechanism of action of the
drug.
xviii. Unexpected Adverse Reaction: An adverse reaction, the nature or
severity of which is not consistent with the applicable product
information or characteristics of the drug.

3.2 Purpose of Toxicology

Toxicology affects us every day. The purpose of toxicology is to provide

workers a safe working environment and to ensure consumers’ products
are safe to use as specified and under foreseeable misuse. Another area of
toxicology is the environment or ecotoxicology, which is concerned with
the quality of the air, water (surface and ground), soil, and bedrock, and
aquatic wildlife (fresh and salt) and terrestrial organisms (flora and fauna).
Toxicology provides information to risk managers about the nature and
severity of effects on human health and the environment as it relates to
specific exposures. Ecotoxicology often drives remediation site clean-ups.
There are approximately 6,000,000 known chemicals; approximately
100,000 currently in use worldwide, and 500 new chemicals being added
annually.

3.3 the Goal of Toxicology

The goal of toxicology is to contribute to the general knowledge of the

harmful actions of chemical substances, to study their mechanisms of
action, and to estimate their possible risks to humans on the basis of
experimental work on biological test systems. To protect human health,
provide information via risk assessments, hazard identification, dose-
response assessment, exposure assessment and risk characterization

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3.4 History of Toxicology

Toxicology is arguably the oldest scientific discipline, as the earliest

humans had to recognise which plants were safe to eat. Most exposure
of humans to chemicals is via naturally occurring compounds consumed
from food plants. Humans are exposed to chemicals both inadvertently
and deliberately. Paracelsus: born Philippus Aureolus Theophrastus
Bombastus von Hohenheimis credited as the founder of toxicology. His
premise of poisons was that “Allthings are poison, and nothing is without
poison; only the dose permits somethingnot to be poisonous.” Simply
stated, “The dose makes the poison”.

Many of the Earliest Practitioners of Toxicology Were Women:

Lucrezia Borgia (food toxicologist): daughter of Rodrigo Lenzuoli
Borgia or Pope Alexander VI, who specialised in faith-based poisoning,
was an early Italian who helped develop poisoning into a simple but fine
art. It is said that the Borgias selected and laid down rare poisons in their
cellars with as much thought as they gave to their vintage wines.
Catherine de Medici of Florence and Queen Consort of France
(experimental toxicologist): tested and carefully studied the effects of
various toxic concoctions on the poor and sick, noting the onset of action
and symptoms that occurred.

Goeie Mie ('Good Mary') of Leiden, The Netherlands (forensic

toxicologist): poisoned at least 102 friends (27 died) and relatives between
1867 and 1884, distributing arsenic trioxide in hot milk to her victims after
opening life insurance policies in their names.
Catherine Deshayes or “La Voisin” (economic toxicologist): who
traded in selling poisons to wives who wished to rid themselves of their
husbands, was later burned at the stake.

Other Historical Examples: Stalin: –Politburo allegedly gave him

warfarin (a synthetic derivative of Coumarin, found naturally in many
plants and used as an anticoagulant medication).
Fidel Castro: CIA, using botulinum-laced pills, made attempts on the life
of the Cuban Dictator.

Viktor Yushchenko: Evidence suggests that the Ukrainian President was

poisoned with dioxin (the common name for the group of compounds
classified as polychlorinated dibenzodioxins) in an attempt to remove him
from office as recently as 2006
Study and Documentation of Poisons: 20th Century: Rachel Carson -
alarmed public about dangers of pesticides in the environment in her book
“Silent Spring”. Late in the 1950s, Carson turned her attention to
conservation, especially environmental problems that she believed were
caused by synthetic pesticides. The result was Silent Spring (1962), which

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brought environmental concerns to an unprecedented share of the

American people. Although Silent Spring was met with fierce opposition
by chemical companies, it spurred a reversal in national pesticides policy,
which led to a nationwide ban on DDT and other pesticides, and it inspired
a grassroots environmental movement that led to the creation of the U.S.
Environmental Protection Agency. Carson was posthumously awarded the
Presidential Medal of Freedom by Jimmy Carter.

1900-1200 . - Egyptian documents that had directions for collection,

preparation, and administration of more than 800 medicinal and
poisonous recipes.

1900-1201 800 B.C. - India - Hindu medicine includes notes on

poisons and antidotes.

50-100 D. - Greek physicians classified over 600 plant, animal,

and mineral poisons.

Swiss physician Paracelsus (1493-1541) credited with being “the father

of modern toxicology.” “All substances are poisons: there is none which
is not a poison. The right dose differentiates a poison from a remedy.”

Italian physician: Ramazzini (1713) published “De Morbis Artificum”

(Diseases of Workers) Describing "asthma" in bakers, miners, farmers,
gilders, tinsmiths, glass-workers, tanners, millers, grain-sifters,
stonecutters, ragmen, runners, riders, porters, and professors. Ramazzini
outlined health hazards of the dusts, fumes, or gases that such workers
inhaled. The bakers and horse riders described by Ramazzini would today
probably be diagnosed as suffering from allergen-induced asthma. The
lung diseases suffered by most of the other workers would now be
classified as "pneumoconiosis," a group of dust-related chronic diseases.
Paul Ehrlich –developed staining procedures to observe cell and tissues
and pioneered the understanding of how toxicants influence living
organisms.

From Killers to Healers: Toxicology Evolves, but Poisonings Still

Occur

Over the years, there have been several cases of human exposures to
chemicals that have led to devastating outcomes and in some instance’s
death. In 2008, one such case of worldwide poisoning was the exposure of
hundreds of thousands of Chinese children to melamine contaminated
milk, with ensuing kidney stones, kidney failure, and death in some of the
children exposed (Xin and Stone, 2008, Yang and Batlle, 2008, Chiu,
2008). Melamine was found in tainted pet food a year earlier with

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hundreds of thousands of dogs and cats being exposed (Dobson et al.,

2008).

The government of Nigeria implemented tighter controls on chemical

imports after 84 children between the ages of two months and seven years
died after consuming a tainted teething syrup, “My Pikin” (Okuonghae
et al., 1992). Authorities believe diethylene glycol [component of
antifreeze] was wrongly labeled as propylene glycol, a chemical generally
recognized as safe for use in food and medicine which was smuggled into
Nigeria before being purchased by a Lagos-based company, which has
since been shut down. To prevent future incidents, The National Agency
for Food and Drug Administration and Control (NAFDAC) required all
propylene glycol imports from India and China to be certified by the
agency’s independent analysts in India and China before shipment and to
be re-certified upon entry into Nigeria. The first case was discovered on
November 3 with symptoms including diarrhea, vomiting, fever,
convulsions and an inability to pass urine. Diethylene glycol was used as
a cheap replacement for the sweetener glycerin in cough syrup and more
than 100 people, mostly children, died in Panama (http://www.cdc.gov/
mmwr/preview/mmwrhtml/mm5848a2.htm). In addition to the United
States and Panama, diethylene glycol-tainted toothpaste was found in
Australia, the Dominican Republic, Costa Rica, Honduras and Nicaragua
(http://www.nytimes.com/2007/06/02/us/02toothpaste.html? _r=0).

In 2009, 121 of 287 children under 14 years of age in Longyan, China had
high blood lead levels
(http://www.nytimes.com/2009/09/28/world/asia/28china.html). A
smelting plant closed after more than 600 children were found to have lead
poisoning and, in another case, 800 children living near a zinc and lead
smelting plant were found to have high blood lead levels.

In the US, the Food and Drug Administration has a limit of 0.5 μl/dL
in products intended for infants and children and has banned the use of
lead-soldered food cans. Each year in the United States, 310,000 1- to 5-
year-old children are found to have unsafe levels of lead in their blood due
to exposure to lead through dust and other sources (https://
www.cdc.gov/nceh/lead/data/). Just recently, Virginia Tech University
researchers brought proof of high lead levels in Flint, MI water to public
attention in September 2015, performing water tests in more than 250 Flint
homes. Lead levels were high enough, up to 38 μl/dL, to warrant urgent
government action (https://www.rt.com/usa/327363-flintchildren-blood-
lead-water/); however, in a similar problem with Washington, D.C.’s tap
water a little over a decade ago, hundreds of homes were found to have
stratospheric lead levels of 300 ppb or more (Guidotti et al., 2007).

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China has 150 parts per billion (ppb) arsenic limit in foods such as rice.
Rice grown in US has an average 260 ppb of arsenic; however, a 100-ppb
action level has been proposed for inorganic arsenic in infant rice cereal
(http://www.philrice.gov.ph/phl-rice-safe-fromarsenic/).

3.5 Toxicology Sub-Discipline

3.5.1 Environmental Toxicology: Studies chemicals that are

contaminants of food, water, soil, or the air. It deals with toxic substances
that enter the water ways, such as lakes, streams, rivers and oceans. Most
common problems include waterborne bacteria and viruses, waste heat
from electrical plants, radioactive wastes, sewage, and industrial pollution.

3.5.2 Occupational (Industrial) Toxicology: studies of protection of

workers from toxic substances and makes their work environment safe.
Occupational diseases caused by industrial chemicals account for an
estimated 50,000 to 70,000 deaths and 350,000 new cases of illness each
year in the United States

3.5.3 Regulatory Toxicology: Gathers and evaluates existing

toxicological information to establish concentration-based standards of
“safe” exposure.

3.5.4 Food Toxicology: Involves delivering a safe and edible supply of

food to the consumer

3.5.5 Clinical Toxicology: Is a study that is concerned with diseases and

illnesses associated with short term or long-term exposure to toxic
chemicals.

3.5.6 Descriptive Toxicology: Is concerned with gathering toxicological

information from animal experimentation. These types of experiments are
used to establish the chemical dosage that would cause illness and death.
The United States Environmental Protection Agency (EPA), the
Occupational Safety and Health Administration (OSHA), and the Food
and Drug Administration (FDA), use information from these studies to set
regulatory exposure limits.

3.5.7 Forensic Toxicology: Helps to establish cause and effect

relationships between exposure to a drug or chemical and the toxic or
lethal effects that result.

3.5.8 Analytical Toxicology: Identifies the toxicant through analysis of

body fluids, stomach content, excrement, skin, or suspected containers

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3.5.9 Mechanistic Toxicology: Makes observations on how toxic

substances cause their effects. The effects of exposure can depend on a
number of factors, including the size of the molecule, the specific tissue
type or cellular components affected, whether the substance is easily
dissolved in water or fatty tissues, all of which are important when trying
to determine the way a toxic substance causes harm, and whether effects
seen in animals can be expected in humans.

3.6 Routes of Drug Toxicity

The common route hard exposure is ocular (Eye), Inhalational (aerosol,
Gasses, particles), Ingestion (Food/drinks, upper respiratory tract, hand to
mouth), Dermal contact, Breast feeding and Placental see diagram below

Figure 17: Routes of toxicity exposure. (Liebler. D.C.et al (2005)

The exposure route is generally further described as intake (taken in

through a body opening, e.g. as eating, drinking, or inhaling) or uptake
(absorption through tissues, e.g. through the skin or eye).

EPA defines exposure as 'contact between an agent and the visible

exterior of a person (e.g. skin and openings into the body)'.

The applied dose is the amount of agent at the absorption barrier that is
available for absorption. The potential dose is the amount of agent that is
ingested, inhaled, or applied to the skin. The applied dose may be less than
the potential dose if the agent is only partly bioavailable.

The internal dose or absorbed dose is the amount of an agent that has been
absorbed and is available for interaction with biologically significant
receptors within the human body. Finally, the delivered dose is the amount
of agent available for interaction with any specific organ or cell.

Range of Exposure. For any specific agent or site, there is a range of

exposures actually experienced by individuals. Some individuals may

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have a high degree of contact for an extended period (e.g. factory workers
exposed to an agent on the job). Other individuals may have a lower
degree of contact for a shorter period (e.g. individuals using a recreational
site downwind of the factory). EPA policy for exposure assessment
requires consideration of a range of possible

3.7 Mechanism of Drug Toxicity

All compounds are toxic at high doses and all are safe at very low doses,
using the axiom of Paracelsus.3) What we are considering here are not
accidental drug overdoses but toxicity and adverse events at doses that are
relevant to patients using a medicine. What the context of toxicity will
affect how one approaches the matter of circumventing toxicity or
developing alternate compounds that will not have this liability. The most
commonly encountered problems are with cardiovascular and hepatic
toxicity

3.7.1 On -Target: The first context of toxicity is on-target (or

mechanism-based) toxicity. That is, the toxicity is due to interaction of the
drug with the same target that produces the desired pharmacological
response. the concept in this mechanism, is based on the biological
response that the drug exhibits upon binding to its target is the same one
that produces both the efficacious and the toxic effects. All statins produce
hypercholesterolemic properties by inhibiting 3-hydroxy-3-
methylglutaryl CoA (HMG CoA) reductase in the liver, i.e. the target.
The adverse effects of statins are also due to inhibition of HMGCoA
reductase in muscle and possibly other tissues, i.e. geranylgeranylation of
proteins) is inhibited.

3.7.2 Hypersensitivity and immunological Toxicity: The second context

of drugtoxicity is hypersensitivity and immune responses. For instance,
allergicreactions to penicillins have been recognised for many years. The
concept, is on the basis that drugs (or their metabolites) react with proteins
in the body (as haptens) to induce antibodies and immune responses. In
this example (penicllins) the chemical is not completely stable and has the
potential to bind covalently to proteins and initiate antibody production.
See table 1.

Table 17: Contexts of drug toxicity

Type Example
On -target (mechanism based Statin
Hypersensitivity and immunological Penicillins
Off -target Terfenadine
Biological activation Acetaminophen
Idiosyncratic Halofantrine
(Liebler. D.C.et al (2005)

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3.7.3 Off target Toxicity: The third context of drug toxicity is off-target
toxicity. The issue here is that the drug is not specific in its interactions.
Binding to an alternate target is the cause of toxicity. With current
knowledge of the complexity of biological regulatory pathways and multi-
gene families (e.g. protein kinases), it is not surprising that a drug might
not be totally specific. The example in Table 2 is terfenadine, which binds
not only to the H1 receptor (eliciting the desired antihistaminic response)
but also to the hERG channel and thus causing arrhythmias. In principle,
this liability can be addressed by more screening and development of drug
candidates with lower IC50 and Kd values, in that a lower dose might avoid
the specificity issue.

3.7.4Bioactivation: The fourth context of drug toxicity is bioactivation.

Many drugs are converted to reactive products (often termed (reactive)
“metabolites”). These entities modify the proteins they react with and
somehow cause toxicity, although mechanisms have been evasive (vide
infra). One theory is that important regulatory or other proteins are
modified, with loss of function. Another possibility is that the modified
proteins induce immune responses, linking with the second context of
toxicity. An analysis of drugs at one company, Bristol-Myers Squibb,
indicated that “metabolism” was an issue in 28% of cases in which drug
candidates had been dropped from development.

Table 2: Mechanistic causes of toxicology attrition. Based on experience

from DuPont-Merck and Bristol-Myers Squibb, 1993–2006. Information
kindly provided by B. D. Car, Bristol-Myers Squib.

Table 18: Mechanistic causes of toxicology attrition

Mechanistic causes % of all advanced moleculesan
Biotransformation related 27
Target Based 28
Single or multichannel inhibition 18
Immune mediated 7
All other mechanisms 36
a
n = 88. Because categories are partially overlapping, the total is > 100%.

3.7.5 Idiosyncratic Reactions; The fifth context of toxicity is

idiosyncratic reactions. Idiosyncratic means “individual,” and these are
rare events (1/103 to 1/104 individuals), which are not well understood.
Such responses are highly problematic in that few (if any) animal models
are very predictive. The low incidence makes such adverse events difficult
to find even in large clinical trials. However, with widely-used drugs for
which millions of prescriptions may be written, even an incidence of
1/104 can yield hundreds of problems.

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3.8 Classification of Toxic Agents

3.8.1 Heavy Metals: Metals differ from other toxic substances in that they
are neither created nor destroyed by humans. Heavy metals, like
lead, cadmium, and mercury, have been harming human health for
millennia their use by humans playsan important role in
determining their potential for health effects.

Their effect on health could occur through at least two mechanisms:

first, by increasing the presence of heavy metals in air, water, soil,
and food, and second, by changing the structure of the chemical.
For example, chromium III can be converted to or from chromium
VI, the more toxic form of the metal.

Heavy metal toxicity can result in reduced mental and central

nervous function, lower energy levels, and damage to blood, lungs,
kidneys, liver, and other organs.

Some heavy metals like zinc that provide a health benefit in small doses
can be toxic at high levels.

3.8.2 Solvents and Vapours: Nearly everyone is exposed to solvents.

Occupational exposures can range from the use of “white-out” by
administrative personnel, to the use of chemicals by technicians in a nail
salon. When a solvent evaporates, the vapours may also pose a threat to
the exposed population. Hydrocarbon Solvents: Aliphatic organic solvents
are Petroleum distillates, Mineral spirits, and hexanes found in Paints,
coating, thinners etc. Aromatic organic solvents such as Toluene, xylene
and benzenes are found in adhesives and printing inks. Some solvents are
associated with neurotoxicity, reproductive toxicity and carcinogenic
effects during short-term high-level exposure and over prolonged periods
of low-level exposure.

3.8.3 Radiation and Radioactive Materials: Radiation is the release and

propagation of energy in space or through a material medium in the form
of waves, the transfer of heat or light by waves of energy, or the stream of
particles from a nuclear reactor.

3.8.4 Dioxin/Furans: Dioxin, (or TCDD) was originally discovered as a

contaminant in the herbicide Agent Orange. Dioxin is also a by-product of
chlorine processing in paper producing industries.

3.8.5 Pesticides: The EPA defines pesticide as any substance or mixture

of substances intended to prevent, destroy, repel, or mitigate any pest.
Pesticides may also be described as any physical, chemical, or biological
agent that will kill an undesirable plant or animal pest.

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3.8.6 Plant Toxins: Different portions of a plant may contain different

concentrations of chemicals. Some chemicals made by plants can be
lethal. For example, taxon, used in chemotherapy to kill cancer cells, is
produced by a specie of the yew plant.

3.8.7 Animal Toxins: These toxins can result from venomous or

poisonous animal releases. Venomous animals are usually defined as those
that are capable of producing a poison in a highly developed gland or
group of cells, and can deliver that toxin through biting or stinging.
Poisonous animals are generally regarded as those whose tissues, either in
part or in their whole, are toxic.

3.9 Poison

3.9.1 Toxicant (Poison): any agent capable of producing a deleterious

response in a biological system. Living organism: a sachet of water with
target sites, storage depots and enzymes. Poison is a more serious public
health problem than generally recognised. Institute of Medicine estimates
that more than 4 million poisoning episodes occur annually (IOM, 2004)
in 2001 (the most recent year for which data from all sources were
available), there were 30,800 poisoning-related deaths in the

United States (based on published figures and specially provided estimates

from Lois. Fingerhut at the National Centre for Health Statistics, 2003).
This estimate makes poisoning the second leading cause of injury-related
death in the United States, behind motor vehicle deaths (N = 42,443) and
ahead of gun-related deaths (N = 29,573). (IOM, 2004). Ninety-two
(92%) percent of all poisonings happen
at home.

The household products implicated in most poisonings are: cleaning

solutions, fuels, medicines, and other materials such as glue and
cosmetics. Certain animals secrete a xenobiotic poison called venom,
usually injected with a bite or a sting, and others animals harbor infectious
bacteria. Some household plants are poisonous to humans and animals.

3.9.2 Population at Risk: Not only have the magnitude and cost of the
poisoning problem that have been underappreciated, but the diverse nature
of poisonings and the populations at risk have changed over time. While
poisoning was initially viewed as a problem of young children, it now
emerges as a concern across the entire lifespan. Half of all poison
exposures reported to TESS occur among children years of age; however,
only 8 percent of the moderate to major effects from poisonings occur
among those in the 5 years and under age group.

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Approximately71% of moderate and major exposures occur in those over

19 years of age. Regulatory agencies (EPA, CPSC, DOT) require that
certain products and chemicals are tested to determine their potential to
cause life-threatening or fatal acute systemic toxicity.

Testing currently involves exposure of rodents by applicable routes and

monitoring whether animals die or exhibit any clinical signs of toxicity.

3.9.3 Poisons that Can Heal: The key points of toxicology are: 1) Dose
matters (and so does timing); 2) people differ; and 3) things change
(Mitchell, 2004). When we explore the concept of dose, there are poisons
such as Botulinum Toxin A (0.00001 mg/kg) that can be poisonous, yet
this toxin can also heal. Botulinum toxin A (0.00001 mg/kg)
Clostridium botulinum is an anaerobic, gram-positive, spore-former
commonly found in soil that produces oval, sub-terminal endospores.

Botulinum toxin A (0.00001 mg/kg) that can be poisonous, yet this toxin
can also heal. One of 7 seven strains [ABCDEG] is responsible for
approximately 145 cases of poisoning annually and is 40 million times
more powerful than cyanide. Because of the widespread occurrence of
spores of C. botulinum in the soil and the typical hand to mouth response
of infants, C. botulinum spores are often consumed by young children.
These spores can germinate in the intestine in infants (approximately 75–
100 cases annually; 2nd month of life), causing often-fatal outcomes. This
poisoning can be treated with an antitoxin (human Botulinum
immunoglobulin) and supportive care. Conversely, Botulinum toxin is a
poison that can heal. In its purified form (type A), it was the first bacterial
toxin to be used as a medicine. In 1989, the FDA licensed Botulinum for
treating two eye conditions characterized by excessive muscle
contractions; blepharospasm (tic or twitch of eyelid) and strabismus (eyes
not properly aligned). As a medicine,

i. type A toxin can be used to control certain conditions marked by

involuntary muscle contractions and can block muscle
contractions.
ii. Another beneficial effect of botulinum toxin is its use in cosmetic
applications, such as Botox and Botox Cosmetic (Botulinum toxin
A).
iii. It is use in the treatment of patients with cervical (neck) dystonia
and to reduce the severity of abnormal head position and neck pain
associated with cervical (neck) dystonia.
iv. Other applications of Botulinum toxin include severe primary
axillary hyperhidrosis (excessive sweating), achalasia (failure of
the lower oesophageal sphincter to relax), neuropathies, migraine
and other headache disorders, although the evidence is conflicting

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in this indication, and overactive bladder and benign prostatic

hyperplasia.

Figure 18: Seventeen-Year-Old Patient with Mild Botulism(@

semanticscholar.org).

3.9.4 Thalidomide (Dose matters as does timing): Another example of

this concept is thalidomide (100+ mg/kg) and its critical timing of
exposure.

Originally developed as a treatment for insomnia and morning sickness in

the 1950s, in1960 report of grossly deformed infants in Germany, of cases
of phocomelia in pediatric clinics leads to the withdrawal recommended.

Thalidomide is an oral drug that has been shown to be highly active against
Myeloma. Many consider thalidomide to be the first new agent with major
antimyeloma activity in more than 30 years. Thalidomide has been FDA
approved for the treatment of not only myeloma, but also Erythema
nodosum leprosum (ENL, treat and prevent skin conditions caused by M.
leprae). It also has had limited success in treating a variety of other
diseases (Kaposi’s sarcoma, primary brain malignancies, chronic graft
versus host disease, Bechet’s disease, aphthous ulcers, systemic lupus
erythematosus (SLE), adult Langerhans cell histiocytosis, rheumatoid
arthritis, and Jessner’s lymphocytic infiltration of the skin). Thalidomide
can inhibit the growth of HIV in test tubes (by selective tumour necrosis
factor [TNF] alpha inhibition) and may alleviate symptoms of HIV
(Gunzler, 1992, Emer, 2009).

3.9.5 Ricin: Source: castor bean (Ricinus communis). Less toxic orally,
500 ug: human lethal dose if exposure by injection or inhalation (pinhead-
sized amount can kill an adult). Eight beans considered toxic for an adult.
It causes inhibition of protein synthesis resulting in severe diarrhoea (die
of shock). Potential Medicinal Use: Ricin may have therapeutic use in the
treatment of cancer, as a so-called "magic bullet" to specifically target and
destroy cancer cell. Ricin could be linked to a monoclonal antibody to
target malignant cells recognised by the antibody. A promising approach
is also to use the non-toxic B subunit as a vehicle for delivering antigens
into cells thus greatly increasing their immunogenicity.
Use of ricin as an adjuvant has potential implications for developing
mucosal vaccines.
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3.9.6 Other: other apparently nontoxic chemical many can be toxic at high
doses. Too much of a good thing can be bad (table 1). Also, highly toxic
chemicals can be lifesaving when given in appropriate doses. Poisons are
not harmful at a sufficiently low dose (Table 2).

Table 19: Showing approximate Lethal Doses of Common Chemicals

(calculated for a 160 lb. human from data on rats).

Chemicals Lethal Dose

Sugar (Sucrose) 3 quarts
Alcohol (ethylalchol 3 quarts
Salt (sodium chloride) 1 quart
Herbicides (2,4 –D) One half cup
Arsenic (arsenic acids) 1 – 2 teaspoons
Nicotine One half teaspoon

Table 20: Showing examples of Varying doses of the same substances

as non-toxic or beneficial, toxic and lethal (Adopted from T. Gossel and
J. Bricker, Eds).

Chemicals Beneficial Toxic Dose Lethal Dose

dose
Alcohol 0.05% 0.1% (ethanol blood 0.5%
level)
Carbon <10% 10 – 20% (% Hg. >60%
monoxide bound)
Secobarbital 0.1g/dL 0.7g/dL Blood levels) >1g/dL
Aspirin 0.65g (2 9.75g (30 tab. acute oral 34g (105
tab) dose) tablets)
Ibuprofen 400mg (2 1,400mg (7 tab. acute 12000mg
tab.) oral dose) (60 tab.)

3.9.6 What makes a Poison?

All substances are poisons; there is none that is not a poison. The right
dose differentiates a poison and a remedy. -Paracelsus (1493-1541)

The following factors determine what is poison or not

Dose matters (and so does timing); 2) people differ; and 3) things change
(Mitchell,
2004).

Dose Matter: In poison interactions between chemicals and biological

systems follow a dose-response relationship.
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Toxicity is quantified through the dose-response relationship. Individual

change in severity of effect with dose is also called a dose-effect
relationship. Population change is the proportion of the population
responding with dose (people differ). There are different relationships for
different effects, and the shape of the dose response curve gives
information about population variability and toxicity of the compound. A
key concept in toxicology is the quantitative relationship between the
concentration of a xenobiotic (foreign chemical) in the body and the
magnitude of its biological effect. The magnitude of the effect is usually a
function of the amount of xenobiotic a person is exposed to. In any given
population, there will be a range of sensitivities to a xenobiotic. It is
extremely useful to know what is the average sensitivity of a population
to a xenobiotic and what the average dose required to elicit a toxic
response will be. This brings us back to the central tenet of toxicology that
the dose makes the poison and that dose matters.

People differ: Classic examples of the fact that people differ include
allergies to food (e.g., peanuts and shellfish) and to drugs (e.g., penicillin).
Severe allergenic reactions are relatively rare, with approximately 120,000
emergency room visits with less than 200 fatalities/year. Eight foods
(peanuts, milk, wheat, eggs, shellfish, soybeans, crustaceans, some tree
nuts) account for approximately 90% of food allergies (US); whereas,
fourteen foods are listed as allergenic in Europe, which are regional and
include Mollusca shellfish, lupine, celery root, mustard and sesame seeds
and sulfites in addition to those outlined for the US. Even more striking
are the differences in the effects of the same chemical on a single
individual that may be observed during various stages of life (in utero,
neonate, young adult, elderly). For instance, infants have an immature
immune system and limited phase II systems (more sulfur conjugation),
and reduced kidney function. The elderly may be similar in their
sensitivities to the adverse effects of chemicals. There is a difference in
sensitivity of new born rats and older rats to DDT. The LD50 of DDT in
young male rats is greater than 4, 000 mg/kg; whereas in adult rats at 1-
year of age, it is approximately 225 mg/kg.

Acetaminophen (Paracetamol) is metabolised 90% by sulfate or

glucuronide conjugation (Phase II). The sulfate pathway predominates in
children less than 12 years of age, while adults primarily use the
glucuronide pathway. Chloramphenicol (chlornitromycin), an antibiotic
for Gram-positive/-negative, [most anaerobic] organisms, is primarily
metabolized by glucuronidation and is a poor substrate for
sulfotransferases. Therefore, this antibiotic is extremely toxic to neonates
(bone marrow) and is responsible for the “Gray baby syndrome”
consisting of progressive cyanosis, metabolic acidosis, vasomotor
collapse, respiratory difficulty, and death (McIntyre and Choonara, 2004).

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Table 21: This is illustrated in the difference in sensitive of new-born

rats and older rats to DDT.DDT LD50 in Male rats of various ages

Age LD50 (mg/kg)

new-born > 4000
10 days 728
2 weeks 437
1 month 355
2 months 250
4 months 194
1 year 225

Individual differences occur due to a number of factors including

i. Age (foetus, neonate, children, adults, elderly)

ii. Gender (male, female, pregnant female)
iii. Inherent drug metabolism
iv. Life style factors (smoking, alcohol use, previous exposures)
v. Health status including various diseases
vi. Pre-existing or simultaneous exposure to environmental agents,
house-hold products, or therapeutic agents.
vii. Individual genetic makeup (polymorphisms)

Things Change: Perfumes were an important part of the court life in

Ancient Egypt. Cleopatra’s perfume factory was (still is) at the southern
end of the Dead Sea. Cleopatra used to drink turpentine (terebinth from
Pistacia terebinthus) to make her urine smell of violets. Presumably
terpenes within the oil being metabolically converted to ionones, with the
volatile organic compounds methanethiol, dimethyl sulfide, dimethyl
disulfide, bis (methylthio) methane, dimethyl sulfoxide, and dimethyl
sulfone are responsible for the smell. As a chemical pass through the body,
it will encounter a number of enzymes that accelerate chemical reactions
(intermediary metabolism) that are necessary for growth, maintenance of
integrity and continuance of life. Distinctive microenvironments exist at
the active sites of each enzyme to assist chemical inter-conversions. It is,
therefore, not unexpected that a chemical undergoes chemical alteration(s)
as it traverses a living system. What is eliminated from the biological
system is not always the same as what entered the system originally.
Sometimes the host (i.e., the organism that is exposed to the chemical)
plays a critical role in the outcome of toxicity. The process by which this
occurs is called biotransformation/metabolism and involves chemical
reactions within the organism in which one chemical is changed to
another. Chemicals can enter the body and be absorbed by the body by a
variety of means such as ingestion, inhalation, and dermal absorption.
They are distributed through many bodily compartments and finally

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excreted. What happens in between entry and exit, though, plays a key role
in toxicity.

Biotransformation usually decreases the ability, and in turn, the likelihood,

of a molecule interacting with a biological system. The probability of
potential damage is offset or lowered. Usually, but not always, the process
makes the molecule more polar (frequently acidic) and thus more water-
soluble. As such, the system can more easily remove the molecule via the
kidneys (urine) or liver (bile). An example is the enzyme epoxide
hydrolase converting ethylene oxide, a chemical with genotoxic and other
chronic toxic properties, into the somewhat less toxic ethylene glycol. On
occasions, the chemical may be activated and converted into a more
dangerous species whereby the body inadvertently poisons itself. For
example, chloroform can be converted to phosgene. Phosgene (COCl2), a
poisonous gas used as a chemical weapon in World War I, is a highly toxic
gas or liquid that is classified as a pulmonary irritant. Exposure to
phosgene gas produces delayed-onset noncardiogenic pulmonary oedema.
Exposures to 50 ppm may be rapidly fatal [http://emergency.cdc.gov/
agent/phosgene/basics/facts.asp].

3.10 Adverse Drug Reaction

In the US, 3 to 7% of all hospitalisations are due to adverse drug

reactions. ADRs occur during 10 to 20% of hospitalisations; about 10 to
20% of these ADRs are severe, making ADR 4th to 6th leading cause of
death among hospitalised patients. These statistics do not include the
number of ADRs that occur in ambulatory and nursing home patients.
Although the exact number of ADRs is not certain, ADRs represent a
significant public health problem that is, for the most part, 30% to 60%
are preventable

A study by the Agency for Healthcare Research and Quality (AHRQ) in

2011, revealed that sedatives and hypnotics were a leading source for
adverse drug events seen in the hospital setting. Approximately 2.8% of
all ADEs present on admission and 4.4% of ADEs that originated during
a hospital stay were caused by a sedative or hypnotic drug. A second study
by AHRQ found that in 2011, the most common specifically identified
causes of adverse drug events that originated during hospital stays in the
U.S. were steroids, antibiotics, opiates/narcotics, and anticoagulants.
Patients treated in urban teaching hospitals had higher rates of ADEs
involving antibiotics and opiates/narcotics compared to those treated in
urban nonteaching hospitals. Those treated in private, non-profit hospitals
had higher rates of most ADE causes compared to patients treated in
public or private, for-profit hospitals.

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In the U.S., females had a higher rate of ADEs involving opiates and
narcotics than males in 2011, while male patients had a higher rate of
anticoagulant ADEs. Nearly 8 in 1,000 adults aged 65 years or older
experienced one of the four most common ADEs (steroids, antibiotics,
opiates/narcotics, and anticoagulants) during hospitalisation. A study
showed that 48% of patients had an adverse drug reaction to at least one
drug, and pharmacist involvement helps to pick up adverse drug reactions.

3.10.1 Adverse Drug Reactionclassification

Adverse drug reactions (ADRs) are global public health problems. In its
severe form it may cause hospital admission, morbidity and mortality.
Early identification and reporting of suspected ADRs to regulatory
authorities such as National Pharmacovigilance centre (NPC) in National
Agency for Food Drug and Administration (NAFDAC) Nigeria, is known
to be one of the appropriate measures in insure health and safety of public
form such as adverse drug reaction of drugs.
There are many classifications of ADR, with most ending at Type A and
Type B. But for academic and clinical application, we present a broader
classification which would be easier for the public health officer to
recognise and identify as follows

Classification according to Onset of event:

i. Acute: - within 60 minutes

ii. Sub-acute: -1 to 24 hours
iii. Latent: - 2 days

CLASSIFICATION – SEVERITY
Severity of reaction: There is no universal scale for describing or
measuring the severity of an adverse drug reaction. Assessment is largely
subjective. Reactions can be described as

iv. Mild:
v. Moderate:
vi. Severe: disabling or life-threatening,
vii. Lethal (deadly)

i. Mild adverse drug reactions: Mild reactions usually described as

bothersome but requires no change in therapy or prolonged
hospitalisation. It is of minor significance include:

Opiates causing digestive disturbances (such as nausea,

constipation, diarrhea) Headaches, Fatigue, Vague muscle aches,
Malaise (a general feeling of illness or discomfort) Antihistamines
and changes in sleep patterns. However, such reactions can be very

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distressing to people who experience them. As a result, people may

be less willing to take their drug as instructed, and the goals of
treatment may not be achieved.

ii. Moderate adverse drug reactions:

may require change in therapy (treatment) e.g., modified dosage,
addition of a drug, but not necessarily discontinuation of the drug.
May required; hospitalisation may be prolonged, or specific
treatment may be required.

Examples include, Rashes (especially if they are extensive and

persistent), Visual disturbances (especially in people who wear
corrective lenses), NSAIDs causing hypertension and oedema.
Difficulty with urination (a common effect of many drugs in older
men).

Any perceptible change in mood or mental function.

Hormonal contraceptives and venous thrombosis.
Also, reactions that are usually described as mild are considered
moderate if the person experiencing them considers them distinctly
annoying, distressing, or intolerable.

iii. Severe adverse drug reactions: An ADR is potentially life

threatening and requires discontinuation of the drug and specific
treatment of the ADRinclude those that may be life threatening
such as ACE inhibitors and Angioedema, Phenothiazines and
abnormal heart rhythm. Certain types of allergic reactions, that
result in persistent or significant disability or hospitalisation, and
that cause a birth defect. Severe reactions are relatively rare. People
who develop a severe reaction usually must stop using the drug and
must be treated. However, doctors must sometimes continue giving
high-risk drugs (for example, chemotherapy to people with cancer
or immunosuppressant to people undergoing organ
transplantation). Doctors use every possible means to control a
severe adverse drug reaction.

iv. Lethal adverse drug reactions: Lethal reactions are those in

which a drug reaction directly or indirectly caused death. These
reactions are typically severe reactions that were not detected in
time or did not respond to treatment. Lethal reactions can be the
reasons that some drugs are withdrawn from the market such
asAcetaminophen over dosage and Liver failure or Anticoagulants
and Haemorrhage

Seriousness: The U.S Food and Drug Administration defines a

serious adverse event as one when the patient outcome is one of the

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following: Death, Life-threatening, Hospitalisation (initial or

prolonged), Disability - significant, persistent, or permanent
change, impairment, damage or disruption in the patient's body
function/structure, physical activities or quality of life, Congenital
abnormality or Requires intervention to prevent permanent
impairment or damage.

Severity is a point on an arbitrary scale of intensity of the adverse

event in question. The terms "severe" and "serious" when applied
to adverse events are technically very different. They are easily
confused but cannot be used interchangeably, requiring care in
usage.

A headache is severe, if it causes intense pain. There are scales like "visual
analog scale" that help clinicians assess the severity. On the other hand, a
headache is not usually serious (but may be in case of subarachnoid
haemorrhage, subdural bleed, even a migraine may temporally fit criteria),
unless it also satisfies the criteria for seriousness listed above.

3.10.2 Types of Adverse Drug Reactions

Adverse drug reaction is mainly classified into two major types;

i. Type -A [Augmented] and

ii. Type B [Bizarre] effects.
iii. Other classifications also include
iv. Type C (‘C’ for continuous or chronic),
v. Type D (‘D’ for delayed)
vi. Type E (‘E’ for end of use), and
vii. Type F (‘F’ for failure) effects.
viii. Types of adverse drug reactions

Type –A [Augmented]adverse drug reaction:

Refers to predictable dose-dependent responses which are exaggerated

pharmacological actions at usual therapeutic doses. This could occur in
everyone if enough of the drug is given because they are due to excess of
normal, predictable dose-related.

Clinical features: Common, there are in many instances avoidable,

extension of pharmacologic effect, often predictable and dose dependent,
can be experimentally reproduced, responsible for at least two-thirds of
ADRs, constitute approximately 80% of adverse drug reactions,
associated with high morbidity and low mortality. Usually known before
licensing.

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Example

i. Acute Liver failure resulting from acetaminophen overdose

ii. Bupropion: Bupropion is useful for depressed people who also
have attention-deficit/hyperactivity disorder or cocaine use
disorder and those trying to stop smoking. But overdose can cause
Headache, agitation, discontinuation syndrome*, high blood
pressure in a few people, and rarely seizures
iii. Lisinopril & postural hypotension,
iv. Insulin & hypoglycemia
v. propranolol and heart block,
vi. anticholinergic and dry mouth
vii. bleeding when using the anticoagulant warfarin

Type B [Bizarre] refers to unpredictable, non-dose dependent, novel

responses to a drug occurs only in some people Most times there are
unavoidable.

Characteristics: idiosyncratic or immunologic reactions or

Drugallergy/hypersensitivity reactions, rare and often unpredictable.
Little or no dose relationship occur in predisposed, intolerant patients may
explain by rare genetic polymorphism.

Examples;

i. chloramphenicol and aplastic anemia

ii. Fixed drug reaction of sulphonamides.
iii. Anaphylactic reactions with Drugs (e.g. as penicillin), insect stings
and animal venoms, Certain foods (particularly eggs, seafood, and
nuts) and Latex etc.
iv. Malignant hyperthermia with anaesthesia
v. Idiosyncrasy: Idiosyncrasy due to enzyme abnormality Hemolysis
with primaquine if glucose 6-phosphate dehydrogenase (G6PD)
enzyme deficiency in any person. If primaquine given -
Hemolysis leading to hemolytic anemia due to receptor
abnormality e.g. Malignant hyperthermia with general anesthetics
(Halothane).
vi. Sudden huge rise in IC calcium concentration, Increase in muscle
contraction.
vii. Increase in metabolic activities.
viii. Rise of body temperature

Drug allergy: Drug allergy also known as hypersensitive reaction due to

Antigen antibody interactions. 1st dose acts as an antigen, in which
antibody is produced against the antigen in the body. With subsequent

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dose causes antigen-antibody reaction e.g. Penicillin induced anaphylaxis

(Type 1 hypersensitivity reaction)

Types of allergic reactions

i. Type I - immediate, anaphylactic (IgE) e.g., anaphylaxis with

penicillins
ii. Type II - cytotoxic antibody (IgG, IgM) e.g., methyldopa and
hemolytic anemia
iii. Type III - serum sickness (IgG, IgM) antigen-antibody complex
e.g., procainamide-induced lupus
iv. Type IV - delayed hypersensitivity (T cell) e.g., contact dermatitis

Other types of adverse drug reactions

Type C is associated with the long-term use of a drug and is related to

cumulative use (‘C’ for continuous or chronic). It is chronic and of delayed
onset. It tends to be both serious and (relatively) common and have
profound effect on public health

Characteristics: associated with long-term therapy, involves dose

accumulation, often no suggestive time relationship, and connection often
difficult to prove, use of drug increases frequency of “spontaneous
reporting” and can be Predicted from the chemical structure of
drug/metabolite

Examples

i. NSAIDS-induced renal failure (Phenacetin and interstitial

nephritis)
ii. Paracetamol – Liver Toxicity
iii. Oral contraceptive induced diabetic microangiopathy
iv. Breast tumors or antimalarial and ocular toxicity.
v. Hypopituitarism- adrenal axis suppression with corticosteroids
vi. Osteoporosis of the jaw with bisphosphonate

Type D refers to a delayed type of reaction (‘D’ for delayed). May present
years after drug was administered. Can be accumulative

Characteristics: Uncommon, usually dose-related and occur sometime

after drug use and delayed effects (dose independent).

Example

i. Carcinogenicity (e.g., immunosuppressants)

ii. Teratogenicity (e.g., fetal hydantoin syndrome)

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iii. Vaginal cancer in daughters whom mother was treated by

diethylstilbestrol or Phenytoin during Pregnancy and Teratogenic
effects
iv. bladder cancers following long term cyclophosphamide,
v. gene toxicity of some drugs,
vi. Leucopenia – Limoustine
vii. Carcinoma of the renal pelvis following phenacetin etc.

Type E refers to withdrawal or end of use adverse drug reactions (‘E’ for
end of use).

Characteristics: Uncommon and related to discontinuation that is too

abrupt.

Examples

viii. Addisonian crisis (adrenal insufficiency) following steroid

withdrawal
ix. opiate withdrawal syndrome
x. rebound convulsions on withdrawal of carbamazepine in non-
epileptic patients or Phenytoin - Seizures
xi. myocardial infarction following beta blocker withdrawal

Type F refers to unexpected failure of therapy (‘F’ for failure).

Characteristics: Often common, -often dose-related, - caused by drug
interactions

Examples

i. inadequate dose of oral contraceptive

ii. Concomitant administration with enzyme –inducing drugs.

Table 22: Comparison between Type A and Type B adverse drug

reactions
Parameters Type A (Augmented Type B (Bizarre
response) response)
Pharmacologically Yes No
Predictable
Dose dependent Yes No
Host factors Genetic factors may be Dependent on host
important factor
Animal Model Usually producible in Unknown in animal
animals models
Incidence and Common Uncommon
morbidity

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Mortality Low High

Detection Early in clinical Post – Licensing
Development
Treatment Adjust (Reduce dose) Stop (Discontinue
Therapy)

3.10.3 Causes of Adverse Drug Reactions

In clinical practice, patients with Type A reaction which are usually dose-
related and predictable can often be managed by adjusting the dose,
substituting a similar but more selective drug or giving additional drugs to
antagonise the unwanted effects of the primary agent. In Type B reactions,
it is usually necessary to withdraw therapy.

Table 23: Causes(a) and Body Systems Commonly Involved in ADR

(b)
a) Common Causes of ADRs b) Body Systems Commonly
Involved
Antibiotics Haematologic
Antineoplastic CNS
Anticoagulants Dermatologic/Allergic
Cardiovascular drugs Metabolic
Hypoglycaemic Gastrointestinal
Antihypertensive Renal/Genitourinary
NSAID/Analgesics Respiratory
Diagnostic agents Sensory
CNS drugs
ART
Account for 69% of fatal ADRs
Body Systems Commonly Involved There are varied complex mechanism
involve in adverse drug reactions. From the patient population
characteristics like age, sex, population size, genetic constitutions, and
tendency to allergy, disease, personality or habit, to Predisposing factors
– renal function, liver function, pharmacokinetic and Pharmacodynamics
factors etc.

3.10.4 Impact of genetics

Genetic constitution of an individual plays a vital role in ADRs, as every

individual responds differently to drugs as a result of their genetic
constitutions. This genetic variation can exist as a result of single mutant
gene (as in polymorphism or discontinuous variation), or polygenic
influences e.g. Drug-induced haemolytic anaemia as a result of G6PD
deficiency with drugs like 8-aminoquinolines, antimicrobials and some
analgesics.

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3.10.5 Factors responsible for Adverse drug reactions (ADR)

i. Age (children and elderly)

ii. Multiple medications
iii. Multiple co-morbid conditions
iv. Inappropriate medication prescribing, use, or monitoring
v. End-organ dysfunction
vi. Altered physiology
vii. Prior history of ADRs
viii. Extent (dose) and duration of exposure
ix. Genetic predisposition

3.10.6 Factors Masking Adverse Drug Reactions

ADR are most times unrecognised due to a number of factors:

i. They may mimic natural disease e.g. phenothiasine - induced

hepatitis.
ii. They may appear as an odd or bizarre reaction from an innocent
drug like pseudo lymphoma from Phenytoin.
iii. The appearance of the reaction may be delayed like in
mucocutaneous syndrome due to practolol, adenocarcinoma of the
vagina in children whose mothers received high dose oestrogen
during pregnancy or valvular heart disease following fenfluramine
administration.
iv. ADR may cause the relapse of a natural disease or evoke a disorder
in a naturally susceptible subject e.g. diabetes by thiazides and
glaucoma by atropine and
v. It may be masked by the nature and complex clinical situation as in
antiarrhythmic drugs with a pro-arrhythmic effect
vi. Environmental factors causing ADRs includes simple pollution e.g.
with Halothane in the air of operating theatre, causing abortion in
female staff; Penicillin in air of hospital or milk cause drug
(hypersensitivity) allergy.

SELF- ASSESSED EXERCISES

i. What are the five contexts of drug toxicity?

ii. Explain the types of drug related hypersensitivity reactions.
iii. Enumerate the causes of drug reactions

4.0 CONCLUSION

In this unit, you have been exposed to the various common define and
terminology used toxicology, and adverse drugs reaction. You have learnt
describe the purpose of toxicology, subdivision and classifications of toxic

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agents including poisons that can heal. Distinguish adverse drug reactions
(ADRs) from adverse drug events, classify an ADR when it presents, types
of populations most at risk of, ADRs and various factors that can mimic
diseases and mask ADR.

5.0 SUMMARY

Toxicology is a field of science that helps us understand the harmful

effects that chemicals, substances, or situations, can have on people,
animals, and the environment. Some refer to toxicology as the “Science of
Safety” because as a field it has evolved from a science focused on
studying poisons and adverse effects of chemical exposures, to a science
devoted to studying safety.

Most exposure of humans to chemicals is via naturally occurring

compounds consumed from food plants.

Toxicology has various sub discipline that made it easy to study and
classify. This includes; Environmental Toxicology-Studies chemicals that
are contaminants of food, water, soil, or the air. Occupational (Industrial)
Toxicology: studies of protection of workers from toxic substances and
makes their work environment safe. Regulatory Toxicology: Gathers and
evaluates existing toxicological information to establish concentration-
based standards of “safe” exposure. Food Toxicology: Involves delivering
a safe and edible supply of food to the consumer. Clinical Toxicology: Is
a study that is concerned with diseases and illnesses associated with short
term or long-term exposure to toxic chemicals. Forensic Toxicology:
Helps to establish cause and effect relationships between exposure to a
drug or chemical and the toxic or lethal effects that result. Etc.

Toxic agents are classified as Heavy Metals, Solvents and Vapours,

Radiation and Radioactive Materials, Dioxin/Furans, Pesticides, Plant
Toxins and Animal Toxins

Not all poisons are deleterious, some poisons that can heal, depending on
dose (Dose matters (and so does timing)); individual (People differ)
differences; and change in times (things change).
WHO definesas an adverse drug reaction as “a response to a drug which
is noxious and unintended and which occurs at doses normally used in
man for prophylaxis, diagnosis, or therapy of disease or for the
modification of physiologic function? This differentiated from an adverse
drug event which is “any untoward medical occurrence that may
present during treatment with a pharmaceutical product but which does
not necessarily have a causal relationship with this treatment” or side
effects which is an unintended effect of a drug occurring at the normal
dose related to the pharmacological properties of the drug.ADR

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definition excludes therapeutic failures, overdose, drug abuse,

noncompliance, and medication errors.

6.0 TUTOR- MARKED ASSIGNMENT

1. Define toxicology and commonly associated terms

2. Differentiate the sub-disciplines of toxicology
3. Describe the classifications of toxic agents
4. a) What is WHO definition of adverse (ADR) drug reaction,
classify ADR according to the onset of events and types of
ADR. Giving definitions, clinical characteristics, and at
least two drugs and ADR caused under each types of ADR.
b) Outline five examples each of the following
i. commonest drug causes of ADR
ii. commonest system(organ) involved/ susceptible to ADR
iii. Risk factors of ADR

7.0 REFERENCES/FURTHER READING

Hayes, A.W. & Dixon, D. (2017).Cornerstones of Toxicology. Toxicol

Pathol, 45(1), 57–63. https: // doi: 10.1177/0192623316675768.

Schatz, S.N. & Weber, R.J. (2015). Adverse Drug Reactions. PSAP 2015
CNS/Pharmacy Practice.

Goldman, S.A., Kennedy, D.L.& Lieberman, R. (1995). Clinical

Therapeutics and the Recognition of Drug-Induced Disease.

Forging a Poison Prevention and Control System. Institute of Medicine

(US) Committee on Poison Prevention and Control. Washington
(DC): National Academies Press (US); 2004.

Matter, B.E., The Science of Toxicology - Scope, Goals and Four Case
Studies. Preclinical Research, Toxicology, SANDOZ, Ltd Basel,
Switzerland.

Liebler. D.C. & Guengerich, F.P. (2005).Elucidating mechanisms of drug-

induced toxicity.Nat. Rev. Drug Discov, 4:410–420. [PubMed]
[Google Scholar].

Toxicology Data Network (TOXNET)- www.toxnet.nlm.nih.gov).

Botulism in the United States, Handbook for Epidemiologists, Clinicians,

and Laboratory Workers. CDC National Centre for Infectious
Diseases, Division of Bacterial and Mycotic Diseases 1998.

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National Research Council (US) Committee on Applications of

Toxicogenomic Technologies to Predictive Toxicologyand Risk
Assessment. Washington (DC): National Academies Press (US);
2007. C, Overview of Risk Assessment. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK10201/.

WHO (2014). Chemicals of public health concern in the African Region

and their management: Regional Assessment Report. WHO
regional assessment report

Lazarou. J., Pomeranz. B.H., & Corey. P.N. (1998). Incidence of Adverse
Drug Reactions in Hospitalised Patients: A Meta-analysis of
Prospective Studies. JAMA, 279(15), 1200–1205. https
doi:10.1001/jama.279.15.1200.

Weiss. A.J., & Elixhauser. A. (2013). "Origin of Adverse Drug Events in

U.S. Hospitals, 2011" (HCUP Statistical Brief #158). Rockville,
MD: Agency for Healthcare Research and Quality.

MedWatch. (2007) What Is a Serious Adverse Event. Archived from the

original on 29 September 2007. Retrieved 4th April 2020.

Guideline for Good Clinical Practice (1996). International Conference on

Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use. 10 June 1996. p. 2. Retrieved 4
April 2020).

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UNIT 3 DISCOVERY/DRUG DEVELOPMENTAND

PHYTOMEDICINE

CONTENTS

1.0 Introduction
2.0 Objectives
3.0 Main Content
3.1 Definition of Terms
3.2 Drug Development
3.2.1 Why are drugs developed?
3.2.2 Preclinical Drug Discovery
3.2.3 Pharmacological Profiling
3.2.3 Safety and toxicity testing
3.3 Clinical drug development
3.3.1 Phases of development
3.3.2 Aims and Objectives of clinical drug developments
3.4 Ethics in Clinical Trials
3.4.1 Non-maleficence
3.4.2 Beneficence.
3.4.3 Justice
3.4.4 Respect for person
3.5 Clinical Trial Design
3.5.1 Phases of Clinical Trials
3.5.2 Laminations of Clinical drug development
3.5.3 How to Appraise a Clinical Trail
3.6 Statistical design
3.6.1 Parallel-group and cross-over trails
3.6.2 Randomisation and masking
3.6.3 Primary outcome
3.6.4 Power calculation
3.7 Phytomedicine
3.7.1 Introduction and Historical Background
3.7.2 Characteristics of Phytomedicines
3.7.3 Uses of Herbal preparations
3.7.4 Preparations of herbal Medicines
3.7.5 Standardized Phytomedicines.
3.7.6 Routes Administration herbal Medicines
3.7.7 Safety Issues in the use of Phytomedicines
3.7.8 Challenges of Phytomedicine
3.7.9 The Future of Herbal Medicine
4.0 Conclusion
5.0 Summary
6.0 Tutor- Marked assignment
7.0 References/Further reading

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1.0 INTRODUCTION

The pharmaceutical industry is skilled at discovering new chemical

entities – millions of novel substances have been produced in the last 50
years. Few of these have the appropriate characteristics to become drugs
for use in humans (preclinical studies in animals may reveal an
inappropriate pharmacokinetic profile, lack of the desired
pharmacological effect, or toxicity), and the industry therefore discards
almost all of its discoveries. Compounds that survive preclinical screening
may enter the drug development process provided an adequate clinical
need exists and the company is confident that it will recoup the costs of
development. These costs vary according to the clinical area and the size
of the programme, but sums in excess of €250,000,000 are not uncommon.
Even for drugs that reach development, success is not guarantee; only 10%
of compounds survive clinical assessment, and though the desire of every
company is to achieve the success of agents like salbutamol, atenolol and
ranitidine, only a few survivors find a significant role in therapeutics.

2. 0 OBJECTIVES

By the end of this unit, you will be able to:

 define terms in drug development and phytomedicine

 recognise the significance of drug development
 identify the pharmacokinetics and pharmacodynamics profiling in
drug development
 state the safety and toxicity testing in drug development
 describe the phases involved in clinical trials
 explain the integration of phytomedicine preparation into
conventional or official medicine
 identify and describe the standardisation and quality evaluation of
herbal drugs
 tell the routes of administration of herbal drugs
 recognise Herb-drug interactions
 explain adulteration and contamination of herbal drugs.

3.0 MAIN CONTENT

3.1 Definition of Terms

i. Phytomedicine: Phytomedicine is modern and science based

herbal medicine. Phytomedicine, also called Botanical/Plant
Medicine. The word ‘phyto’ derives from the Greek work plant;
hence it means plant-based medicine. Phytomedicine is rooted in
scientific research and therefore not to be confused with
homeopathy. The methods used to evaluate plant-based medicines
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are similar to those used by orthodox medicine. Yet, an herb

contains many active chemicals, unlike conventional drugs, which
focuses on specific chemicals. Hence botanical or herbal medicines
may combine several actions to support the body’s health.

ii. Phytotherapy (Henri Leclerc): The branch of herbal medicine

that describes the potentials and limitations of herbal drugs in the
treatment of human diseases. It should be practiced by physicians
trained in herbalism

iii. Phytotherapists: qualified Phytotherapists use herbs to treat the

diseases the methods used to evaluate plant-based medicines are
similar to those used by orthodox medicine, they are safe for many
conditions. Phytotherapists conduct individual consultation and
then dispense a medicine. It does not use any other therapies like
acupuncture; panchkarma etc. pharmacognosy is at the heart of
Phytomedicine.

iv. Phytopharmacy Preparation of natural drugs. Either in natural

forms (teas) or in pharmaceutical preparation.

v. Phytochemistry: The study of the chemical constituents in the

plants.
vi. Phytopharmacology: Natural drugs which have multiple effects
must be tested in humans.

3.2 Development

3.2.1 Why are drugs developed?

Drugs are developed so that we can turn fatal or non-fatal diseases into a
routine therapeutic exercise (Figure1) or instance, before the development
of anti-hypertensive drugs, hypertension was a fatal disease with people
dying in a year or two of developing high blood pressure. Now, millions
of people with hypertension are successfully managed long term with anti-
hypertensive drugs. Drug development is divided into preclinical and
clinical drug development.

The process of drug development includes the activities that take the
prospective new drug into the market-place where it becomes available for
use by doctors and patients. Development of a new drug is therefore a vast
project that lasts many years and involves clinical investigators in
specialist department or in departments of clinical pharmacology, as well
as experts from different disciplines in the pharmaceutical company.This
collaboration is vital for successful drug development, but it is important
to recognise that each party has its own agenda and properties. It is not

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realistic to develop a drug exclusively in one country; international

expertise must be coordinated, taking account of differences in clinical
practice and approach around the world. Drug discovery usually exploits
advances in knowledge that are available within the research community
and it is therefore not surprising to find several companies pursuing
similar lines of research. It is often the activities of drug developers that
determine which company I first to the Market-place. Companies
constantly examine their processes for greater efficiencies, to contain costs
and to minimise the duration of drug development. Phase 3 clinical studies
(see below) are important determinants of the overall timing because they
are perfumed on the critical path, and participating clinicians are likely to
feel pressure from the company to complete the trial on schedule.
Development times vary between areas of therapeutics, but generally
companies expect to develop drugs in 6-7 years (compared with about 12
years two decades ago).

3.2.2 Preclinical Drug Discovery

Preclinical drug discovery is the process before clinical testing of drugs.

The first step in preclinical drug development is the discovery or synthesis
of a new drug. At least, 10,000 new molecules are discovered/synthesised
for each successful new drug introduced. Extensive preclinical safety and
efficacy testing of new drugs are required in animals, and this takes an
average of 1.5-3 years. There are three mains ways in which new drugs
are derived; chemical modification, rational drug design, and random
screening.

3.2.3 Serendipity: Serendipity (accidental discovery of something

fortunate) may also have a role in drug development.

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Figure 20: Three methods of drug discovery (Copyright QUT, Sheila

Doggrell)

An important group of drugs that were made by chemical modification

were the diuretics. However, the initial step was serendipity; an observant
physician noticed that sulfanilamide (antibiotic) caused a sodium
bicarbonate diuresis the loss of sodium, bicarbonate and water from the
kidney. Thus, it was reasoned that a sulphanilamide-like drug could be
made that promoted water loss fromthe body. After a string of chemical
modification, chlorothiazide was synthesised.

Chlorothiazide increases sodium chloride and water excretion. Further

modification of the structure of chlorothiazide led to the discovery of
frusemide, which is a very potent diuretic. The thiazide diuretics, such as
chlorothiazide, and frusemide are commonly used in the treatment of
hypertension and heart failure to promote water loss. The second method
for drug discovery is rational drug design, and we will consider a new
example of this (zanamivir – Relenza).

Rational drug design usually includes computer design, which is known

as in silico. A computer model is made of the site that you want the drug
to bind to, and then of the drug with best fit for binding. Then the chemical
is synthesised, and then tested pharmacologically to determine, whether
the chemicals do as predict.

A drug that was developed in this way is zamanivir (Relenza). Zamanivir

can prevent or shorten the flu, which is a virus. Neuramidinase is an
enzyme involved in viral replication, and the structure of this enzyme has
been determined. The structure shows a pocket, where we may be able to
get a drug in to inhibit the enzyme. Zamanivir binds in the pocket to inhibit
the activity of Neuramidinase, and consequently, the replication of the flu

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virus. A third approach to drug discovery is random screening. This uses

high throughput screening managed by robotics. There is random
screening for biological activity. The screening can be of banks of
previously discovered chemical entities, a large number of natural
products, and libraries of peptides and nucleic acids. Random screening
led to the discovery of the immunosuppressant cyclosporine.

3.2.4 Pharmacological Profiling

Once a lead compound has been discovered (e.g. a drug with activity at a
certain binding site), the compound undergoes pharmacological profiling.
A large number of experiments are undertaken, mainly using animals, to
determine the pharmacokinetics and pharmacodynamics of the drug.
Questions asked include; does the drug do what we expect? Does it do
anything else? Is it active after oral administration? The initial profiling
usually depends on the pharmacological goal e.g. anti-infective will be
tested against infectious organisms. Anti-diabetic drugs will be tested for
their ability to lower blood glucose in animal models of diabetes.

3.2.4 Safety and Toxicity

New drugs undergo extensive safety and toxicity testing in animals. This
testing was increased after the thalidomide disaster. Thalidomide was
developed as a hypnotic (calming) and anti-emetic drug in the 1950s. It
was used as a hypnotic and extensively to prevent morning sickness. For
severe morning sickness, it was more beneficial than any other drugs
available at the time. Limited toxicity testing in rats had suggested it was
safe in pregnancy. To women who took thalidomide during pregnancy,
10,000 children were born with phocomelia, which is the absence of arms
or legs with hands or feet attached to body trunk. Obviously, when it was
shown that thalidomide was the causative agent, it was withdrawn and
litigation followed, costing the pharmaceutical company responsible to
pay millions in compensation.

What was learnt from the thalidomide disaster? The animal rights
movement claimed that the thalidomide disaster showed that the testing of
drugs in animals was not predictive of toxicity in humans, and should be
abandoned. Toxicity testing should be in humans. There is another
interpretation, birth defects are rare in rats. Rats are more likely to
reabsorb defective foeti. Closer analysis of toxicity testing of thalidomide
showed lower litter numbers, which probably indicated the potential to
cause birth defects in humans. More extensive toxicity in animals
probably would have prevented the thalidomide tragedy. More extensive
toxicity in animals is now undertaken. This preclinical safety and toxicity
testing take 2 -5 years, and involves the collection and analysis of lots of
data. This testing is closely supervised by an independent Animal Ethics

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Committee that works to minimise the number of animals used, and the
harm done to animals. Acute toxicity of single doses and chronic toxicity
of repeated doses of drugs are often tested on mice. The effects of drugs
on reproductive function and teratogenicity (ability to cause birth defects)
are tested in a variety of animal species. For drugs that are going to be
used long term in chronic illness, the carcinogenic potential has to be
tested in animals long-term. Mutagenic potential is undertaken in bacteria

3.3 Clinical Drug Development

3.3. 1 Phases of development

It is convenient to describe clinical drug development in terms of phase.

The boundaries between the phases are not rigid, and in some
developments phases 2 and 3 are merged. Overlap between phases may
occur; for example, pharmacokinetic assessments in patients with hepatic
or renal impairment are usually undertaken later in the programme
alongside phase 2 or 3. Whether healthy volunteers or patient volunteers
are used in phase 1 studies depends on the therapeutic class of the agent.
The duration of phase 1 is about 1 year; the duration of phases 2 and 3
together is about 4 years. Submission to regulatory is based on the clinical
data obtained from the studies in phases 1, 2 and 3.

3.3.2 Aims and Objectives of clinical drug developments

The aims of clinical development are to determine the following

i. How the recipient handles the potential drug – absorption,

distribution, metabolism and excretion (commonly abbreviated to
ADME); this may include special populations such as the elderly
or those with liver or kidney impairment
ii. How the new agent affects physiological systems relevant to its
efficacy or safety – for example, dose-response relationships and
the duration of action of a β-adrenoceptor antagonist can be
investigated using the agent’s effect on heart rate during exercise.
iii. Whether the new agent has efficacy against the target disease and
how efficacy relates to the dosing regiment
iv. How the agent is tolerated at different dose and in different groups
of patients – every patient must be monitored closely for adverse
events and routine screening is conducted to assess whether the
new agent adversely affects liver or kidney function or blood
constituents
v. The potential for interactions with other drugs

At some stage in the drug development procedure, a drug patent

has to be applied for, to protect your discovery from other

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companies. Patents are valid for 15-17 years. During the patent,
all monies made by that drug are returned to the pharmaceutical
company that invested in the development. However as preclinical
testing takes on average 1.5 to 5 years, and clinical trialling take 5
to 7 years on average, there may not be much time for the
developing company to recoup their investment. After a patent
expires, the generic drug can be made by other companies,
commonly known as generic companies. The generic companies
make drugs but they do not pay towards the development of the
drug. After the patent expires, the pharmaceutical company that
discovered the drug, no longer receives all the money from that
drug.

After successful preclinical testing, a few new drugs enter the next
stage, which is clinical trialling. Clinical trials are experiments in
humans to evaluate drugs, medical devices, biologics etc. Thus,
clinical trials are to evaluate interventions in general. The results
of clinical trials are presented to the authorities for assessment.
This assessment is carried out by the Federal Drug Administration
(FDA) in US, or the National Agency for Food and Drug
Administration and Control (NAFDAC) Nigeria or by any
countries drug regulatory agency. If the FDA or NAFDAC accept
that the drug does better than harm, it is registered for clinical use.
The clinical development of drugs does not stop at registration, as
there is ongoing preclinical and clinical assessment. It is presently
considered that it costs A$1.2 billion for a single, successful new
drug.

Only about 10% of compounds that enter clinical trial are

approved/registered for sale. Clinical trials are under stringent law
enforced guidelines. These guidelines include ethics, which is
assessed by human ethics committee, and patient consent. For
patient consent, they must be fully informed in lay language of
exactly what is happening in the trial. Clinical trials of drugs are
often funded by pharmaceutical company with independent
investigators. Without this funding, there would be little
development of new drugs. There is some government funding
available for clinical trials of complementary and alternative
medicines in the US, which allow these medicines to be properly
evaluated. Clinical trials are not quick, as they take 7-9 years.

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3.4 Ethics in Clinical Trials

The atrocities of the Nazis on concentration camp inmates, such as cutting

people and seeing how long they bled for, were investigated after World
War II in Nuremberg Tribunal. The tribunal developed the Nuremberg
Code, which started the modern era of ethics. There are 4 main principles
of modern ethics (Figure 1).

i.Non-maleficence: non-maleficence, means to do no harm.

ii. Beneficence: The second aspect, is the reverse of this, it is
beneficence, which is to do good. Combining non-maleficence and
beneficence means that clinical trials have to maximise benefits
and minimise harm to the patient.
iii. Justice: The third aspect of ethics in clinical trials is justice, which
means that the benefits of research should be distributed fairly, not
just to the rich and powerful.
iv. Respect for person: Respect for person has three parts, Firstly,
individuals be regarded as autonomous agents, and their opinions
and choices respected, regardless of how daft or illogical they are.
The second part is veracity, the truth must be told to participants.
Participants have to be able to understand the clinical trial, and the
benefits and risks, and these are provided in a Plain Language
Statement, prior to consent being asked for. Finally,
confidentiality, the participants name, details etc. are to be kept
confidential.

Ethics are policed by IRBs, Institutional Research Boards, which are also
known as Ethics committee. This process involves peer review of
proposed research. Peer review is independent review of the proposed
clinical trial to determine whether the trial is appropriate. Universities
often have ethics committees both for peer reviewing animal experiments
and human experiments. For instance, QUT has a Human Research Ethics
committee, an Animal Ethics committee and a Biosafety committee.

3.5 Clinical Trial Design

There are a number of factors that make a good clinical trial design. There
should be similarity of the control group, who do not receive the drug,
with the group receiving the intervention (drug). Otherwise any difference
between the control and intervention group, may be due to other
differences between the groups, other than due to the drug intervention.
One way of achieving similarity between groups is the random assignment
of patients to control and intervention group. In initial clinical trials, the
control group was untreated whereas the treated group were given the
drug. This is almost guaranteed to show a beneficial effect with the drug,
as people like to believe the drug is going to do them good. To avoid this,

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the control group are given an inert replica of the drug, which is known as
the placebo. Placebos are very good for you! The placebo response
(which means “I shall please”) is 40% of relief of pain in labour, and up
to 60% in relieving depression. This is the key reason for not accepting
anecdotal evidence, and requiring placebo-controlled clinical trials.

Another danger in clinical trials is observer bias. The observer of the

patients will want the patient to get better and will be looking for signs of
benefit with the drug, which may or may not be present. To avoid this
problem, blinding is used. There are two types of blinding. In single
blinded clinical trials, only the study participants are blinded, not the
investigator, and this happens when it is considered important that the
investigator knows which participant has the active drug. In double-
blinded clinical trials, neither the participants nor the investigator knows
who is taking the active drug. The best design for a clinical trial is the
randomised, double-blind, placebo-controlled trial. Such a trial has the
highest likelihood of revealing the truth about the effects of a drug. The
randomised, double-blind, placebo-controlled trial has a very simple
design (Figure 22).

Figure 21: Randomized, double-blind, placebo-controlled trial

(Copyright QUT, Sheila Doggrell)

In a randomized, double-blind, placebo-controlled trial, the selected

patient population is randomised to either the placebo (dummy tablet) or
the drug, and the health of the participants is monitored.

3.5.1 Phases of Clinical Trials

In drug development, it mandated that new drugs have to go through 4

Phases with each phase having different requirements. Each drug has to
successful pass Phase I before moving onto Phase II, and so on (Figure…).
Clinical trialing usually starts with small numbers of participants and is
mainly to test safety, and is often in health volunteers (Figure 4.5). Only
when some safety has been established, does testing

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Figure 22: The Phases of clinical trials (Copyright QUT, Sheila

Doggrell)

Phase I clinical trials are often performed in University Hospitals using

experts in clinical pharmacology. They are open with both subject and
observer knowing what is happening. Phase I clinical trials use small
numbers (20-80) of healthy volunteers. The exception to this is when
testing toxic drugs for cancer and HIV. As these would be toxic to healthy
volunteers, the Phase I testing of cancer and HIV drugs is in patients. The
dose tested in Phase I will be a small fraction of that shown to cause
toxicity in animals. The main reason for the trial is to establish safety, and
the trial will measure toxicity and, possibly, efficacy. In Phase I, provided
an assay is available to measure the drug, blood samples may be taken to
measure the pharmacokinetics of the drug. If a drug shows unacceptable
toxicity, the clinical trial will stop after Phase I.

Phase II clinical trials are also often performed in University Hospitals

using experts. They are single-blinded i.e. they use placebo/dummy
tablets to prevent the subject knowing which is active drug, but the
physician does know which is the active drug. Phase II trials may have a
comparison with standard treatment. If there is a standard drug available
for a certain condition, it has to be established that the new drug is better
than the standard drug before it can be registered. Phase II trials are in 10-
200 patients with the disease the drug is indicated for. The Phase II trial

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is to establish the efficacy and toxicity of the drugs. This information is

needed for more extensive Phase III trialing. If a drug does not show
efficacy in Phase II trial, it will not go forward to Phase III.

Phase III clinical trials are usually performed in the setting the drug will
eventually be used in. Thus, if a drug is to be used in hospital, it will be
tested in hospital, whereas if a drug is used in general practice, it will be
tested in general practice. The investigators are usually specialists in the
disease being treated. Phase III trials are double-blinded; neither the
observer nor the subject knows which is active drug. A third person holds
the code identifying the drug, which is not broken until the trial is
completed. Phase III trials enrol large numbers of patients, and are
expensive. Phase III clinical trials establish efficacy and toxicity.

Positive results in Phase III lead to applications for registration to market

the drug to the Therapeutics Goods Administration (TGA).

Phase IV clinical trial is also known as post-marketing surveillance. Even

though Phase III trials enrol large numbers of patients, this may not be
large enough to detect any rare or long-term adverse effects, and this is
done in Phase IV. Phase IV is under the actual conditions the drug will be
used. It is monitoring safety in large numbers of patients and over longer
periods of time than previous Phase. Phase IV clinical trials, especially
the monitoring of adverse effects, involves, all health professionals, not
just investigators.

3.5.2 Laminations of Clinical drug development

A typical clinical drug development may provide information on 5000

patients. This appears to be an impressive body of information, but some
of these patients will have been exposed to the comparator treatments
rather that to the agent under trial. Furthermore, many patients given the
new agent may have been given non-therapeutic doses or may have been
treated for short periods only. Programmes involving drugs that will be
given chronically usually include at least 100 patients treated for at least
1 year; this is an important ‘safety platform’ but has limitations,
particularly in detecting adverse event with an incidence of less than 1%.
Post-marketing surveillance is therefore important and clinicians should
report adverse events seen in clinical practice (see page 25).

There are also limitations in the assessment of efficacy. Chronic

degenerative disease is a challenging therapeutic target but the
improvement may be limited by pathology that is largely irreversible.
Modest efficacy may be the consequence, and effects that are statistically
significant in large trials may be difficult to extrapolate to individual
patients; it may be necessary to debate the clinical significance, for

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example, a 5% increase in peak flow rate or a 10% increase in a quality-

of-life measure. Evaluation of dose-response, which is a long-standing
area of weakness in drug development, becomes even more difficult when
changes in the end-points are small. Also, clinical trials tend to be
conducted in well-defined at controlled settings. How well result of a
clinical programme predicts the real world of clinical practice is a matter
of concern to regulatory authorities and clinicians.

Practice points

i. Clinical evaluation of new drug is a collaborative process involving

clinical pharmacological industry
ii. Clinical development of a new drug is divided into phases 1-4
iii. Even after a through clinical trial programme, experience with a
new drug is limited and much remains to be discovered in clinical
practice
iv. Reporting of adverse events is the responsibility of all clinicians

3.5.3 How to Appraise a Clinical Trail

Readers of the medical regularly encounter descriptions of clinical
trials forming the basis for recommendations about medical
practice. The ability to practice. The ability to appraise these
reports critically is essential if they are to be given appropriate
weight. Only a limited appraised can be conducted from a
published most important supporting document is the protocol. It is
worth trying to obtain a copy for trails of special interest – protocols
of important trials are increasingly being published.
The overall purpose of a clinical trial may be exploratory or
confirmatory:

i. Confirmatory trials are intended to provide a definitive answer to a

question based on earlier indicative research (e.g. the efficacy of a
new medicinal product in its intended manner of use).
ii. Exploratory trails are intended to suggest ideas for later
confirmation.

This contribution focuses on confirmatory trials because these are

the trails which primarily influence practice. Confirmatory trials
are usually controlled and randomised to achieve the high degree
of scientific rigour necessary to ensure the validity of their
conclusions.

The three aspects of a clinical trial that most affect its interpretation are
design, conduct and analysis. The most important aspect is design,
because serious flaws I design are generally irretrievable.

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3.6 Statistical Design

3.6.1 Parallel-group and cross-over trails– in most clinical trials,

patients are randomised to one of two or more treatment arms, which are
subsequently compared (parallel-group). This is the most robust design
and minimal assumptions underlie its use. The second most commonly
used design is the cross-over trail, which requires fewer subjects, but at
the expense of additional assumptions for valid use. Cross-over trails
should be used only in stable disease, and carry-over trails should be used
only in stable disease, and carry-over of treatment effects from one period
to the next should be avoided. The cross-over design is standard in
bioequivalence studies and some other early-phase studies, but outside
these applications its use should always be carefully justified.

3.6.2 Randomisation and masking – the most reliable control group is

randomised and double-masked (double-blind). Details should be
provided of the means by which randomisation was achieved and its
security maintained. In double-masked trails, numbered supplies of drug
can be given to individual trial lists pre-packed according to a properly
generated random scheme. Alternatively, a telephone randomisation
system may be used; this is particularly advantageous. when masking is
impossible – the entry criteria can be checked when the call is made and
if these are satisfactory the patient is irrevocably entered into the trail.
Other randomisation methods (e.g. sealed envelopes) should be regarded
with scepticism and confirmation of diligent and secure operation with
scepticism and confirmation of diligent and secure operation should be
sought. If code-breaks are supplied for emergencies, they should be
tamperproof and individualised.

If the trial is not double-masked (single-masked or open), the other steps

taken to avoid bias should be described and their success evaluated; for
example, it may be possible to use independent refers who are ignorant of
treatment to take the key measurements.

3.6.3 Primary outcome: the aim of the trail should lead to the choice of
a key measurement as the primary outcome in the protocol, and this
outcome should be the main focus of attention in the report. This ensures
that the main test of statistical significance undertaken at the end of the
trail is not affected by multiplicity (figure 2). Post hac selection of the
outcome that achieves the highest level of significance is a biasing
procedure. Sometimes, however, insistence on a unique choice of outcome
presents difficulties. This situation can be dealt with by statistical means;
the method chosen should be described clearly.

3.6.4 Power calculation: an ell-designed trial should include sufficient

patients to make achieving the trail aim likely. The basis for this number

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is usually found in the power calculation, which should be written into the
protocol and also reported in the publication.

The prospective power calculation is a valuable source of information for

the appraiser when doubts arise. It identifies the planed primary outcome,
the treatment comparison of greatest interest and the size of difference that
the study was intended to detect. These factors should correspond to those
used during analysis and interpretation.

Once the trail is complete retrospective power calculations are of little

value because the precision achieved can be illustrated better in other ways
(confidence intervals).

3.7 Phytomedicine

3.7.1 Introduction and Historical Background

Phytomedicine or the use of herbal medicine with therapeutic properties

have played a significant role throughout history. Although its usage
greatly diminished during the dawn of the scientific era, there is a revival
of interest in its potential by late 20th century, especially in the
development of new drugs.

The history of herbal medicine can be traced back to thousands of years in

both Western and Eastern tradition. It came into existence since the advent
of human civilisation. Sheng-Nongs Herbal Book, one of the earliest
sources of folk knowledge on the use of herbs in China, dated back to 3000
B.C. and included knowledge of 365 plants, animals and minerals useful
as medication. It encompasses the details of almost 365 plants, animals,
and minerals that find a place in medication. Our Earth houses
approximately 420,000 species of plants; however, there is a lack of
appropriate knowledge about them and their varied uses. There are three
major areas, namely, food (foodstuffs), medicine (folk and traditional
medicines), and research (phytochemical analysis), that predominantly
find an immense use of herbal preparations and products and hence can be
explored further. Although the industrial revolution and the development
of organic chemistry resulted in a preference for synthetic products, World
Health Organisation (WHO) reports that between 70% and 95% of citizens
in a majority of developing countries still rely on traditional medicine as
their primary source of medication. The role of herbal medicine started to
decline after the 1960s as vast quantities of resources and money were
used to promote synthetic medication. Besides this, advances in the human
genome, increase knowledge of the structure and function of proteins and
the notion that synthetic drugs are safer with fewer side effects (which
does not necessarily be true) also contributed to the rise in the popularity
of synthetic drugs. However, these advancements have several major

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constraints. The large number of possible new drug targets has already
outgrown the number of existing compounds that could potentially serve
as drug candidates and the field of chemistry has limitation when it comes
to synthesising new drug structures.

In the last decade, herbal medicine has seen some form of revival,
advancing at a greater pace in community acceptance of their therapeutics
effects. This field is bringing forward new lead drug discoveries as well
as safe and efficacious plant-based medicines. In turn, this leads to
growing number of sales of commercialised medicinal herbs and most
importantly, growing number of pharmaceutical companies that involve
in the research and development of plants as a source for modern
medicine. What chemists have been desperately seeking, Mother Nature
has already plenty of stock. Phytomedicine, in amalgamation with various
other health-care fields, have indeed revolutionised and strengthened the
foundation of the existing health-care system and occupies a major stake
in the industry. Reports gathered from all over the world indicate there are
around 35,000 species of plants that are currently being used in herbal
therapies/recipes. Although according to research data available only 20%
of the total undergoes the stage of phytochemical analysis while 10%
reach the biological screening stage. The remaining still needs some
amount of exploration making use of modern technologies. The future of
medicinal plant–derived drugs therefore seems to have tremendous scope
for discovering some new and novel therapeutic strategies and products
(Khan, 2015). Herbal medicine can be categorized into phytotherapy,
over-the-counter herbal and traditional herbalism. There is an increase of
interest in the pharmaceutical industry to develop new medications from
plants. Phytomedicine research has employed high-throughput screening
methods and the increasingly popular “reverse pharmacology” methods.

There is some documentation on a wide range of plants used in sub‐

Saharan Africa to treat ailments (Okigbo 2006; Verzar 1987), but there
has been little in the way of systematic appraisal of their benefits in
randomised controlled trials.

In Nigeria, one of these phytomedicines is collectively known as

Niprisan® (also known as Nicosan®), a freeze‐dried extract of Piper
guineenses seeds, Pterocarpus osun stem, Eugenia caryophyllum
fruit and Sorghum bicolor leaves. Niprisan® has been investigated in vitro
and in animal studies (Adzu 2001; Awodogan 1996; Iyamu 2002). Others
are Ciklavit® (Cajanus cajan seed extract as base) and Zanthoxylum
(Fagara) zanthyloides, which are also being researched (Imaga 2013).
There may well be other potential phytomedicines available for people
with SCD, but their safety and efficacies will have to be scientifically
evaluate

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3.7.2 Characteristics of Herbal Drugs

i. The pharmacologically active compounds in herbal drugs are

present in lower concentrations than the conventional tablets and
capsules. This fact generally means that risks associated with crude
herbal drugs are minimal with moderate use. Many herbal drugs
have been safely used for centuries.
ii. They contain a wide variety of different compounds, some
pharmacologically active (2ry metabolites) and some not (such as
cellulose, starches and sugars).
iii. Herbs contain mixture of components that may have synergistic or
antagonistic effects e.g. Rhubarb (anthraquinone & tannin).
iv. Plants may also contain active and toxic compounds such as
pyrrolizidine alkaloids which are converted in the liver into
hepatotoxic and carcinogenic metabolites.
v. Herbal medicines are less expensive i.e. cheaper than conventional
medicines. In fact, the WHO is encouraging developing countries
to develop their own herbal formula, from local herbs within each
country.

3.7.3 Uses of Phytomedicines

Common Parts Use: Specific parts of plants species aerial parts rhizome
leaf root flower bark fruit, stems are accordingly store properly.
Predominant terrain, north direction, are usually use. Extraction of
phytochemicals mainly use alcohol to extract the plant’s active
constituents from dry or fresh plants alcoholic extracts are prepared by
maceration and/or percolation most phytomedicines are prescribed as
alcoholic tinctures, taken twice daily with a dose of 15 ml each time.
The role of phytomedicines is unique because the appropriate drugs
stimulate or strengthen the body’s own functions and immune system,
hence support the body to restore itself to health.

Phytomedicine consultation assessment of the person as a whole detailed

medical history, lifestyle, diet and other causes are considered rather than
focusing on disease or symptoms required investigations.

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Table 24: Showing Conventional medicineversus Herbal medicine or

Phytomedicine
Conventional medicine Herbal medicine or
Phytomedicine
Uses of pure chemicals in the Uses plants or their crude products
treatment of disease, regardless of for the treatment of diseases. It
their origin, whether of plant, may include also animal, fungi or
animal, micro-organism, synthetic bacteria
or semi-synthetic, organic or
inorganic nature.
Is simple often with single Is complex promoted for several
indication divergent uses
contains one active principle in high contains several active principles in
concentration low concentrations

Table 25: Table Plants as Identified by traditional use, types

of Toxic and Physical Symptoms Some commonly used herbal
supplements.

ant (Family) Traditional UseArea Part Used; Physical Signs

of Extraction of Toxicity
Plan Solvent (Animal
t Model)
Coll
ectio
n
Acanthus montanus Pain, female Cam Leaves; Kidneys
(Acanthaceae) infertility,and eroo water revealed
threatened abortion n crystals
resulting in
glomeruloscler
osis
Annona Sleeping sickness, Nige Liver sections Liver
showed degeneration and
senegalensis (Anno malaria,anthelminti ria necrosis of thedegeneration
hepatocytes
naceae) c, etc and necrosis of
the hepatocytes
Anacardium Diabetes and Cam Leaves; anorexia and
occidentale (Anacar hypertension eroo methanol weight gain,
diaceae) n and syncopal
observed
(mice). liver
and kidney
injury
Butyrospermum Trypanosomiasis Nige Stem bark; Anorexia,
paradoxum and several human ria ethanol dehydration,
(Sapotaceae) & animal diseases depression,

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prostration,
coma, and
death. and the
kidney,
hepatomegaly.
Chrysophyllum cancers and cancer- Nige Root bark. Fairly toxic to
albidum related problems ria 80% ethanol brine shrimps
(Sapotaceae)
Corrigiola Dermatological Mor Roots; Decrease in the
telephiifolia diseases, flu, ulcer, occo ethanol: relative body
(Caryophyllaceae) cough, jaundice, water (75:25) weight
anaesthesia
diuretic, and
parturient women
Cylicodiscus GIT disorder, Stem bark; Decrease
Cameroon in
gabunensis rheumatism, ethyl acetate relative weight
(Mimosaceae) filariasis, and of the spleen.
headache Toxic effect on
liver, kidneys
and lungs (rats)
Entada Coughs, diarrhoea, Tanz Stem bark; At doses
abyssinica (Fabacea fever, gonorrhoea, ania 80% ethanol 2000 mg/kg
e) prevent body wt., the
miscarriage, mice exhibited
rheumatic increased
respiratory rate
and scruffy hair.
Mice died at the
dose of
3000 mg/kg
body wt.
Erythrina Cam Stem bark; Reduction
Malaria, hepatitis jaundice, gastrointestinal disorders, inamenorrhea, dysmenorrhea,
senegalensis (Fabac sterility, pains, eron water locomotion,
eae) onchocerchosis, exploration,
and headache aggressiveness,
touch,
sensibility, and
pain sensibility
(mice)
Ficus exasperata Cardiac Nige Leaves; Water
(Moraceae) arrhythmias, ria
asthma, enhance
expulsion of
placenta, etc
000Garcinia Bronchitis, URTI, Nige Root; 80% Toxic to brine
kola (Guttiferae) colic, head or chest, ria ethanol shrimps

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liver disorders, and

as a chewing stick,
purgative,antimicro
bial
Glinus Anthelmintic and Ethi Seeds; 60% No physical
lotoides (Mollugina tapeworm opia methanol sign of toxicity
ceae) infestation was observed
(rats)
Hydnora Diarrhoea, cholera, Suda Roots; Toxic effect on
johannis Becca. and swelling n ethanol liver, kidney,
(Hydnoraceae) tonsillitis. and spleen
(Wistar rats)
Senecio Wounds, burns, and Sout Leaves; A dose-related
latifolius (Asteracea abortion h water toxicity of
e) Afric hepatocytes,
a with apoptosis,
and necrosis
was observed
(rats)
Leonotis Epilepsy, coughs, Nige Shoots; water Decreased
leonurus (Lamiacea influenza, ria respiratory rate
e) bronchitis,diabetes, and motor
snakebites, and activity, loss of
muscular cramps righting reflex,
ataxia and death
(rats). Marked
hyperplasia of
pulmonary
arteries;
glomerulonephr
itis; necrosis,
and mild
hemosiderosis
in the liver.
Pteleopsis Measles, dropsy, Cam Stem bark; Growth
hylodendron (Comb chickenpox, STD, eroo methanol retardation,
retaceae) female sterility, n inflammation
liver and kidney and vascular
disorders congestion in
the liver and
kidneys (rats)

i. Ginkgo (Ginkgo biloba) standardised extract improves awareness,

judgment, and social function in people with Alzheimer's
ii. St. John's wort (Hypericum perforatum) antidepressant effects

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iii. Saw palmetto (Serenoa repens) for the treatment of benign prostatic
hyperplasia (BPH) improvement in urinary symptoms and flow
compared to finasteride (Proscar), a pharmaceutical drug used in
BPH.
iv. Valerian (Valeriana officinalis) a sleep-inducing agent, (no
hangover feeling the next day)
v. Echinacea (Echinacea purpurea) and other Echinacea species) may
improve the body's natural immunity.

Table 26: Examples of Phytomedicine: A few very well-known IN

Orthodox Medicines

Anti-cancer drug Taxol Taxusbrevifolia 1971

Strychnine Strychhnos 1817
Emetine Ipecacuanha 1817
Caffeine Coffee shrub 1821
Atropine Belladonna 1833
Qininine from cinchona bark 1820
Salicin Also known as willow bark 1838
Aspirin)
Morphine opium poppy 1923
Benzylpenicillin 1928
Tamiflu shikimic Anis seed acid

3.7.3 Herbal preparations

i. Botanical: Macroscopically – shape, external, marking,

microscopically quality, quantity, scanning electron microscopy
(SEC) studies, powder study.
ii. Physical: Moisture constituents, extract values, Ash values Fluores.
iii. Chemicals: Qualitative, quantitative using Chromatography –
HPTLC, GLC, HPLC, DNA Finger printing etc.
iv. Biological: such as Microbial contamination, Toxicological and
Pharmacological.
v. Other specific activities: Antagonistic.
vi. Orgnoleptic: colour, odour, taste, texture and fracture

Methods of purification include washing, decoloration, sifting, boiling,

elutriation, rubbing, lixiviation, dipping, percolation, sublimation,
maceration, bachnag, dialysis, and despumation.

Preparations: Active ingredients of plants can be first tasted – sweet,

sour, salty, pungent, bitter and astringent. Treatment is nothing but
restoration of deranged body potency – cold and hot elements –
anatomically and physiologically unique and specific taste after digestion

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– actions sweet, sour and pungent. A phytopharmaceutical preparation or

herbal medicine is any manufactured medicine obtained exclusively from
plants, either in the crude state or as pharmaceutical formulation.

3.7.5 Standardisation and quality evaluation of herbal drugs

Several methods of standardisation may determine the number of herbs

used. One is the ratio of raw materials to solvent. However different
specimens of even the same plant species may vary in chemical content.
For this reason, thin layer chromatography is sometimes used by growers
to assess the content of their products before use. Another method is
standardisation on a signal chemical.

3.7.6 Routes of administration: There are many forms in which herbs

can be administered, the most common of which is in the form of liquids,
tinctures topical, herbal wines, essential oils tisanes oils, balms,
decoctions, creams, lotions, macerate poultice, vinegar syrups,
compressions extract and inhalations.

i. Liquid that is drunk by the patient either an herbal tea or a

(possibly diluted) plant extract.
ii. Herbal teas, or tisanes, are the resultant liquid of extracting herbs
into water, though they are made in a few different ways. Infusions
are hot water extracts of herbs, such as chamomile or mint, through
steeping.
iii. Decoctions are the long-term boiled extracts, usually of harder
substances like roots or bark.
iv. Maceration is the cold infusion of plants with high mucilage-
content, such as sage or thyme. To make macerates, plants are
chopped and added to cold water. They are then left to stand for 7
to 12 hours (depending on herb used). For most macerates, 10 hours
is used.
v. Tinctures are alcoholic extracts of herbs, which are generally
stronger than herbal teas. Tinctures are usually obtained by
combining 100% pure ethanol (or a mixture of 100% ethanol with
water) with the herb. A completed tincture has an ethanol
percentage of at least 25% (sometimes up to 90%). Non-alcoholic
tinctures can be made with glycerine but it is believed to be less
absorbed by the body than alcohol-based tinctures and has a shorter
shelf life.
vi. Herbal wine and elixirs are alcoholic extract of herbs, usually with
an ethanol percentage of 12–38%. [32]. Extracts include liquid
extracts, dry extracts, and nebulises. Liquid extracts are liquids
with a lower ethanol percentage than tinctures. They are usually
made by vacuum distilling tinctures. Dry extracts are extracts of

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plant material that are evaporated into a dry mass. They can then
be further refined to a capsule or tablet.

vii. Topical Many herbs are applied topically to the skin in a variety of
forms. Essential oil extracts can be applied to the skin, usually
diluted in a carrier oil. Many essential oils can burn the skin or are
simply too high dose used straight; diluting them in olive oil or
another food grade oil such as almond oil can allow these to be used
safely as a topical. Salves, oils, balms, creams and lotions are other
forms of topical delivery mechanisms. Most topical applications
are oil extractions of herbs. Taking a food grade oil and soaking
herbs in it for anywhere from weeks to months allows certain
phytochemicals to be extracted into the oil. This oil can then be
made into salves, creams, lotions, or simply used as an oil for
topical application. Many massage oils, antibacterial salves, and
wound healing compounds are made this way.

viii. Inhalation, as in aromatherapy, can be used as a treatment.

3.7.7 Safety Issues in the use of Phytomedicines

Although many consumers believe that herbal medicines are safe because
they are "natural", herbal medicines and synthetic drugs may interact,
causing toxicity to the patient. Herbal remedies can also be dangerously
contaminated, and herbal medicines without established efficacy, may
unknowingly be used to replace medicines that do have corroborated
efficacy. For example; Datura stramonium has been used in Ayurveda for
various treatments, but contains alkaloids, such as atropine and
scopolamine, which may cause severe toxicity. Examples of herbs where
a high degree of confidence of a risk long term adverse effects can be
asserted include ginseng, which is unpopular among herbalists for this
reason, the endangered herb goldenseal, milk thistle, senna, against which
herbalists generally advise and rarely use, aloe vera juice, buckthorn bark
and berry, cascara sagrada bark, saw palmetto, valerian, kava, which is
banned in the European Union, St. John's wort, Khat, Betel nut, the
restricted herb Ephedra, and Guarana.

Therefore, some safety issues in the use Phytomedicines can be from;

i. Adverse Effects: There is also concern with respect to the

numerous well-established interactions of herbs and drugs. In
consultation with a physician, usage of herbal remedies should be
clarified, as some herbal remedies have the potential to cause
adverse drug interactions when used in combination with various
prescription and over-the-counter pharmaceuticals, just as a patient

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should inform an herbalist of their consumption of orthodox

prescription and other medication.
ii. Effect on Blood Pressure: dangerously low blood pressure may
result from the combination of an herbal remedy that lowers blood
pressure together with prescription medicine that has the same
effect. Some herbs may amplify the effects of anticoagulants.
iii. Examples of herbal treatments with likely cause-effect
relationships with adverse events include aconite, which is often a
legally restricted herb, ayurvedic remedies, broom, chaparral,
Chinese herb mixtures, comfrey, herbs containing certain
flavonoids, germander, guar gum, liquorice root, and pennyroyal.
iv. Drug Interactions: Certain herbs as well as common fruits
interfere with cytochrome P450, an enzyme critical to much drug
metabolism.
v. Undisclosed Additives: a 2018 study, FDA identified active
pharmaceutical additives in over 700 of analysed dietary
supplements sold as "herbal", "natural" or "traditional". The
undisclosed additives included "unapproved antidepressants and
designer steroids", as well as prescription drugs, such as sildenafil
or sibutramine. False adulteration, inappropriate formulation, or
lack of
vi. understanding of plant and drug interactions have led to adverse
reactions that are sometimes life threatening or lethal.
vii. Labelling accuracy: A 2013 study found that one-third of herbal
supplements sampled contained no trace of the herb listed on the
label. The study found products adulterated with contaminants or
fillers not listed on the label, including potential allergens such as
soy, wheat, or black walnut. One bottle labelled as St. John's Wort
was found to actually contain Alexandrian senna, a laxative.
viii. Lack of Registration: Researchers found in 2014 that almost 20
per cent of herbal remedies surveyed were not registered with the
Therapeutic Goods Administration, despite this being a condition
for their sale. They also found that nearly 60 per cent of products
surveyed had ingredients that did not match what was on the label.
Out of 121 products, only 15 had ingredients that matched their
TGA listing and packaging.

In 2015, the New York Attorney General issued cease and desist
letters to four major U.S. retailers (GNC, Target, Walgreens, and
Walmart) who were accused of selling herbal supplements that
were mislabelled and potentially dangerous. Twenty-four products
were tested by DNA barcoding as part of the investigation, with all
but five containing DNA that did not match the product labels.

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3.7.8 Challenges

There are at least five major limitations in the development of herbal

medicine: the reproducibility of biological activity of herbal extracts;

i. Its toxicity and adverse effects;

ii. Its adulteration and contamination;
iii. Herb drug interactions issues; and
iv. Standardisation issues.

Brief description of each of these limitations.

i. Reproducibility of biological activity of herbal medicine: One

of the most problematic issues faced by the field of Phytomedicine
is the high failure rate to reproduce the biological activity of
individual herbal extracts after the success of initial screening
process. Over 40% of plant extracts found actually lack this
reproducibility31. Although this failure in re-sampled and re-
extracted batches points towards the variation of biochemical
profiles of plants harvested at different times and locations, as well
the existence of unique variation in the same type of plant, put
challenge to scientific confidence on the efficacy. Nonetheless,
sometimes in our pursuit to isolate an active compound from a
particular plant, we might inadvertently exclude phytocompounds
with relevant pharmacological activities.
ii. Toxicity and adverse effects of herbal medicine: There is a
predominant myth in society that medicinal herbs or plants are
much safer than conventional pharmaceuticals due to its “natural”
origin. This cannot be further than the truth! Like all other
medicines, there is a specific dosage threshold for each herbal
medicine to be efficacious as well as to be toxic. There have been
reports in the literature 32, 33 that many herbal medicine
preparations are potentially toxic and some are even carcinogenic.
For example, aristolochic acid derived from Aristolochia spp. is
associated with the development of nephropathy and urothelial
cancer. The toxic effect of herbal medicines may be due to
(i) existence of phytotoxins in some unadulterated herbal medicines;
(ii) (ii) mistakes in botanical identification;
(iii) (iii) unsuitable combinations of plants; and
(iv) (iv) usage of plants that interfere with conventional
pharmacotherapy.

Adulteration and contamination of herbal medicine: Herbal medicine

may become adulterated and contaminated in countries that are lax in their
purity control regulation. This may cause significant medical problems,
especially in children. A recent cross-sectional study among 13,504 adults

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in the USA showed that women using herbal supplements (including

Ayurvedic or traditional Chinese medicine herbs, St. John’s Wort, and
“other” herbs) had blood lead levels that were 10% higher than women
non-users, although these increased levels were not seen among men.

Herb drug interactions issues: Not surprisingly, the pharmacokinetic

profile of administered conventional pharmaceuticals can be changed by
the usage of herbal medicine. These interactions may potentiate or
antagonise the absorption and metabolism of drugs, as well as cause
adverse effects like allergy. However, it is worthy of note that herbal
medicine has the lowest level (7.6%) of reported adverse effects compared
to other modes of complementary and alternative medicine.

Herbal medicine standardisation issues: Herbal medicine rarely meet

the standard of standardisation, which is partially due to the scarcity of
scientific information about the acting pharmacological principles of the
extracted phytocompounds and the fact that the plants are not cultivated
under controlled condition. The significant variability in content and
quality of commercialised herbal products are the result of variability in
the content and concentration of phytocompounds within the extract as
well as the different extraction and processing techniques employed by
different producers.

Aside from the limitations discussed above, among the problems faced
from plant-based drug development is the issue of eco-sustainability.
Taxol, an anti-tumour agent, is isolated from the bark of Taxus brevofolia
and Taxus bacata 43. In order to produce 2.5kg of Taxol, 27,000 tons of
bark is required, equivalent to 12,000 trees. We can imagine that if there
was no alternative to the natural phytocompound extraction method, then
the mass production of Taxol would cause the extinction of these unique
tree species. Hopefully, the problem of low yield will be outdated with the
advancement in combinatorial organic chemistry, with the creation of
semi-synthetic analogues and better method of extraction and purification
that will result in higher yield.

3.7.9 The Future of Herbal Medicine

What does the future hold in store for herbal medicine? Socio-cultural and
economic problems, lack of well-planned and integrated strategies, as well
as poor access to scientific information must be dealt with in order to fully
utilise the available resources for the modern concept of drug
development. It is important to encourage more ethnobotanical studies
among indigenous people before their way of life or they themselves
disappear. Besides this, the problem of patents, intellectual property and
rights of the native population where the phytomedicine knowledge
originated should be addressed adequately. This native population is often

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found to be in need of better care, but they do not usually benefit from
sharing their knowledge to the rest of the so-called “modern world”. It is
curious to note that drug companies generate more than USD 100 million
each year from the sale of drugs from natural compounds, without
returning profits to the countries where the compounds were found.
Protecting and compensating local groups for their indigenous knowledge
as well as providing access to modern medicine should be seen as a
reasonable expectation from the conventional pharmaceutical or herbal
medicine companies that stand to benefit greatly from this “collaboration”.
Meanwhile, it is unfortunate that current herbal medicine companies are
still mainly small businesses and as a result, products sold are of inferior
quality and frequently mixed with contaminants and sometimes toxin.
Professional links must be forged between these businesses, the
government, large pharmaceutical companies, academic institution and
the local community to continue the expansion and development of herbal
medicine in the right direction. This will promote the rational and
responsible exploitation of biodiversity as a source of chemical
compounds that can be used for developing new drugs. For example, the
International Cooperative Biodiversity Group (ICBG) programme, which
is currently based in Peru, has been established to form interdisciplinary
collaboration between universities, research institutions, government and
pharmaceutical companies. In China, Yunnan Institute of Tropical Botany
(YITB) has collaborated with Yamanouchi Pharmaceutical of Japan,
resulting in the development of seven patents from 1988 to 19911. Similar
programs should be encouraged worldwide.

Besides this, the improvement of drugs found in nature is now possible by

organic chemistry, gene amplification and recombinant procedures, high-
throughput screening, gene chip technology, or chemo systemic. Through
these methods, now there are new local anaesthetics derived from cocaine
without its original dangerous effects and there is also chloroquine that is
less toxic than quinine.

SELF- ASSESSED EXERCISES

i. List the methods of purifying herbal preparations.

ii. Discuss the safety issues that can arise from the use of
phytomedicines.

4.0 CONCLUSION

In this unit, you have learnt key words in drug development, preclinical
drug discovery, pharmacological profiling, safety and toxicity, clinical
trials, ethics in clinical trials, clinical trial design, Phases in clinical trials,
Therapeutics Goods Administration, Pharmaceutical Benefits Scheme.
You have also learnt what is phytomedicine or the use of herbal medicine

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with therapeutic properties and its significant role throughout history, the
various methods of preparations, indications and types of some example
medicinal plants in sub-Saharan Africa including Nigeria.

5.0 SUMMARY

The process of drug development includes the activities that take the
prospective new drug into the market-place where it becomes available for
use by doctors and patients.

Drug discovery usually exploits advances in knowledge that are available

within the research community and it is therefore not surprising to find
several companies pursuing similar lines of research. Development times
vary between areas of therapeutics, but generally companies expect to
develop drugs in 6-7 years (compared with about 12 years two decades
ago).

Preclinical drug discovery is the process before clinical testing of drugs.

The first step in preclinical drug development is the discovery or synthesis
of a new drug. At least, 10,000 new molecules are discovered/synthesized
for each successful new drug introduced. Extensive preclinical safety and
efficacy testing of new drugs are required in animals, and this takes an
average of 1.5-3 years. There are three main ways in which new drugs are
derived; chemical modification, rational drug design, and random
screening. Many a times Serendipity (accidental discovery of something
fortunate) may also have a role in drug development.

Once a lead compound has been discovered (e.g. a drug with activity at a
certain binding site), the compound undergoes pharmacological profiling.
A large number of experiments are undertaken, mainly using animals, to
determine the pharmacokinetics and pharmacodynamics of the drug.

New drugs undergo extensive safety and toxicity testing in animals. This
preclinical safety and toxicity testing take 2 -5 years, and involves the
collection and analysis of lots of data.

It is convenient to describe clinical drug development in terms of phase.

The boundaries between the phases are not rigid, and in some
developments phases 2 and 3 are merged. Overlap between phases may
occur. The duration of phase 1 is about 1 year; the duration of phases 2
and 3 together is about 4 years. Submission to regulatory is based on the
clinical data obtained from the studies in phases 1, 2 and 3.

Only about 10% of compounds that enter clinical trial are

approved/registered for sale. Clinical trials are under stringent law
enforced guidelines.

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Phytomedicine or the use of herbal medicine with therapeutic properties

has played a significant role throughout history. Phytomedicine, in
amalgamation with various other health-care fields, has revolutionized
and strengthened the foundation of the existing health-care system and
occupies a major stake in the industry.

In Nigeria, one of these phytomedicines is collectively known as

Niprisan® (also known as Nicosan®), a freeze‐dried extract of Piper
guineenses seeds, Pterocarpus osun stem, Eugenia caryophyllum fruit and
Sorghum bicolor leaves. Niprisan® has been investigated in vitro and in
animal studies. Others are Ciklavit® (Cajanus cajan seed extract as base)
and Zanthoxylum (Fagara) zanthyloides, which are also being researched.
There may well be other potential phytomedicines available for people in
Nigeria. The sustain used of herbal medicine over the years is based on
the believe of the following characteristics of herbal medicines That; 1-
The pharmacologically active compounds and this fact generally means
that risks associated with crude herbal drugs are minimal with moderate
use. 2-They contain a wide variety of different compounds, some
pharmacologically active (2ry metabolites) and some not (such as
cellulose, starches and sugars).3-Herbs contain mixture of components
that may have synergistic or antagonistic effects e.g. Rhubarb
(anthraquinone & tannin). 4-Plants may also contain active and toxic
compounds such as pyrrolizidine alkaloids which are converted in the liver
into hepatotoxic and carcinogenic metabolites. And 5- Herbal medicines
are less expensive i.e. cheaper than conventional medicines. Common
Parts Use: Specific parts of plants species aerial parts, rhizome, leaf root
flower, bark, fruit and stems are accordingly store properly.

6.0 TUTOR- MARKED ASSIGNMENT

1. What is Phytomedicine and what are their main differences with

traditional (orthodox medicine)?
2. Classify some African medicinal plants, their uses, indications
and adverse effects
3. What are the main challenges of using Phytomedicines

7.0 REFERENCE/FURTHER READING

WHO traditional medicine strategy: 2014-2023. (www.who.int).

Rang, H., Dale, M., Ritter, J. & Flower, R (2007). Rang & Dale’s
Pharmacology (6th ed.). London, UK: Churchill Livingstone.
Phytomedicine is a plant-based traditional medicinal practice that
uses various plant materials in preventive and therapeutic
processes (Wallis, 2005; Ali, 2008).

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Mohamed, I.S., Borhanuddin, A. & Fozi B.N. (2012). The Application

of Phytomedicine in Modern Drug Development. The Internet
Journal of Herbal and Plant Medicine, 1(2), 1-9.https: //
DOI:10.5580/2c1f/ Corpus ID: 13662919.

Khan, M.S., Chattopadhyay, D. & Ahmad, I (2019). New look to

phytomedicine: Advancements in herbal products as novel drug
lead. Academic press. https://doi.org/10.1016/C2017-0-01165-5.

Oniyang, O. & Cohall, D.H. (2018). Phytomedicines (medicines derived

from plants) for sickle cell disease. Cochrane Database Syst Rev,
2 (2):CD004448.; Feb 15. doi:10.1002/14651858.CD004448.
(Site 6th May 2020).

Robinson, M.R., & Zhang, X. (2011). The world medicines situation;

Traditional medicines: global situation, issues and challenges).
Geneva: World Health Organisation.

Schulz, V., Hansel, R. & Tyler, V.E. (2001). Rational phytotherapy: a

physician’s guide to herbal medicine. Berlin: Springer-Verlag.

Erah, P.O. & Nwazuoke, J.C. (2002).Identification of Standards for

Pharmaceutical Care in Benin City.Tropical Journal of
Pharmaceutical Research,
1 (2): 53-54. http: // DOI: 10.4314/tjpr. v1i2.14585.

Kuete, Victor (2014). Toxicological Survey of African Medicinal Plants.

Elsevier. https://doi.org/10.1016/C2013-0-15406-2.

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MODULE 2 APPLIED PHARMACOLOGY IN PUBLIC

HEALTH

Unit1 Principles of Drug Action (Pharmacodynamics)

Unit2 Mode of Action of Antimicrobial and Chemotherapeutics
Drugs
Unit3 Mode of Drug Action in Diseases

UNIT1 PRINCIPLES OF DRUG ACTION

(PHARMACODYNAMICS)

CONTENTS

1.0 Introduction
2.0 Objectives
3.0 Main Content
3.1 Definition of Terms
3.2 Drug action in Man
3.3 Site of Drug Action
3.4 Types of Drug Action Effect (Type of Responses)
3.5 Mechanism of Drug action in Man
3.5.1 Drug action via receptors
3.5.2 Drug action via (indirect alteration) endogenous
agonist
3.5.3 Drug activation via the inhibition of transport
processes
3.5.4 Drug action via enzyme inhibition
3.5.5 Drug action via enzyme activity activation
3.5.6 Miscellaneous drug action
3.6 Receptor Function
3.6.1 Reorganisation of specific ligand molecule (Ligand
binding domain)
3.6.2 Transduction of signal into response (Effector
domain)
3.7 Receptor families
3.7. 1 Ligand-gated ion channels (inotropic receptors)
3. 7.2 G-protein coupled receptor (Metabotropic receptors)
3. 7.3 Enzymatic receptors (tyrosine kinase)
3.7.4 Receptor regulating gene expression (transcription
factors/ Steroids)
3.7.5 Receptor regulation theory
3.8 Agonists and Antagonists
3.8.1Types of agonism
3.8.2 Types of antagonism
3.9 Graded Drug Dose Response
3.9.1 Dose-Response Relationship

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3.9.2 Dose-response curve: Clinical Applications

3.9.3 Dose-Response Curve – Advantages
3.10.3 Potency and Efficacy
3.10.4 Therapeutic window
3.10.5 Factors Modifying Drugs
3.10.6 Effects in Man
3.10.7 Assaying receptor binding
3.10.8 monitoring drug therapy
4.0 Conclusion
5.0 Summary
6.0 Tutor Marked Assignment
7.0 References/Further Reading

1.0 NTRODUCTION

The measurement of the effects of drugs on humans (or, in basic

pharmacology, an organ system) is termed Pharmacodynamics refers to
the relationship between drug concentration at the site of action and the
resulting effect, including the time course and intensity of therapeutic and
adverse effects. The effect of a drug present at the site of action is
determined by that drug’s binding with a receptor. Receptors may be
present on neurons in the central nervous system (i.e., opiate receptors) to
depress pain sensation, on cardiac muscle to affect the intensity of
contraction, or even within bacteria to disrupt maintenance of the bacterial
cell wall. For most drugs, the concentration at the site of the receptor
determines the intensity of a drug’s effect. However, other factors affect
drug response as well. Density of receptors on the cell surface, the
mechanism by which a signal is transmitted into the cell by second
messengers (substances within the cell), or regulatory factors that control
gene translation and protein production may influence drug effect.

In the simplest examples of drug effect, there is a relationship between the

concentration of drug at the receptor site and the pharmacologic effect,
this lecture series is designed to facilitate the learning of key principles
and concepts regarding the basic pharmacodynamics principles of drugs,
drug receptors and interactions at these receptors. This knowledge will be
critical in the understanding of the various drugs and drug classes to be
discussed throughout this course. Understand drug safety and
effectiveness like factors affecting drug action in man. More specifically
this information will be used to facilitate the understanding of the
receptors in the autonomic nervous system and the drugs that interact at
these receptors.

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2.0 OBJECTIVES

By the end of this unit, you will be able to:

 list different types of receptors at which drugs can act

 identify concept of affinity and those factors that cause a drug to
bind to a receptor
 state concept of intrinsic activity
 differentiate between full and partial agonists
 give the definitions of potency and efficacy
 apply the information regarding drugs that can be obtained from
the log-dose response curve
 explain the properties of a competitive antagonist and how it differs
from an irreversible receptor agonist.

3.0 MAIN CONTENT

3.1 Definition of Terms

i. Pharmacodynamics. This term encompasses both mechanism of

action and endpoint (e.g. heart rate, blood pressure).
ii. In Greek Pharmacon = Drug Dynamics = Action/Power It covers
all the aspects relating to “What a drug does to the body”
Mechanism of action.
iii. Action: How and where the effect is produced is called as Action.
iv. Effect: The type of response producing by drug

3.2 Drug Action in Man

The action of drugs on the human body and the mechanism of interaction
between drugs and human to produce effects is described.

3.3 Site of Drug Action

The receptors sites where a drug acts to initiate a group of functions is that
drugs site of action. This a can either:

i. Extra cellular
ii. Cellular
iii. Intracellular

a. Types of Drug Action (Type of Responses): -

iv. Stimulation
v. Inhibition/Depression
vi. Replacement

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vii. Irritation
viii. Cytotoxic

3.5 Mechanism of Drug Action in Man

The types of an effect produce by a drug is called mode of action of that

drug. For example, Morphine, by depressing the function of the cerebral
cortex, hypothalamus and medullar centre, it depresses pain perception
(analgesia), Heavy sedation (Narcosis), and depressing cough centre
(antitussive effect). Initially it stimulates, then depressing the vomiting
centre and depressing respiration.

3.5.1 Drug action via Receptors

Definition: Receptors are macromolecules involved in chemical

signalling between and within cells; they may be located on the cell
surface membrane or within the cytoplasm. Operationally receptor denote
any cellular macromolecules to which a drug binds to initiate the response
to it, but itself has no other function, e.g. Muscarinic (M type) and
Nicotinic (N type) receptors? of Cholinergic system. Most are proteins,
some receptor sites are intracellular (e.g. steroid) cytoplasm
or in the nucleus. The drug-receptor interaction leads to a molecular
change in the receptor, which triggers a chain of events leading to a
response. Receptors tend to be highly specific, interacting with a limited
number of structurally related molecules. For some drugs, the receptor is
nonspecific in terms of cell function (e.g. an alkylating agent that cross-
binds molecule within DNA).

Other ways, in which drug acts on receptors includes: Agonist,

Antagonists and partial antagonists.

3.5.2 Drug action via indirect alteration of the effect of an

endogenous agonist

I. Physiological
ii. Increase endogenous release
iii. Inhibition of endogenous re-uptake
iv. Inhibition of endogenous metabolism
V. Prevention of endogenous release

3.5.3 Drug activation via the inhibition of transport processes

3.5.4 Drug action via enzyme inhibition.

3.5.5 Drug action via enzyme activity activation.

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3.5.6 Miscellaneous drug action

i. Chelating
ii. Osmotic diuresis
iii. Volatile general anaesthetics
vi. Replacement drugs

3.5.7 Receptor Functions

Two essential functions (see diagram below), Reorganisation of specific

ligand molecule (Ligand binding domain) and Transduction of signal into
response(Effector domain).

3.5.8 Reorganisation functions (signal into response)

Two Domains:

i. Ligand binding domain (coupling proteins)

ii. Effectors Domain – undergoes functional conformational change

Action”: Initial combination of the drug with its receptors resulting in a

conformational change (agonist) in the later, or prevention of
conformational change (antagonist).

“Effect”: It is the ultimate change in biological function brought about as

a consequence of drug action, through a series of intermediate steps
(transducers).

3.5.9The Transducer mechanism: Most transmembrane signalling is

accomplished by a small number of different molecular mechanisms
(transducer mechanisms). Large number of receptors share these handful
of transducer mechanisms to generate an integrated and amplified
response.

There Mainly 4 (four) major categories:

i. G-protein coupled receptors (GPCR)

ii. Receptors with intrinsic ion channel
iii. Enzyme linked receptors
iv. Transcription factors (receptors for gene expression)

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Table 27: Receptor and coupling mechanisms

S/N Receptor Location Coupling Examples
O type mechanism
1. Receptor Membrane Entry/exit of Nicotinic,
controlled ions acetylcholine
- ion - γ-aminobutyric acid,
channels Depolarization Glutamate
or
hyperpolarizati
on
2. Ligand Membrane Receptor Muscarinic/acetylchol
Gated - G protein ine, β-adrenergic
– Protein associated with Dopaminergic
receptors a G-protein Serotoninergic
which may: Opiate
Activate
messenger
Adenylate
cyclase –
cAMP
Phospholipase
C–inositol
triphosphate,
diacylglycerol
Activate an ion
channel
3. Receptor- Membrane Initiate protein Insulin
controlled phosphorylatio Atrial natriuretic
enzymes n (e.g. tyrosine peptide
kinase,
guanylate
cyclase)
4 Intracellul Intracellul Stimulate steroid hormones,
ar ar mRNA Thyroid hormones,
receptors, synthesis in the vitamin D
Gene cell nucleus,
leading to
protein
synthesis

Drug +Receptor - Drug receptor complex = Response

Drug receptor interaction: -

i.Selectivity: - Degree of complimentary correlation between drug and

receptor. Ex: - Adrenaline Selectivity for α, ß Receptor

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ii.Affinity: - Ability of drug to get bound to the receptor.

iii.Intrinsic activity (IA) or Efficacy: - Ability of drug to produce a
pharmacological response after making the drug receptor complex

3. 6 Receptor Families

Four types of receptors families are Ligand-gated ion channels (inotropic

receptors), G-protein coupled receptor (Metabotropic receptors),
Enzymatic receptors (tyrosine kinase), and receptor regulating gene
expression (transcription factors/ Steroids). The interaction of a ligand
with a receptor protein induces a conformational change that eventually
initiates an intracellular signal.

3.6.1Ligand-activated ion channels (a signal transduction mechanism):

Ion gated receptors: - Localised on cell membrane and coupled directly to
an ion channel acetylcholine interacting with a nicotinic receptor that is a
nonspecific Na1/K1 transmembrane ion channel. Interaction of a molecule
of acetylcholine with each subunit of the channel produces a
conformational change that permits the passage of Na1 and K1. Other
channels that are targets for various drugs include specific Ca21 and K1
channels.

3.6.2G-protein coupled receptors: G-protein–coupled receptors

compose the largest class of receptors. All the receptors have seven
transmembrane segments, three intracellular loops, and an intracellular
carboxyl-terminal tail. The biologic activity of the receptors is mediated
via interaction with a number of G (GTP binding) proteins. Bound to inner
face of plasma membrane (2nd messenger)

Varieties of G-protein

i. Gα2 s-coupled receptors a β-adrenoceptor, which when activated

by ligand binding (e.g., epinephrine) exchanges GDP for GTP. This
facilitates the migration of Gαs (Gαstimulatory) and its interaction
with adenylyl cyclase (AC). Gαs-bound AC catalyses the
production of cyclic AMP (cAMP) from adenosine triphosphate
(ATP); cAMP activates protein kinase A, which subsequently acts
to phosphorylate and activate a number of effector proteins. The βγ
dimer may also activate some effectors. Hydrolysis of the
guanosine triphosphate (GTP) bound to the Gα to guanosine
triphosphate (GDP) terminates the signal.
ii. Gα1 (G-inhibitory)-coupled receptors. Ligand binding (e.g.,
somatisation) to Gα1 (Gαinhibitory)-coupled receptors similarly
exchanges GTP for GDP, but Gαi inhibits AC, leading to reduced
cAMP production.

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iii. Gq (and G11)-coupled receptors. Gq (and G11) interact with

ligand (e.g., serotonin)-activated receptors and increase the activity
of phospholipase C (PLC). PLC cleaves the membrane
phospholipid phosphatidylinositol 4, 5-bisphosphate (PIP2) to
diacylglycerol (DAG) and inositol 1, 4, 5-triphosphate (IP3). DAG
activates protein kinase C, which can subsequently phosphorylate
and activate a number of cellular proteins; IP3 causes the release of
Ca21 from the endoplasmic reticulum into the cytoplasm, where it
can activate many cellular processes.
iv.Go: Neurotransmitters in brain, Not yet clear

G-protein effector systems

• Adenylase cyclase: cAMP system

• Phospholipase –C: Inositol phosphate system
• Ion channels

Ion channel regulation; G-protein coupled receptors can control the

functioning of ion channel by not involving any second messenger; e.g.: -
In cardiac muscles.

3.6 Enzymatic receptors:

Receptor-activated tyrosine kinases. Many growth-related signals (e.g.,

insulin) are mediated via membrane receptors that possess intrinsic
tyrosine kinase. Ligand binding causes conformational changes in the
receptor; some receptor tyrosine kinases are monomers that dimerize upon
ligand binding. The liganded receptors then auto - phosphorylate tyrosine
residues, which recruit cytoplasmic proteins to the plasma membrane
where they are also tyrosine phosphorylated and activated. Receptor
regulating: gene expression (transcription factors) unfolds the receptor and
expose normally masked DNA binding site Increase RNA polymerase
activity.

i. Intracellular nuclear receptors. Ligands (e.g., cortisol) for

nuclear receptors are lipophilic and can diffuse rapidly through the
plasma membrane. In the absence of ligand, nuclear receptors are
inactive because of their interaction with chaperone proteins such
as heat-shock proteins like HSP-90. Binding of ligand promotes
structural changes in the receptor that facilitate dissociation of
chaperones, entry of receptors into the nucleus, hetero- or
homodimerization of receptors, and high-affinity interaction with
the DNA of target genes. DNA-bound nuclear receptors are able to
recruit a diverse number of proteins called coactivators, which
subsequently act to increase transcription of the target gene.

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ii. Alteration of the activity of enzymes by activation or inhibition

of the enzyme’s catalytic activity.
iii. Antimetabolite action in which the drug, acting as a non-
functional analogy of a naturally occurring metabolite, interferes
with normal metabolism.
iv. Nonspecific chemical or physical interactions such as those
caused by antacids, osmotic agents, and chelators.

3.6.4 Receptor regulation theory

Receptors are in dynamic state. The affinity of the response to drugs is not
fixed. It alters according to situation.

3.6.5 Up regulation of receptors: In topically active systems, prolonged

deprivation of agonist (by denervation or antagonist) results in super
sensitivity of the receptor as well as to effector system to the agonist.
Sudden discontinuation of Propranolol, Clonidine etc. after prolong use,
produce withdrawal symptoms. Rise Blood Pressure, induce of angina.
Unmasking of receptors or proliferation or accentuation of signal
amplification.

3.6.6Receptor down regulation: Continued exposure to an agonist or

intense receptor stimulation causes desensitisation or refractoriness:
receptor become less sensitive to the agonist, e.g. beta adrenergic agonist
and levodopa causes:

i.Masking or internalisation of the receptors

ii.Decreased synthesis or increased destruction of the receptors (down
regulation). Tyrosine kinase receptors.

3.6.7Ligand gated G-protein coupled Enzymatic Nuclear Location

Membrane Intracellular Effector Ion Channel, Ion Channel or enzyme
Gene coupling Direct G-protein Direct via DNA, example: Nicotinic,
Muscarinic, Insulin Steroid and hormone.

3.6.8G-protein coupled receptors: Membrane bound, which are coupled

to effector system through GTP binding proteins called as G-proteins
bound to inner face of plasma membrane (2nd messenger)

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Figure23: Receptor Function

3.7 Function of Receptors

i. To Regulate signals from outside the cell to inside the effector

cell – signals not permeable to cell membrane.
ii. To amplify the signal.
iii. To integrate various intracellular and extracellular signals
iv. To adapt to short term and long-term changes and maintain
homeostasis.

3.8 Agonists and Antagonists

3.8.1 Agonists: are drugs that activate a receptor producing response. An

agonist can be defined as a ligand, the binding of which to a receptor
protein produces a conformational change necessary to initiate a signal
that is coupled to a biological response. When all available receptors are
occupied, a maximal response in produced. Example of such receptor
systems include:

i. adrenergic (agonist – salbutamol, antagonist – atenolol)

ii. dopaminergic (agonist – dopamine, antagonist – haloperidol)
iii. cholinergic (agonist – bethanechol, antagonist – atropine)

Agonist: Both the high affinity as well as intrinsic activity (IA=1). These
drugs trigger the maximal biological response or mimic effect of the
endogenous substance. e.g.: - Methacholine is a cholinomimetics drug
which mimics the effect of Ach on cholinergic receptors.

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Types of agonism:

i. Summation: - Two drugs eliciting same response, but with

different mechanism and their combined effect is equal to their
summation. (1+1=2) Aspirin inhibit Prostaglandin = analgesic +,
Codeine stimulate Opioids receptor = Analgesic+ + +.
ii. Additive: combined effect of two drugs acting by same mechanism
Aspirin PG Analgesic+ Analgesic+. Together analgesic effect is +
+.
iii. Synergism (Supra additive): - (1+1=3) the combined effect of
two drug effect is higher than either individual effect e.g.
Sulfamethoxazole+ Trimethoprim, Levodopa + Carbidopa.
iv. Partial agonist: Some ligands have properties intermediate
between agonist and antagonists and are known as ‘partial agonist’.
Example: Pindolol, Pentazocine.
They are unable to produce a maximal signalling effect even when
all available receptors are occupied. However, partial agonists also
block receptor sites that could potentially be occupied by the full
agonist and this competition for receptors means that, in some
circumstances, partial agonists may also appear to be the full
agonist when they bind to a receptor and are known as ‘inverse
agonists.
V. Inverse agonist: These have full affinity towards the receptor but
intrinsic activity is zero to -1 i.e., produces effect is just opposite to
that of agonist. e.g.: - ß-Carboline is inverse agonist for
Benzodiazepines receptors

3.8.2 An antagonist: is a ligand that binds to a receptor but (that block

receptor does not produce the conformational change that initiates
an intracellular signal. Occupation of the receptors by an antagonist
prevents the binding of any other ligand and so ‘antagonises’ the
biological response to the agonist.

Antagonism: Effect of two drugs is less than sum of the effects of the
individual drugs.
i.Chemical antagonism e.g.: -heparin (-ve) protamine +ve, Chelating
agents
ii.Physiological /Functional antagonism
iii.Pharmacokinetic antagonism
iv.Pharmacological antagonism (Competitive (Reversible)/Non-
competitive (Irreversible)

Pharmacokinetic antagonism

One drug affects the absorption, metabolism or excretion of other drug

and reduce

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their effect. e.g. Warfarin in presence of phenobarbitone, warfarin

metabolism is increased, its effect is reduced.

Pharmacological antagonism
Pharmacodynamic antagonism between two drugs acting at same
receptors. Two important mechanisms according to which these
antagonist, Reversible antagonism (Competitive antagonism) and
Irreversible Antagonism (Non)

Reversible antagonism (Competitive antagonism): These inhibitions

are commonly observed with antagonists that bind reversibly to the same
receptor site as that of an agonist. These type inhibitions can be overcome
increasing the concentration of agonist e.g. Atropine is a competitive
antagonist of Ach.

Irreversible Antagonism: It occurs when the antagonist dissociates very

slow or not at all from the receptors result that no change when the agonist
applied. Antagonist effect cannot be overcome even after increasing the
concentration of agonism.

For a drug to produce a physiologic effect it must first bind to a

receptor. Two factors, related to the chemical nature of a drug, determine
the interaction of drugs with receptors and hence the effect a drug will
have on physiologic processes.

Affinity is a measure of the tightness with which a drug binds to the

receptor.

Intrinsic activity is a measure of the ability of a drug that is bound to the

receptor to generate an activating stimulus and produce a change in
cellular activity.

Both agonists and antagonists can bind to a receptor. However, only

agonist molecules can activate the receptor.

Partial agonists can occupy receptors but cannot elicit a maximal

response. Such drugs have an intrinsic activity of 1 (Fig. 1.3; drug C).
antagonists bind to the receptor but do not initiate a response; that is, they
block the action of an agonist or endogenous substance that works through
the receptor.

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Figure 24: Graded dose–response curves for two agonists (A and B)

and a partial agonist (C).(@ Pharmacodynamics
(RousselPharmacology\ memorangapp.com).

i. Competitive antagonists combine with the same site on the

receptor but their binding does not activate the receptor (i.e., their
intrinsic activity 5 0) so they have no efficacy per se but may cause
a pharmacological response in some cases by inhibiting the actions
of endogenous substances or other drugs. Competitive antagonists
may be reversible or irreversible. Reversible, or equilibrium,
competitive antagonists are not covalently bound, shift the dose–
response curve for the agonist to the right, and increase the ED50;
that is, more agonist is required to elicit a response in the presence
of the antagonist (Fig. 1.4). Because higher doses of agonist can
overcome the inhibition, the maximal response can still be
obtained.
ii. Non-competitive antagonists bind to the receptor at a site other
than the agonist binding site (Fig. 1.5) and either prevent the
agonist from binding correctly or prevent it from activating the
receptor. Consequently, the effective amount of receptor is
reduced. Receptors unoccupied by antagonist retain the same
affinity for agonist, and the ED50 is unchanged.

3.9 Graded Dose–Response Curve

This expresses an individual’s response to increasing doses of a given

drug. The magnitude of a pharmacologic response is proportional to the
number of receptors with which a drug effectively interacts (Fig. 2). The
graded dose–response curve includes the following parameters:

i.Magnitude of response is graded; that is, it continuously increases

with the dose up to the maximal capacity of the system, and it is

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often depicted as a function of the logarithm of the dose administered (to

see the relationship over a wide range of doses).

ii.ED50 is the dose that produces the half-maximal response; the

threshold dose is that which produces the first noticeable effect.

Figure 255: Graded dose -response(@ Pharmacodynamics (Roussel

Pharmacology .memorangapp.com ).

Intrinsic activity is the ability of a drug once bound to activate the receptor.
A. Agonists are drugs capable of binding to, and activating, a receptor. (1)
Full agonists occupy receptors to cause maximal activation; intrinsic
activity.

3.9.1 Dose-Response Relationship

Drug administered – 2 components of dose- response – Dose-plasma

concentration – Plasma concentration (dose)-response relationship E is
expressed as Emax X [D] Kd + [D] E is observed effect of drug dose [D],
Emax = maximum response, KD = dissociation constant of drug receptor
complex at which half maximal response is produced E max

Figure 26: The dose which 50% of the maximal effect is observed is
referred to as the ED50. ((@ Pharmacodynamics (Roussel

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PHS 810 MODULE 2

Pharmacology .memorangapp.com ).
Dose-Response Curve, Log-dose %response, %response 100% - 50% -
100% - 50% - E = Emax X [D] Kd + [D]

3.9.2 Dose-response curve: Clinical Applications

When the relation between drug dose (X-axis) and drug response (Y-axis)
is plotted on a linear scale, the resulting curve is usually
hyperbolic. Clinical responses that might be plotted in this way include
change in heart rate, blood pressure, gastric pH or blood glucose. Non-
clinical (biochemical) responses can also be plotted in this way including
enzyme activity, accumulation of an intracellular second messenger,
membrane potential, secretion of a hormone, or contraction of a muscle.
If the drug dose is plotted on a base 10 logarithmic scale, this produces a
sigmoidal dose-response curve. This representation is more useful
because it expands the dose scale in the region where drug response is
changing rapidly and compresses the scale at higher doses where large
changes have little effect on response. Note that, in reality, it is ligand
concentration (and resulting receptor occupation) that affects response -
the term ‘dose-response curve’ assumes that the drug dose and ligand
concentration are closely linked

Figure 27: Treatment comparison of dose response relationship(@

Pharmacodynamics (Roussel Pharmacology .memorangapp.com ).

Drug X has greater biologic activity per dosing equivalent and is thus
more potent than drug Y or Z. Drugs X and Z have equal efficacy,
indicated by their maximal attainable response (ceiling effect). Drug Y
is more potent than drug Z, but its maximal efficacy is lower.

3.9.3 Dose-Response Curve - Advantages:

i. Stimuli can be graded by Fractional change in stimulus intensity

ii. A wide range of drug doses can easily be displayed on a graph

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iii. Potency and efficacy can be compared

iv. Comparison of study of agonists and antagonists become easier

3.10 Potency and Efficacy

3.10.1 Potency of a drug is the relative measure of the amount of a drug

required to produce a specified level of response (e.g., 50%) compared
with other drugs that produce the same effect via the same receptor
mechanism. The potency of a drug is determined by the affinity of a drug
for its receptor and the amount of administered drug that reaches
thereceptor.

Figure28: Dose response curves for drugs with high, medium and low
potency acting on the same target. Note that the drug with the highest
potency has the lowest efficacy and vice versa. (@Pharmacodynamics |
Pharmacology ...pharmacologyeducation.org).

3.10.2 Efficacy

Efficacy is the term used to describe the extent to which a drug can
produce a response when all available receptors or binding sites are
occupied (i.e. Emax on the dose–response curve). When comparing drugs
acting at the same receptor, a full agonist will have the greatest efficacy
and can produce the maximum response of which the receptor is capable.
A partial agonist at the same receptor, by definition, will have a lower
efficacy, even when all receptor sites are occupied. The concept of
efficacy is not restricted to comparing the effects of drugs that act at the
same receptor. The term therapeutic efficacy is used to describe the
comparison of drugs that produce the same therapeutic effects on a
biological system but do so via different pharmacological mechanisms
(e.g. loop and thiazide diuretics, proton pump inhibitors and H2-
antagonists). Potency is a term used to describe the amount of a drug

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required for a given response. More potent drugs produce biological

effects at lower doses (or concentrations), which means that they have a
lower ED50 (Fig)

The potency of a drug is related to its affinity for the receptor (i.e. how
readily the drug-receptor complex is formed). Less potent drugs can have
an efficacy similar to that of a more potent one; the difference in potency
can be readily overcome by giving the less potent drug in higher doses.
This is illustrated by the varying recommended dose ranges of drugs acting
at the same drug target (e.g. H2 antagonists, ACE inhibitors).

When choosing between drugs with a similar beneficial effect (e.g.

analgesia) from a group of similar drugs it might seem logical to choose
the one with the greatest therapeutic efficacy. However, in some cases the
most efficacious drug may be less favourable because the same
mechanism of action that leads to clinical benefits may also be responsible
for causing dose-limiting adverse-effects (e.g. opioids, β1-adrenoceptor
blocking drugs). When the same action leads to both beneficial and
adverse effects, the latter can be minimised by carefully increasing
(titrating) the dose. However, some drugs have a steeper dose–response
curve, which makes it more difficult to titrate to the dose that is effective
but avoids adverse effects.

The potency of a drug is rarely a reason for choosing one out of a

collection of drugs with similar beneficial therapeutic effects. This is
because any differences in potency can be overcome simply by giving
higher doses. Although differences in relative potency can be overcome
by altered dosage, it should be remembered that most of the adverse effects
of drugs are also dose-related. Potency may be relevant if these occur by
a mechanism other than the receptor–ligand interaction that mediates the
beneficial effect (because only the more potent drug will be active at
concentrations that avoid unwanted adverse effects).

For these reasons greater potency or efficacy does not necessarily mean
that one drug is preferable to another. When judging the relative merits of
drugs for a patient, prescribers should also consider other important
factors, such as the overall adverse effect profile, therapeutic index, ease
of administration for the patient, duration of effect (i.e. the number of
doses needed each day) and cost.

Dose: It is the required amount of drug in weight, volumes, moles or IU

to provide a desired effect. In clinical it is called as Therapeutic dose; in
experimental purpose it is called as effective dose.

The therapeutic dose varies from person to person. For example,

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Single dose of;

1. Piperazine (4-5g) is sufficient to eradicate round worm.

2. Single IM dose of 250mg of ceftriaxone to treat gonorrohoea.

Daily dose: It is the quantity of a drug to be administered in 24hr, all at

once or equally divided dose. For example;

1.10mg of cetirizine (all at once) is sufficient to relive allergic reactions.

2. Erythromycin is 1g per day to be given in 4 equally divided dose
(i.e.250mg every 6 hr.).

Total dose: It is the maximum quantity of the drug that is needed to

complete course of the therapy e.g. procaine penicillin in early syphilis is
6 million units, given as 0.6 million units per day for 10days.

Loading dose: - It is the large dose of drug to be given initially to provide

the effective plasma concentration rapidly. The drugs having high Vd of
distribution. Chloroquine in Malaria – 600 mg Stat 300mg after 8 hours
300 mg after 2 day

Maintenance dose: Loading dose normally followed by maintenance

dose. Needed to maintain the steady state plasma concentration attained
after giving the loading dose.

MAXIMAL DRUG RESPONSES AND SPARE RECEPTORS

3.11Therapeutic window

Therapeutic window: Optimal therapeutic range of plasma

concentrations at which most of the patients experience the desired effect.
It is also called Therapeutic range. It is the gap between Sub optimal drug
level and Toxic drug level.

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Figure 29: Dose-response relationships are a common way to portray

data in both basic and clinical science ( @ CONTENT uky.edu ).

Figure30: Therapeutic window(@ pharmacologyeducation.org)

[TUSOM .tmedweb.tulane.edu ).

3.11.1 Therapeutic index: Margin of safety

Depend upon factor of dose producing desirable effect and dose eliciting
toxic effect.

Therapeutic Index = TD50 or LD50

ED50
TI - should be more than one

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Table 28: Example of drugs with narrow therapeutic Window

Drug Therapeutic Range
Cyclosporine 100-400ng/ml
Carbamazepine 4-10µg/ml
Digoxin 0.8-2ng/ml
Lithium 0.8-1.4 mEq/L
Phenytoin 10-20µg/ml
Quinidine 2-6µg/ml

3.12 Factors Modifying the Effects of Drugs In Man

Individuals differ both in the degree and the character of the response that
a drug may elicit. The aeration in response to the same dose of a drug
between different patients and even in the same patient on different
occasions.

One or more of the following categories of differences among individuals

are responsible for the variations in drug response: Individuals differ in
pharmacokinetic handling of drug, Variation in number or state of
receptors, coupling proteins or other components of response and
Variation in neurogenic/ hormonal tone or concentrations of specific
constituents.

These factors modify drug action either

i. Quantitatively: The plasma concentration and / or the drug action

is increased or decreased or
ii. Qualitatively: The type of response is altered, e.g. drug allergy
and idiosyncrasy.

The various factors are:

i. Body weight/size: It influences the concentration of drug attained

at the site of action. The average adult dose refers to individuals of
medium built. For exceptionally obese or lean individuals and for
children dose may be calculated on body weight basis

Individual dose = BW (Kg) X adult Average dose

70

Individual dose = BSA (m2) X adult Average dose

1.7

BSA= BW (Kg) 0.425 x Height (cm) 0.725 x 0.007184

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ii.Age: Infants and Children: The dose of drug for children is often
calculated from the adult dose

Child dose = Age X adult dose ……. (Young’ formula)

12+Age

Child dose = Age x adult dose......... (Dilling’ formula).

20

However, infants and children have important physiological differences

Higher proportion of water
Lower plasma protein levels
More available drug

iii.Immature liver/kidneys
Liver often metabolises more slowly
Kidneys may excrete more slowly

iv.Age: Elders: In the elderly

renal function progressively declines (intact nephron loss) and
drug doses have to be reduced in Chronic disease states,
decreased plasma protein binding, Slower metabolism, Slower
excretion, Dietary deficiencies, Use of multiple medications and
Lack of compliance

v.Sex: Females have smaller body size, and so require doses of drugs on
the lower side of the dose range. They should not be given uterine
stimulants during menstruation, quinine during pregnancy and sedatives
during lactation.

vi.Pregnancy: Profound physiological changes which may affect

drug responses:
GI motility reduced –delayed absorption of orally administered
drugs
Plasma and ECF volume expand
Albumin level falls
Renal blood flow increases markedly
Hepatic microsomal enzyme induction

vii.Food: Delays gastric emptying, delays absorption (ampicillin) and

Calcium in milk interferes with absorption of tetracycline and iron
by chelation.
Protein malnutrition may result in
Loss of BW
Reduced hepatic metabolising capacity
Hypoproteinaemia

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viii.Species and race: Rabbits resistant to atropine

Rat & mice are resistant to digitalis
In humans: blacks require higher Mongols require lower
concentrations of atropine and ephedrine to dilate their pupil

ix.Route of drug administration:

I.V route dose smaller than oral route - Magnesium sulfate:
Orally –purgative
Parenterally –sedative
Locally –reduces inflammation.

x.Biorhythm: (Chronopharmacolgy)
Hypnotics –taken at night
Corticosteroid –taken at a single morning dose

xi.Psychological state: Efficacy of drugs can be affected by patients’

beliefs, attitudes and expectations  particularly applicable to centrally
acting drugs  in some patients’ inert drugs - (placebo) may produce
beneficial effects equivalent to the drug, and may induce sleep in
insomnia.

xii.Presence of diseases/pathological states: Drug may aggravate

underlying pathology
Hepatic disease may slow drug metabolism
Renal disease may slow drug elimination
Acid/base abnormalities may change drug absorption or
elimination
Severe shock with vasoconstriction delays absorption of drugs
from S.C. or i.m
Drug metabolism in hyperthyroidism is enhanced where as in
hypothyroidism, it is diminished.

xiii.Cumulation: Any drug will cumulate in the body if rate of

administration is more than the rate of elimination e.g.: digitalis,
heavy metals etc.

xiv.Genetic factors:
Lack of specific enzymes
Lower metabolic rate
 Acetylation
 Plasma cholinesterase (Atypical pseudo cholinesterase)
 G-6PD Glucuronide conjugation
xv.Tolerance: It means requirement of a higher dose of the drug to
produce an effect, which is ordinarily produced by normal
therapeutic dose of the drug. Usually seen with alcohol, morphine,

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barbiturates, CNS active drugs. Drug tolerance may be: Natural, Acquired,
Cross tolerance, Tachyphylaxis (ephedrine, tyramine, nicotine) or Drug
resistance

Reverse tolerance: Same amount of drug produces increase

pharmacological response. Cocaine, amphetamine, rats- increase motor
activity

Acquired tolerances: Occurs due to repeated use of drug under 3

processes Pharmacokinetic tolerances, Pharmacodynamics tolerance and
Acute tolerance

Pharmacokinetic tolerances: Repetitive administration causes decrease

absorption or increase metabolism e.g. Alcohol decrease Absorption of
Barbiturates increases its own metabolism

Pharmacodynamics tolerance

i. Down regulation of receptors

ii. Impairment in signal transduction
iii. Example: Morphine, caffeine, nicotine.

Acute tolerance: Tachyphylaxis: Acute development of tolerance after

a rapid and repeated administration of a drug in shorter intervals
Example; Ephedrine, tyramine. Monday disease. - Nitro glycerine taken
on Monday, by Tuesday workers get headache, after they get tolerances.
After holiday (Sunday) they get again headache.

Cross tolerances: Cross tolerance among drugs belonging to same

category. Morphine, Heroin and Narcotic etc.

3.13 Other Effects of Drugs in Man: By interactions in many

ways:

Alterations in receptors responsiveness

In the short term, most receptor-mediated responses are altered by

changing the local concentration of agonist around the receptors. It is now
recognised that, in the longer term, it is possible for changes to occur in
the response of the tissue to a given concentration of agonist which can be
attributed to altered receptor function. These changes (loosely termed ‘up-
regulation’ and ‘down-regulation’) may involve alterations in receptor
numbers on the cell surface or in the coupling of receptor occupation to
the intracellular response. Down-regulations is usually seen in response to
chronic receptor over stimulation as a result of long-term administration
of a drug (exogenous agonist) or in a disease process (endogenous

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agonist). In some cases, this can occur quickly, leading to the phenomenon
of tachyphylaxis, in which repeated administration of a drug is associated
with rapidly diminishing efficacy. Adaptive down-regulations is a
potential disadvantage of developing partial agonist drugs for therapeutic
use-the full receptor occupancy required for a response makes down –
regulation more likely.

In Parkinson’s disease, the term on-off phenomenon is used to describe

the rapid swing form mobility to immobility that occurs some hours after
administration of L-dopa. It has been attributed to down-regulation of
dopaminergic receptors in the brain following prolonged treatment with L-
dopa. Which renders the extrapyramidal pathways usually sensitive to the
falling concentrations of dopamine.

In patients will pheochromocytoma with high endogenous catecholamine

concentrations, receptor numbers are down-regulated, leading to a relative
insensitivity to catecholamine.

In automatic neuropathy, receptor up-regulation renders the

cardiovascular system hypersensitive and exaggerated responses to
catecholamine may occur.

3.14 Assaying Receptor Binding

Assays for receptors are designed to detect binding sites, not all of which
are coupled to a signal. Most assays use radiolabelled ligand and measure
the amount of radioactivity bound to cell membranes, whole cells or tissue
sections fixed to a microscope slide. Nonspecific binding can be assessed
by displacing the radiolabelled ligand by addition of large quantities of
unlabelled ligand. This procedure exploits a fundamental property of
receptor binding – that it is saturable, unlike nonspecific binding.
Mathematical manipulation of the data allows the number of receptors and
their affinities to be calculated; however, these calculations are often
inaccurate when high-affinity and low-affinity binding sites are present,
and is preferable to use a reiterative computer programmer to analyses the
raw data.

In receptor autoradiography, images are obtained by exposing section of

radiographic film after incubation and washing steps. Various image
analysis programs allow Colour-coded pictures to be obtained after
subtraction of the nonspecific image form the total binding. Another
example of receptor up-regulation is the use of 3-bydroxy-3-
methylglutaryl coenzyme A inhibitor to lower plasma cholesterol
concentrations. These drugs inhibit the rate-limiting enzyme in the
synthesis of cholesterol in hepatocytes, promoting increase and expression
of receptors for low-density lipoprotein (LDL) particles. As a

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consequence, the rate of uptake of cholesterol-laden LDL particles from

the circulations is increase and the plasma cholesterol concentration is
reduced. Sometimes, receptor responses are regulated by changes in the
coupling of receptor occupation of intracellular signalling. Chronic β-
adrenoceptor blockade potentialities the response of the adenylate cyclase-
cAMP system and consequently up-regulates the response to other
receptors that are linked to it.

3.14.1 Selectivity

Receptors are usually subtyped on the basis of their selectivity for agonist
selectivity is determined by the ratio of EC50 at the two receptor subtypes.
In the case of β-adrenoceptor, the concentration of noradrenaline
(norepinephrine) required to cause Broncho dilatation (β2) is ten times
higher than that required to cause tachycardia (β1); therefore, the
selectivity of noradrenaline (norepinephrine) for β1-receptors with respect
to β2-receptors is 10.

Antagonist selectivity is measured as the relative shift of the agonist dose-

response curves achieved by a single dose of antagonists infecting
responses mediated through the two receptors. For example, if the non-
selective β-adrenoceptor agonist isoprenaline was used in the situation
above, the concentration of atenolol achieved in the bloodstream after
administration of a 50mg dose would shift the dose-response curve at the
bronchus by only 10% of that at the heart, giving selectivity for β1-
receptors of 10. Thus, a ten times greater concentration of atenolol is
required to produce a shift in the agonist response curve for the lung equal
to that for the heart.

It must be remembered that selectivity for a receptor subtype is only a

relative concept and does not equate with specificity. Drugs with
selectivity for one receptor subtypes can produce a maximum effect at
other subtypes if enough is given. This is particularly important if the
beneficial effects are activated by one receptor subtypes and the unwanted
effects by another; for example, atenolol is considered a β1-selective
adreno receptor antagonist but has some effects but has some effects at β2-
receptors, and is therefore absolutely contraindicated in asthmatic patients
in whom any reduction in β2-mediated bronchodilator may be dangerous.
Selectivity is useful in clinical practice only when the ratio of the impact
of the drug at the two receptor sites is 100 or more. When selectivity is
lower, it is difficult to predict drug doses that will exploit the difference in
subtype’s activity. Selectivity is most likely to be achieved at the lowest
effective dose.

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3.14.2 Practice points

Many drugs are used clinically at the top of their dose-response curve;
thus, increasing the drug dose does not increase the response and may only
expose the patient to a greater risk of side-effects – it may be possible to
reduce a drug dose to prevent unwanted side-effects without a significant
reduction in the response.

-Drugs that are partial agonists produce significant of a full agonist; in the
presence of full agonist, the same drug used at the same dose may produce
the opposite response because it competes for receptor binding with the
more effective agonist.

i.-Receptor-medicated responses can adapt to chronic exposure to

agonists or antagonists by down-regulation or up-regulations or
receptor function
ii.-Selectivity of an agonist or antagonist between two receptors
subtypes is only ‘relative’ and is manifest

3.11 Therapeutic window

Therapeutic window: Optimal therapeutic range of plasma

concentrations at which most of the patients experience the desired effect.
It is also called Therapeutic range. It is the gap between Sub optimal drug
level and Toxic drug level in a narrow concentration range above which
the drug is active at both receptors.

3.15 Drug Monitoring

Therapeutic drug monitoring is defined as the use of assay procedures for

determination of drug concentrations in plasma, and the interpretation and
application of the resulting concentration data to develop safe and
effective drug regimens. If performed properly, this process allows for the
achievement of therapeutic concentrations of a drug more rapidly and
safely than can be attained with empiric dose changes. Together with
observations of the drug’s clinical effects, it should provide the safest
approach to optimal drug therapy. The usefulness of plasma drug
concentration data is based on the concept that pharmacologic response is
closely related to drug concentration at the site of action. For certain drugs,
studies in patients have provided information on the plasma concentration
range that is safe and effective in treating specific diseases—the
therapeutic range (Figure 1-7). Within this therapeutic range, the desired
effects of the drug are observed. Below it, there is greater probability that
the therapeutic benefits are not realized; above it, toxic effects may occur.
No absolute boundaries divide sub-therapeutic, therapeutic, and toxic drug
concentrations. A grey area usually exists for most drugs in which these

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concentrations overlap due to variability in individual patient response.

Numerous pharmacokinetic characteristics of a drug may result in
variability in the plasma concentration achieved with a given dose when
administered to various patients (Figure 1-8). This inter-patient variability
is primarily attributed to one or more of the following:

i. Variations in drug absorption

ii. Variations in drug distribution
iii. Differences in an individual’s ability to metabolize and eliminate
the drug (e.g., genetics)
iv. Disease states (renal or hepatic insufficiency) or physiologic states
(e.g., extremes of age, obesity) that alter drug absorption,
distribution, or elimination
v. Drug interactions

Therapeutic monitoring using drug concentration data is valuable when:

i. A good correlation exists between the pharmacologic response

and plasma concentration. Over at least a limited
concentration range, the intensity of pharmacologic effects
should increase with plasma concentration. This
relationship allows us to predict pharmacologic effects with
changing plasma drug concentrations (Figure 1-9).
ii. Wide inter-subject variation in plasma drug concentrations results
from a given dose.
iii. The drug has a narrow therapeutic index (i.e., the therapeutic
concentration is close to the toxic concentration).
iv. The drug’s desired pharmacologic effects cannot be assessed
readily by other simple means (e.g., blood pressure
measurement for antihypertensive).

The value of therapeutic drug monitoring is limited in situations in which:

i. There is no well-defined therapeutic plasma concentration range.

ii. The formation of pharmacologically active metabolites of a drug
complicates the application of plasma drug concentration data to
clinical effect unless metabolite concentrations are also considered.
iii. Toxic effects may occur at unexpectedly low drug concentrations
as well as at high concentrations.
iv. There are no significant consequences associated with too high or
too low levels.

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4.0 CONCLUSION

In this unit, you have learnt the description of the principles governing
drug actions in humans and the principles of receptor theory, identifying
different types of drug targets and their relevant use. The difference
between potency and efficacy, drug agonist and antagonist and factors
modifying drug action in man.

5.0 SUMMARY

Pharmacodynamics refers to the relationship between drug concentration

at the site of action and the resulting effect, including the time course and
intensity of therapeutic and adverse effects. The effect of a drug present at
the site of action is determined by that drug’s binding with a receptor. This
can occur either extracellular, cellular or intracellular.

The expression of an individual’s response to increasing doses of a given

drug is known as graded dose response. The relative measure of the
amount of a drug required to produce a specified level of response (e.g.,
50%) compared with other drugs that produce the same effect via the same
receptor mechanism is called Potency of a drug. The potency of a drug
is determined by the affinity of a drug for its receptor and the amount of
administered drug that reaches the site of action, whereas efficacy of a
drug is the term used to describe the extent to which a drug can produce a
response when all available receptors or binding sites are occupied (i.e.
Emax on the dose–response curve).

Optimal therapeutic range of plasma concentrations at which most of the

patients experience the desired effect is also called Therapeutic range
(Therapeutic window). It is the gap between Sub optimal drug level and
Toxic drug level.

Many factors can modify the effects of drugs in man. Individuals differ
both in the degree and the character of the response that a drug may elicit.
Therapeutic drug monitoring which is defined as the use of assay
procedures for determination of drug concentrations in plasma. The
interpretation and application of the resulting concentration data to
develop safe and effective drug regimens.

SELF ASSESSED EXERCISES

i. List the various types of G- proteins.

ii. Discuss the concept of receptor regulatory theory in relation to drug
interaction.

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6.0 TUTOR- MARKED ASSIGNMENT

1. Main sites of drug actions (receptors, enzymes... etc.)

2. Elaborate, with examples, on your understanding of the following
terms with respect to drug action (pharmacodynamics):

(a) Competitive vs. non-competitive antagonism

(b) Receptor selectivity vs. specificity
(c) Inhibition of carrier molecules

3. From your pharmacodynamics and drug-receptor interactions

define: Efficacy, potency, therapeutic index, graded dose
response, quantal dose-response, and spare receptors. Give
examples and graphical representation whenever possible.
4. Briefly discuss the following pharmacological concepts, using
examples where appropriate:
(a) Receptor down regulation
(b) Therapeutic index
5. Write about the factors modifying drug action.

7.0 REFERENCES/FURTHER READING

Farinde, A. (April2020).Overview of Pharmacodynamics. MSD Manuals.

Retrieved from https://www.msdmanuals.com/home/drugs/drug-
dynamics/drug-action.

Ratain, M.J., Plunkett, W.K Jr., (2003). General Mechanisms of Drug

Action. In: Kufe DW, Pollock RE, Weichsel Baum RR, et al.,
editors. Holland-Frei Cancer Medicine. (6th ed.). Hamilton (ON):
BC Decker; Available from
https://www.ncbi.nlm.nih.gov/books/NBK13703/.

Goodman & Gilman’s The Pharmacological Basis of

Therapeutics by. Joel Griffith Hardman, Lee E. Limbird, Alfred G.
Gilman. (10th ed.). McGraw-Hill Professional); 1462(1st ed.).
(1994).

Rang, H., Dale, M., Ritter, J. & Flower, R (2007). Rang &Dale’s
Pharmacology (6th ed.). London, UK: Churchill Livingstone.

Unwin, N. (2005). Refined structure of the nicotinic acetylcholine

receptor at 4A resolution. J Mol Biol 346: 967–989.

DiPiro, J.T. (ASHP, 2010) Concepts in Clinical Pharmacokinetics:

introduction to Pharmacokinetics and Pharmacodynamics. Pp1

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113. Retrieved
from.https://books.google.com.ng/books/about/Concepts_in_Clini
cal_Pharmacokinetics.html?id=vMI_cPtEqdQC&source=kp_book
_description&redir_esc=y.

Bourne, H.R.& Roberts, J.M. (1992). Drug receptors and

pharmacodynamics. In: Katzung (5th Ed.) “Basic and Clinical
Pharmacology,” Chapter 2, pp. 10-34.

Introduction to Pharmacology. Online Medical Courses, From Harvard

Medical. Retrieved from. School.
https://www.googleadservices.com.

Introduction to Pharmacology
https://med.libretexts.org/Bookshelves/Pharmacology_and_Neuro
science.

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UNIT 2 MODE OF ACTION OF ANTIMICROBIAL DRUGS

CONTENTS

1.0 Introduction
2.0 Objectives
3.0 Main Content
3.1 Definition of terms
3. 2 Antimicrobials
3.2.1 Sources of Antimicrobials
3.2.2Features of Antimicrobial Drugs
3.3 Antibacterial Drugs
3.4 Antifungal
3.5 Antiviral
3.6 Anticancer
3.7 Antiprotozoal
4.0 Conclusion
5.0 Summary
6.0 Tutor- Marked Assignment
7.0 References/Further reading

1.0 INTRODUCTION

Antimicrobial compounds include antibacterial, antiviral, antifungal and

antiprotozoal agents. Antimicrobial Chemotherapy Control or the
destruction of microorganisms that reside within the bodies of humans &
other animals is of tremendous importance. This unit introduces the
principles of chemotherapy & discusses the ideal characteristics for
successful chemotherapeutic agents. The course unit also presents
characteristics of some commonly used antibacterial, antifungal, and
antiviral drugs and mechanism of antimicrobial resistance and rational use
of antibiotics.

2.0 OBJECTIVES

By the end of this unit, you will be able to:

 define terms use in antimicrobial chemotherapy

 state types and sources of antimicrobial chemotherapy
 identify the basic Mechanisms of action of antimicrobial
 explain the mechanisms of antimicrobial resistance
 give the strategies for Avoiding Resistance
 describe the rational use of antimicrobial chemotherapy

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3.0 MAIN CONTENT

3.1 Definition of Terms

i. Antimicrobial Drugs: The word antimicrobial was derived from

the Greek words anti (against), mikros (little) and bios (life) and
refers to all agents that act against microbial organisms. This is not
synonymous with antibiotics, a similar term derived from the Greek
word anti (against) and biotikos (concerning
life). An ANTIMICROBIAL is any substance of natural,
semisynthetic or synthetic origin that kills or inhibits the growth of
microorganisms but causes little or no damage to the host.

ii. Antibiotics: By definition, the word “antibiotic” refers to

substances produced by microorganisms that act against another
microorganism. An antibiotic is a low molecular substance
produced by a microorganism that at a low concentration inhibits
or kills other microorganisms.

iii. Antibiotic Resistance: Antibiotic Resistance is defined as micro-

organisms that are not inhibited by usually achievable systemic
concentration of an antimicrobial agent with normal dosage
schedule and / or fall in the minimum inhibitory concentration
(MIC)range. Antibiotic Resistance (DR) = MIC / MCC > Toxic
Plasma Concentration

3.1 ANTIMICROBIALS

Different types of “antimicrobials” include all agents/drugs that act

against all types of microorganisms:

i. Bacteria (Antibacterial) drugs

ii. Fungi (Antifungal) drugs
iii. Protozoa (Antiprotozoan) drugs
iv. Antihelminthic drugs
v. Viruses (antiviral) drugs.

3.1.1 Sources of Antimicrobial Drugs: Most modern antibiotics come

from species of microorganisms that live in the soil. To
commercially produce antibiotic:

vi. Select strain and grow in broth

vii. When maximum antibiotic concentration reached, extract from
medium
viii. Purify
ix. Chemical alter to make it more stable

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3.1.2 Features of Antimicrobial Drugs

i. Selective Toxicity: Cause greater harm to microorganisms than to

host
ii. Chemotherapeutic index: lowest dose toxic to patient divided by
dose typically used for therapy
iii. Activity Against Bacteria: Antimicrobial medications vary with
respect to the range of microorganisms they kill or inhibit
iv. Bacteriostatic: inhibit growth of microorganisms; inhibit or delay
bacterial growth and replication (static drugs stop multiplication;
body’s immune system clears). Examples of such include
tetracyclines, Sulfonamides, and macrolides.
v. Bactericidal: Kill microorganisms hence preferred in
immunocompromised patients e.g. of bactericidal drugs include
aminoglycosides, cephalosporins, penicillins, and quinolones.
vi. Spectrum of Activity
Narrow-spectrum: Some kill only limited range. Narrow-
spectrum antimicrobial Aminoglycosides and Sulfonamides are
only effective against aerobic organisms, while nitroimidazoles are
generally only effective for anaerobes.
Broad-spectrum: While others kill wide range of microorganisms.
Broad-spectrum antimicrobial is active against both Gram-positive
and Gram-negative organisms. Examples include: tetracyclines,
phenicols, fluoroquinolones, “third-generation” and “fourth-
generation” cephalosporins.
vii. Effects of Combining Drugs: Combinations are sometimes used
to fight infections
Synergistic: action of one drug enhances the activity of another or
vice versa. Antagonistic: activity of one drug interferes with the
action of another.
viii. Adverse Effects
Allergic Reactions: some people develop hypersensitivities to
antimicrobials
Toxic Effects: some antimicrobials are toxic at high concentrations
or cause adverse effects
ix. Suppression of normal flora: when normal flora killed, other
pathogens may be able to grow to high numbers
x. Resistance to Antimicrobials: Some microorganisms inherently
resistant to effects of a particular drug. Other previously sensitive
microorganisms can develop resistance through spontaneous
mutations or acquisition of new genes (more later).
xi. Concentration dependent: Maximum kills depends on
concentration achieved
• High doses as shorter infusions or lesser frequency are better
• Has post antibiotic effect Time dependent

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• Maximum kills depending on time achieved

• Optimal doses as longer infusions or at higher frequency
• No post antibiotic effect. Minimum bactericidal concentration

3.3 Antibacterial Drugs

i. Inhibit cell wall synthesis: A drug that targets cell walls can
therefore selectively kill or inhibit bacterial organisms. Examples:
penicillin, cephalosporins, bacitracin and vancomycin.
ii. Injury to plasma/Cell membrane: Cell membranes are important
barriers that segregate and regulate the intra- and extracellular flow
of substances. A disruption or damage to this structure could result
in leakage of important solutes essential for the cell’s survival.
Examples: polymixin B and colistin.
iii. Inhibit protein synthesis: Enzymes and cellular structures are
primarily made of proteins. Several types of antibacterial agents
target bacterial protein synthesis by binding to either the 30S or 50S
subunits of the intracellular ribosomes. Examples:
Aminoglycosides, macrolides, lincosamides, streptogramins,
chloramphenicol and tetracyclines.
iv. Inhibit nucleic acid synthesis: Some antibiotics work by binding
to components involved in the process of DNA or RNA synthesis,
which causes interference of the normal cellular processes which
will ultimately compromise bacterial multiplication and
survival. Examples: quinolones, metronidazole, and rifampin.
v. Inhibit synthesis of essential metabolites: Other antibiotics act on
selected cellular processes essential for the survival of the bacterial
pathogens. For example, both Sulfonamides and trimethoprim
disrupt the folic acid pathway, which is a necessary step for bacteria
to produce precursors important for DNA synthesis. -
Sulfonamides target and bind to dihydropteroate synthase, -
trimethophrim inhibit dihydrofolate reductase; both of these
enzymes are essential for the production of folic acid, a vitamin
synthesised by bacteria, but not humans.

3. 3.1Antituberculosis (TB) drugs

Tuberculosis (TB) is an air-borne infectious disease caused by bacteria,

which primarily affects the lungs. Infection with Mycobacterium
tuberculosis begins when a susceptible person inhales airborne droplet
nuclei containing viable organisms. Tubercle bacilli that reach the alveoli
are ingested by alveolar macrophages. Infection follows if the inoculum
escapes alveolar macrophage microbicidal activity.

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Mycobacterium tuberculosis, the organism that causes tuberculosis

infection and disease, infects an estimated 20 – 43% of the world’s
population with 3 million people worldwide die each year from the disease

TB is both preventable and curable.

Multi-drug resistant (MDR) TB is TB that is resistant to any of the first-

line drugs, specifically Rifampicin and Isoniazid.

Tuberculosis

The World Health Organisation (WHO) declared TB a global emergency

in 1993 and it remains one of the world’s major causes of illness and death.
Tuberculosis is one of the world’s most widespread and deadly illnesses.
More than 90% of new TB cases and deaths occur in developing countries.

Nigeria ranks 10th among the 22 high-burden TB countries in the world.

WHO estimates that 210,000 new cases of all forms of TB occurred in the
country in 2010, equivalent to 133/100,000 population? There were an
estimated 320,000 prevalent cases of TB in 2010, equivalent to
199/100,000 cases.

Tuberculosis occurs disproportionately among disadvantaged populations

such as the malnourished, homeless, and those living in overcrowded and
sub – standard housing.

TB poses significant challenges to developing economies as it primarily

affects people during their most productive years.

The proportion of TB patients tested for HIV was 79% in 2010, with a
25% TB-HIV co-infection rate. 59% of these patients were started on
cotrimoxazole (CPT) prophylaxis and 1.8% provided with isoniazid (IPT)
prophylaxis.

The proportion of TB/HIV co-infected patients on anti-retro viral (ARV)

therapy was 33% in 2010.

The proportion of HIV cases that developed TB was 4% in 2010 and 3%

in 2011.

Once infection is established, lymphatic and haematogenous

dissemination of tuberculosis typically occurs before the development of
an effective immune response. This stage of infection, primary
tuberculosis is usually clinically and radiologically silent.
In most persons with intact cell – mediated immunity, T cells and
macrophages surround the organisms in granulomas that limit their

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multiplication and spread. The infection is contained but not eradicated,

since viable organisms may lie dormant within granulomas for years to
decades.

Tuberculosis
Symptoms and Signs: Malaise, Anorexia, Weight loss, Fever, Night
sweats, Chronic cough, blood with sputum and Rarely, dyspnea.

3.3.2Mycobacterial Drugs

Mycobacteria are intrinsically resistant to most antibiotics. They grow

slowly compared with other bacteria, antibiotics that are most active
against growing cells are relatively ineffective. so, that’s why we use
combination of drugs. Mycobacterial cells can also be dormant and thus
completely resistant to many drugs or killed only very slowly.
The lipid rich mycobacterial cell wall is impermeable to many agents (e.g.
drugs).

Mycobacterial species are intracellular pathogens, and organisms residing

within macrophages are inaccessible to drugs that penetrate these cells
poorly.

Combinations of two or more drugs are required to overcome these

obstacles and to prevent emergence of resistance during the course of
therapy.

The response of mycobacterial infections to chemotherapy is slow, and

treatment must be administered for months to years, depending on which
drugs are used.

First-line drugs:

i. Rifampin,
ii. Isoniazid (INH),
iii. Pyrazinamide,
iv. Ethambutol, and
v. Streptomycin

These drugs are the first-line agents for the treatment of tuberculosis.
Isoniazid and Rifampin are the two most active drugs.

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i. ISONIAZID (INH)

Isoniazid is the most active drug for the treatment of tuberculosis caused
by susceptible strains. It is small (MW137) and freely soluble in water,
with structural similarity to pyridoxine = (Vit.B6)
It is bactericidal for actively growing tubercle bacilli. It is less effective
against atypical mycobacterial species.

Mechanism of Action: INH, a prodrug is activated by KatG enzyme, a

mycobacterial catalase peroxidase enzyme. It penetrates into macrophages
and is active against both extra- and intracellular organisms.

The activated form of isoniazid forms a covalent complex with an acyl

carrier protein (AcpM) and KasA, a ß-ketoacyl carrier protein synthetase,
which blocks mycolic acid (Mycolic acid, essential component of cell
wall) synthesis and kills the cell.

USES: All infections caused tuberculosis, along with other antitubercular

drug.

Dosage: 5mg/kg/day, usually up to 300mg/day per oral adults, or 900mg

twice/week. INH is the primary drug used to treat latent TB, caseous
disease, tuberculous meningitis, Pyridoxine 10 -20mg od will also be
needed to prevent peripheral neuropathy

Adverse Reactions of INH: The incidence and severity of untoward

reactions related to dosage and duration of administration.
Direct toxicity - Isoniazid induced hepatitis (most common major toxic
effect). The risk of hepatitis is higher in alcoholics, pregnancy and
postpartum period.

Peripheral neuropathy in 10-20% of patients given dosages greater than

5mg/kg/day but infrequently seen with the standard 300mg adult dose. It
is more likely to occur in slow acetylators and patients with malnutrition,
alcoholism, diabetes and AIDS. Neuropathy is due to relative deficiency
of pyridoxine.

CNS toxicity, which is less common includes. Optic neuritis or atrophy,

Various mental disturbances (memory loss, psychosis), dizziness, ataxia
and seizures.

Immunologic reactions - Fever, Skin rashes and drug induced systemic

erythematous.

Miscellaneous adverse effects - Provocation of pyridoxine deficiency

anaemia, tinnitus and gastrointestinal discomfort.

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Drug interactions- isoniazid can reduce the metabolism of phenytoin.

i.RIFAMPIN
Rifampin is a semisynthetic derivative of rifamycin, an antibiotic
produced by Streptomyces Mediterranean. It is active in vitro
against gram positive and gram-negative cocci, some enteric
bacteria, mycobacteria and chlamydia.

Mechanism of Action

Rifampin acts by binds to theβ subunit of bacterial DNA–dependent

RNA polymerase and thereby inhibits RNA synthesis in bacteria but
not mammalian cells. Human RNA polymerase does not bind torifampin
and is not inhibited by it. Rifampin is bactericidal for mycobacteria. It
readily penetrates most tissues and phagocytic cells.

Resistance results from any one of several possible point mutations in

rpoB, the gene for the β subunit of RNA polymerase. These mutations
result in reduced binding of rifampin to RNA polymerase.

USES: It can kill organisms that are poorly accessible to many other
drugs, such as intracellular organisms and those sequestered in abscesses
and lung cavities.

Mycobacterial infections: Rifampin 10mg/kg/day (usually600mg/day),

orally must be administered with isoniazid or other ant tuberculosis drugs
to patients with active tuberculosis to prevent emergence of drug resistant
mycobacteria.

Atypical mycobacterial infections and Leprosy. In these two conditions

rifampin 600mg daily or twice weekly for 6 months is effective in
combination with other agents.

As alternative of isoniazid in prophylaxis of latent tuberculosis 600mg/day

as a single agent for 4 months, in patients with isoniazid-resistance or
rifampin-susceptible bacilli.

In exposure to a case of active tuberculosis caused by an isoniazid

resistant, rifampin susceptible strain.

To eliminate meningococcal carriage,600mg, twice daily, for 2 days.

To eradicate staphylococcal carriage with combination to another agent.
Osteomyelitis and prosthetic valve endocarditis caused by staphylococci
in combination therapy with another agent.

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Adverse effects: Rifampin imparts a harmless Pink to frank red (blood –

like) colour to urine, sweat, tears and contact lenses.

Less common adverse effects include facial flushing, itching, rashes or

eye irritations can occur 2 -3 hours after a dose.

Cholestatic jaundice

Flu –like syndrome at high doses characterised by fever, chills, myalgias,

anaemias, thrombocytopenia and acute tubular necrosis

Hepatitis: Liver damage and death

Nephritis: Acute renal failure

Drug interactions: Rifampin strongly induces most cytochrome p450

isoforms (3A4,2C9,2D6,2C19,1A2).Anticoagulants, cyclosporine,
anticonvulsants, contraceptives, methadone, protease inhibitors, non-
nucleoside reverse transcriptase inhibitors. Administration of rifampin
results in significantly lower serum levels of these drugs.

NB

HIV patients, Women on contraceptives and warfarin requiring

rifampicin, alternative treatment should be sort

ii.Ethambutol
Mechanism of action:It is bacteriostatic to mycobacteria by an
unknown mechanism. However, it is believed to inhibit
mycobacterial arabinosyl transferases. Arabinosyl transferases are
involved in the polymerization reaction of arabinoglycan, an
essential component of the mycobacterial cell wall.
Its action on the bacterial cell wall integrity may be related to its
action as a chelating agent, by inactivation of bacterial zinc and
copper.
Resistance to ethambutol is due to mutations resulting in
overexpression of emb gene products or within the emb B structural
gene. This resistance to ethambutol emerges rapidly when used
alone, therefore it is always given with other antitubercular agents.

Uses:Tuberculosis: Ethambutol hydrochloride 15-25mg/kg/d is usually

given as a single daily dose in combination with isoniazid or
rifampin.

Adverse effects: Retrobulbar (optic) neuritis resulting in loss of visual

acuity and ocular scotoma or Colour (red green colour blindness).

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Usually occur at doses of 25mg/kg/day continued for several

months.

Precaution & contraindication: Periodic visual acuity testing is

desirable if the 25mg/kg/day dosage is used. It is relatively
contraindicated in children too young to permit assessment of
visual acuity and red green colour discrimination.

iii. Pyrazinamide (PZA)

Pyrazinamide (PZA) is a relative of nicotinamide, stable and

slightly soluble in water.

It is inactive at neutral PH, But at PH 5.5 it inhibits tubercle bacilli,

and some other mycobacteria at concentrations of approximately
20mcg/ml.

Mechanism of Action: The drug target and mechanism of action are

unknown. The drug is taken up by macrophages and exerts its activity
against mycobacteria residing within the acidic environment of
lysosomes. Pyrazinamide is converted to pyrazinoic acid, the active form
of the drug, by microbial pyrazinamide, which is encoded by pncA.

Resistance may be due to impaired uptake of pyrazinamide or mutations

in pncA that impair conversion of pyrazinamide to its active form.

Uses:Pyrazinamide is an important front-line drug used in conjunction

with isoniazid & rifampin in short course (i.e. 6 months) regimens as a
sterilizing agentactive against residual intracellular organisms that may
cause relapse.

Adverse Effects: Hepatotoxicity (in 1-5% of patients-major adverse

effect).

Hyperuricemia (it may provoke acute gouty arthritis).

Nausea, vomiting, & drug fever.

iv.Streptomycin
Streptomycin was isolated from a strain of Streptomyces griseus.
Mechanism of action: Like all aminoglycosides, streptomycin
irreversibly inhibits bacterial protein synthesis. Protein synthesis is
inhibited in at least three ways; interference with the initiation complex of
peptide formation, misreading of mRNA, which causes incorporation of
incorrect amino acids into the peptide, resulting in a non-functional or
toxic protein and breakup of polysomes into non-functional monosomes.

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Streptomycin penetrates into cells poorly and is active mainly against

extracellular tubercle bacilli. Streptomycin crosses the blood brain barrier
and achieves therapeutic concentrations with inflamed meninges.

Mechanism of resistance:

 Production of a transferase enzyme or enzymes inactivates the

aminoglycosides by acetylation, adenylation or phosphorylation
(major action).
 Impaired entry of drug into the cell.
 The receptor protein on the 30s ribosomal subunit may be deleted
or altered as a result of mutation.

Uses: Tuberculosis: Streptomycin is used when an injectable drug is

needed, principally in individuals with severe, possibly life-threatening
forms of tuberculosis e.g., meningitis and disseminated disease.

Adverse Effects: Ototoxicity and Nephrotoxicity are common. Toxicity

is dose related and the risk is increased in elderly

Alternative Second-Line Drugs for Tuberculosis

v.ETHIONAMIDE

Ethionamide is chemically related to isoniazid. It is poorly water soluble

and available only in oral form.

Mechanism of action: Ethionamide blocks synthesis of mycolic acids in

susceptible organisms.

Adverse effects: Intense gastric irritation, Neurologic symptoms and

Hepatotoxicity. Neurologic symptoms may be alleviated by pyridoxine.

vi.CAPREOMYCIN

Capreomycin is an antibiotic from streptomyces capreolus

Mechanism of action: It is a peptide protein synthesis inhibitor.

Capreomycin is an important agent for the treatment of drug resistant
tuberculosis.
Strains of M tuberculosis that are resistant to streptomycin or amikacin
usually susceptible to capreomycin

Adverse drug reactions: Nephrotoxicity, Ototoxicity – tinnitus,

deafness, vestibular disturbance may occur and Local pain & sterile
abscesses due to injection.

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i. CYCLOSERINE

ii. Cycloserine is an antibiotic produced by streptomyces

orchidaceous, a structural analogy of D- alanine.

iii. Mechanism of action: It inhibits the incorporation of D- alanine

into peptidoglycan pentapeptide by inhibiting alanine racemase,
which converts L-alanine to D- alanine, and D- alanyl-D –alanine
ligase (finally inhibits mycobacterial cell wall synthesis).
iv. Uses: Cycloserine used exclusively to treat tuberculosis caused by
mycobacterium tuberculosis resistant to first line agents
v. Adverse effects: CNS dysfunction, including depression and
psychotic reactions (Peripheral neuropathy, Seizures, and Tremors
etc.).
Pyridoxine 150mg/day should be given with Cycloserine because
this ameliorates neurologic toxicity.

vi. Amino salicylic acid (PAS): Amino salicylic acid is a folate

synthesis antagonist that is active almost exclusively against
mycobacterium tuberculosis. It is structurally similar to p-
aminobenzoic acid (PABA) and the Sulfonamides.
vii. Adverse effects:Peptic ulcer and gastric Hemorrhage.
Hypersensitivity reactions (manifested by fever, joint pain,
hepatosplenomegaly, hepatitis, granulocytopenia, adenopathy)
often occur after 3-8 weeks of amino salicylic acid therapy.

viii. Fluoroquinolones: (Ciprofloxacin, Levofloxacin, Gemifloxacin,

moxifloxacin) can inhibit strains M tuberculosis. The eye are also
active against atypical mycobacteria.
Moxifloxacin is the most active against M tuberculosis.
Fluoroquinolones are an important addition to the drugs available
for tuberculosis, especially for strains that are resistant to first line
agents.
ix. Mechanism of action: They inhibit bacterial DNA synthesis by
inhibiting bacterial topoisomerase II (DNA Gyrase) and
topoisomerase IV.
Inhibition of DNA Gyrase prevents the relaxation of positively
supercoiled DNA that is required for normal transcription and
replication. Inhibition of topoisomerase IV interferes with
separation of replicated chromosomal DNA into the respective daughter
cells during cell division.
Adverse effects: Nausea, vomiting, diarrhoea (most common), Headache,
dizziness, insomnia, skin rash, photosensitivity, Damage growing
cartilage and cause an arthropathy and Tendinitis, tendon rupture.

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vii. Kanamycin & Amikacin: Kanamycin has been used for the
treatment of tuberculosis caused by streptomycin – resistant strains,
but the availability of less toxic alternatives (e.g. capreomycin and
amikacin) has rendered it obsolete.
Amikacin’s role in the treatment of tuberculosis has increased with
the increasing incidence and prevalence of multidrug resistant
tuberculosis.
Prevalence of amikacin resistant strains is low and most multidrug
–resistant strains remain amikacin susceptible. Amikacin is also
active against atypical mycobacteria.

USES: Amikacin is indicated for the treatment of tuberculosis suspected

or known to be caused by streptomycin resistant or multi drug
resistant strains.

viii. LINEZOLID: Linezolid has been used in combination with other

second and third line drugs to treat patients with tuberculosis
caused by multi drug resistant strains.

Uses: used as a drug of last resort for infection caused by multi drug
resistant strains that are also resistant to several other first and
second line agents.

Adverse effects: Bone marrow depression, Irreversible peripheral and

optic, neuropathy reported with prolonged use of drug

ix. RIFABUTIN

Rifabutin is derived from rifamycin and is related to rifampin. It

has significant activity against mycobacterium tuberculosis, M
avium- intracellular and mycobacterium fortuitum

Uses: Rifabutin is effective in prevention and treatment of disseminated

atypical mycobacterial infection in AIDS.

As preventive therapy of tuberculosis.

It is a hepatic enzyme inducer of cytochrome P450 enzymes.

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Adverse effects: insomnia, skin -

x. Rifapentine

Rifapentine is an analog of rifampin.It is active against both M

tuberculosis and M avium

Mechanism of action: It is a bacterial RNA polymerase inhibitor.

Rifapentine and its active metabolite, 25 deacetyl rifapentine have an
elimination half-life of 13 hours.

uses: It is indicated for treatment of tuberculosis caused by rifampin-

susceptible strains during the continuation phase only (i.e. after the 2
months of therapy and ideally after conversion of sputum cultures to
negative).

3.3.3 Anti-leprosy drugs

Leprosy is a chronic infectious disease caused by the acid – fast rod

Mycobacterium leprae. The mode of transmission probably is respiratory
and involves prolonged exposure in childhood.

Symptoms and Signs:

onset is insidious, Lesions involve the cooler body tissues: skin,

superficial nerves, nose,pharynx, larynx, eyes, and testicles.
Skin lesions may occur as pale, anaesthetic macular lesions 1 – 10 cm in
diameter. Discrete erythematous, infiltrated nodules 1- 5 cm in diameter;
or a diffuse skin infiltration. Neurologic disturbances are manifested by
nerve infiltration and thickening, with resultant anaesthesia, neuritis and
paranaesthesia. Bilateral ulnar neuropathy is highly suggestive. In
untreated cases, can result in disfigurement due to the skin infiltration and
nerve involvement may be extreme, leading to trophic ulcers, bone
resorption, and loss of digits.

DRUGS USED IN LEPROSY:

i. DAPSONE& OTHER SULFONES: Are used effectively in the

long-termtreatment of leprosy.

Mechanism of action: Dapsone like the Sulfonamides, inhibits folate

synthesis (PABA antagonist). It is bacteriostatic
Resistance can emerge in large populations of M leprae, e.g. in
lepromatous leprosy, if very low doses are given. Combination of
dapsone, rifampin and clofazimine is recommended for initial therapy.

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uses:Leprosy: Tuberculoid leprosy (combine with rifampin),

Lepromatous leprosy (combine with rifampin and clofazimine) and
Prevention and treatment of pneumocystis jiroveci pneumonia in AIDS
patients.

Adverse effects: Haemolysis (in patients having G6PD deficiency),

Methemoglobinemia, GI intolerance, Fever, Pruritus and various rashes.

Erythema nodosum leprosum develops during dapsone therapy of

lepromatous leprosy. Suppressed by corticosteroids or thalidomide

ii. CLOFAZIMINE

Clofazimine is a phenazine dye that can be used as an alternative to

dapsone.

Mechanism of action: Unknown, but may involve DNA binding and &
inhibits template function. Its redox properties may lead to generation of
cytotoxic oxygen radicals that are also toxic to the bacteria. It is
bactericidal.

Adverse effects: Skin discoloration ranging from red brown to nearly

black (major adverse effect), Gastrointestinal intolerance occurs
occasionally (eosinophilic enteritis).

3.4 Antifungal Drugs

Fungal infections are more difficult to treat than bacterial infections,

because the greater similarity between fungi and host limits the ability of
a drug to have a selective point of attack; furthermore, many fungi have
detoxification systems that inactivate drugs

3.4.1 Superficial mycoses: are infections of superficial tissues and can

oftenbetreated by topical application of antifungal drugs such as
Miconazole, Nystatin, and griseofulvin, thereby minimising systemic side
effects

3.4.2 Systemic mycoses: are more difficult to treat and can be fatal;
however, amphotericin B and flucytosine have been used with
limited success; amphotericin B is highly toxic and must be used
with care; flucytosine must be converted by the fungus to an
active form, and animal cells are incapable of this; some
selectivity is possible, but severe side effects have been observed
with both drugs.

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3.4.3 Drug resistant fungal strains: Drug resistant fungal strains are
alsobeginning to emerge.

3.5 Antiviral Drugs

Selectivity has been a problem because viruses use the metabolic

machinery of the host. Antiviral drugs target specific steps of life cycle,
especially enzymes that function in the life cycle (e.g. amantadine,
vidarabine, acyclovir, and azidothymidine). Human interferon is used to
treat some viral infection

3.5.1 Introduction

Rational drug design approaches now dominate the drug discovery

process. HIV infection and AIDS represent one of the first diseases for
which the discovery of drugs was performed entirely via a rational drug
design approach.

3.5.2 HIV life cycle

i. Free Virus
ii. Binding and Fusion: Virus binds cell at two receptor sites
iii. Infection: Virus penetrates cell. Contents emptied into cell.
iv. Reverse transcriptase: single stranded viral RNA is converted into
double stranded DNA by the reverse transcriptase enzyme
v. Integration: viral DNA is combined with the cells own DNA by
integration enzyme
vi. Transcription: when the infected cell divides, the viral DNA is
“read” and long chains of proteins are made.
vii. Assembly: Sets of viral protein chains come together.
viii. Budding: immature virus pushes out of the cell, taking some cell
membrane with it.
ix. Immature virus breaks free of the infected cell
x. Maturation: Protein chains in the new viral particles are sort by the
protease enzyme into individual proteins that combine to
make a working virus.

3.6 Classification of Antiretroviral Agents

i.Nucleoside/Nucleotide ReverseTranscriptase Inhibitors (NRTI’s)-

Zidovudine (AZT, ZDV), Didanosine (ddI), Stavudine (d4T),
Lamivudine (3TC), Abacavir (ABC), Tenofovir (TDF),
Emtricitabine (FTC)
ii.Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) -
Nevirapine (NVP), Delavirdine (DLV, Efavirenz (EFV),
Etravirine (ETR), and Rilpivirine (Edurant)

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iii.Protease Inhibitors (PIs) - Saquinavir- (SQV-HGC), Ritonavir-

(RTV), Indinavir - (IDV), Nelfinavir - (NFV), Saquinavir- (SQV-
SGC), Amprenavir - (APV), Lopinavir/ritonavir - (KAL),
Ritonavir (RTV), Atazanavir - (ATV), Fosamprenavir - (fos-
APV), Tipranavir - (TPV) and Darunavir - (DRV)
iv.Integrase Inhibitors - Raltegravir (RAL), Dolutegravir (DTG)
v.Fusion Inhibitors - Enfuvirtide (T-20, Fuzeon)
vi.Chemokine Receptor Antagonists - Maraviroc (MVC, Selzentry)

3.6.1 Mechanism Action of Antiretroviral Therapy (Art)

The mechanism of action of ART is best understand through their

chemical classifications. They act at different stages of the viral life cycle
best on the nature of their amino acid basis.

The Nucleoside Groups - Also called Nucleoside/Nucleotide Reverse

Transcriptase Inhibitors (NRTIs). These are divided into

Pyrimidines-Thymidine: Zidovudine (AZT) and Stavudine (d4T),

Cytosine: Lamivudine (3TC) and Emtricitabine (FTC)
Purines - Guanosine: Abacavir (ABC),
Adenosine: Didanosine (ddI), Tenofovir (TDF)

NRT are known as the Nukes, Nucleoside analogues or sometimes called

‘backbone of combination therapy. The first group of antiretroviral drugs
are the Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs).
These were the first type of drug available to treat HIV infection in 1987.
NRTIs interfere with the action of an HIV protein called reverse
transcriptase, which the virus needs to make new copies of itself.
Nucleoside Analogs are analog of thymidine, cytosine, adenine, or
guanine, activated intracellularly by phosphorylation by cellular kinases
inside lymphocytes. The triphosphate form acts by competitive inhibition
of HIV-1 reverse transcriptase. Incorporation into HIV DNA results in
chain termination.

All except tenofovir (TDF), does NOT need to be tri-phosphorylated only

di-phosphorylated to active compound. After incorporation of the NRTI,
viral DNA synthesis will be terminated. They prevent the addition of the
natural nucleosides into the DNA strand. This halts the production of new
virions.

NRTI’s mainly undergo renal excretion EXCEPT, Zidovudine (AZT)

undergoes glucuronidation and Abacavir metabolised by alcohol
dehydrogenase.

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3.6.2 Drug specific mode of action and adverse effects

All has tendency to cause Lactic acidosis with hepatic steatosis however,
it’s a rare but serious complication of NRTI therapy. Signs/Symptoms:
Abdominal distention, abdominal pain, nausea, vomiting, diarrhoea,
weight loss, difficulty breathing, generalised weakness and myalgias.
Risk Factors: Stavudine and Didanosine use during pregnancy, Female
gender, Obesity and Prolonged use of NRTIs.

i.Zidovudine (AZT/ZDV): Adverse effects

Chronic AZT therapy may cause nail hyper-pigmentation, myopathy,

hepatic toxicity (with or without steatosis) and lactic acidosis.

Anaemia - (anaemia, neutropenia, thrombocytopenia), may develop as

early as four weeks in about 7% of patients with advanced HIV/AIDS
possibly due to toxic effects of AZT on erythroid stem cells.
This effect is characterised by depletion of bone marrow red cell
precursors, elevated serum erythropoietin levels, and normal serum folate
and vitamin B12 levels.

Do not commence Patient on ZDV if Hb < 8.0 g/dL (PCV <24%)

GI intolerance (hypersalivation, nausea, anorexia, fatigue and abdominal
discomfort).

Other toxicities include: Nausea, insomnia and headache effects,

convulsions and encephalopathy

ii.Didanosine: (ddI)

Didanosine is a synthetic analog of deoxyadenosine. Food decreases

absorption: Take at least 30 minutes before meal, or 2 hrs. after meal or
administered on an empty stomach!

Adverse Effects: Transient / minor Events, Primarily GI-related

(Abdominal cramps and Diarrhoea). EC caps < chewable tabs
Serious Events: Pancreatitis - effect is worse when combined with
hydroxyurea, Painful Neuropathy, Lactic acidosis and Hepatic steatosis.

Avoid use of ddI + d4T à additive toxicities!

iii.Stavudine: (d4T)
It is a thymidine analog, originally development was 4-10 mg/kg, but this
was stopped due to liver toxicity in phase I. 1 mg/kg eventually
approved…hence weight-based dosing.

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Has antagonistic effects when combined with zidovudine (AZT). Major

dose limiting effects are peripheral neuropathy. Chronic toxicity became
significant over time; the drug has been virtually abandoned since 2010 in
Nigeria treatment programme.

Other side effects include; Lipodystrophy - Peripheral fat atrophy, and

ascending motor weakness resembling Guillain-Barre syndrome may
occur. Neuropathy - Numbness, tingling sensation and pain in the feet
sensations worst in the lower than upper limb, usually resolves on stopping
the drug. It is more common in patients with advanced HIV/AIDS, Lactic
acidosis (potentially fatal), Hepatic steatosis - Lactic acidosis with hepatic
steatosis; is worse when d4T is used in combination with ddI. Minor
toxicities: Moderate transaminase elevation, headache, nausea, and skin
rash also seen are Insomnia, anxiety, panic attacks, Monitoring/
management. Periodic serum triglycerides should be monitored; suspicion
of lactic acidosis – measure serum lactate and/or anion gap and serum
bicarbonate; When there are signs of mitochondrial toxicity, stavudine
should be substituted.

iv.Lamivudine (3TC):

It is a cytosine analog Improves. Reduces viral fitness and is an Important

nucleoside analog in HBV treatment

Almost didn’t get developed because of low resistance threshold. Now the
#1 selling anti-HIV drug in the world. First approved combination therapy
– Combivir. Resistance common – M184 mutation. Has benefit noted
when continued in presence of M184 associated with less fit virus and 0.5
log decrease from baseline VL

Side effects Very safe; occasional side effects are – headache and
insomnia. Serious toxicities are rare, and generally well tolerated.
Extensive long-term use in patients with chronic hepatitis B (100 mg
daily). Primary toxicities: Pancreatitis, liver toxicity, Mild peripheral
neuropathy. Minor toxicities: Skin rash, headache.

v.Emtricitabine: It is a fluorinated lamivudine (analog),

Structurally similar to lamivudine. It is Important nucleoside
analogue for HBV treatment.

Adverse effects: Hyper pigmentation of palm and soles Lactic acidosis

and hepatitis.

vi.Zalcitabine: (ddC): It is a cytosine analog – has antiviral activity

against zidovudine sensitive and resistance strains.
Adverse effects: Pancreatitis and Peripheral neuropathy.

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vii.Tenofovir (TDF): Nucleotide analog, Good tolerability, acute and

chronic. Very active against Hepatitis B.

Adverse effects: TDF causes renal failure - Renal Tubular Necrosis,

Hypophosphatemia, Hepatitis B exacerbation, Fanconi’s syndrome (rare).
Other effects may not be serious and may lessen or disappear with
continued use of TDF. include abdominal discomfort, diarrhoea,
dizziness, intestinal gas, headache, and rash.
Avoid in patients with borderline renal dysfunction. Renal dosing
necessary.
Risk factors: Existing renal disease, hypertension, Advanced HIV disease
(AIDS), Concomitant protease inhibitor use and Concomitant nephrotoxic
agents

viii.Abacavir: It is a Guanosine analog

Abacavir adverse effects: Hypersensitivity: Reported rates 3-8% (true

incidence lower) Genetic predisposition HLA B*5701 allele in 94.4%
confirmed cases. Not common in African populations. Onset: 90% within
1st 6 weeks; median: 9 days. Présentation : Fever, rash (diffuse), malaise,
headache, chills, nonspecific GI symptoms (abdominal pain, N/V/D),
respiratory symptoms (dyspnea, tachypnea, pharyngitis).
Stop abacavir! If confirmed, do NOT rechallenge!

Non- Nucleotide Reverse Transcriptase Inhibitors (NNRTIs)

Available NNRTIs in the Nigeria: Nevirapine, Efavirenz, Delavirdine
and Etravirine (TMC-125)

Mechanism of Action: NNRTIs causes non-competitive inhibition with

the viral reverse transcriptase enzyme RT (near catalytic site) but have a
different mechanism of action compared to NRTIs. They Do NOT require
intracellular phosphorylation (unlike NRTIs), but instead bind directly to
the reverse transcriptase enzyme Viral RNA double stranded DNA. The
result RNA unable to undergo transcription to DNA therefore replication
cycle
cannot continue

NNRTI Adverse Effects

Nevirapine: The most common side effect with Viramune is skin rash that
occurs among 17% of patients. The majority of severe rashes occur within
the first four weeks of therapy. A 14 day "lead-in" dose of one 200 mg
tablet daily is used for adults, in combination therapy. This decrease the
rate of rash. The dose can then be increased to 1 tablet bid (if no rash,
hepatitis, or other serious adverse effect)

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Severe, life-threatening hepatotoxicity; Often associated with rash.

Greatest risk in women with CD4 >250 (12-fold greater risk). Increased
risk for men with CD4 > 400 (3-fold greater risk) and greatest risk during
1st 6 weeks (continued risk through 18 weeks)
Hepatotoxicity more common in women with pre-treatment CD4+ cell
counts > 250 cells/mm3, men with CD4+ cell counts > 400 cells/mm3 and
patients co-infected with hepatitis B or C.
Monitor LFTs minimally at baseline, 2 weeks, monthly for the 1st 3
months in all patients

ii.Efavirenz: Many patients taking efavirenz can experience nervous

system symptoms (for example, dizziness, vivid dreams, decreased
concentration, and insomnia) which are generally mild to moderate and
resolve after 2 to 4 weeks.

Rash is also a potential but uncommon side effect Rash (1.7%), increased
transaminase levels should be used with caution in patients who have a
history of psychiatric illness due to side effects including vivid (sometimes
disturbing) dreams, insomnia, somnolence, difficulty concentrating,
dizziness, amnesia, confusion or agitation. Some concern that efavirenz
can trigger cravings in patients with a history of substance abuse. Mental
health and/or substance abuse supports should be available. Should be
taken before bedtime to avoid daytime difficulties

PROTEASE INHIBITORS (PIS)

Mechanism of Action: Protease enzyme is responsible for cleaving

(cutting up) larger polyproteins into structural proteins and reverse
transcriptase enzyme. Protease is needed to form a fully mature, functional
virus that is able to replicate and produce more virus. Protease inhibitors
prevent this enzyme from doing its job in the later steps of the viral life
cycle. Hence PIs, Inhibit HIV-1 protease, prevents cleavage of Gag-Pol
poly-proteins individual structural and enzymatic proteins necessary for
the formation of mature virions are NOT produced. Net

Result: Immature, non-infectious virions are released.

Protease inhibitors provide a beneficial Drug Interaction: Ritonavir

INHIBITS cytochrome p450 metabolism in liver and gut when co-
administered with other PI, result increased absorption (bioavailability)
and Decreased metabolism in liver.

Class adverse effects: Hyperglycemia, lipodystrophy, hyperlipidaemia

(less with atazanavir), increased transaminases.

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PIs Containing Sulfa Moieties (Darunavir, Fosamprenavir and

Tipranavir)
– Above agents are not contraindicated with sulfa allergy
– History of sulfa allergy did not correlate with rash in studies and
patients with history of sulfa allergy were not excluded
– Use with caution
• Metabolic Complications of PIs
– Glucose intolerance: Rare diabetes, diabetic ketoacidosis
– Lipodystrophy: Central obesity, “buffalo hump”, peripheral fat
wasting
– Hyperlipidaemia: Hypertriglyceridemia and/or
hypercholesterolemia
– Osteonecrosis, osteopenia, osteoporosis
– Lipoatrophy
– Facial Wasting

3.6.3 New ARV Targets Against HIV: Fusion Inhibitor

Enfuvirtide (T-20, Fuzeon®): Approved March 2003

Mechanism of Action

Inhibits entry of HIV into the CD4 cell. T-20 binds to glycoprotein gp41
(a protein on the viral membrane). This binding prevents a change in the
shape of the membrane protein and prevents fusion of the virus and the
CD4 cell membrane

Enfuvirtide, unfortunately, is only active when injected subcutaneously

This aspect (in addition to its high cost) severely limits it use in the
correctional setting

Adverse effects:

 injection site Rxn, hypersensitivity (rare)

 resistance: changes in gp41 (cell surface protein)

3.5.7 Integrase Inhibitors

Raltegravir (Isentress™)

Atazanavir must be boosted with ritonavir if used in combination with

tenofovir

Tipranavir - Approved June 2005

Darunavir - Approved June 2006
MK-0518 (Raltegravir) - Investigational integrase inhibitor available via
EAP

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Maraviroc - Investigational CCR5 inhibitor available via EAP

– Approved August 6th, 2007

Tipranavir

– AEs: Hepatotoxicity-monitor LFTs, closely, rash (8-14%) of

patients, diarrhoea, nausea, vomiting, rare cases of intracranial
haemorrhage
– Caution with sulfa allergy
Darunavir
• Patient Counselling Points
– Take with food
– AEs: Rash (7%), abdominal pain, constipation, headache
– Caution with sulfa allergy

3.6.4 ARV Drug Interactions

“The modification of the effect of one drug by the prior or concomitant

administration of another.”

PIs and NNRTIs

Primarily metabolised by the cytochrome P450 3A4 (CYP3A4) enzyme

system., hence inhibit or induce the CYP450 enzyme system
Clinically Significant Drug Interactions – Due to Effect on
Antiretrovirals

i. Rifampin, Phenytoin, phenobarbital, carbamazepine: Decrease PI

and NNRTI levels?
ii. Ketoconazole: Increase in NVP concentrations by 30% and
Decrease in ketoconazole concentrations by 40-60%.
iii. St. John’s Wort: Concern with other herbal products
a. Clinically Significant Drug Interactions – Concern for the
Co-Administered Drug
iv. Warfarin: Often PIs decrease potency of warfarin – HIGHER
warfarin doses needed

3.7 Overview of Cancer Chemotherapeutic Agents

3.7.1 Introduction

Cancers account for 20-25% of deaths in clinical practices. In the US,

cancer is the 2nd cause of death highest cause of death due to cardiac
disease. Result from alteration of DNA within the cells.

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Human body contains 5x1013 cells. Tumour becomes clinically detectable

when there is a mass of 109 cells (1g). About 109 new cells are
manufactured in the body through cell division daily. This must be
balanced by an output of similar number.

Table 29: Cancers with 5 years’ survival Rate

Types of Cancer Percentage of 5 years
survival
Childhood acute lymphoblastic Leukaemia 50 -80
Adult acute lymphoblastic Leukaemia 20 -60
childhood Myeloblastic Leukaemia AML 20 -60
Adult acute myeloblastic Leukaemia 10 -20
AAML
Breast Cancer 5 -20
Hodgkin’s Lymphoma 40 -80

3.7.2 Goals of Cancer Chemotherapy

Goals of Cancer Chemotherapy: Cure induction of Remission: cure or

induction of prolonged remission so that macroscopic and microscopic
features of cancer disappear, though disease is known to persist e.g. in
Acute lymphoblastic leukaemia, Wilm’tumours, Ewing’s sarcoma in
children, Hodgkin’s Lymphoma, testicular teratoma and choriocarcinoma.

Palliation: Shrinkage of evident tumour, alleviation of symptoms &

prolongation of life. E.g. in breast cancer, Ovarian canacer,
endocarcinoma, CLL, CML Small cell cancer of the lungs & Non-Hdgkins
Lymphoma

Insensitive or less sensitive: but may prolong life. Carcinoma

oesophagus, cancer of stomach, squalors cell carcinoma of lung,
melanoma, Panreatic cancer, melonomasand colorectal cancer

i. Treatment Options for malignancies: Chemotherapy is the use

of drugs to inhibit or kill proliferating cancer cells, while leaving
host cells unharmed, or at least recoverable.4 - basic treatment
options of malignancies; Surgery, Radiotherapy, chemotherapy and
Immunotherapy and Gene therapy (including biological response
modifiers {BRMs}).
Surgery is the most effective treatment of cancer but it is ineffective
for metastasized or disseminated tumours. Radiation is the next
most effective treatment after surgery.
Rapidly dividing cells are the most sensitive. It is useful primarily
in cancers that are not widely disseminated. It is often combined
with surgery and chemotherapy
i. No Treatment: Before 1940

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ii. Surgery: Before 1955

iii. Radiotherapy: 1955 – 1965
iv. Chemotherapy: After 1965
v. Immunotherapy and Gene therapy; Currently

3.7.3 Cell Cycle (cell proliferation)

Tumour cells can be classified as proliferating cells and non-proliferating

cells based on the DNA changes in cells, proliferating cycle of tumour
cells can be divided into 4 phases

G1; Pre-synthetic phase (Gap 1 phase or G1 phase). Cell chiefly makes

preparations for the synthesis of DNA.

S; Synthetic phase (S phase). Cells are synthesizing their DNA. Here,

chromosome material is doubled, with the production of sister chromatids.

G2; Post-synthetic phase; Preparation for Division. (Gap 2 phases or G2

phase). Where a sequence of biochemical materials occurs. In this phase
DNA synthesis has stop while RNA and protein synthesis continue and is
the second resting phase in the cell cycle.
Mitosis phase (M Phase). follows the G2 where two genetically identical
daughter cells are formed by division of the nucleus through the four
stages of prophase, metaphase, anaphase and telephase.

The daughter cell proceeds either to G1 phase or enter G0 phase.

Cell in G0 phase are not out of the cycle (but resting), because they are
still capable of proliferating.

G2 phase is also a resting phase where DNA synthesis has stop but RNA
and protein synthesis occur normally (the new cells here undergo growth
and differentiation) and finally the remaining cycle is repeated. Cell
division requires controlled timing of two events of the cell cycle.
Generally, in the early stage, the GF of a tumour is bigger and the
effect of a drug on the tumour is better. Cells in G0 phase can be
activated by chemical stimuli into G1 phase. e.g. skin cells can be
stimulated by a wound into dividing and repairing the lesion. Growth
factor – many stimuli can initiate Go cells into G1 cells, but the most
important is Growth factor acting on growth factor –receptor. GF
stimulate the production of signals of two types; Positive regulators of
cells cycle that control the changes necessary for cell division and
Negative regulators that control the positive regulators

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3.7.4 Classifications and Mechanisms of Action of Antineoplastic

Drugs

Classifications of Anticaner Drugs

i. Alkylating agents:nitrogen mustards, busulfan, nitrosoureas,

mitomycin
ii. Procarbazine, dacarbazine
iii. Taxanes: paclitaxel, docetaxel
iv. Topoisomerase II inhibitors: etoposide
v. Platinum Complexes: cisplatin, carboplatin
vi. Anthracyclines: doxorubicin, daunorubicin, mitoxantrone
vii. Antimetabolites: methotrexate, purine antagonists, pyrimidine
antagonists
viii. Tubulin interactive agents: vincristine, vinblastin
ix. Miscellaneous agents: bleomycin, asparaginase, hydroxyurea

3.7.5Mechanisms of Action of Antineoplastic Drugs

Most antineoplastic drugs act on the proliferating cycle of cell

i. Inhibition of nucleic acid (DNA and RNA) synthesise.g. 5-

fluorouracil, 6-mercaptopurine, methotrexate, cytarabine, etc.
ii. Destruction of DNA or inhibition of DNA duplicatione.g.
alkylating agents, mitomycin C.
iii. Interfering with the transcription to inhibit RNA synthesis e.g.
dactinomycin, dauoruicin, and doxorubicin.
iv. Inhibition of protein synthesise.g. vinca alkaloids,
epipodophylotoxins, and paclitaxel.
v. Interfering with hormone balance e.g. adrenal corticosteroids,
oestrogens, tamoxifen etc.

3.7.6 Principles of cancer chemotherapy

All Cell- normal cell or neoplastic cell must traverse before and during
cell division.

vi. Malignant cells spend times in each phase – longest in G1, but may
vary.
vii. In adult most of the cells do not constantly divide
viii. Most spent a varying time outside the cell in a quiescent non-
proliferating cell called G0 phase cells (resting-phase cells),
ix. Neurons and skeletal muscle cells spent most of their time in G0
phase.
x. Bone marrow & GIT Cells divide daily – Hence are more sensitive

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xi. When proliferating cells suffered heavy casualties, G0 phase cells

will get into proliferating cycle and become the reasons of tumour
recurrence.
xii. G0 phase cells are usually not sensitive to antineoplastic drugs,
which is the important obstacle to tumour chemotherapy.
xiii. Many of the effective anticancer drugs exert their action on cells
while traversing the cell cycle – cell specific (CCS) drugs
xiv. Cell cycle – Non-specific (CCNSs) drugs- sterilize tumours cells
whether they are cycling or resting in the G0 components

3.7.7 Factors That Determine Cancer Drug Response

i. The effect of the GF on the response to chemotherapy: Tumours with

a high growth fraction are more susceptible to the Cytotoxic drugs than
those with a high percentage of dormant cells (G0 phase). Normal tissues
with high GF (bone marrow, oral/intestinal mucosa, hair follicles) are also
damaged by anticancer drugs, and treatment with many of these drugs may
produce bone marrow depression (leukocytopenia and infection,
thrombocytopenia and bleeding), stomatitis, GI tract ulceration, and
alopecia.

ii. The effect of the speed of cell cycle on response to chemotherapy:

The faster the cell cycle proceeds, the more likely that treatment with
cytotoxic drugs will ‘catch’ the cells in a sensitive phase. This forms the
basis why cytotoxic drugs are usually given in cycles of treatment at
intervals of 3-4 weeks, rather than continuously, since this allows recovery
of susceptible tissues, such as the bone marrow.

iii. Synchrony of the cell cycle in the cells of a tumour: if more tumour
cells are synchronized in a sensitive phase of the cycle, there will be better
chance of respond to a pulse of cytotoxic drug therapy. Attempt is usually
made to recruit cells into cycle (for example the recruiting of breast cancer
cells with oestrogens). Alternatively, cytotoxic drugs can be used to arrest
cells at different point of the cycle, thus modifying the effects of other
treatment for instance as it has been demonstrated with a mitotic spindle
poison, such as Vinca alkaloids, which might arrest cell in their cycle after
which they could be treated with an inhibitor of DNA synthesis like
cytarabine as they progress through S-phase.

iv. The effect of tumour size on response to chemotherapy: Large

tumours respond poorly to chemotherapy because many of the cells tends
to be in G0 phase in which cells are unresponsive to drugs; and penetration
of drugs through a poor as vasculature is insufficient to achieve cytotoxic
concentrations for a long enough time without producing severe systemic
toxicity.

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v. Kinetic of cell kill: In general, tumour cell is killing after drug treatment
follows first order kinetics, i.e., each treatment results in killing of a
constant proportion, rather than a constant number of tumour cells. After
initial treatment, the rate of cell kill may change because the growth
fraction and mass doubling time change as the tumour mass decreases
from a large, bulky tumour to a smaller tumour (this is called
"RECRUITMENT"). The slope of the response curve is also different for
the residual cells because they are likely to be less sensitive to the drug or
present in sites where drug does not penetrate as well. Treatment must
continue even in the face of clinical remission until the tumour is totally
eradicated. Cure is considered achieved when the DISEASE-FREE
SURVIVAL PLATEAU is reached. This time is different for different
tumours (e.g., Burkitt's' lymphoma - 8 months; testicular cancer - 1 year).
NOTE: There is no clear survival plateau for certain cancers (e.g., breast
cancer).

vi. Tumour heterogeneous: in their cell populations, there may be great

variability in the responses of individual cell types. Some of these cells
are proliferating, some can proliferate but are dormant and others are
dying. The fact that tumours are not uniform must be considered. For any
tumour therapy to be completely effective the most invasive metastatic
cells must be killed. It is therefore difficult to kill every tumour cell during
chemotherapy, although, if cure is the aim, this is essential.

vii. Cell cycle phase: The response to certain cell phase-specific drugs
depends on the percent of cells in a sensitive phase during the time of
exposure. In general, for cycle phase specific agents such exposure should
be for at least two cell cycle times. Cells in the G0 phase are, for the most
part, refractory to chemotherapy. These cells may re-enter the cell cycle
and result in disease recurrence. Most anticancer drugs are effective
against cells in one particular phase of the cycle (e.g., vincristine during
M; cytarabine during S, etc.). Most drugs have their greatest activity
during S phase when cells are undergoing DNA synthesis.

3.7.8 Resistance of cancer cells to chemotherapy.

This is one of the most important problems with cancer chemotherapy. As

many as 40-45% of cancers patients may have or may develop resistance
to anticancer drugs. The differences in the responsiveness of some cancer
cells to drugs as noted, to a specific form of multiple drug resistance
(MDR), which seems to be important in many solid tumours is mediated
by a P-glycoprotein, which pumps Cytotoxic drugs out of cells before they
can act. This pump is inhibited by a Varity of structurally unrelated drugs
including nifedipine, verapamil, cyclosporine and tamoxifen, etc. There is

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however several different biochemical Mechanisms by Which Tumour

cells Develop Resistance to Anticancer Drugs. These include:

i. Decreased intracellular drug levels. This could result from

increased drug efflux or decreased inward transport. Among the
drugs which become resistant by this mechanism are the
anthracyclines, dactinomycin, vinca alkaloids, and
epidopodophyllotoxins.
ii. Increased drug inactivation. Included in this group are the
alkylating agents, antimetabolites and bleomycin.
iii. Decreased conversion of drug to an active form. This
mechanism is most common among the antimetabolites which must
be converted to the nucleotide before they are active. G1
iv. Altered amount of target enzyme or receptor (gene
amplification). Methotrexate is a classic example here as often in
methotrexate resistant tumours there is amplification in the target
enzyme dihydrofolate reductase.
v. Decreased affinity of target enzyme or receptor for drug.
Examples are the antimetabolites and hydroxyurea.
vi. Enhanced repair of the drug-induced defect. The alkylating
agents typically show resistance by this mechanism although other
mechanisms are also important with these drugs.
vii. Decreased activity of an enzyme required for the killing effect
(topoisomerase II). This is a newly recognised target but decreased
activity is important for resistance to doxorubicin, m-AMSA, and
the epipodophylotoxins.

Multidrug Resistance (MDR): This is a phenomenon whereby tumours

become resistant to several, often unrelated drugs, simultaneously. The
multidrug Resistance (MDR1) gene encodes an ATP-dependent efflux
pump, called p-glycoprotein that may become amplified in drug-resistant
tumours. MDR activity may be reversed by drugs such as calcium channel
blockers (e.g., verapamil), cyclosporine, or tamoxifen. Multidrug
resistance occurs between several different structurally unrelated
antitumor agents that apparently have different mechanisms of action.

3.7.9 Adverse effects of Antineoplastic Drugs

i. Short-term toxicity: Common adverse reactions usually appear

earlier and many of them occur in rapidly proliferating tissues such
as; marrow, gastrointestinal tract, and hair follicle,
myelosuppression, gastrointestinal tract symptom and alopecia.

ii. Long-term toxicity: The long-term toxicity mainly occurs in the

patients who received chemotherapy for many years ago.
Examples: carcinogenesis, teratogenesis and sterility.

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iii. Common Toxicities: Most chemotherapy drugs are active in cells

that are rapidly multiplying. Chemotherapy may not be very active
in indolent or slow growing tumours, Because of cytotoxic action
on rapidly dividing cells they are toxic to normal cells that are
actively multiplying. Bone marrow, GI tract, hair follicles are all
rapidly multiplying. Thus, common toxicity of chemo agents is -
Neutropenia, anaemia, and thrombocytopenia (collectively called
myelosuppression or bone marrow (suppression), Mucositis,
Nausea, anorexia, vomiting and diarrhoea (GI toxicity). Nausea
and vomiting, Alopecia or hair loss, Sterility/Infertility (especially
sterility in males), Skin changes, Anxiety, sleep disturbance,
altered bowel elimination, Decreased mobility, Hematopoietic
system changes and Hypersensitivity (esp. Taxanes, platinum)

Figure 31: Showing Side Effects of Chemotherapy

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Figure 32: Extravasation of Cytotoxic drug ( @ chemotherapy

extravasation injuries
cancerjournal.net).

Figure 33: Alopecia (hair loss)(@ medicinenet.com )

Common anticancer drug involved are; Anthracyclins, Etoposide,
Irinotecan, Cyclophosphamide, Taxanes, Ifosphamide, Vindesine,
Vinorelbine and Topotecan

Alopecia can occur 2-3 days after or within a few weeks of

commencement of treatment. Baldness may be temporary, partial or total.
Patient can regain hair 3-6 months after stopping treatment

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iv. Hand-Foot Syndrome

A local cutaneous reaction can occur and be seen on palms 2-12 days after
chemotherapy. It is usually associated with tingling, burning of palms,
hand, feet, Pain and peeling. Resolution occurs in 7-14 days after stopping
medication

Figure 34: Hand-Foot Syndrome(@cureus.com)

3.8 antiprotozoal Drugs

3.8.1 Antimalarial (Introduction)

Malaria is a major public health problem in warm climates especially in

developing countries. It is a leading cause of disease and death among
children under five years, pregnant women and non-immune
travellers/immigrants.

Malaria parasites are transmitted from one person to another by the bite of
a female anopheles’ mosquito. The female mosquito bites during dusk and
dawn and needs a blood meal to feed her eggs. Like all mosquitoes,
anopheles breed in water - hence accumulation of water favours the spread
of the disease.

Plasmodium infects the human and insect host alternatively and several
phases of the parasite life cycle is described.

3.8.2 Malaria Treatment is classified into two types of drugs

Malaria infection is classified into two broads’classes-based on the main

stages of drug targets.1. Tissue Schizonticides, drugs that eliminate
development or dormant form of the parasites and 2. Blood
Schizonticides, drugs that act on erythrocytic Parasites

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Therapeutic classification of antimalarial drugs`

i. Causal prophylaxis: (Primary tissue schizonticides): These drugs

prevent the maturation or destroy parasite (sporozoites) within
infected liver (hepatocytes) cells and thus prevent invasion of
erythrocytes. Example; Primaquine: Treat all species of malaria;
both are commonly used due to high toxicity. Proguanil: Primarily
used for P. falciparum. It’s not effective against P. Vivax (weak
activity) & rapid development of resistance. The only drugs that
kills hepatic Parasites
ii. Suppressive Prophylaxis: These are Schizonticides, they inhibit
erythrocytic phase & prevent the rapture of the infected
erythrocytes, which leads to relief of Rigor & Pyrexia. Examples;
Quinine, Chloroquine, Proguanil, Mefloquine, Pyrimethamine,
artemisinin & Doxycycline.
iii. Clinical cure: erythrocytic schizonticides: These are erythrocytic
schizonticides basically used to terminate an episode of malarial
fever examples; Artemisinin, Quinine, Mefloquine, Atovaquone,
Proguanil, Pyrimethamine, Chloroquine, Sulfonamides and
Tetracyclines;
iv. Fast acting, high efficacy drugs: Artemisinin, Quinine,
Mefloquine, halofantrine and Chloroquine. Used singly to treat
malaria and is usually the drug of choice in P. falciparum, where
delayed treatment could lead to death even if the parasites are
cleared from the blood and slow acting, low efficacy drugs:
Proguanil, Pyrimethamine, and Sulfonamides& Tetracycline. Used
in combinations.
v. Radical curatives: These drugs attack exoerythrocytic stage
(hypnozoites) resulting in clinical curative for total eradication all
forms parasites of P. vivax&P. ovale,P. malarae, P. falciparum etc.
from the body.

Suppressive drugs + hypnozoitocidal drugs

Radical cure of the P. falciparum malaria can be achieved by suppressive
only

Gametocidal: Destroy gametocytes and prevent transmission -

Artemisinin; against all plasmodia, Primaquine, Chloroquine and
quinine

Radical cures of P. Vivax infections – Proguanil, Pyrimethamine; prevent

development of sporozoites.

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3.7.3 Mode of Action of Specific Agents

i. The quinolones (Quinine, Chloroquine, Lumefantrine and

Amodiaquine}
Mechanism of action: The asexual malaria Parasites multiply in
the erythrocytes by digestion haemoglobin. The digested
haemoglobin generates free radicals and haem as highly reactive
by-products. Haem is sequestered as insoluble material pigment
known as Haemozoin. Quinolones are thought to interfere with
haem handling as by blocking the conversion of haem to
haemozoins. Failure to inactivate haem or even enhanced toxicity
of drug haem complexes is thought to kill the parasite via oxidative
reactions.

ii. Chloroquine: Well absorbed after oral IM, and SC administration.

Selective accumulation in retina: ocular toxicity. T1/2 = 3-10 days,
can increase from few days to weeks. tmax 2-3 hrs. 60 % protein
bound. Bio transform via Hepatic CYPs in to two active
metabolites – dihydrochloroquine & bisedesthychloroquine

Therapeutic uses: Prophylaxis and treatment of acute malaria

infections, Hepatic amoebiasis, Giardiasis, Clonorchis sinensis,
Rheumatoid arthritis, Discoid Lupus Erythematosus, Control
manifestation of lepra reaction, Infectious mononucleosis and
Prophylaxis. Chloroquine is inexpensive and safe but it useful has
declined. No longer used in Nigeria.

Adverse drug reactions: Cinchonism: Flushed and sweaty skin,

ringing in the ears (tinnitus), blurred Vision. Impaired hearing and
confusion
Others – skin rashes, angioneurotic oedema, photosensitivity,
pigmentationand exfoliative dermatitis
Long term therapy may cause bleaching of hair, rarely
thrombocytopenia, agranulocytosis, and pancytopenia. Ocular
toxicity: High dose, in prolonged therapy
Insomnia, transient depression seizures, rarely neuromyopathy &
ototoxicity. Usually following parenteral administration - ST & T
wave abnormalities, abrupt fall in BP & cardiac arrest in children
reported.

iii. Amodiaquine: Pharmacological actions similar, less cutaneous

side effects, Bitter Taste and faster acting than chloroquine. Widely
used; reduced cost, safety & activity against chloroquine resistant
P. falciparum. Chloroquine resistant strains may be effective.

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Adverse events: headache, photosensitivity. Major reports of toxicities,

including agranulocytosis, and hepatotoxicity (on long term
administration), have limited the use of the drug for prophylaxis
(long-term).

Therapeutic Uses: Can be used for clinical cure of falciparum malaria

with or without CQ resistance. Not used for prophylaxis. Combined
formulation with artesunate has been recently approved for use in
uncomplicated falciparum malaria irrespective of CQ resistance
status; it is preferred in African countries.
i. Quinine &Quinidine: Quinine remain the mainstay in the
treatment chloroquine and multidrug resistant P. Falciparum
Malaria.

Therapeutic Uses: Malaria (uncomplicated resistant falciparum malaria

&severe malaria including cerebral malaria).

Adverse drug reactions: Cinchonism: Tinnitus, headache mental

confusion, vertigo, difficulty in hearing & visual disturbances, flushing &
marked perspiration. Still higher doses, exaggerated symptoms with
delirium, fever, tachypnea, respiratory depression, cyanosis. Myotonia
congenita: 300 to 600 mg BD/ TDS. Nocturnal muscle cramps: 200 – 300
mg before sleeping.Varicose veins: along with urethane causing
thrombosis & fibrosis of varicose vein mass.

Idiosyncrasy: similar to Cinchonism but occurs in therapeutic doses.

Cardiovascular toxicity: cardiac arrest, hypotension and fatal arrhythmias.

Black water fever, Hypoglycaemia.

C/I in Pregnancy: Causes abortion in early Pregnancy by stimulating

Myometrium & Premature labour by stimulating Uterus

vi.PRIMAQUINE: 8-aminoquinoline: Mechanism of action:

Primaquine is converted to electron to generate reactive oxygen
radical which interferes with oxygen transport system in the
parasites. It is use in preerythrocytic schizonticides, not useful for
acute attack. Highly active against gametocytes and hypnozoites.

Therapeutic Uses: Radical cure of relapsing (Vivax) malaria &ovale.

Gametocidal for all species of plasmodia. Can be transmission through
mosquitoes.

Adverse effects: Nausea, headache, epigastric pain, and abdominal

cramps occasionally

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Avoid during pregnancy, G6PD deficient: Those with G-6-PD deficiency

are highly sensitive and haemolytic anaemia can occur even with 15-30
mg/day.

Atovaquone: Attack mitochondria, hence preventmalaria parasites from

making energy. Active against Merozoites (asexual stage of cycle). Other
drugs that target food metabolism of the parasites -Prevent formation of
Folate e.g. Sulfonamides, Diaminopyrimidines.

vii. Artemisinin: Artemisinin: The weed Artemisia annua has been

used for many centuries in Chinese herbal medicine as a treatment
for fever and malaria. In 1971, Chinese chemists isolated from the
leafy portions of the plant the substance responsible for its reputed
medicinal action. The compound, artemisinin (qinghaosu,
arteannuin) derivatives includes: Artemether, Arteether,
Artesunate, Arrerolane, Artemether, Arteether, Artesunate,
Arrerolane, Artemisinins are prodrugs of the biologically active
metabolite dihydroartemisinin, activated by haem and form free
radicals which damages lips & vacuole of Parasites membranes.
Inactivation of plasmodium proteins, alkylations of haem &
interferencewith haems – haemozoins – haematin metabolism.

viii. Artemisinin & Derivatives: Artemisinin is not very soluble either

in water or oil. Artemisinin derivatives have half-lives of the order
of an hour. All artemisinin derivatives are characterised by their
extremely rapid elimination from plasma, with elimination half-
lives that are mostly less than a few hours. Elimination T1/2 =
Artemisinin = 2.9hrs. Dihydroartemisinin = 40 min, Arteether =
3.6hrs, Arteether = 12.4 -30hrs and Artesunate = 2.5mins.

Both Artemether and artesunate are metabolised to dihydroartemisinin by

rapid esteratic hydrolysis of artesunate or slower cytochrome P450-
mediated demethylation of artemether. Dihydroartemisinin itself
and artemisinin are probably metabolised in the liver to inactive
metabolites.

Artemisinin, dihydroartemisinin, Artemether and artesunate are

available for oral and rectal use in several countries). Artemisinin,
Artemether and artesunate can also be given by intramuscular
injection. However, artesunate is the only drug that can be
administered intravenously. Artesunate is clearly the most rapidly
absorbed with time to maximal concentration (T max 15 -30min)
considerably shorter than those of the other derivatives.

ix. Arteether: A longer t1/2 better and more lipophilic properties than
Artemether favouring accumulation in brain tissue and thus the

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treatment of cerebral malaria was regarded as advantages over the

other compounds.

x. Artesunate: Water soluble hemisuccinate derivative. Used for

oral, rectal, intravenous and intramuscular administration.
Available as tablets and as powder with separate vial containing 5
sodium bicarbonate.

xi. Antibiotics; Doxycycline & Tetracyclines Are Protein synthesis

inhibitors.

Side effects – esophagitis, photosensitivity.

xii. Proguanil (Chloroguanide): Biguanide converted to cycloguanil

active compound. Slow-acting erythrocytic schizontocide, also
inhibits the pre-erythrocytic stage of P. falciparum. Not kill
gametocytes but inhibit their development in the mosquitoes.
Proguanil, is cyclized in the body to cycloguanil which inhibits
plasmodial DHFRase in preference to the mammalian enzyme.
Acts slowly on erythrocytic stage of Vivax& falciparum. Prevents
development of gametes.

Therapeutics Uses: Current use of Proguanil is restricted to

prophylaxis of malaria in combination with chloroquine in areas of
low-level chloroquine resistance among P. falciparum. Causal
prophylaxis: 100 – 200 mg daily. Safe during pregnancy.

Adverse effects: Stomatitis, mouth ulcers, depression of

myocardium, megaloblastic anaemia, Not a drug for acute attack.

xiii. Pyrimethamine; It is a diaminopyrimidines more potent than

Proguanil. Inhibitor of plasmodial DHFRase.Tasteless so suitable
for children.

Its Selective anti-malarial action depends on high affinity for

plasmodial enzyme. In contrast to trimethoprim, it has very poor
action on bacterial DHFRase. Pyrimethamine is a slowly acting

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erythrocytic schizontocide, but does not eliminate the pre-

erythrocytic phase of P. falciparum.

Therapeutic Uses: Pyrimethamineused only in combination with a

sulfonamide (S/P) or dapsone. Addition of sulfonamide, retards
the development of resistance.

If used alone, resistance develops rather rapidly by mutation in the

DHFRase enzyme of the parasite.

Adverse events: megaloblastic anaemia, thrombocytopenia and

agranulocytosis

3.7.4 Nigeria National Antimalarial Treatment Policy: Regimen

Guidelines

Combination Therapy: Antimalarial combination therapy (CT) is

the simultaneous use of two or more blood schizonticides drugs with
different biochemical targets in the parasites and independent modes
of action. Artemisinin-based combination therapy -(ACT) is antimalarial
combination therapy with an artemisinin derivative as one component of
the combination. Artemisinin combination therapy is what constitute the
current national antimalarial treatment guidelines as summary in the tables
below.

I. Theoretical basis of ACT

 protect individual drug against occurrence of resistance
 to decrease rate of decline in efficacy
 interrupt spread of resistant strains
 decrease transmission in a region

Combinations Recommended

For uncomplicated malaria

i. Artemether + Lumefantrine
ii. Artesunate + Amodiaquine
iii. Artesunate + SP
iv. Artesunate + Mefloquine
v. Amodiaquine + SP
vi. Artemether + Lumefantrine

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ii. Advantages and gains of Artemisinin-based combination

therapy

These includes;

i. in uncomplicated malaria Improve clinical cure rates

ii. Delay emergence of resistance
iii. Reduce transmission and widespread use of 1st line Rx with

Artemisinin-based Combination
iv. Therapy Cost effective

Table 30: Current Drugs for Treatment of uncomplicated malaria

Drugs Dosage Strength

form
Artemether+ Tablets 20mg Artemether + 120m
Lumefantrine Lumefantrine
Use of the different components of these drugs as monotherapy is not
recommended

Table 31: Artemether – Lumefantrine (Coartem)

Weight (Kg) Age Dosage
5 - < 15 6 months - < 3 -4 years 1 tablet b.d x 3/7
15 - < 25 4 years - < 9years 2 tablets b.d x 3/7
25 < 35 9years - < 15years 3 tablets b.d x 3/7
≥ 35 > 15years 4 tablets b.d x 3/7

Drugs Dosage Strength

form
Amodiaquine- Tablet Amodiaquine10mg/kg & Artesunate
Artesunate 4mg/kg
Artesunate + Tablet Artesunate 4mg/kg/Mefloquine 15 -
Mefloquine 25mg/kg

Table 32: Artesunate + Amodiaquine (Fixed dose combination)

Weight Age Tablet Dosage
(Kg) (strength)
≥ 4. 5 - < 9 2 - 116 months 25/67.5 1 tablet b.d x 3/7
≥ 9 - < 18 1 year - < 50/135 1 tablets b.d x 3/7
5years
≥ 18 < 36 6 years - < 13 100/270 1 tablets b.d x 3/7
years
≥ 36 > 14years 100/270 2 tablets b.d x 3/7

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Table 33: Artesunate + Amodiaquine (co-blistered)

Weight Age (Years) Tablet Dosage
(Kg) (strength)
10 – 20 1 year - < 50/150 1 white tablet + yellow
5years tablet
21 – 40 7 years - < 13 50/150 2 white tablets + yellow
years tablet
≥ 36 Adults 50/150 4 white tablets + yellow
tablet

Table 34: Other drugs available for treatment of malaria

Drugs form Dosage Strength
Amodiaquine Tablets 200mg (153.1mg
base)
Halofantrine Tablets 250mg (233 mg
base)
Dihydroartemisinin (and other ACT Tablets 20, 60 or 80mg
derivatives)

Table 35: Currently Available Drugs for severe Malaria

Quinine Injection 300mg/ml in 2 ml
ampoule
Artemether Injection 80mg / ml in 1 ml
ampoule
Artesunate Injection 60 mg /1 ml vial

v. Artemisinin and Prophylaxis: Prophylaxis of malaria are not

considered to be indications for the artemisinin group of drugs.

3.9 Other Antiprotozoal

3.9.1Trypanosomiasis:

i. African Trypanosomiasis (sleeping disease: It is caused by the

hemoflagellates Trypanosoma brucei rhodesiense and
Trypanosoma brucei gambiense.
The organisms are transmitted by bites of tsetse flies (genus
Glossina), which inhabit shaded areas along streams and rivers.
The largest number of cases is in the Congo. Annual incidence
estimates are about 100 000 cases and 48 000 deaths.
ii. American Trypanosomiasis (Chagas’ disease) is caused by
Trypanosoma cruzi

Drug: benznidazole, pentamidine, melarsoprol, Eflornithine,

benznidazole and nifurtimox

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African trypanosomiasis – treatment: Suramin or pentamidine is effective

during the early stages but not for the later neurological manifestations for
which melarsoprol should be used.
Eflornithine is effective for both early and late stages.
American Trypanosomiasis – treatment: Prolonged (1–3 months)
treatment with benznidazole or nifurtimox may be effective.

3.9.2 Leishmaniasis (zoonosis).

i. Visceral leishmaniasis (kala azar) is caused mainly by

Leishmania donovani in the Indian subcontinent and East Africa.

Treatment: Sodium stibogluconate or meglumine antimoniate; resistant

cases may benefit from combining antimonials with allopurinol,
pentamidine, paromomycin, or amphotericin B.

ii. (Muco-) Cutaneous leishmaniasis is caused mainly by

Leishmania tropica, L. major, and L. donovani.

Treatment: Mild lesions heal spontaneously, antimonials may be injected

intralesionally.

3.9.3 Toxoplasmosis: T. gondii, an obligate intracellular protozoan, is

found worldwide in humans and in many species of animals and
birds. The definitive hosts are cats. Humans are infected after
ingestion of cysts in raw or under- cooked meat, ingestion of
oocysts in food or water contaminated by cats, transplacental
transmission of trophozoites or, rarely, direct inoculation of
trophozoites via blood transfusion or organ transplantation. Most
infections are self-limited in the immunologically normal patient.
Pyrimethamine with sulfadiazine is used for treatment of
chorioretinitis, and active toxoplasmosis in immunodeficient
patients; folinic acid is used to counteract the fatal megaloblastic
anaemia. Alternatives include pyrimethamine with clindamycin or
clarithromycin or azithromycin. Spiramycin is for treatment of
primary toxoplasmosis in pregnant women. Expert advice is
essential.

I. Human Trichomoniasis Human trichomoniasis caused by Tr.

vaginalis, seen in both females and males. It is usually transmitted
by coitus and is sometimes asymptomatic. The symptomatic
condition in females may take the form of a severe vaginitis
associated with discharge, burning, and pruritus. In males it may
produce urethritis, enlargement of the prostate, and epididymitis.

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Treatment: Metronidazole or tinidazole is effective.

3.9.4 Giardiasis:

Giardiasis is a common infection of the human small intestine with the

protozoan Giardia lamblia, spread via contaminated food or water, or by
direct person-to-person contact.
Treatment: Metronidazole, mepacrine, or tinidazole

3.9.5Pneumocystis

Pneumocystis carinii, the causative agent of interstitial plasma cell

pneumonia, which can also cause extrapulmonary disease in
immunocompromised patients (AIDS, etc.)
Treatment: Co-trioxazole: i.v/p.o. in high daily doses

3.10. Pharmacology of Antihelmintics Drugs

3.10.1 Helminths infections: Human is the primary host for most

helminthes infections. Most worms produce eggs and larva. These
pass out of human body and infect secondary host; immature
forms invade humans via skin or GIT

3.10.2 Types of worms: Worms live in host’s alimentary canal:

Roundworms (nematodes) & Tapeworms. Worms or larvae live
in muscles, viscera, menninges, lungs. Subcutaneous tissues:
Flukes (trematodes) & Intestinal Worms
i.Round worms (Nematodes); Ascaris Lumbricods (most common),
Enterobius vermicularis (pin worm), Trichris trichuria (whip worm),
Strongyloides stercoralis (thread worm), and Ankylostoma dudenale
(hook worm).
ii.Tape worms (cestodes): Taenia saginata (Beef) & Taenia solium
(pork)

Humans become infected by eating raw or under cooked meat containing

larvae of infected cattle or pig.
In some cases, the larva gets encysted in muscles, viscera, brain, and eye
resulting in cysticercosis.

iii.Tissue worms; Filariae (bancrofti, Loa loa) Adult Filariae live in the
lymphatics, causing lymphadenitis, swelling of limb. Microfilaria goes
to blood stream to be ingested by mosquitoes.
iv.Trichnella spiralis: larva migrates from intestine to tissues of leg or
foot producing ulcer

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3.10.3 Classifications of antihelmintics

i. Benzimidazole and probenzimidazoles derivatives:

Thiabendazole, Mebendazole, Flubendazole, and Albendazole.
ii. Piperazine derivatives: -piperazine citrate, diethylcarbamazine
citrate.
iii. Vinylpyrimidine derivatives: -Pyrantel pamoate.
iv. Dyes:( cyanine dyes): -Pyrivinium pamoate
v. Imidazothiazoles: Levimasole.
vi. Macrocyclic lactones: -Ivermectin
vii. Chlorinated compounds: -CCl4, tetrachloroethylene
viii. organophosphates
ix. more recently introduced,
a. the amino-acetonitrile derivatives,
b. the cyclic octadepsipeptides, and - the Spiroindoles.

3.10.4 Characteristics of Ideal Antihelmintics:

i. Orally active.
ii. Effective in single dose.
iii. Inexpensive.
iv. Wide safety margin between toxicity to worm and toxicity to host

3.10.5 Mechanism of Actions

The pharmacological basis of the treatment for helminthes generally

involves interference with the integrity of parasite cells, neuromuscular
coordination, or protective mechanisms against host immunity, which lead
to starvation, paralysis, and expulsion or digestion of the parasite.

Cellular Integrity: Many antihelmintics impair cell structure, integrity,

or metabolism: e.g. Inhibitors of tubulin polymerization—Benzimidazole
and probenzimidazoles (which are metabolized in vivo to active
benzimidazoles and thus, act in the same manner); Uncouples of oxidative
phosphorylationsalicylanilides and substituted phenols; and
Inhibitors of enzymes in the glycolytic pathway—clorsulon. Specific
categories include drugs that act via

i. nicotinic acetylcholine receptors agonists: imidazothiazoles,

tetrahydropyrimidines; allosteric modulator: monepantel;
ii. nicotinic acetylcholine receptors antagonist: spiroindoles,
iii. glutamate-gated chloride channels: ivermectin, milbemycins,
iv. GABA-gated chloride channels: piperazine,
v. Inhibition of acetylcholinesterases: coumaphos, naphthalophos.
vi. Organophosphates inhibit many enzymes, especially
acetylcholinesterases, by phosphorylating etherification sites. This

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phosphorylation blocks cholinergic nerve transmission in the

parasite, resulting in spastic paralysis.
i. Neuromuscular Coordination: This process may occur by
inhibiting the breakdown or by mimicking or enhancing the action
of neurotransmitters. The result is paralysis of the parasite, either
spastic or flaccid paralysis of an intestinal helminth allows it to be
expelled by the normal peristaltic action of the host.
ii. Benzimidazole: Benzimidazole and probenzimidazoles
derivatives: These are broad spectrum agents’ examples include -
Thiabendazole, Mebendazole, Flubendazole, and Albendazole.
iii. Mebendazole blocks glucose uptake: They act by inhibiting the
polymerization of helminthes (Nematodes) β – tubulin, thus
interfering with microtubules dependent function such as glucose
uptake.

They have selective inhibitory action being 250 -400x more effective in
producing effects in helminthes than humans.
Cure rate is about 80 -100%

Thiabendazole inhibits cellular enzymes of susceptible helminthes.

Mechanisms of Action
Albendazole is similar to mebendazole
Broad spectrum
Drug of choice for treatment of hydrated disease and cysticercosis.
Used for the treatment of (intestinal nematodes) e.g. ascariasis, tricurasis
and strongyloidiasis, pinworm and hookworm

Indication: Hookworm &Roundworms

Side effects: Gastrointestinal, neurological and hypersensitivity reactions,

liver damage, and crystal Luria may be induced.

i. Thiabendazole: Rapidly metabolized from the liver & excreted in

urine in conjugated form

Indication: Treatment of strongyloides & Hookworm.

Side Effects: occasional transient headache, dizziness and drowsiness

have been reported & allergic reactions (fever, rashes) can occur.

iv. Albendazole: Is also poorly absorbed but, like mebendazole this

might be increased by food especially fats. It is extensively
metabolized by first pass to sulfoxide & sulfones metabolites.
Sulfoxides may be pharmacologically active

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Side effects: - Mild GI disturbances may be caused, and it should not be

used inpregnancy or in children under the age of 2years.

v. Vinylpyrimidine derivatives: Pyrantel pamoate.

Praziquentel: Very effective broad-spectrum antibiotics,
introduced into clinical practice 20years ago. Drug of choice for all
forms of schistosomiasis Mechanism of Action: Praziquentel:
Disrupts Ca2+ homeostasis in the parasites by binding to consensus
protein kinase C-binding sites in a β – subunit of schisomes voltage
gated – calcium channels. This leads to Influx of ion. A rapid
prolonged contraction of musculature & paralyses & death of both
adult worms and larvae. It also destructs the teguments of the
parasite, unmasking novel antigens, & as a result it may become
more susceptible to the normal host immune response.

Adverse effects: Praziquntel is considered to be very safe & effective

drug, however little adverse effects do occur which has insignificant
clinical consequences. This includes GIT disturbance e.g. nausea,
Headache, dizziness, and drowsiness; it cures with a single dose (or
divided doses in one day). Aching in the muscles & joints, Skin eruptions
& low-grade fever.

ADR may be more marked in patients with heavy Work load.

Praziquentel is considered safe in Pregnancy – commonly use in public
health programmes.

vi. Piperazine derivatives: piperazine citrate, diethylcarbamazine

citrate

Piperazine: It irreversibly inhibits neuromuscular transmission in the

worm Piperazine citrate, probably by acting on GABA, the inhibitory
neurotransmitter, or GABA gated- gated chloride channels in nematodes
muscles. The response of Nematodes muscle to acetylcholine at
neuromuscular junction causing flaccid paralysis in worms which
becomes easily dislodged by gut movement, & expelled in faeces.
Adverse effect: Piperazine may cause hypersensitivity reactions
(Urtecaria & Bronchospasm), GIT disturbances, Neurological symptoms
(including “worm wobble”), Parasthesiaes Occasional dizziness, vertigo
& incoordination and may precipitate epilepsy.

C/I: In pregnancy and Patients with Liver & Renal compromise

DiethylCarbamazine Citrate (DEC): DEC is a Piperazine derivatives
(same to that of piperazine citrate due to piperazine moiety). DEC causes
alterations in the microfilarial surface membranes, thereby rendering them
recognized as foreign bodies by the host and destroyed by its defence
mechanism. It may also interfere with parasite Arachidonate metabolism.

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(Note that piperazine citrate and diethyl carbamazine citrate are

vermifuges and note the mechanism, while diethylcarbamazine citrate is
vermicide for filarial).

Indication: Drug of choice in treatment of filariasis and its active against

ascariasis.

Side effects: ADR though common, it’s usually transient GIT

disturbances e.g. Nausea, anorexia & vomiting, Arthralgia's. General
feeling of weakness malaise, fever, headache. Allergic reaction
(urticarial), and asthmatic attacks following the first dose are due to
products of destruction of (dying microfilariae) the parasite, and reactions
are minimised by slow increase in dosage over the first 3 days.
After symptom of reaction subsides, larger doses can be given without
problem.

viii. Macrocyclic lactones: -Ivermectin

Ivermectin acts by opening helminthes glutamate - gated chloride

channels (found only in invertebrates) & increasing chloride conductance;
by binding to novel allosteric sites on Ach – Nicotinic receptors to cause
an increase in transmission leading to motor paralysis; or by binding to
aminobutyric acid receptors. May cause immediate reactions due to the
death of the parasites.

Indication: Drug of choice for treatment of filaria & strongyloidiasis

Side effects: It may cause immediate Mazotti reactions (fever, headache,
dizziness, somnolence, hypotension, tachycardia, peripheral oedema,
urticaria, swollen and tender lymph nodes and abdominal pain) due to the
death of the microfilaria (early stage in the lifecycle of certain parasitic
nematodes).

It can be effective in a single dose, but it works best if repeated at 6–12-

month intervals. Fatigue, dizziness, GI disturbance, corneal opacities &
other eye lesions.

Ix .Niclosamide: Used to treat tapeworm with Praziquentel.

Synthesis of niclosamide.

Niclosamide: blocks glucose uptake by intestinal tapeworms. Irreversibly

damage the worm scolex (i.e. the head that is usually attached to the host
intestine, making the worm to separate & expelled from the intestine. It
interferes with helminthes metabolism where it inhibits mitochondrial
oxidative phosphorylation, inhibits respiration, block glucose uptake by
the cestodes. After initial attack of the drug, helminthes (Taenia solium)

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become highly sensitive to the proteolytic enzymes of the host intestine

and undergo partial digestion.

Indication: The drug of choice in treatment of most tapeworm

infestations. (Cestodes) such as Taenia saginata, Taenia

soliumandHymenolepis nana.
No systemic absorption of the drug occurs. The digestive juice of the host
facilitates the drug penetration into various cestodes.

Very important note: In case of Taenia solium, (pork tapeworm): -

laxative should be given within 1-2 hours after drug use to expel the dead
worms and to avoid cysticercosis [ as the drug is not active against the
larval form (cystcerci)]. This cysticerci results from release of live ova
from worm segments damaged by the drug and migrate to the stomach.
Now Praziquantel is the drug of choice in case of Taenia solium to avoid
such limitation.

Side effects: It may cause some mild GI symptoms: Infrequent and

transient nausea & vomiting may occur.

i.Levimasole: Levimasole has Nicotine – like actions, stimulating &

subsequently blocking the neuromuscular junctions as in Pyrantel
pamoate resulting in the paralysis and expelled worm in faeces.
Ova are not killed

Potent stereo specific inhibitor of fumarate reductase in various

nematodes, such inhibition causes contraction in helminthes, followed by
tonic paralysis and subsequent elimination of the worm.

Indications: used for treatment of round worm as Ascariasis, and hook

worm as ancylostomiasis.

Side effects: Following single dose, adverse effects are few & transient
GIT disturbances it may cause abdominal pain, nausea &vomiting.
Headache, and dizziness and skin eruptions. Higher concentration has
nicotinic actions on autonomic ganglion

4.0 CONCLUSION

You have learnt in this section definition terms use in antimicrobial

chemotherapy, Types and sources of antimicrobial chemotherapy, the
basic Mechanisms of action of antimicrobials and the mechanisms of
antimicrobial resistance. We also discuss various drugs used in protozoal,
helminthes and viral infection and details discussion on antimalarials,
antituberculosis and anticancer drugs.

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5.0 SUMMARY

Infectious diseases are still a serious problem, compounded by the

development of antibiotic resistance in many bacteria and the relative lack
of newer antimicrobial agents to combat these multi-resistant organisms.
Appropriate aggressive short-course treatment is recommended for
ensuring clinical and microbiologic cure, optimal patient adherence, and
minimal generation of antibiotic resistance.
The word “antimicrobials” include all agents/drugs that act against all
types of microorganisms (Bacteria (Antibacterial) drugs, Fungi
(Antifungal) drugs, Protozoa (Antiprotozoan) drugs, Antihelminthic drugs
and Viruses (antiviral) drugs. Most modern antibiotics come from species
of microorganisms that live in the soil to commercially produce synthetic
antibiotic.

Features of ideal antimicrobial drugs are, antimicrobial agents should

possess 1. Selective toxicity; it causes greater harm to microorganisms
than to host, 2. spectrum of activity that should be effective and kill wide
range of microorganisms, 3. effective of combining drugs with good
synergistic effects in fight infections, 4, minimal or no adverse Effects,
Allergic Reactions to the host 5. It should not suppress normal GIT flora
and should be effective against microbial resistant.

General Mechanisms of action of Antibacterial Drugs includes, Inhibition

of cell wall synthesis e.g. penicllins, cephalosporins. Injury to plasma/Cell
membrane: e.g. polymixin B and colistin, inhibition of protein synthesis
e.g. Aminoglycosides, macrolides, inhibition of nucleic acid
synthesis: e.g. quinolones, metronidazole, and rifampin and Inhibition of
essential metabolites synthesis e.g. Sulfonamides and trimethoprim.

Antiviral Drugs selectivity has been a problem because viruses use the
metabolic machinery of the host. Antiviral drugs target specific steps of
life cycle, especially enzymes that function in the life cycle (e.g.,
amantadine, vidarabine, acyclovir, and azidothymidine). Human
interferon is used to treat some viral infections.

Antiprotozoal drugs

Major antiprotozoal are malaria; Malaria infection is classified into two

broad classes based of the main stages of drug targets.1. Tissue
Schizonticides, drugs that eliminates development or dormant form of the
parasites and 2. Blood Schizonticides, drugs that act on erythrocytic
Parasites. Antimalarial drugs can be classified based on therapeutic
antimalarial activity which are 1. Causal prophylaxis: (Primary tissue
schizonticides): Primaquine, Proguanil, 2. Suppressive Prophylaxis:

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These are Schizonticides. Examples; Quinine, Chloroquine, Proguanil,

Mefloquine, Pyrimethamine, artemisinin and Doxycycline, 3. Clinical
cure: erythrocytic schizonticides examples; Artemisinin, Quinine,
Mefloquine, Atovaquone, Proguanil, Pyrimethamine, Chloroquine,
Sulfonamides, Tetracyclines, 4. Fast acting, high efficacy drugs:
Artemisinin, Quinine, Mefloquine, halofantrine and Chloroquine. Slow
acting, low efficacy drugs: Proguanil, Pyrimethamine, and
Sulfonamidesand Tetracycline. Used in combinations and 5. Radical
curatives: These drugs attack exoerythrocytic stage (hypnozoites)
resulting in clinical curative for total eradication all forms parasites of P.
vivax&P. ovale,P. malarae, P. falciparum etc. from the body.
Gametocidal: Destroy gametocytes and prevent transmission -
Artemisinin; against all plasmodia, Primaquine, Chloroquine, quinine.
Radical cures of P. Vivax infections – Proguanil, Pyrimethamine; prevent
development of sporozoites.

Nigeria National Antimalarial Treatment Policy is Artemisinin

Combination Therapy: Antimalarial combination therapy (CT) is
the simultaneous use of two or more blood schizonticides drugs with
different biochemical targets in the parasites and independent modes
of action. Artemisinin-based combination therapy (ACT) is antimalarial
combination therapy with an artemisinin derivative as one component of
the combination. Artemisinin combination therapy is what constitutes the
current national antimalarial treatment guidelines as summary in the tables
below.

Advantages and goals of Artemisinin-based combination therapy include

improve clinical cure in uncomplicated malaria, delay emergence
of resistance, reduce transmission and widespread use of 1st line Rx with
Artemisinin-based Combination and Cost-effective therapy.

Currently recommended combination antimalarial on the national malaria

treatment guidelines for uncomplicated malaria in are Artemether +
Lumefantrine, Artesunate + Amodiaquine, Artesunate + SP, Artesunate +
Mefloquine, Amodiaquine + SP, and Artemether + Lumefantrine.

Artemisinin and Prophylaxis: Prophylaxis of malaria is not considered to

be indications for the artemisinin group of drugs.

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Antiprotozoal

i. Trypanosomiasis: benznidazole, pentamidine, melarsoprol,

Eflornithine, benznidazole and nifurtimox, Leishmaniasis
(zoonosis). Sodium stibogluconate or meglumine antimoniate
ii. Toxoplasmosis: Pyrimethamine with sulfadiazine Alternatives
includes pyrimethamine with clindamycin or clarithromycin or
azithromycin. Spiramycin is for treatment of primary
toxoplasmosis in pregnant women. Expert advice is essential.
iii. Human Trichomoniasis Treatment: Metronidazole or tinidazole is
effective
iv. Giardiasis: Treatment: Metronidazole, mepacrine, or tinidazole
v. Pneumocystis: Cotrimoxazole: i.v/p.o. in high daily doses
vi. Helminthes infections: Human is the primary host for most
helminthes infections. Most worms produce eggs and larva. These
pass out of human body and infect secondary host; immature forms
invade humans via skin or GIT.

Types of worms: Worms live in host’s alimentary canal: Roundworms

(nematodes) & Tapeworms. Worms or larvae live in muscles, viscera,
menninges, and lungs. Subcutaneous tissues: Flukes (trematodes) &
Intestinal Worms.

An ideal Antihelmintics should be orally active, effective in single dose,

inexpensive and wide safety margin between toxicity to worm and toxicity
to host.

Final Thought: “The desire to take medicines is one feature which

distinguishes man, the animal from his fellow creatures. It is one of the
most serious difficulties with which we have to contend” - Sir William
Osler (1894)

SELF ASSESSED EXERCISES

i. Explain the various adverse effects of antineoplastic drugs.

ii. Outline the features of antimicrobial drugs.

6.0 TUTOR- MARKED ASSIGNMENT

1. define antibiotic and antimicrobial? What are the characteristics

of an Ideal antimicrobial?
3. what are the rational for ideal antimicrobial. Outline national
malaria treatment plan for uncomplicated malaria.
4. Classify antiretroviral according to their mechanisms of actions
and outline the adverse effects of one NNRTI, NRTI drugs PI
drug.

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5. Discuss the mechanisms of actions of anticancer chemotherapy

and principles of cancer chemotherapy

7.0 REFERENCES/FURTHER READING

Katzung, B.G., Masters, S.B. & Trevor, A.J. (2012). Basic and clinical
pharmacology. (12th ed.). New Yock: McGraw Hill.

Srivastava, S.K. (2017). A complete textbook of medical pharmacology

(Vol. II). APC books.

Bruton, L., Chabner, Bruce. & Knollman, B. (2011). Goodman and

Gilman's the Pharmacological Basis of Therapeutics. (12th ed.).
McGraw-Hill Education.

Nigeria National Drug Policy, (2005).

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UNIT 3 MODE OF ACTION OF DRUG ACTING ON

SPECIFIC DISEASES

CONTENTS

1.0 Introduction
2.0 Objectives
3.0 Main Content
3.1 Definition of Terms
3.2 Drug Action the Uterus (Uterotonics and Tocolytics)
3.2.1 Drug Use on The Uterus (Uterotonics)
3.2.2 Tocolytic: Utrine Rexants
3.2.3 Hypertensive Disorders in Pregnancy
3.2.4 Anticonvulsants
3.2.5 Contraception and Pregnancy
3.3 Anti-Diabetes
3.3.1 Two types of DM
3.3.2 Mode of Action of Specific Antidiabetic Agents
3.4 Drug Acting Cardiac Failure
3.4.1 Main causes Heart Failure
3.4.2 Cardiac Function
3.4.3 Pathophysiology of Cardiac Performance
3.4.4 Drug Used to treat CHF
3.5 Antihypertension
3.5.1 Normal Blood Pressure Regulation
3.5.2 Causes of Hypertension
3.5.3 Antihypertensive Agents: Classifications
3.5.4 Mode of Action of Specific Antihypertensive
Agents
3.6 Drug Acting on Pain
3.6.1 Introduction
3.6.2 Clinical types of pain
3.6.3 Analgesic Classifications
3.6.3 Mode of Actions Specific Analgesics
3.7 Prescription in Pregnancy & Lactation
3.7.1 Introduction
3.7.2 How a drug affects the foetus
3.7.3 Potential impact of drugs on fetal growth and
development
3.7.4 Clinical example of approach to drug therapy in
pregnant woman
3.7.5 Principles of Prescribing in Pregnancy
3.7.6 Medications You Should Avoid During Pregnancy
3.7.7 Drug Use during Lactation
3.6 Special issues needing Prescription in Prescription
Pregnancy

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3.8.1 Drug Management of Cough, Cold, and Allergy in

Pregnancy
3.8.2 Drug management of Pain in Pregnancy
3.8.3 Management of GIT Disorders in Pregnancy
3.8.4 Immunisations
3.8.5 Learning deficits &/or behavioural abnormalities.
3.7 Principles of Drug Therapy During Breastfeeding
3.8 Strategies to minimise infant exposure to drug
4.0 Conclusion
5.0 Summary
6.0 Tutor- Marked Assignment
7.0 References/Further Reading

1.0 INTRODUCTION

The course provides knowledge of the basic principles of

pharmacotherapy, with special attention to mode of action topical diseases
of public health importance. Here you will be expose to the drugs used in
obstetrics and Gynaecology and principles of drug prescription in
pregnancy and its dangers.
Diabetes Mellitus (DM) is a chronic disease resulting from deficiency in
glucose metabolism, caused by relative or complete deficiency in insulin
secretion from the beta cells of the pancreas resulting in chronic increase
blood sugar (hyperglycaemia).

DEFINITION OF TERMS

 Abortion: The termination of pregnancy before the foetus reaches

the stage of viability which is usually less than 21 to 22 weeks
gestation (or less than 600 gm in weight).
 Amniotic fluid: Approximately one litre of fluid in a sac which
surrounds the foetus. This fluid protects and cushions the foetus
during its development.
 Apgar scoring: Rating system for new-born babies, measuring the
baby’s general condition on a scale from 1 to 10.
 Obstetrics: Obstetrics deals with the care of women's reproductive
tracts and their children during pregnancy, childbirth and the
postnatal period. A doctor performing such practice is called
Obstetrician.
 LMP: Last Menstrual Period. It is the time elapsed for 14 days
prior to fertilization
 EDC or EDD: The Due Date. EDC stands for the old-fashioned
"estimated date of confinement." EDD is the more modern
"Estimated Day of Delivery." The average pregnancy “gestation”
is 40 weeks or 280 days from the first day of the last menstrual
period (LMP). For a 28-day cycle, EDD is calculated by taking the

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LMP and adding 9 months and 7 days to it. If the cycle is longer
than 28 days, add the difference between cycle length and 28 days.
Nagele’s Rule: Subtract 3 months from the 1st day of the LMP and
add 7 days.
i. Gravida: It is the number of times the mother has been pregnant,
regardless of whether these pregnancies were carried to term. A
current pregnancy, if any, is included in this count. A nulligravida
or gravida 0 is a woman who has never been pregnant. A
primigravida or gravida 1 is a woman who is pregnant for the
first time or has been pregnant one time. A multigravida or more
specifically a gravida 2 (also secundigravida), gravida 3, and so
on, is a woman who has been pregnant more than one time. An
elderly primigravida is a woman in her first pregnancy, who
is at least 35 years old.
ii. Parity: It is the number of times the woman has delivered after the
age of viability. It includes the births after 24 weeks or those having
weight of 500 grams. TPAL method Para is often recorded in 4
numbers: T= the number of term deliveries (after 37 weeks) P= the
number of premature deliveries (> 20 and < 37 wk.) A= the number
of abortions either spontaneous of therapeutic) L= the number of
living children There can be 4 numbers after the "P" for "Para." The
first number is how many term pregnancies. The second number is
how many premature babies. The third number is how many
abortions or miscarriages the fourth number is how many living
children survive.
iii. Gestation: Gestation is the carrying of an embryo or foetus inside
a female viviparous animal. Mammals during pregnancy can have
one or more gestations at the same time (multiple gestations). The
time interval of a gestation is called the gestation period.
iv. Trimester: The pregnancy is divided into 3 trimesters. The first
one is from LMP up until 12 or 13 weeks. The second trimester is
from 12-13 weeks until 28 weeks. The third trimester is from 28
weeks until delivery.
v. Miscarriage: Miscarriage is the spontaneous end of a pregnancy
before 24 weeks of gestation.
vi. Stillbirth: It is the birth of a baby after the age of viability when it
has no vital functions at birth, i.e. no heart rate, no umbilical cord
pulsation, etc.
vii. Ectopic Pregnancy: An ectopic pregnancy, or eccysis, is a
complication of pregnancy in which the embryo implants outside
the uterine cavity.
viii. Hyperemesis: Hyperemesis gravidarum (HG) is a severe form of
morning sickness, with "unrelenting, excessive pregnancy-related
nausea and/or vomiting that prevents adequate intake of food and
fluids

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ix. Ante partum Haemorrhage: Also called prepartum haemorrhage,

it is the bleeding from the vagina during pregnancy from the 24th
week gestational age to term.
x. Postpartum Haemorrhage: It is the loss of greater than 500 ml of
blood following vaginal delivery, or 1000 ml of blood following
caesarean section.
Pregnancy Induced Hypertension It is the condition of high blood
pressure during pregnancy. It is also called Gestational
hypertension.
xi. Pre-eclampsia: It is when a pregnant woman develops high blood
pressure and protein in the urine after the 20th week of pregnancy.
xii. Eclampsia: It is an acute and life-threatening complication of
pregnancy, is characterised by the appearance of tonic-clonic
seizures, which are not due to preexisting or organic brain
disorders, usually in a patient who has developed pre-eclampsia.
Pre-eclampsia and eclampsia are collectively called Hypertensive
disorder of pregnancy and toxemia of pregnancy. Symptoms:
Typically, patients show signs of pregnancy-induced hypertension
and proteinuria prior to the onset of the hallmark of eclampsia, the
eclamptic convulsion. Other cerebral signs may precede the
convulsion such as nausea, vomiting, headaches, and cortical
blindness.
xiii. Polyuria: increase in the frequency of urine output
xiv. Polydipsia: excessive thirst
xv. Polyphagia: increase in hunger.
xvi. Heart failure: As a state in which the heart cannot provide
sufficient cardiac output to satisfy the metabolic needs of the body.
Heart failure occurs when cardiac output is inadequate to provide
the oxygen needed by the body
xvii. Definition of pain: Unpleasant sensory and emotional experience
associated with actual or potential damage Pain is redefined as a
perception instead of a sensation because it is always a
psychological state.
It was coined from the Latin word "peona " meaning punishment.
Pain is always subjective• It is differently experienced by each
individual.
xviii. Nociception: Coined by Sherrington – Latin: noxa means injury –
it means the ´perception of noxious stimuli´
Mechanism by which noxious peripheral stimuli are transmitted to
the central nervous system to elicit a mechanical response.
Potentially damaging stimuli (mechanical, thermal, or chemical)
xix. Pain – Receptors: Specialised naked nerve endings found in
almost every tissue of the body, usually activated by stimuli
(mechanical, thermal, chemical).

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Distinguished from other receptors by their higher threshold, and

they are normally activated only by stimuli of noxious intensity-
sufficient to cause some degree of tissue damage.
xx. Location of nociceptors: Superficial skin layers, Deeper tissues,
Periosteum, joints, arterial wall, liver capsule, pleura. Other deeper
tissues are sparse pain nerve endings. But wide spread tissue
damage results in pain.
Large internal organs do not contain nerve endings. Polymodal
nociceptors respond to all three types of stimulus
xxi. Chemical Neurotransmitters of Pain: Histamine, bradykinin,
acetylcholine, serotonin, and substance P are chemicals that
increase transmission of pain
xxii. Prostaglandins: are chemical substances that are believed to
increase the sensitivity of pain receptors by enhancing the pain
provoking effect of bradykinin
There are 2 main types of fibres involved in the transmission of
nociception: Myelinated, A delta fibre – “fast pain”, Type C
fibres – “second pain”
Chemicals that reduce or inhibit the transmission or perception of
pain include endorphins and enkephalins.

2.0 OBJECTIVES

By the end of this unit, you will be able to:

 define terms use in specific diseases

 classify drugs use in obstetrics and gynaecology
 identify the basic mechanism of actions of drugs use in obstetrics
and gynaecology
 state the adverse effects and contraindications of drugs use in
obstetrics and gynaecology
 describe the causes of specific diseases
 explain the types of drugs use in specific diseases
 describe the adverse effects and contraindications of drugs use in
obstetrics and gynaecology
 classify analgesics and Describe the adverse effects, drug
interactions and contraindications of analgesics use in the
management of pain
 give prescription of drugs in pregnancy and lactation
 list vaccines use in pregnancy.

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3.0 MODE OF ACTIONOF DRUG USE IN OBSTETRICS AND

GYNAECOLOGY

3.1 Drug use on the Uterus (UTEROTONICS)

Medications that relax the muscle in the pregnant uterus – Tocolytics – or

increase uterine contraction – uterotonics – play a vital role in modern
obstetric care.

Uterine stimulants: oxytocic or abortifacients

Posterior Pituitary hormones: Oxytocin, Desamino oxytocin
Ergot alkaloids: Ergometrine, Methylergometrine
Prostaglandins: PGE2, PGF2α, Misoprostol
Miscellaneous: ethacridine and quinine
The other hormone is vasopressin

iii. Oxytocin

It is synthesised in the supra-optic and para ventricular nuclei of the

hypothalamus. Sensory stimuli from cervix, vagina and breast suckling
stimulate the Secretion of oxytocin. The expulsive phase is triggered by
sustained distension of uterine cervix and vagina, increased by Oestrogen
secretion, while ovarian polypeptide Relaxin inhibits its release.
Antidiuretic hormone (ADH), pain, haemorrhage and dehydration
increase secretion.
Mode of action: Receptor and voltage mediated calcium channels &
amniotic and prostaglandin decidual production
Oxytocin: Preparations used includes; Synthetic oxytocin, Syntometrine,
Desamino oxytocin and Oxytocin nasal solution. Etc.

Physiological Role of oxytocin

On Uterus: Uterine contraction. Oxytocin is very important for cervical

dilation before birth and causes contractions during the second and third
stages of labour. It assists the uterus in clotting the placental attachment
point postpartum- during the first few weeks of lactation. However, in
knockout mice lacking the oxytocin receptor, reproductive behaviour and
parturition are normal. Sensitivity increases to 8-fold in last 9 weeks and
30 times in early labour. Clinically oxytocin is given only when uterine
cervix is soft and dilated.

Breast; Stimulates my epithelial cells leading to milk ejection, milk-let-

down / milk ejection reflex’. This reflex (naturally) is initiated by the
stimulus of suckling, which leads to the release of oxytocin. Sensitivity
increases to 8-fold in last 9 weeks and 30 times in early labour.

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Oxytocin Effects on other systems: CVS: Small doses cause

vasodilatation, producing diastolic hypotension, reflex tachycardia and
flushing. Kidneys: Higher doses (100 m.I.U.) produce Anti-Diuretic
Action leading to decreased urine output, due to constriction of renal
cortical vessels (in the presence of oestrogens). Pulmonary oedema can
get precipitated if large amounts of i.v fluids and oxytocin are infused
together CNS: Appears to function as a peptide neurotransmitter in
hypothalamus and brainstem to regulate autonomic neurons, can produce
emotional behaviours, maternal bonding, adult bonding, enhance social
behaviours in autism.

Pharmacokinetics of oxytocin: Not effective when administered orally,

intravenously and also as nasal spray (impaired milk ejection Metabolised
by liver & kidneys. Half-life = has a half-life of 3-5 minutes and duration
of action of approximately 20 minutes.

Therapeutic Indications of Oxytocin: Therapeutic indication in

Pregnancy:

Early: to accelerate abortion, to stop bleeding following evacuation of the

uterus and used as an adjunct of abortion along with other abortifacient
agents.

Late: To induce labour, to facilitate cervical ripening for effective

induction, Augmentation of labour, and Uterine inertia.
Labour: In active management of third stage of labour, following
expulsion of placenta.

Puerperium: To minimise the blood loss and to control the PPH.

Diagnostic: Contraction stress test to the determination of respiratory
function of the feta placental unit during induced contractions.
Induction & augmentation of labour (Mild preeclampsia, Uterine inertia,
Incomplete abortion (Post maturity and maternal diabetes etc.).

Post-partum uterine haemorrhage.

Impaired milk ejection.

Adverse effects: At recommended doses relatively safe when used, and

side effects are uncommon, excessive dosage or long-term administration
over a period of 24 hours or longer, can cause tetanic uterine contractions,
uterine rupture, postpartum haemorrhage, and water intoxication,
sometimes fatal. Decreased heart rate, arrhythmia, brain damage, seizures,
death in the foetus/neonate, due to increased uterine motility.

Maternal death due to: a) Hypertension, b) Uterine rupture

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Water intoxication

Contraindications: Hypersensitivity, Prematurity, Abnormal fetal

position, evidence of fetal distress and Cephalopelvic disproportion.
Precautions: Multiple pregnancy, Previous suction and Hypertension

ii. Carbetocin: A newer analogue of Oxytocin. has advantages quoted

are, much rapid onset and longer duration of action. The half-life is
much longer (45 minutes) as compared to that of oxytocin (4- 10
minutes). Reported to be successful in controlling uterine atony in
nearly 84 – 94 % patients.

Side effects include: nausea, vomiting, diarrhoea, headache, hypertension

and bronchospasm.
C/I: Should not be used in patients with CVS, pulmonary, hepatic and
renal diseases.

iii. Vasopressin: Not commonly used as an oxytocic. It has more

prominent oxytocic effect on non-pregnant uterus than oxytocin.
Foetal hypoxia is a powerful stimulus for its release and foetal
distress can lead to high umbilical cord blood levels of
vasopressin. If this vasopressin passes from foetal to maternal
circulation, significant oxytocic potency can be added to the
maternal oxytocin.

iv. Amide Alkaloids (Ergometrine &) Methylergometrine -

Selectively contracting uterus smooth muscle

Ergotamine: Contracting arteries and veins

Pharmacological effects

Uterine smooth muscle stimulation: Selectively and determined by the

functional state of the uterus.

Vessel-contracting effect: Directly contract artery and venous vessels,

which can damage vascular endothelial cells at high dose, lead to dry
gangrene of the extremities after long term use

α-receptor blocking effect: Reverse the BP-elevating effect of NA

Ergot poisoning was once common associated with abortion, until 1935,
when ergometrine was isolated and recognised as the oxytocic principle
in ergot. Active substances: Alkaloids, LSD, histamine, Ach and other
amines. Onset of ergometrine is quicker (45-60 secs) than methergine (90
secs). Duration is similar (3hrs)

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Ergot derivatives: includes Ergometrine & Methyl ergometrine are

ergot alkaloids, closely related to lysergic acid (LSD) derived from a
fungus, claviceps purpurea a Fungus that grows on rye, wheat etc.
Methergine is semi synthetic, derived from lysergic acid.

Mechanism of Action/Effects on the Uterus: Ergometrine is known to

act at dopamine, serotonin and α-adrenergic receptors, but its powerful
effect in causing uterine muscle contraction is not associated with any one
particular receptor type - partial agonistic.
Indications

• Post-partum haemorrhage (3rd stage of labour)

• Used for prevention/control of PPH (delivery/LSCS) bleeding
after abortion and to ensure normal involution of uterus

Side effects

- Nausea, vomiting, diarrhoea, abdominal pain, chest pain

- Hypertension (palpitation, severe HTN, Stroke & MI)
- Vasoconstriction of peripheral blood vessels (toes & fingers)
- Gangrene

Contraindication- Hypertension, Cardiac disease

v. Prostaglandins (PGs) (Dinoprostone（PGE2, Dinoprostone（

PGF2a, sulprostone and carboprost) are Prostaglandins (PGs) are C 20
fatty acid compounds containing cyclopentane ring, derivatives of
Prostanoic acid were first isolated from human seminal fluid with
probable origin from prostate gland, hence named Prostaglandins
act as local hormones. PGE2, PGF2α and recently PGE1, found useful
for the induction of abortion, induction/augmentation of labor and
control of PPH.

The pharmacological effects are: Contraction of smooth muscles of

uterus, blood vessels, GIT and bronchioles, Prostaglandins (PGs)
Clinical effects: Myometrial contraction• Softening and dilatation of
cervix, inhibition of secretion of progesterone by corpus luteum. Response
of the uterus to PGs is maximum in the middle trimester (13th to 20th
weeks). Prior administration of mifepristone (anti-progestin drug)
sensitizes the uterus to the action of PGs.
Therapeutic uses: Induction of abortion (pathological), Induction of
labour (fetal death in utero) and Postpartum haemorrhage.

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Side effects: Nausea, vomiting, diarrhoea, fever, flushing and

bronchospasm.

CVS side effects: tachycardia, increased mean arterial pressure and

pulmonary artery pressure.

Use caution in hypertension, diabetes, angina epilepsy and raised intra-

ocular pressure.

Contraindicated in bronchial asthma, uterine scar, cardiac renal or

hepatic diseases.

Anaesthetic implications: Because of their action on the bronchiolar tone

and pulmonary vasculature, they can lead to V/ Q mismatch and arterial
desaturation.

vi. Dinoprostone is a PGE2 - Use as Vaginal pessary/gel

Clinical use: In late (2nd Trimester) therapeutic abortion, Also for
cervical ripening and induction of labour

Advantages: Mobile patient, Reduce need for syntocinon

Side effect: Nausea, vomiting, diarrhoea, fever, uterine hyper stimulation,
HTN and bronchospasm

vii. Carboprost

Clinical use: Postpartum haemorrhage (Usually in patients that did not

respond to ergometrine).

Side effects: Nausea, vomiting, diarrhoea, fever, bronchospasm,

dyspnoea, pulmonary oedema, HTN and cardiovascular collapse

vii. Mifepristone: Antiprogestogenic steroid, sensitizes myometrium

to prostaglandin-induced contractions & ripens the cervix

Clinical use: Medical termination of pregnancy up to 63days of

Gestation& Medical management of miscarriage/IUD
Side effects: Gastro intestinal cramps, rash, urticarial, headache and
dizziness,

Contraindication: severe asthma

Misoprostol: Misoprostol is a synthetic analogue of PGE1, and was

originally developed to prevent gastric ulceration in patients using long-
term non-steroidal anti-inflammatory drugs (NSAID) therapy.

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It acts through PG receptors to initiate uterine contractions. Because it is

inexpensive and does not need refrigeration, it is a useful adjunct to other
uterotonics in the management of postpartum haemorrhage, as well as
early pregnancy loss.

3.1.2 Tocolytic: Uterine Relaxants

Decrease uterine contractility/motility in patients who are experiencing

true Preterm Labour (with cervical changes). Used to delay/postpone
labour, arrest threatened abortion & treatment of dysmenorrhea.
Suppression of labour to create additional time for in utero fetal
maturation, delay delivery so antenatal corticosteroids can be delivered to
facilitate fetal lung maturation and to allow safe transport of mother to an
appropriate facility.

They are likely to succeed only if cervical dilatation is < 4 cms, taking up
of the lower segment is minimal, effective in reducing the risk of delivery
within 24 to 48 hours only.

Classification of Tocolytics

i.β2 adrenergic receptor agonists: Terbutaline, salbutamol, Retodrine

and Isoxsuprine
ii.Oxytocin receptor antagonist: Atosiban
iii.Magnesium Sulphate
iv.Others. Calcium channel blockers: Nifedipine & Nicardipine,
Prostaglandin synthetase inhibitors: Indomethacin, aspirin,
ibuprofen, sulindac, Nitric oxide donors: Nitro-glycerine and
Anaesthesia Halothane

Contraindications: Rupture of membranes, Placenta previa, abruption

placenta, severe toxemia of pregnancy, Intra uterine infection and Intra
uterine death of the foetus.

i. Tocolytic: Terbutaline

Prototype: – Terbutaline -most commonly used, β 2 adrenergic receptor

agonists

Mechanism of action is through beta 2 receptor stimulation, causing

smooth muscle relaxation. Used in uncomplicated premature labour
between 24th to 33rd weeks of gestation. Should not be administered for
more than 48 hours, as it can lead to increased risk to the mother.

Adverse Effects: maternal side effects include tremors, malaise,

weakness, dyspnea, tachycardia, chest pain, vomiting, diarrhoea,

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constipation, pulmonary oedema, dysrrhythmias, and anaphylactic shock.

Fetal side effects include tachycardia and potential, hypoglycaemia

Drug interactions: General anaesthetics--- can produce additive

hypotension, Corticosteroids--- pulmonary oedema

iv. Tocolytic therapy – Magnesium Sulfate

Calcium antagonist and CNS depressant----relax smooth muscles of the

uterus through calcium displacement, increases uterine perfusion---
beneficial for the foetus, less expensive with lesser adverse effects than
beta-sympathomimetics, excreted by the kidneys and crosses the placenta,
Maintenance dose be titrated to keep uterine contractions under control.
Contraindicated for clients with migraine, impaired kidney function and
recentmyocardial infarction.

Adverse Reactions: – Mother: flush, feelings of increased warmth,

perspiration, dizziness, nausea, headache, lethargy, slurred speech,
sluggishness, nasal congestion, decreased GI action, increased pulse rate,
and hypotension.

– foetus: decreased heart rate and slight hypotonia with diminished

reflexes and lethargy for 24 to 48 hours
– Toxicity: respiratory depression and arrest, circulatory collapse,
cardiac arrest – Antidote for toxicity: calcium gluconate (10mg IV
push over 3 minutes.

v. Atosiban (Tractocile): A β –adrenoceptor agonists (Oxytocin

receptor antagonist)

Used inhibition of uncomplicated preterm labour between 24-33 weeks

(Tocolytic). Given as IVI then continue infusion until no contraction for 6
hrs.

Contraindication: severe PET, eclampsia, IUGR, IUD, placenta previa,

placental abruption, abnormal CTG, SROM after 30/40
Side effects: Nausea, vomiting, headache, hot flushes, tachycardia,
hypotension and hyperglycemia

3.2. Hypertensive Disorders in Pregnancy

It is associated with severe maternal obstetric complications. Incidence is

5-10%., The most frequent cause of iatrogenic prematurity, Preterm
delivery, Intrauterine growth restriction (IUGR), Perinatal death, Maternal
cerebrovascular accidents, Placental abruption

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Hypertension in Pregnancy: Systolic B.P. ≥ 140 mmHg and/or Diastolic

B.P. ≥ 90 mmHg. Documented on two occasions At least 6 hours apart not
more than 7 days apart. Readings should be confirmed using appropriate
measurement technique, and should be remeasured after 10-15 minutes of
rest.

Other Criteria (Not part of definition currently):

i. SBP increased by 30mmHg DBP increased by 15mmHg Mean

Arterial Pressure increased by 20mmHg
ii. Non-severe hypertension: SBP 140-159 mmHg or DBP 90-109
mmHg.
iii. Mild: SBP 140-149 mmHg or DBP 90-99mmHg.
iv. Moderate: SBP 150-160 mmHg or DBP 100-110 mmHg.
v. Severe hypertension: SBP > 160 mm Hg or DBP > 110 mmHg or
both.

Anti-Hypertensive Therapy in Pregnancy: the following class of drugs

are drug of choice during Pregnancy; Sympathomimetics, adrenergic
Receptor blocking agent, Alpha and Beta Blockers: Labetalol, Alpha
Blockers: Methyldopa, Vasodilators (Hydralazine, Prazosin and Sodium
nitroprusside), calcium channel blockers (Nifedipine, Nocardia), and
ACEI Inhibitors (Captopril, lisinopril)

Anti-hypertensive drugs contraindicated in pregnancy: These drugs

should be avoided because they may cause poor fetal renal function,
malformation or can cause IUGR; ACE inhibitors, 2. Minoxidil, Sodium
Nitroprusside, diltiazem, Atenolol and Propranolol

Antihypertensives of Choice (DOC) in Pregnancy

JNC 8: labetolol (first line), nifedipine, methyldopa

The choice of drugs given during pregnancy are: - Alpha and Beta
blockers (Labetalol hydrochloride), calcium channel blockers
(Nifedipine), alpha blockers (Methyldopa), and Vasodilators (Hydralazine
hydrochloride).

Mild /Moderate Hypertension/PET:

Alpha Methyldopa

Mechanism of action: Drugs of first choice. Central and peripheral anti-

adrenergic action. It is effective and safe for both mother and foetus.

Side effects maternal: postural hypotension, haemolytic anaemia,

sodium retention excessive sedation and coomb’s test may be positive.
fetal: intestinal ileus

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Other Side effects: Headache, dizziness, dry mouth, postural hypotension,

nightmares, mild psychosis, depression, hepatitis & jaundice. Important to
stop drug in postnatal period

Contraindications: hepatic disorders, psychic patients and -CCF

Dose: orally 250mg bid may be increased to 1 gm tid depending upon the
response. IV infusion 250-500mg

Labetolol 100-200mg BD/TDS PO max 2.4g/24hr

ACE inhibitors are contraindicated in pregnancy
Severe Pre-eclampsia / HTN

IV Labetolol (ß blocker): - Side effects: headache, nausea, vomiting,

postural hypotension & liver damage. Contraindication: Asthma, marked
bradycardia

IV hydralazine (vasodilator): Acts mainly on arteries and arterioles,

causing a fall in Blood Pressure accompanied by reflex tachycardia and an
increase cardiac output.
Side effects headache, nausea, vomiting, dizziness, flushing, tachycardia,
palpitation & hypotension. Because of hypotension preload with gelofusin
adv.

- Contraindication- SLE, severe tachycardia and myocardial infarction.

Magnesium Sulphate: Clinical use: Prevention & treatment of seizure in

eclampsia / severe pre-eclampsia
Dose: 4g IV stat then 1g/hr to be continued 24hr after last seizure
Side effects: nausea, vomiting, flushing, drowsiness, confusion, loss of
tendon reflexes, hypotension, decrease U/O, respiratory depression,
arrhythmias and cardiac arrest. Because of toxicity, Mg levels monitored.
It is associated with severe maternal obstetric complications.
Incidence is 5-10%., The most frequent cause of iatrogenic prematurity,
Preterm delivery, Intrauterine growth restriction (IUGR), Perinatal death,
Maternal cerebrovascular accidents and Placental abruption.

3.2.1anticonvulsants Used in Pregnancy

Magnesium Sulphate

Mechanism of Action: Decreased acetylcholine in motor nerve terminals,

which is responsible for anticonvulsant properties, thereby reduces
neuromuscular irritability. It also decreases intracranial oedema & helps
in diuresis. Its peripheral vasodilatation effect improves the uterine blood
supply. Has depressant action on the uterine muscles & CNS.
Dose: 4g IV stat then 1g/hr to be continued 24hr after last seizure

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Indications: It is a valuable drug lowering seizure threshold in women

with pregnancy induced hypertension (eclampsia / severe pre-eclampsia),
Used in preterm labour to decrease uterine activity.

Contraindications: Heart block, impaired renal function and Pregnant

women actively progressing labour.

Adverse effects

Magnesium Sulphate (MgSO4) is relatively safe and is the drug of

choice. Muscular paresis [diminished knee jerks]and respiratory failure.
Also, nausea, vomiting, flushing, drowsiness, confusion, loss of tendon
reflexes, hypotension, decrease U/O, respiratory depression, arrhythmias,
cardiac arrest can occur. Renal function to be monitored. Because of
toxicity, Mg levels monitored; Maternal (Severe CNS depression and
Evidence of muscular paresis), Fetal (Tachycardia, Hypoglycaemia)
Antidote: Injection of calcium gluconate 10% 10 ml IV.

3.2.2 Contraception and Pregnancy

i. Progesterone: Diazole - Synthetic progestin (but not low doses

used in oral contraceptives), when given during first 14 weeks, it
causes masculinization of female foetus’s genitals. FDA
pregnancy (cat X). Progestin exposure is associated with increase
prevalence of cardiovascular abnormalities
ii. Combined Oral contraceptive pills, when taken during early
stages of unrecognised pregnancy, are believed to be teratogenic
agents.
iii. Diethylstilboestrol [DES] (Human teratogen Cat X):
Commonly used in 1940’s & 1950’s to prevent abortion; in 1971
determined that DES caused increase incidence of vaginal &
cervical cancer in women who had been exposed to DES in utero.
In addition, high percentage suffers from reproductive
dysfunction (Vaginal adenosis, cervical erosions, Transverse
vaginal ridges and vaginal adenocarcinoma).

3.3 Mode of Action of Drug Used in Diabetes Mellitus (Dm)

Diabetes Mellitus (DM) is a chronic disease resulting from deficiency in

glucose metabolism, caused by relative or complete deficiency in insulin
secretion from the beta cells of the pancreas resulting in chronic increase
blood sugar(hyperglycaemia).

Symptoms of DM includes Polyuria, Polydipsia, and Polyphagia. For

public health purposes, patient will notice presence of ants where they pass

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urine and often in severe cases crystal where deposit where the sites.
Urine also tastes sweet. Patient with NIDDM tends to lose weight despite
excessive eating.

3.3.1 Two types of DM

i.Insulin dependent diabetes mellitus (IDDM) or type -1, often referred as

referred to as juvenile-onset with no insulin secretion.
ii.Non-insulin-dependent diabetes mellitus (NIDDM) or type. Referred to
as maturity onset or adult onset diabetes with relative (deficiency)
secretion of insulin.

Insulin is released from the beta cells of the islet of Langerhans in the
pancreas in response to an increase in blood glucose. Insulin promotes the
uptake of glucose, protein (amino acids), and fatty acids transport and
storage in the liver and body tissues.

Glucose is converted to glycogen for future needs in the liver and muscle
after meals. Usual blood glucose level in the blood is 70 – 110mg/dL).
Blood glucose greater than 180mg/dL result in secretion of sugar in urine
with diuretic effects – Polyuria.

Drugs used to control diabetes mellitus – a chronic disease that affects

carbohydrate metabolism.

There are two groups of antidiabetic agents: insulin and oral

hypoglycaemic agents

i.Oral hypoglycaemic agents are synthetic preparations that stimulate

insulin release or alter metabolic response to hyperglycaemia
ii.ii. Insulin is a protein secreted from the beta cells of the pancreas, it is
necessary for carbohydrate metabolism and plays an important role in
protein and fat metabolism.

3.3.2 Mode of action of specific antidiabetic agents

i. Insulin: Mode of Action

Insulin can be produced from animals (Pork or Beef), or from
humans using DNA technology. Insulin promotes the uptake of
glucose, protein (amino acids), and fatty acids transport and
storage in the liver and body tissues.

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Types of insulin: there are 3types of insulin

Rapid -acting – regular insulin: onset of action = 30 -60 minutes; with

duration 6 to 8 hours.

Intermediate -acting – NPH, Lente- contain protamine (a protein that

prolongs the action of insulin): onset of action = 1 – 2hours; peak = 6 to
12 hours with duration 18 to 24hours

Long -Acting – Ultra Lente – contain 1g crystal which dissolves slowly

to prolong duration. Duration: onset of action is 4 to 8hour and peak 14 to
20hour; duration of action is 24 to 36hours.
Available also are

Insulin lispro (Humalog) – a new rapid onset insulin approved in 1996

ha on of onset in 5 minutes; but duration of actions is 2 -4hours. It can be
administered 5 minutes before meal time.

Insulin Combinations: There are combinations of insulin commercially

premixed; Humulin 70/30, Novolin 70/30 and Humulin 50/50 (70/30 =
70% NPH and 30% regular).
Usually concentrations of insulin are 100U/mL, and insulin is packaged in
a 10mL vial.

Insulin is given parenterally only.

Insulin Cannot be administered orally. It is destroyed by first pass
metabolism in the GIT

Adverse effects of Insulin: Hypoglycaemia, Hypersensitivity reactions

and Lipodystrophy (tissue atrophy or hypertrophy at injection site)

Oral Hypoglycaemic Agents

ii.Sulphonylureas: (Tolbutamide – short acting, Chlorpropamide –

long acting)

Mechanism of action: Stimulates beta cells to secrete insulin

Uses: Non-insulin dependent Diabetes Meletus (NIDDM)

Adverse effects: Similar to Insulin-Hypoglycaemia and Hypersensitivity

reactions.

Drug-drug interactions: Aspirin, anticoagulant, anticonvulsants,

Sulfonamides and some NSAIDs.

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iii.Non-sulfonylureas: (Newer agents)

Biguanides: (Metformin (Glucophage)

Mechanism of action

It decreases hepatic production of glucose from stored glycogen which

result in decrease blood glucose level after meals. Decrease absorption of
glucose from the small intestine. Also increase in insulin receptor
sensitivity. And advantage of no hypoglycaemia effects.

Adverse effects: Nausea, anorexia and vomiting. Abdominal

crampingand flatulence.

iv.Alpha - Glucosidase inhibitor (Acarbose)

Mechanism of Action: Inhibits the digestive enzyme in small
intestine responsible for the release of glucose from the complex
carbohydrates (CHO) in diets. This prevent CHO absorption and
therefore excretion without absorption.

Uses: For patients who do not achieve result with diet alone.

Adverse effects: Weight loss

v.Thiazolidinediones: Troglitazones: (Troglitazones Unrelated to

other antidiabetic drugs)

Mechanism of action:Decreases insulin resistance, and helps muscle

cells respond to insulin and effect to utilisation of glucose.
Uses: May be used with sulfonylureas, metformin, or insulin
Adverse effects: Similar to sulfonylureas but do not cause hypoglycaemia

vi.Hyperglycaemic Drugs (Glucagon):

Mechanism of Action: A Hyperglycaemic hormone secreted by alpha

cells of the islets of Langerhans. Glucagon causes increase blood sugar by
stimulating glycogenolysis (breakdown to glucose) in the liver (protects
body cells).

Uses: Insulin induced hypoglycaemia when other methods are not

available or not working

Adverse effects: Commonly causes hypoglycaemia

vii.Diazoxides (Proglycem)
This is chemically related to thiazides diuretics

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Mechanism of action: Increase blood sugar by inhibiting insulin release

from the beta cells and stimulating release of epi (adrenaline from the
adrenal medulla).

Uses: Chronic hypoglycaemia caused by hyperinsulinism due to islet cell

carcinoma or hyperplasia. Parenteral form is used for malignant
hypertension.

Adverse effects: Usually do not cause hypoglycaemia.

3.4 Mode of Action of Drug Used in Cardiac Failure

Heart failure occurs when cardiac output is inadequate to provide the

oxygen needed by the body. As a state in which the heart cannot provide
sufficient cardiac output to satisfy the metabolic needs of the body
It is commonly termed congestive heart failure (CHF) since symptoms of
increase venous pressure are often prominent. Heart Failure is the final
common pathway for many cardiovascular diseases whose natural history
results in symptomatic or asymptomatic left ventricular dysfunction.
Cardinal manifestations of heart failure include dyspnea, fatigue and fluid
retention. Risk of death is 5-10% annually in patients with mild symptoms
and increases to as high as 30-40% annually in patients with advanced
disease.

3.4.1 Main causes of heart failure

Coronary artery disease, Hypertension, Valvular heart disease,

Cardiomyopathy and Cor pulmonale.

Causes of left ventricular failure: This includes; Volume over load:

Regurgitate valve High output status, Pressure overload: Systemic
hypertension, outflow obstruction; Loss of muscles: as in Post MI,
Chronic ischemia Connective, tissue diseases Infection, Poisons (alcohol,
cobalt, Doxorubicin) and Restricted Filling: Pericardial diseases,
Restrictive, cardiomyopathy and tachyarrhythmia.

3.4.2 Cardiac Function

Dependent upon: Adequate amounts of ATP, Adequate amounts of Ca++,

Coordinated electrical stimulus and Adequate Amounts of ATP, which is
needed to maintain electrochemical gradients; Propagate action potentials,
Power muscle contraction, Adequate Amounts of Calcium
Calcium is ‘glue’ that links electrical and mechanical events.
Coordinated Electrical Stimulation
Heart capable of automaticity

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3.4.3 Pathophysiology of Cardiac Performance

From haemodynamic stand point HF can be secondary to systolic

dysfunction or diastolic dysfunction

i.Preload: is the volume of the blood that fills the ventricles in diastole,
when it is increase, it causes the overfilling of the heart which
increases the work load. Starling Law: within limits, the
Ventricular performance is related to the degree of myocardial
stretching. When Lt Ventricular performance (e.g. stroke volume
or CO) is plotted as a function of LV function curve, therefore
when preload is increase, it leads to increase in ventricular
stretching and will enhance the ventricular function. The limit is
End Diastolic Pressure (EDP) of 15mmHg when plateau of
performance.

On the other hand, marked stretching causes deterioration of ventricular

function and EDP of 20mmHg or more result in pulmonary congestion. In
HF, preload usually increases because of increase in blood volume and
venous return. Reduction of preload is the goal of salt restriction and
diuretic therapy. Vasodilators also reduce preload by redistributing the
blood into peripheral veins away from the heart.

ii. Afterload – is the systemic vascular resistance against the heart

must pump the blood, this frequentlyincreases CHF which leads
to decrease CO.
This set the stage for the use of drugs that decrease arterial tone in
CHF.

iii. Contractility: in patient with low output failure, there is

reduction in the intrinsic contractility of myocardium resulting in
reduction of pump performance; here comes the role of +ve
inotropic drugs
iv. Heart Rate: which is the major determinant of CO (i.e. CO =
S.V. x Heart rate). The heart rate increases as the SV decreases,
this is the 1st compensatory mechanism
Neurohormonal changes

Neuro - hormonal reflex involves; The sympathetic nervous and the renin–
angiotensin–aldosterone system. These compensatory mechanisms
increase the work of the heart and can further contribute to the decline in
the cardiac function.

v. Myocardial Hypertrophy: Is the most important intrinsic

compensatory mechanism, the increase in myocardial mass helps

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to maintain cardiac performance in the phase of pressure or volume

overload. However, after initial beneficial effect, hypertrophy can lead to
ischaemic changes, impairment of diastolic filling and alteration in
ventricular geometry (remodelling) due to proliferations of abnormal
myocardial cells and CT which die at the accelerated rate leaving the
remaining myocardial cells subject to even greater overload.

Symptoms HF: Orthopnoea, paroxysmal nocturnal dyspnea, Low

cardiac output symptomsand Abdominal symptoms: Anorexia, nausea,
abdominal fullness, Rt hypochondrial pain.

3.4.4 Drug Used to treat CHF

i.Cardiac inotropic agents: Cardiac Glycosides (Digoxin, Digitoxin,

Ouabain)
ii.Sympathomimetics (Β1 -adrenergic agonist): (dopamine, dopamine)
iii.Phosphodiesterase inhibitors (amrinone, milrinone)
iv.Diuretics (Loop diuretics e.g. Frusemide, K+ sparing diuretics e.g.
Spironolactone)
v.ACI –Captopril, Enalapril, Lisinopril
vi.ARB – Candesartan, Losartan, Valsartan
vii.Beta Blockers - Bisoprolol, Carvedilol
viii. Other possible medications that might be prescribed are
anticoagulants (blood thinners). These drugs may be prescribed if
you are a heart failure patient with atrial fibrillation, or have
another problem with your heart where adding this drug is
indicated. Anticoagulants are not used to treat heart failure without
the presence of atrial fibrillation. Cholesterol lowering drugs
(statins)
Your doctor may prescribe this class of medication if you have high
cholesterol or have had a heart attack in the past.

CARDIAC GLYCOSIDES

i.Digoxin

Cardiac glycosides come from the plants of foxglove family (Digitalis

spp) & related plant. Digitalisis one of the oldest drugs in clinical use
(1200AD). There are two types in clinical use –Digoxin and Digitoxin
Digoxin -Chemistry: The basic structure of glycosides consists of three
components; A sugar moiety, A steroid moiety & A lactone.
The sugar moiety consists of unusual 1 -4 chains linked monosaccharides
A steroid nucleus containing an unsaturated lactone at C- 17 position and
Glycosides residue at C-3. The lactone ring is essential for activity and can
retain biological activity even when the steroids is removed.

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Digoxin –Mode of Action

It is thought that digitalis increases vagal activity and inhibits Na+/K+

ATPase in myocytes this leads to a transient increase’s intracellular
concentration of Na+ leading to increases influx of Ca++ via Na/Ca2+
exchanger. This result in increased contractility (Positive inotropic effect).
Increased parasympathetic (Vagal) tone and decreased sympathetic effect
on the heart this suppressed AV node conduction increasing refractory
period, thereby decrease conduction velocity and result in decreased heart
rate.

This result in increased CO through their +ve inotropic effect. They slow
heart rate by relieving the sympathetic tone & through their vagotonic
effects. They reduce the heart size by reliving Frank –Starling relationship.

They increase cardiac efficiency by increasing CO, force of cardiac

contractility, decrease O2 consumption (decrease heart size & rate).
Blood Pressure – Remain unchanged following the administration of
cardiac glycosides.

In CCF, the CO is reduced but the total peripheral resistance is increased,

& these effects are reversed by cardiac glycosides.

Cardiac glycosides bring about diuresis by increasing both CO & renal

blood flow; the latter in turn reverses the renal compensatory mechanism
activated in CCF. Consequently, the production of aldosterone is reduced,
sodium retention is reversed, & the excretion of oedematous fluid. Cardiac
glycosides have vagotonic effect & may decrease impulse formation in the
SA nodes. Although automaticity is not directly influenced by digitalis
conductance velocity is decreased. The electrophysiologic properties of
digitalis make it a useful compound in the treatment of atrial arrhythmias
(for its vagotonic effect).Atrial flutter (for its depressant effect on
atrioventricular conductance). Atrial fibrillation (also for its vagotonic
effects)

Digoxin: Clinical Benefit: Decreases morbidity in patients with heart

failure, does not decrease mortality, improves symptoms of CCHF, CHF
refractory to other drugs, can be combined with other drugs and
Withdrawal of digoxin in stable patients carries considerable risk.

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Indications: Moderate/severe systolic CHF and bradycardia

Digoxin: Adverse Effects: This is frequent and may be fatal. Toxicity

may result from overdose or decrease in metabolism and excretion.
Hypokalaemia (stemming from the use of thiazides diuretics, diarrhoea &
vomiting), Arrhythmias occurring de novo –Atrial/Ventricular ectopic,
bradycardia (pulse < 60b/min). CHF exacerbation, Visual disturbances
(blurred or yellow vision, halos), Gastrointestinal (Anorexia, nausea,
vomiting and diarrhoea), Psychiatric (Delirium, fatigue, malaise,
confusion, dizziness and abnormal dreams and Headache), Pulmonary
disease, Renal insufficiency and Hypoestrogenism.

Contraindications: The following agent are C/I

Quinidine – Should not be used with digoxin because it displaces digoxin

from binding sites.

Bretylium should not be used with digoxin because it releases

Norepinephrine.
Carotid sinus stimulation should be discouraged as it may precipitate
ventricular fibrillation.

Drug treatment of Digoxin toxicity

Antidigoxin Antibodies: The antidigoxin or the antidigoxin antibodies

(Digibind) have been used to control digoxin intoxication.
β Stimulants: Dopamine; Peripheral dopaminergic receptor agents are
useful in the useful in the treatment of CCF

Diuretics: These include; Thiazides: (chlorothiazide &

hydrochlorothiazide

(HCTZ), Loop Diuretics (furosemide, bumetanide) and Potassium Sparing

Diuretics (spironolactone).

Mechanism of Actions: Diuretics derived its mode of action from the

principle that water follows Sodium(Na+). 20-25% of all Na+ is
reabsorbed into the blood stream in the loop of Henle. 5-10% in distal
tubule & 3% in collecting ducts. If it cannot be absorbed it is excreted with
the urine.

Diuretics reduces venous pressure and ventricular preload. This results in

reduction of oedema and cardiac size, which improves pump efficiency.
Aldosterone: Aldosterone may cause myocardial and vascular fibrosis
and baroreceptor dysfunction in addition to its renal effects. For this
reason, the aldosterone antagonists, spironolactone and eplerenone,

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decrease morbidity and mortality in severe heart failure. (M.H., Farjoo

Jan. 2007)

Adverse effects of Diuretics: Side effects of diuretics include; electrolyte

losses [Na+ & K+], Dehydration fluid losses [dehydration], Myalgia,
Nausea, Vomiting and diarrhoea, Dizziness and Hyperglycemia.

Contraindications: Renal Failure.

iii. Other drugs use in heart failure

Angiotensin Converting Enzyme Inhibitors (ACEI).

ACE Inhibitors & ARBs
These drugs reduce peripheral resistance and afterload.
They also reduce salt and water retention and, in that way, reduce preload.
The reduction in tissue angiotensin also reduces sympathetic activity.
These drugs reduce the long-term remodelling of the heart and vessels.

Calcium Channel Blockers (CCB) (diltiazem, verapamil, nifedipine)

Mechanisms of Action CCB:

i. Decrease automaticity & conduction in SA & AV nodes

ii. Decrease myocardial contractility
iii. Decreased smooth muscle tone
iv. Decreased Peripheral vascular resistance (PVR)

Adverse effects of CCBs: Cardiovascular: hypotension, palpitations and

tachycardia, Gastrointestinal: constipation & nausea and Others: rash,
flushing & peripheral oedema

3.5ANTIHYPERTENSIVE DRUGS

3.5.1 Normal Blood Pressure Regulation

Blood Pressure = Cardiac output (CO) X Resistance to passage of blood
through precapillary arterioles (PVR)
Physiologically CO and PVR are maintained minute to minute by
arterioles

v. Post capillary venules and Heart

vi. Kidney is the fourth site
vii. Volume of intravascular fluid
viii. Baroreflex, humoral mechanism and renin-angiotensin-
aldosterone system regulates the above 4 sites
ix. Local agents like Nitric oxide

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In hypertensives – Baroreflex and renal blood-volume control system –

set at higher level. All antihypertensives act via interfering with normal
mechanisms

Table 36: Classification of Blood Pressure levels

Category Systolic blood Diastolic blood
Pressure Pressure
(mmHg) (mmHg)
Optimal blood pressure < 120 < 80
Normal blood pressure < 130 < 85
High -normal blood pressure 130 -139 85 -89
Grade 1 Hypertension (Mild) 140 -150 90 -99
Grade 2 Hypertension (Moderate) 160 -179 90 -100
Grade 3 (Hypertension) ≥ 180 ≥ 110
Isolated systemic hypertension 140 -150 < 90
(Garde 1)
Isolated systemic hypertension ≥ 160 ≥ 90
(Garde)

3.5.2 Causes of Hypertension

i.Genetics-some people are prone to hypertension simply because of

their genetic makeup
ii.Family History- your risk for high blood pressure/hypertension
increases if it is in your family history
iii.Environment, Inactivity, Stress, Obesity, Alcohol, High Sodium
Diet, Tobacco Use, Age and Menopausal Medications
iv.intrauterine factors (the ‘Barker hypothesis’) is supported by the
finding that hypertension in adult life is strongly associated with
low birth weight.

3.5.3 Antihypertensive Agents: Classifications

i. Angiotensin-converting enzyme inhibitors (ACEI) & Angiotensin

II receptor blockers (ARBs)
ii. Diuretics
iii. Calcium channel blockers
iv. Adrenergic agents

Alpha1 blockers & Beta blockers (cardio selective and nonselective)

Centrally acting alpha blockers
Combined alpha-beta blockers
Peripheral-acting adrenergic agents

v.Vasodilators

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3.5.4 Mechanisms of Action of Specific Antihypertensive Agents

i.ACE inhibitors: Captopril, Lisinopril, Enalapril, ramipril and

fosinopril etc.

Mode of Action for ACEIs: ACE Inhibitors work in the lungs to inhibit
Angiotensin Converting Enzyme from turning Angiotensin I into
Angiotensin II. This result in decreased BP due to a decrease in blood
volume, PR, & cardiac load. ACEI causes an increase of bradykinin which
causes protracted dry cough.

ACEI, inhibits vasoconstriction and release of aldosterone which inhibits

the retention of sodium and water

Indications for Use

Hypertension: Hypertension especially for malignant hypertension and,

Hypertension secondary to renal arterial stenosis. ACE inhibitors reduce
the risk of cardiovascular mortality caused by hypertension.”

Heart Failure: By decreasing arteriolar tone & improves blood flow to

the heart, by decreasing afterload, cardiac output increases and venous
dilation increase causing a decrease in pulmonary congestion and
peripheral oedema.
Dilates the vessels of the kidneys increasing renal flow and helps to
excrete sodium and water. This helps to decrease oedema and blood
volume. Prevents pathologic changes in the heart that result from reducing
the angiotensin II levels in the heart.

Myocardial Infarction (MI): Decreases the chance of heart failure after

an MI. Should be given for 6 weeks post MI. If heart failure occurs, it
should be considered for permanent use.

Nephropathy: Slows renal disease of diabetic or nondiabetic origins.

Decreases glomerular filtration pressure.

Indications for Use: Type 2 Diabetes -It decreases morbidity in high risk
patients. Increased levels of angiotensin II have a correlation to type 2
diabetes.

ACE inhibitors increase kinin levels, which increase production of

prostaglandins and nitric oxide. Prostaglandins and nitric oxide improve
muscular sensitivity to insulin. May preserve pancreatic function and
prevent onset of diabetes especially with people who have hypertension.

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Adverse Effects

First-Dose Hypotension: Usually occurs with initial dose. Worse in

patients with severe hypertension, or are on diuretics, or are sodium or
volume depleted.

Cough: Persistent, dry, irritating, non-productive cough can develop with

all ACE inhibitors.” (Lehne, 2007, pg. 466) Due to rise in bradykinin
which occurs due to inhibition of kinase II. Occurs in 5-10% of patients
and is more common in women and the elderly.

Hyperkalaemia: Potassium levels rise due to the inhibition of

aldosterone, which causes potassium to be retained by the kidneys.

Renal Failure: Can cause renal insufficiency in people who have bilateral
renal artery stenosis, because dropping the pressure in the renal arteries in
these patients can cause glomerular filtration to fail.

Fetal Injury: In the second and third trimesters a foetus can experience
hypotension, hyperkalaemia, skull hypoplasia, renal failure, and death.

Angioedema: swelling of lips, mouth, nose etc. Kinin accumulation may

also underly angioedema (painful swelling in tissues which can be life-
threatening if it involves the airway).

Others (Rare): Rashes, urticaria, Dysgeusia: loss or alteration of taste,

and Neutropenia etc.

Drug Interactions: Antihypertensive agents can cause an increased effect

of medications especially with diuretics.
ACEI causes Potassium increasing effects of result in an increased risk of
hyperkalaemia due to the suppression of aldosterone.

Lithium: ACEI causes an increase to risk of lithium toxicity.

Allopurinol: Increases hypersensitivity to medication

NSAIDS: Reduce antihypertensive effects of medication

Contraindications: Pregnancy: ACEI causes fetal death due bilateral

renal artery stenosis, hypersensitivity and hyperkalaemia

ii.Angiotensin Receptor Blockers (ARBs)

Examples of ARBs: Candesartan, Losartan, Valsartan, Irbesartan,
Telmisartan, eposartan and Olmesartan

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Mode of Action of ARBs: Inhibit synthesis of Angiotensin II, by

competitive inhibition of angiotensin -11 at tissue binding sites. Resulting
in decrease in peripheral resistance and blood volume. Block the receptors
in brain, kidneys, heart, vessels and adrenal tissue

Clinical indications of ARBs; Their uses include the following:

Hypertension, especially in:

a. young patients (who have higher renin than older ones)

b. diabetic patients
c. hypertension complicated by left ventricular hypertrophy.

Heart failure.

Diabetic nephropathy.

Advantage

Less likely to cause hyperkalaemia

Persistence of cough is rare
Adverse effects of ARBs
Upper respiratory infections
May cause occasional dizziness, inability to sleep, diarrhoea, dyspnea,
heartburn, back pain and fatigue

The AT1 antagonists are extremely well tolerated but are

TERATOGENIC.

iii.Direct Renin Inhibitors (Aliskiren)

Orally active renin inhibitors reduce plasma renin activity.
Licensed for treatment for essential hypertension.

iv.Calcium Channel Blockers (CCBs) (

Phenylalkylamines: Verapamil
Benzothiazepines: Diltiazem
Dihydropyridines (DHPs); 1st Generations: Nifedipine, 2nd Generations:
Isradipine, Nicardipine, Felodipine and 3rd Generations: Amlodipine

Mechanism of action (CCBs): CCBs blocks influx of Ca++ in smooth

muscle cells – relaxation of SMCs – decrease BP. Three types Ca+
channels in smooth muscles. Normally, L-Type of channels admit Ca+
and causes depolarization (excitation), contraction coupling through
phosphorylation of myosin light chain, contraction of vascular smooth
muscle – elevation of BP.

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CCBs block L-Type channel: Resulting in smooth Muscle relaxation and

causes negative chronotropic, ionotropic and chronotropic effects in heart

Dihydropyridines (DHPs) drugs have highest smooth muscle relaxation

and vasodilator action followed by verapamil and diltiazem
Other actions: DHPs have diuretic action

CCBs: Indications: Hypertension: Useful in hypertension as peripheral

arteries dilators leading to decrease peripheral vascular resistance by
relaxing vascular smooth muscle. Dysrrhymias, Angina, Migraine and
Headaches.

CCBs are used as monotherapy or in combination and is tolerated well in

renal failure. Calcium Channel Blockers has advantages of, unlike
diuretics no adverse metabolic effects, except mild adverse effects like –
dizziness, fatigue etc.

Do not compromise haemodynamic – no impairment of work capacity

No sedation or CNS effect
Can be given to asthma, angina and PVD patients
No renal and male sexual function impairment
No adverse fetal effects and can be given in pregnancy
Minimal effect on quality of life

Adverse effects: Cardiovascular: hypotension, palpitations, tachycardia.

Gastrointestinal: constipation, nausea. Other: rash, flushing, peripheral
oedema and dermatitis.
Contraindications: CCBs is contraindications unstable angina, Heart
failure, Hypotension, Post infarct cases and Severe aortic stenosis.

v.Potassium (K+) Channel activators: Diazoxide, minoxidil, pinacidil

and nicorandil.
Mode of Action: Leaking of K+ due to opening and result in
hyper polarization of SMCs and relaxation of SMCs

vi.ADRENERGIC BLOCKERS
Centrally acting Adrenergic Blockers: Alpha Methyldopa,
Clonidine
alpha-adrenergic blockers: α – adrenergic blockers: Prazosin,
Terazosin, Doxazosin, Phenoxybenzamine and Phentolamine
Non selective alpha blockers: Phenoxybenzamine, Phentolamine
Specific alpha-1 blockers: Prazosin, Terazosin and Doxazosin
Beta-adrenergic blockers
I. Non selective: Propranolol
ii. others: (nadolol, timolol, pindolol and labetolol) and
Cardioselective:

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Metoprolol (others: atenolol, acebutolol, esmolol, betaxolol)

Centrally acting Adrenergic Blockers (Alpha Methyldopa, Clonidine)

Mechanism of Action: They act on alpha-2 receptors in the brain and
causes inhibition of adrenergic discharge in medulla (inhibit sympathetic
outflow)– fall in PVR and fall in BP.
Uses: Central acting Adrenergic blockers are use in hypertension, either
alone or with other agents. Usually used after other agents have failed due
to side effects.

Alpha-Methyldopa (Aldomet): Is a prodrug, a precursor of Dopamine

and Noradrenaline’. It is converted to alpha methyl noradrenaline which
acts on alpha-2 receptors in the brain and causes inhibition of adrenergic
discharge in medulla.

Uses: Drug of Choice in Hypertension during pregnancy. Also, may be

used for treatment of severe dysmenorrhea, menopausal flushing, and
glaucoma.

Adverse effects: Various adverse effects –Sedation, Dry mouth, blurred

vision, cognitive impairment, postural hypotension and positive coomb`s
test etc.

Contraindications – Depression, Caution in renal impairment.

vii.Beta-adrenergic blockers

Non selective: Propranolol (others: nadolol, timolol, pindolol and

labetolol) and Cardioselective: Metoprolol (others: atenolol, acebutolol,
esmolol, betaxolol)

Mechanism of Actions: Bind to beta adrenergic receptors and blocks the

activity. All beta-blockers have similar antihypertensive effects –
irrespective of additional properties. They cause reduction in CO but no
change in BP initially but slowly. Adaptation by resistance vessels to
chronically reduced CO – antihypertensive action.

Other mechanisms included decreased renin release from kidney (beta-1

mediated), reduction decreased central NA outflow, reduction in
glomerular filtration rate (non-selective ones) and reduction in heart rate
and CO (ISAs).

Contraindications: Partial and complete heart block, COAD and asthma,

Peripheral vascular disease.

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Adverse effects: Major drawbacks are Rebound hypertension, Raised

LDL and lowered HDL and impaired carbohydrate tolerance in diabetics,
Fatigue, lethargy (low CO?) – decreased work capacity, Loss of libido –
impotence, Cognitive defects – forgetfulness and nightmares etc.
Difficult to stop suddenly, therefore cardio-selective drugs are preferred
now

Cardio- selective Beta-adrenergic blockers: Metoprolol (others: atenolol,

acebutolol, esmolol, cetamolol).

Mechanism of Action: Vasodilators: Directly relaxes arteriolar smooth

muscle Result: decreased systemic vascular response, decreased afterload,
and peripheral vasodilation.

Advantages of cardio-selective over non-selective and can be use in

patients with asthma, diabetes mellitus, peripheral vascular disease and
also lower incidence of changes in lipid profile

Advantages: Overall: beta-blockers as first line of drug

i. No postural hypotension
ii. No salt and water retention
iii. Low incidence of side effects
iv. Low cost
v. Once a day regime
vi. Cardio protective potential

Preferred: In young non-obese patients, Prevention of sudden cardiac

death in post infarction patients and progression of CHF, Angina pectoris
and post angina patients, Post MI patients – useful in preventing mortality
and in old persons, carvedilol – vasodilatory action can be given

Uses: Treatment of hypertension, may be used in combination with other

agents, Sodium nitroprusside and diazoxide IV are reserved for the
management of hypertensive emergencies.

Adverse Effects: Hydralazine: dizziness, headache, anxiety, tachycardia,

nausea and vomiting, diarrhoea, anaemia, dyspnea, oedema and nasal
congestion.
Sodium nitroprusside: bradycardia, hypotension, possible cyanide
toxicity.

Vasodilators: Hydralazine: Directly acting vasodilator

Mechanism of Action: Hydralazine molecules combine with receptors in
the endothelium of arterioles causing NO release consequent relaxation of

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vascular smooth muscle – fall in BP. Causes fall in BP due to stimulation

of adrenergic system leading to

Uses: Moderate hypertension when 1st line fails – with beta-blockers and
diuretics, Hypertension in Pregnancy,

Adverse Effects: Cardiac stimulation producing palpitation and rise in

CO even in IHD and patients – anginal attack resulting in tachycardia,
increased Renin secretion – Na+ retention. These effects are countered by
administration of beta blockers and diuretics (controversial).

Sodium Nitroprusside: Rapidly and consistently acting vasodilator

Mechanisms of Actions: RBCs convert nitroprusside to NO – relaxation

also by non-enzymatically to NO by glutathione and relaxes both
resistance and capacitance vessels and reduces total peripheral resistance
and CO (decrease in venous return). Unlike hydralazine it produces
decrease in cardiac work and no reflex tachycardia.

Uses: Hypertensive Emergencies: in saline/glucose and infused slowly

with 0.02 mg/min initially and later on titrated with response (wrap with
black paper).

Improves ventricular function in heart failure by reducing preload

Adverse effects: palpitation, pain abdomen, disorientation, psychosis,

weakness and lactic acidosis.

3.6 Mode Action of Drug Use in Pain Management

3.6.1 Introduction

Pain is the most COMMON reason clients seek medical advice. Pain is a
protective mechanism or a warning to prevent further injury
“But pain is a perfect misery the worst of evils Excessive Overturns All
patience” John Milton in Paradise Lost.

3.6.2 Clinical types of pain

Pain stimuli (Mechanical / thermal stimuli) Fast pain: Sharp well
localized, pricking type.
Chemical stimuli; Slow pain: poorly localised, dull, throbbing (K+, ADP,
ATP – Bradykinin, histamine – Serotonin, Prostaglandins, Substance P,
CGRP)
Somatic, Visceral, Referred pain: Convergence & facilitation theory
Projected pain: Radiating Pain, Hyperalgesia

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3.6.3 Analgesic classifications:

Analgesics: Drugs which relieve pain due to multiple causes without

causing loss of consciousness.

Drugs which relieve pain due to single cause or specific pain syndromes
(ergotamine, carbamazepine, nitrates) are not classified as analgesics.
Corticosteroids also not classified as analgesics
Analgesics are classified as: Opioid analgesics e.g. Morphine and
morphine like drugs, Non-steroidal anti-inflammatory drugs (NSAIDs)
e.g. Paracetamol, diclofenac, ibuprofen etc.

Mechanisms of actions specific analgesics

i.Opioid Analgesics: All opioid analgesics mimic endogenous endorphins

by stimulating opioid receptors in the central and peripheral nervous
systems which results in relief of pain. Opioids are particularly useful in
pain management as they: Hyperpolarize second-order pain transmission
neurons by increasing K+ conductance, evoking an inhibitory
postsynaptic potential reduce transmitter release from presynaptic
terminals of nociceptive primary afferents the descending control system,
showing the main sites of action of opioids on pain transmission.

Adverse Effects: The toxic effects of morphine are an extension of their

pharmacological effects. Idiosyncrasy and allergy – Urticaria, itch,
swelling of lips and bronchospasm (these are rare). A local reaction at
injection site may occur due to histamine release. Allergy is uncommon
and anaphylactoid reaction is rare. Apnoea This may occur in new born
when morphine is given to mother during labour. Others are death due to
respiratory failure, Respiratory depression, Nausea and vomiting,
Constipation and Drowsiness and sedation.

Contraindications: Some reasons that people should not use opioids

include:

Significant respiratory disease; Comatose patients, unless near death; and

Pheochromocytoma (in some cases).

Precautions: Care should be exercise in the following conditions; Infants

and the elderly, patients with Bronchial asthma, Head injury, Hypotensive
states and hypovolemia, Undiagnosed acute abdominal pain,
Hypothyroidism, liver and kidney disease and patients with Unstable
personalities.

Drug interactions: Drugs which potentiate morphine are Phenothiazines,

TCA, MAO inhibitors, Amphetamine and Neostigmine. Morphine retards

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absorption of many orally administered drugs by delaying gastric

emptying.
Uses: Morphine / parenteral congeners indicated as analgesic in traumatic,
visceral, ischaemic (myocardial infarction), Postoperative, burns, and
cancer pain. Relieves anxiety and apprehension in serious and frightening
disease accompanied by pain: myocardial infarction, Surgeries: Epidural
and intrathecal injection of Morphine is being used for analgesia in
abdominal, lower limb and pelvic surgeries, labour, postoperative, cancer
and other intractable pain.
Preanesthetic medication. produces segmental analgesia for 12 hours
without affecting sensory, motor or autonomic modalities.

ii. Codeine (Methyl Morphine)

Codeine is low-efficacy opioid a prodrug (t1/2 3 h). It lacks efficacy for
severe pain, most of its actions 1/10th those of morphine. Large
doses cause excitement. Dependence much less than with
morphine.
Uses: principal use: mild to moderate pain & cough. It is said that
60 mg codeine = 600 mg aspirin.

iii. Pethidine
Pethidine differs from morphine in that it does not usefully
suppress cough, less likely to constipate, less likely to cause urinary
retention & prolong childbirth little hypnotic effect. shorter
duration of analgesia (2-3 h).

iv. Methadone
Principal feature of methadone is long duration, analgesia may last
for 24 h. If used for chronic pain in palliative care (12- hourly) an
opioid of short t ½ should be provided for breakthrough pain rather
than an extra dose of methadone. Also used in opioid withdrawal•
Dose: 2.5 mg to 10 mg oral or IM

v. Fentanyl: Pethidine congener 80-100 times potent than morphine

in analgesia and resp. depression

Uses: Injectable form exclusively used in anaesthesia. Transdermal patch

available used in cancer or other types of chronic pain.

vi. Dextropropoxyphene: Less analgesic, antitussive, and less

dependence. Its analgesic usefulness equal to codeine. Commonly
combined with paracetamol. Dextropropoxyphene interacts with
warfarin, enhancing its anticoagulant effects.

vii. Tramadol: Relieves pain by opioid as well as other mechanisms,

100 mg IV Tramadol = 100 mg IM morphine.

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Adverse effects: Less respiratory depression, sedation, constipation,

urinary retention, increase intraciliary pressure & dependence than
morphine. As effective as pethidine for postoperative pain and as
morphine for moderate chronic pain.

viii. Pentazocine: Weak µ antagonist action and marked κ agonist

action. Analgesia is primarily spinal (K1). can cause a withdrawal
syndrome in addicts. shorter duration of pain relief 4-6 hrs, less
dependence, sedation & resp. depression• Use: post-operative,
moderately severe burns.

ix. Non-opioid analgesics

Non-opioid analgesics include nonsteroidal anti-inflammatory
drugs (NSAIDs), selective COX-2 inhibitors, and acetaminophen.

Mechanisms of Actions: NSAIDs inhibit cyclooxygenases (COX-1 and

COX-2), thereby disrupting the production of prostaglandin, an
important mediator of pain and inflammation. Consequently,
NSAIDs possess antipyretic, analgesic, and anti-inflammatory
effects, and are particularly effective in the management of
musculoskeletal pain (e.g., rheumatic disorders, inflammatory joint
pain).
Acetaminophenpossesses antipyretic and analgesic effects and is
the most commonly used over-the-counter (OTC) oral analgesic
drug. It is generally well tolerated, but overdose can result in
significant hepatotoxicity with the risk of acute liver failure.

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Table 37: Classification of NSAIDs

Drug Class Common Activity Side effects
agents profile
Nonsteroidal •Ibuprofen •Analgesic •Gastric and
anti- •Diclofenac •Antipyretic intestinal ulcers,
inflammatory •Indomethacin •Anti- bleeding, and
drugs •Naproxen inflammatory perforation
•Ketorolac •Antiplatelet •Renal function
•Aspirin effect impairment
•Meloxicam •Acute renal failure
•Deterioration of
chronic renal failure
•Chronic analgesic
nephropathy
•Increased risk of
heart attack and
stroke (with the
exception of aspirin
and naproxen).
COX-2 •Celebrex Celebrex •Increased
inhibitors (celecoxib) (celecoxib) cardiovascular risk
(selective •Renal side effects
NSAID) •Deterioration of
chronic renal failure
•Increase in blood
pressure
Other non- •Acetaminophen •Analgesic •Hepatotoxicity
opioid •Antipyretic •Acute liver failure
analgesics in cases of
intoxication
•Limited
nephrotoxicity
@AMBOSS

NSAIDs Agents: (Ibuprofen, diclofenac, indomethacin, naproxen,

aspirin)

Mechanism of action
Reversible inhibition of the enzyme’s cyclooxygenase 1 and 2 (COX-1
and COX-2) → decreased prostaglandin synthesis.
Effects includes Analgesic, Antipyretic and Anti-inflammatory
(antirheumatic).
With the exception of aspirin, only minor antiplatelet function

Adverse effects: Gastric and duodenal ulcers with the risk of

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gastrointestinal bleeding and perforation, Risk increases with duration and

dose of treatment, Prophylaxis: simultaneous administration of proton
pump inhibitors, Increased risk of heart attack and stroke (with the
exception of aspirin and naproxen), Renal function impairment:
prostaglandins normally maintain renal blood flow by inducing
vasodilation of the afferent arterioles. NSAIDS inhibits prostaglandin
production, which leads to harmful hypoperfusion of the kidneys and
reduced GFR. Electrolyte and fluid abnormalities (oedema,
hyperkalaemia, hyponatremia). Worsening of hypertension. In rare cases,
acute renal failure

Analgesic nephropathy: prolonged NSAID use results in tubulointerstitial

nephritis and papillary necrosis (increase creatinine/BUN ratio, slight
increase K+). Pseudo allergic reactions, Urticaria and angioedema and
Asthma - Aspirin-exacerbated respiratory disease (AERD)

Indications
i. Acute pain, rheumatoid arthritis, non-rheumatoid joint pain
ii. Especially as an alternative to nonselective NSAIDs for patients
with a history of peptic ulcer disease and platelet disorders (e.g.,
Glanzmann thrombasthenia)
iii. Contraindications
iv. Severe heart failure, recent myocardial infarction, gastrointestinal
bleeding

Other non-opioid analgesics Agent

Acetaminophen

Mechanism of Action: Reversibly inhibits cyclooxygenase in the CNS.

Is peripherally inactivated no anti-inflammatory effect, minimal gastric
side effects

Effects: antipyretic and analgesic effects

Adverse effects

i. Hepatotoxicity due to acetaminophen overdose

ii. Minimum toxic dose: 7.5 g/day in adults
iii. Leading cause of acute hepatic failure in the US. Exhaustion of
hepatic metabolic pathways causes increased formation of a
toxic metabolite of acetaminophen, N-acetyl-p-
benzoquinoneimine (NAPQI). Glutathione initially inactivates
NAPQI, but its reserves are eventually depleted, leading to
NAPQI build-up. NAPQI causes irreversible oxidative
hepatocyte injury → liver cell necrosis.
iv. Acute kidney failure occurs in approx. 50% of patients with acute
hepatic failure.

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Uses: Fever and pain (Good tolerability)

Preferred analgesic/antipyretic drug during pregnancy
Contraindications: Severe liver impairment - Maximum daily dose of
acetaminophen: 4 g (adults).

3.7 Prescription in Pregnancy And Lactation

3.7.1 Introduction

The prevalence of medication use during pregnancy is widespread and on

the rise. More than 80% of pregnant women take over the counter (OTC)
or prescription drugs during pregnancy, with only 60% of these patients
consulting a health care professional when selecting a product. There is a
delicate risk-benefit estimation concerning the health of both the mother
and the foetus that must be considered in the use of drugs during
pregnancy. There is limited research data on drugs during pregnancy and
breast-feeding. Women of reproductive age, infants and children were
historically excluded from drug research trials. Hence data from adult men
had to be “translated” or “extrapolated” to pregnant/ nursing women as
well as children until in the 1990’s, research standards shifted.

In general, drugs should NOT be used during pregnancy unless absolutely

necessary as many can harm foetus. About 2-3% of all birth defects result
from drugs that are taken to treat disorder or symptom.
Physicians, Pharmacists and Public health practioners play a vital role in
educating and counselling pregnant women on the risks associated with a
drug. Informing a pregnant woman of the risks and possible fetal defects
can reduce the number of complications. Certain health conditions and/or
risk factors that may pose significant risks to woman and/or foetus. These
are; Asthma, Anaemia/ blood disorder, Diabetes, Epilepsy, Hypertension,
infection, pre-existing obesity and underlying mental health conditions
etc. Others are maternal advanced age, maternal personal and family
medical history and lifestyle choices etc.

3.7.2 How a drug affects the foetus:

How a drug affects the foetus depends on the foetus’s stage of

development and the strength and dose of the drug. Generally, women who
are at the risk of conceiving or who wish to become pregnant should
withdraw all unnecessary medications 3-6 months before conception.
Certain drugs taken early in pregnancy (15-21 days after fertilization)
during the period of blast genesis may act in an all or nothing fashion;
Killing the foetus or not affecting it at all. During this early stage the foetus
is highly resistant to birth defects.

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The foetus is highly vulnerable to birth defects between 3rd week and 8th
week after fertilization; which is the period of organogenesis. At this stage
drugs may cause a miscarriage, an obvious birth defect, or a permanent
but subtle defect, that is noticed later in life. At 9th week the embryo is
referred to as a foetus. Development during this time is primarily
maturation and growth. Exposure to drugs during this period is not
associated with major congenital malformations but they may alter the
growth and function of normally formed organs and tissues.

3.7.3 Potential impact of drugs on fetal growth and development

i.Teratogen: a medicine or other chemical capable of producing a

permanent structural or functional birth defect, growth
impairment, or fetal death.

Teratogen acts with specificity to produces a specific abnormality or

constellation of abnormalities. Example, thalidomide produces
phocomelia, and valproic acid produces neural tube defects. Teratogens
demonstrate a dose-effect relationship.
Teratogen must reach the developing conceptus in sufficient amounts to
cause their effects. The effect that a teratogenic agent has on a developing
foetus depends upon the stage during development when the foetus is
exposed.

ii.Teratogenic agents

Infections: collectively grouped under the acronym TORCH for

Toxoplasmosis, Other organisms (parvovirus, HIV, Epstein-Barr, herpes
6 and 8, varicella, syphilis, enterovirus), Rubella, Cytomegalovirus and
Hepatitis etc.

Maternal diet: the best characterised is the role of low folic acid and
Neural Tube Defects (NTDs). More recently the focus has been on dietary
iodine levels and the role they also play on neural development.

Maternal drugs: affects either prescription drugs (therapeutic

chemicals/agents, thalidomide limb development), non-prescription drugs
(smoking), and illegal drugs (Cannabis/Marijuana,
Methamphetamine/Amphetamine, Cocaine, Heroin and Lysergic Acid
Diethylamide).

Environment Factors: (smoking, chemicals, heavy metals, radiation) and

maternal endocrine function (maternal diabetes, thyroid development) and
maternal stress.
Teratogen synergism, different environmental effects can act individually
or in combination on the same developing system. For example, neural

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development can be impacted upon by alcohol (fetal alcohol syndrome),

viral infection (rubella) and/or inadequate dietary folate intake (neural
tube defects). These effects may also not be seen as a direct effect on a
system or systems but result in a reduced birth weight and the potential
postnatal developmental effects. Consider also this in relation to the
increasing support to the fetal origins hypothesis

Table 38: Effects of teratogens at various stages of fetal development

Stages of Fetal development Effects of teratogen exposure
Pre-implantation “All or Nothing”
Conception - week 2
Embryonic Period Gross Malformations,
Week 3 -8 Anatomic abnormalities
Fetal Period Effects are usually functional
Week 9 – term (Rather than anatomic structure)

Figure35: Effects of teratogens at various stages of development of the

foetus. (@ Moore KL1993.)

iii. Teratogenesis: A teratogen is a chemical substance that can induce

a malformation during development.
It is the greatest concern for many, the incidence of major structural
abnormalities (i.e. life-threatening or require surgical correction)
is between 1-3% of births. Half are identified at/near birth; half are
identified later or on autopsy. The incidence of minor structural
abnormalities is unknown as well as the incidence of functional
abnormalities.

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Mechanisms of Teratogenesis: Genetic interference (25%), gene

mutation, chromosomal breakage, interference with cellular
function, enzyme inhibition, and altered membrane characteristics.
The response of the developing embryo to these result in failure of
cell–cell interaction crucial for development, interference with cell
migration, or mechanical cellular disruption.

iv. Pregnancy Risk categories: FDA Risk Categories (Do the Benefits
Outweigh the Risks?)

Drug use during pregnancy continues to remain a major concern due to

the unknown effects on mother and foetus. To help guide physicians in
their selection and interpretation of the risks associated with the drug, the
FDA introduced a drug classification system in 1979 (Table.). 1983 FDA
classified drugs into 5 categories according to probable risks to foetus see
table below. Most information provided in this classification is derived
from animal studies and uncontrolled studies in humans such as post
marketing surveillance reports. To date, very few well-controlled studies
have been conducted in pregnant women, most likely due to ethical
considerations. Two important limitations of the classification include:

All new FDA-approved medications are classified as Category C

There are no FDA regulations requiring further studies or seeking more
data; therefore, changes in the classification are rare.
In addition, the classification is often not changed when new data become
available.

Drugs in categories A and B most likely carry little or no risk to the foetus.
Drugs in categories C and D most likely carry some risk to the foetus.
Drugs in category X are contraindicated during pregnancy.

Table 39: Risk Category of drugs during Pregnancy

Category Study outcome/Abnormality Examples
A Adequate studies in pregnant women inj. Mag sulfate,
have failed to demonstrate a risk to the thyroxine
Foetus
B Adequate human studies are lacking, but Penicillin V,
animal studies have failed to Amoxicillin,
demonstrate a risk to foetus cofactor,
Or erythromycin,
Adequate studies in pregnant women paracetamol,
have failed to demonstrate a risk to the lignocaine
foetus, but animal studies have shown
adverse effects on the foetus

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C No adequate studies in pregnant women Morphine,

and animal are lacking or have shown an codeine,
adverse effect on foetus, but potential corticosteroids,
benefit may warrant use of the drug in adrenaline,
pregnant women despite potential risk thiopentane,
bupivacaine
D There is evidence of human foetal risk, Aspirin,
but the potential benefit from use of the phenytoin,
drug may be acceptable despite the carbamazepine,
potential risk valproate,
lorazepam
E Studies in animals or humans have Oestrogen,
demonstrated foetal abnormalities, and isotretiroin,
potential risk clearly outweighs the ergometrine
possible benefit

If possible, drug therapy should be delayed until after the first trimester,
especially when there is danger of drug-induced developmental defects.
Potential fetal risks must be compared to maternal benefits when drug
therapy is required. Minimum therapeutic dose should be used for as short
a time period as possible.

3.7.4 Clinical example of approach to drug therapy in pregnant

woman

Case 1: Thlama is a 30 years old farmer with a seizure disorder who is

now pregnant. She presented you in antenatal that she in on
Carbamazepine for epilepsy. She seeks your advice on how to prevent
seizures during the pregnancy.

What would be your decision? To treat or not to treat?

i.Can the expectant woman safely go without medications to control the

condition? – No, unsafe.
ii.Can the condition be safely managed without meds? -No
iii.What med does she currently use to prevent seizures?
Carbamazepine (anticonvulsant, mood stabilizer) is in Pregnancy
Category D, and is one of the “Drugs that Should Be Avoided during
pregnancy because of proven or strongly suspected teratogenicity.”
Which antiepileptic drug (AED) is best for Thlama?

The drug should be with least teratogenic and effective for her disorder.
AEDs such as valproate and phenobarbital were associated with a higher
risk of major malformations than newer AEDs such as lamotrigine and
levetiracetam. Topiramate was associated with an increased risk of cleft
lip compared with that of a reference population.

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Lamotrigine = C, levetiracetam = C. Pregnancy Category C meds pose

LESS risk to foetus than Pregnancy Category D.
Decision: Discuss with Physician/neurologist and arrange provider-
patient counselling discussion. Obtain new medication order as
appropriate. Provide patient education.

3.7.5 Principles of Prescribing in Pregnancy

Prescribing in pregnancy is a balance between the risk of adverse drug

effects on the foetus and the risk of leaving maternal disease untreated.

Principles of minimise prescribing;

i. Where possible use non-drug therapy. Prescribe drugs only when

definitely needed.
ii. As far as possible, avoid medication in initial 10 weeks of gestation
d Use ‘tried and tested’ drugs whenever possible in preference to
new agents; use the smallest effective dose;
iii. remember that the foetus is most sensitive in the first trimester;
iv. consider pregnancy in all women of childbearing potential;
v. discuss the potential risks of taking or withholding therapy with the
patient;
vi. seek guidance on the use of drugs in pregnancy in the British
National Formulary, Drug Information Services, National
Teratology Information Service (NTIS);
vii. As far as possible, avoid medication in initial 10 weeks of gestation
viii. Warn the patient about the risks of smoking, alcohol, over-the-
counter drugs and drugs of abuse.
ix. Use drugs for the shortest period necessary  If possible, give drug
intermittent
x. Over-the-counter drugs cannot be assumed to be safe

3.7.6 Medications You Should Avoid During Pregnancy

Rules about pregnancy medications are constantly changing, such that it

can be over whelming for the physician to know what to prescribe to sick
pregnant woman. It usually comes down to weighing the benefits for a
mother with a health condition even one as simple as a headache, against
potential risks to her developing baby. The major challenges to
prescription in pregnancy are that Scientists can’t ethically perform drug
studies on a pregnant woman. Therefore, it’s not accurate to say a
medication is 100 percent safe for a pregnant woman (simply because it’s
never been studied or tested).

In the past, medications were assigned to five letter categories based on

their level of risk. Category A was the safest category of drugs to take.

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Drugs in Category X were never to be used during pregnancy. In 2015,

the Food and Drug Administration (FDA) started to implement a new
labelling system for drugs. Below is a sampling of a few of the drugs that
we know pregnant women should avoid.
The following drugs are common example of drugs that should generally
be avoided in pregnant women.

i.Antibiotics: Some examples of antibiotics often linked to adverse

drug reactions in pregnant includes Tetracycline,
Chloramphenicol, Ciprofloxacin and levofloxacin, Primaquine,
Sulfonamides, Trimethoprim, etc.

Tetracyclines: Discoularation and deformation of teeth, retarded bone

growth.

Chloramphenicol: Chloramphenicol is an antibiotic that’s usually given

as an injection. This drug can cause serious blood disorders and Gray baby
syndrome.

Ciprofloxacin and levofloxacin: Ciprofloxacin and levofloxacin are also

the types of antibiotics drugs that ca cause problems with the baby’s
muscle and skeletal growth as well as joint pain and potential nerve
damage in the mother.

Fluoroquinolones can increase the risk of aortic tears or ruptures trusted

Source. This can result in life-threatening bleeding. People with a history
of aneurysms or certain heart diseases may be at an increased risk of side
effects. Fluoroquinolones may also increase the chances of having a
miscarriage.

ii.Antimalarial - Primaquine: Primaquine is a drug that’s used to

treat malaria. There isn’t a lot of data on humans who’ve taken
this drug during pregnancy, but animal studies suggest it’s
harmful to developing foetuses. It can damage blood cells in a
foetus.

Sulfonamides: Sulfonamides are a group of antibiotic medications.

They’re also known as sulfa drugs. The majority of these types of drugs
are used to kill germs and treat bacterial infections. They can cause
jaundice in new-borns. Sulfonamides may also increase the chances of
having a miscarriage.

Trimethoprim: Trimethoprim is a type of antibiotic. When taken during

pregnancy, this drug can cause neural tube defects. These defects affect
brain development in a developing baby.

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iii.Analgesics

Codeine: Codeine is a prescription drug used to relieve pain. The drug has
the potential to become habit-forming. It can lead to withdrawal symptoms
in new-borns.

Ibuprofen: Most experts agree that ibuprofen is probably safe to use in

small to moderate doses in early pregnancy. It’s especially important to
avoid ibuprofen during the third trimester of pregnancy, however. During
this stage of pregnancy, ibuprofen is more likely to cause heart defects in
a developing baby.

Indomethacin: Premature closure of ductus arteriosus

Thalidomide : Phaecomelias, multiple defects

iv. Anticancer drugs: (Methotrexate) Cleft palate,

hydrocephalus, multiple defects, foetal death.

v. Antithyroid: Foetal goitre, other abnormalities

Iotretitoin- Craniofacial, heart and CNS defects

vi. Contraceptives:
Androgens Virilization, limb, oesophageal, cardiac defects,
Progestin Virilization of female foetus
Stiboestrol Vaginal carcinoma in teenage female offspring

vii. Anticoagulants: Warfarin It can cause birth defects

viii. Antihypertensives: ACI inhibitors: Hypoplasia of organs,

growth retardation, foetal loss

ix.CNS Agents

Alcohol: Low IQ baby, growth retardation, foetal alcohol syndrome

Lorazepam: birth defects or life-threatening withdrawal symptoms in a

baby after birth

Clonazepam: withdrawal symptoms in new-borns

Phenytoin: Hypoplastic phalanges, cleft lip/palate,
microcephaly
Phenobarbitone Various malformations
Carbamazepine Neural tube defects, other abnormalities
Valproate acid Spina bifida and other neural tube defects

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Lithium Foetal goitre, cardiac abnormalities, other abnormalities

3.7.7 Drug Use during Lactation

Most drugs administered to lactating women are detectable in breast milk.

Fortunately, the concentration of drugs achieved in breast milk is usually
low. Infant would receive in a day is substantially less than what would be
considered a “therapeutic dose.”

However, if the nursing mother must take medications and the drug is a
relatively safe one, she should optimally take it 30–60 minutes after
nursing and 3–4 hours before the next feeding. Particular caution should
be applied to sedative-hypnotics, Lithium Tetracyclines, antihistamines,
morphine and tetracycline are excreted in milk so should be avoided to
mothers who are breast feeding

i. Maternal Drug Actions

Effect on reproductive tissue may be altered by endocrinal
environment due to pregnancy. Effect on other tissues not changed
much, but altered physiologic context may require treatment e.g.
cardiac glycosides & diuretics for heart failure and insulin for
pregnancy induced diabetes

ii. Therapeutic Drug Actions: The Foetus emerging area of ‘Fetal

Therapeutics’

Corticosteroids: e.g. dexamethasone for lung maturation in premature

labour

Phenobarbitone: for neonatal jaundice or decrease intra cranial bleeding

Zidovudine or nevirapine: alone or in combination to prevent vertical

transmission Pharmacodynamics.

iii. Predictable Toxic Effects

Opioids: dependance, neonatal withdrawal syndrome, respiration

depression

ACE inhibitors: renal damage

Diethylstilboestrol: adenocarcinoma of vagina after puberty

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iv. Teratogenic Drug Actions: Birth Defects

Incidence of major structural defects (abnormalities) is about 6%
of all pregnancies. 3% are caused by drugs or environmental
factors/exposure. 3% have a genetic or unknown cause 1/2 of the
birth defects are obvious at birth.
Toxic Effects of Drugs on the Embryo, Foetus, or Neonate may
vary from no effect, Little, Serious- fetal toxicity, Spontaneous
abortion, Death, Fetal malfunction to Fetal malformations.
Some abnormalities have multiple causes- genetic factors,
environmental factors, chemicals or drugs.

3.7 Special Issues Needing Prescription in Pregnancy

3.8.1 Drug Management of Cough, Cold, and Allergy in Pregnancy

It is very common for women to experience cough, cold, or allergy

symptoms during pregnancy. The use of multiple OTC medications to
treat these symptoms increases from the first to the third trimester. It had
revealed that, 92.6% of the obstetric population interviewed self-
medicated with OTC medications.

i. The common cold is typically caused by numerous viruses and,

therefore, is usually self-limiting. Pregnant women should be
advised to first try non-pharmacologic treatments such as a saline
nasal spray, the use of a humidifier, and increased hydration. The
most commonly used cough, cold, and allergy products include
antihistamines, decongestants, antitussives, and expectorants.
ii. It appears that the older sedating antihistamines, also known as
first-generation agents, are safe in pregnancy. The recommended
first-line agent is chlorpheniramine (Piritin), which is Category B.
According to the Collaborative Perinatal Project, chlorpheniramine
use during pregnancy was not associated with an increased risk of
malformations.

iii. Diphenhydramine (Benadryl) is also an option in patients who

need symptomatic relief from allergy or cold symptoms. It is also
Category B and was not associated with an increased risk of
malformations; however, it can cross the placenta and has been
reported to have possible oxytocin-like effects at high doses when
used during labour. The newer non-sedating or second-generation
antihistamines, such as loratadine, fexofenadine, and cetirizine,
have not been extensively studied.

iv. Cetirizine may be alternative to chlorpheniramine in the second or

third trimester if a first-generation antihistamine is not tolerated.

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v. Oral decongestants: Administration of both inhaled and oral

decongestants occurs during pregnancy. Pseudoephedrine and
phenylephrine are the most common oral OTC decongestants used,
with 25% of pregnant women using pseudoephedrine as their oral
decongestant of choice. However, its use should be avoided during
the first trimester due to associated risk of defects from vascular
disruption known as gastroschisis. Inhaled decongestants such as
oxymetazoline and phenylephrine are both Category C and appear
to be safe for use.
vi. Dextromethorphan: The primary cough remedy used during
pregnancy is dextromethorphan. Many studies however, suggest
that there is no association between dextromethorphan use and an
increased risk of birth defects. However, many of the OTC products
containing dextromethorphan also contain alcohol and should be
avoided during pregnancy.
vii. Guaifenesin: Guaifenesin is the expectorant typically found in
most OTC cold medications. Its use appears to be safe during
pregnancy, with the exception of the first trimester.

3.8.2 Drug management of Pain in Pregnancy

i. Acetaminophen: is the most commonly used OTC analgesic in

pregnancy, with at least 65.5% of women taking it at some point
during pregnancy and 54.2% taking it during the first trimester. The
use of single-ingredient acetaminophen products during pregnancy
has not been associated with increased risk of a broad range of birth
defects. Due to its antipyretic effects, single-ingredient
acetaminophen products have been associated with a decreased risk
of some birth defects arising from febrile infection during
pregnancy.
ii. Aspirin and other nonsteroidal anti-inflammatory drugs
(NSAIDs): should be avoided if possible, during pregnancy.
Although recent study found that the use of NSAIDs in early
pregnancy does not appear to be a major risk factor for birth
defects, there were a few moderate associations between NSAIDs
and specific birth defects. Another major concern is the increased
risk of miscarriage that has been associated with the use of non-
aspirin NSAIDs during pregnancy. The use of NSAIDs during
pregnancy is also associated with premature closure of the ductus
arteriosus, foetal renal toxicity, and inhibition of labour. Although
there are limited reproductive studies involving the use of narcotic
analgesics in human pregnancies, these drugs have been used in
therapeutic doses for many years by pregnant women without a link
to an elevated risk of birth defects.

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iii. Opioids: The use of opioids should be reserved for pain that is not
managed with acetaminophen and, when possible, the lowest
effective dose should be used.

3.11.3 Management of GIT Disorders in Pregnancy:

The most common GI problems that occur during pregnancy include

nausea, vomiting, acid reflux, diarrhoea, and constipation. Drug therapy
may be required when lifestyle modifications cannot provide adequate
relief of symptoms.

i. Nausea & Anorexia: While nausea and vomiting are common

indicators of early pregnancy, an extreme manifestation of the
condition is termed hyperemesis gravidarum. Severe hyperemesis
gravidarum complications—including weight loss >5% of initial
body weight, electrolyte imbalance, and dehydration— are the
second most common reason for prenatal hospitalisation. A variety
of medications with different mechanisms of action that have been
used to treat nausea and vomiting of pregnancy.
ii. Dyspepsia: Acid reflux is another common problem estimated to
occur in 30% to 50% of all pregnancies. Due to the pressure on the
uterus, acid reflux during pregnancy is less likely to respond to
lifestyle modifications such as elevation of the head when sleeping,
eating small frequent meals, or avoiding eating within 3 hours of
bedtime.

iii. OTC antacids: OTC antacids are considered the agents of first
choice with the exception of magnesium trisilicate and sodium
bicarbonate, which should be avoided during pregnancy. Long-
term use of high-dose magnesium trisilicate has been associated
with increased risk of foetal nephrolithiasis, hypotonia, and
respiratory distress; sodium bicarbonate has been associated with
metabolic acidosis and fluid overload. A variety of agents that have
been used to treat acid reflex during pregnancy Non-absorbable
antacids like aluminium hydroxide [Cat B] If taken in early
pregnancy, increase of congenital malformations. Sucralfate [Cat
B], H2 blockers [Cat B] are safe. All PPIs (Cat B), except
Omeprazole [Cat C], Lansoprazole Safest PPI in pregnancy.

iv. Diarrhoea and constipation are also frequent problems associated

with pregnancy. Lists agents used to treat these conditions includes
Loperamide (Cat3)
v. Castor oil and mineral oil should be avoided for the treatment of
constipation. Alosetron is only indicated for irritable bowel
syndrome (IBS)–associated diarrhoea. Bismuth subsalicylate
(Pepto-Bismol, Kaopectate) should be avoided in pregnancy

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because the salicylate moiety can lead to increased perinatal

mortality.
vi.Bulk laxatives [Cat B] containing bran, isapghula or methylcellulose
are best for simple constipations.

3.8.4 Immunisations:

Women who are considering pregnancy or those already pregnant should

be advised on the importance of receiving vaccines. Informing these
patients of the benefits of receiving certain vaccinations can significantly
reduce the occurrence of preventable diseases. With the many vaccines
available, and pharmacists at the front lines as immunisers, it is important
to discuss the agents utilised for specific groups of patients. The following
are a few of the current recommendations for vaccine use during
pregnancy.

The most current update to the immunisation schedule was the

recommendation to administer tetanus, diphtheria, and acellular pertussis
(Tdap) vaccine with each pregnancy during the 27th to 36th week of
gestation. This is different from prior recommendations that were
dependent upon previous vaccination history. Waiting until the second
trimester is reasonable to minimise concerns about possible adverse
reactions. Healy et al concluded that the infants of mothers immunised
either before their pregnancy, or in early gestation, displayed insufficient
antibodies to aid in infant protection from disease. Furthermore, the
antibodies that were transferred were lost within a 6-week period, which
could possibly place the infant at risk of infection.

Influenza vaccination should be recommended for all pregnant women for

prevention of seasonal influenza and can be administered in any trimester.
It is most beneficial when given as early as available in the flu season. The
immunisations contraindicated during pregnancy are live vaccinations,
which include Live attenuated vaccines (influenza (LAIV); measles,
mumps, zoster varicella, MMR & polio) should be given 3 months before
pregnancy or post-partum. Live virus vaccines are contra-indicated in
pregnancy secondary to potential risk of fetal infection. Killed virus,
toxoid, or recombinant vaccines may be given during pregnancy

3.8.5 Learning deficits and /or behavioural abnormalities

There are certain situations that require judicious use of drugs during
pregnancy such as Hypertension, Epilepsy, Diabetes and infections that
could seriously endanger the mother and foetus. Drugs which may
stimulate uterine smooth
muscles are contraindicated during pregnancy e.g. purgatives, anti-
malarial drugs and ergot alkaloids.

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Drugs capable of crossing placenta and affecting the foetus are

barbiturates, alcohol, narcotic and nonnarcotic analgesic.

3.9 Principles of Drug Therapy During Breastfeeding

i. Is the drug therapy necessary?

ii. What is the safest option for the infant?
iii. If there is the possibility of harm, monitor infant blood levels of
the drug
iv. Minimise infant exposure

a. Strategies to minimise infant exposure to drug

v. Postpone pharmacotherapy until the baby is weaned if possible; use

nonpharmacological strategies when possible.
vi. Although most maternal medications probably pose no harm to the
breastfeeding infant, their effects have not been fully studied.
vii. If drug needs to be used, then, when possible:

viii. Mother should take the medication immediately AFTER feeding

the baby… to reduce (if possible) the amount of drug in the breast
milk
ix. Avoid breast-feeding during peak effect
x. Avoid drugs with long half-life or active metabolites
xi. Drugs that are highly protein-bound are preferred
xii. Use caution if baby is severely ill; a neonate; or preterm. They may
not have adequate drug metabolizing enzymes
xiii. Herbs: Herbs to Be Avoided During Lactation. Herbal remedies
for nursing mothers pose a health risk to their infants.

4.0 CONCLUSION

In this unit, you have learnt examples of mode of actions of drugs used in
different diseases and outlined in pharmacodynamic principles.

5.0 SUMMARY

Digoxin, a Cardiac glycoside come from the plants of foxglove family

(Digitalis spp) & related plant. Digitalis-is one of the oldest drugs in
clinical use (1200AD). There are two types in clinical use –Digoxin and
Digitoxin

Digoxin is thought to increase vagal activity and inhibits Na+/K+ ATPase

in myocytes this leads to a transient increase’s intracellular concentration
of Na+ leading to increases influx of Ca++ via Na/Ca2+ exchanger. This

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result in increased contractility (Positive inotropic effect), Increased

parasympathetic (Vagal) tone and decreased sympathetic effect on the
heart this suppressed AV node conduction increasing refractory period,
thereby decrease conduction velocity and result in decreased heart rate.

This result in Increase CO through their +ve inotropic effect, they slow
heart rate by relieving the sympathetic tone & through their vagotonic
effects and reduce the heart size by reliving Frank –Starling relationship.
Digoxin: Clinical Benefit includes; decreases morbidity in patients with
heart failure, improves symptoms of CCHF

Toxicity may result from overdose or decrease in metabolism and

excretion, hypokalaemia (stemming from the use of thiazides diuretics,
diarrhoea & vomiting). Arrhythmias occurring de novo –
Atrial/Ventricular ectopic, visual – blurred or yellow vision, halos and
Psychiatric manifestations (– Delirium, fatigue, malaise, confusion,
dizziness and abnormal dreams and Headache) etc.

Blood Pressure = Cardiac output (CO) X Resistance to passage of blood

through precapillary arterioles (PVR). All antihypertensives act via
interfering with normal mechanisms
Mode of Action of Specific Antihypertensive Agents

ACE inhibitors: Captopril, Lisinopril, Enalapril, ramipril and fosinopril

etc. CE Inhibitors work in the lungs to inhibit Angiotensin Converting
Enzyme from turning Angiotensin I into Angiotensin II. This result in
decreased BP due to a decrease in blood volume, PR, & cardiac load.
ACEI causes an increase of bradykinin which causes protracted dry cough.

ACEI, inhibits vasoconstriction and release of aldosterone which inhibits

the retention of sodium and water

Indications for Use in Hypertension, Heart Failure, Myocardial Infarction

(MI) and type 2 Diabetes.

Adverse Effects are First-Dose Hypotension: Usually occurs with initial

dose. Worse in patients with severe hypertension, or are on diuretics, or
are sodium or volume depleted. Cough: Persistent, dry, irritating, non-
productive cough can develop with all ACE inhibitors.” Other adverse
effects include Hyperkalaemia, Renal Failure, Fetal Injury, Angioedema
and Rarely Rashes, urticaria, Dysgeusia: loss or alteration of taste, and
Neutropenia etc.

Pain is the most COMMON reason clients seek medical advice. It is a

protective mechanism or a warning to prevent further injury

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Analgesics are among drugs which relieve pain due to multiple causes
without causing loss of consciousness. Drugs which relieve pain due to
single causes or specific pain syndromes (ergotamine, carbamazepine,
nitrates) are not classified as analgesics. Corticosteroids also not classified
as analgesics

Analgesics are classified as Opioid analgesics e.g. Morphine and

morphine like drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) e.g. Paracetamol,

diclofenac, ibuprofen etc. adverse effects can usually an extension of their
pharmacological effects, idiosyncrasy and allergy – Urticaria, itch,
swelling of lips and bronchospasm (these are rare), allergy is uncommon
and anaphylactoid reaction is rare, apnoea This may occur in new born
when morphine is given to mother during labour.

Others are death due to respiratory failure, Respiratory depression, Nausea

and vomiting, Constipation and Drowsiness and sedation.;
NSAIDs Agents such as Ibuprofen, diclofenac, indomethacin, naproxen,
aspirin reversibly inhibition of the enzyme’s cyclooxygenase 1 and 2
(COX-1 and COX-2) → decreased prostaglandin synthesis resulting in
analgesic, Antipyretic and Anti-inflammatory (antirheumatic). with the
exception of aspirin, only minor antiplatelet function

Adverse effects include gastric and duodenal ulcers with the risk of
gastrointestinal bleeding and perforation, risk of increases with duration
and dose of treatment. Renal function impairment: prostaglandins
normally maintain renal blood flow by inducing vasodilation of the
afferent arterioles. NSAIDS inhibits prostaglandin production, which
leads to harmful hypoperfusion of the kidneys and reduced GFR.

Pregnant and lactating women are commonly orphaned from benefits of

drug therapy, even when solid data on safety/effectiveness exist. If “Safe
use of a drug in pregnancy has not been established. It should not be
administered to women of childbearing age unless, in opinion of treating
physician, expected benefits to patient markedly outweigh possible
hazards to child or foetus”. Allow evidence-based counselling and always
consider risk of untreated maternal condition

Drugs and Age of Patients - The adjustment of dose and dosing regimen
for children and the elderly needs a special consideration because of
several differences as compared to an adult individual. The differences
may be due to many factors which include changes in Pharmacokinetic
parameter, Body weight, Surface area and Genetic predisposition. An
important determinant of drug distribution is the volume of distribution,
and the determinant for drug metabolism and excretion is elimination half-

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life. It is an established fact that the volume of distribution and elimination

half-lives of drugs in new born, adults and elderly have considerable
differences.

SELF ASSESSED EXERCISES

i. Discuss the medications to avoid in pregnancy.

ii. Give the classes of NSAIDs and the corresponding side effects.

6.0 TUTOR- MARKED ASSIGNMENT

1. What is Teratogenesis? Briefly outline FDA 2015 categories

teratogenic drugs
2. What are the Principles of drug prescription in Pregnancy?
3. Classify antihypertensives, discuss the pharmacology of cardiac
Glycosides
4. Lists tocolytics and the mechanisms of actions and adverse
effects.
5. Tabulate drugs use in the management of pain. Mention
mechanisms of action, indications and adverse effects of a named
analgesic.

7.0 REFERENCES/FURTHER READING

Katzung, B.G., Masters, S.B. & Trevor, A.J. (2012). Basic and clinical
pharmacology. (12th ed.). New Yock: McGraw Hill.

Srivastava, S.K. (2017). A complete textbook of medical pharmacology

(Vol. II). APC books.

Sannerstedt et al. (1996). Drugs During Pregnancy. An Issue of Risk

Classification and Information to Prescribers. Drug Safety, 14 (2):
69-77.

Bruton, L., Chabner, Bruce., & Knollman, B. (2011). Goodman and

Gilman's the Pharmacological Basis of Therapeutics. (12th ed.).
McGraw-Hill Education.

5.www.cdc.gov/media/dpk/2013/docs/dpk- safe-meds-doc1.pdf 66
(2016). (Acssesd14 May 2020). From

http://www.cdc.gov/reproductivehealth/maternalinfanthealth/pregcompli
cations. htm.

Veroniki et al. (2017). Comparative safety of anti-epileptic drugs during

pregnancy: a systematic review and network meta-analysis of

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congenital malformations and prenatal outcomes. BMC Med, 15

(95) 2017. https://doi.org/10.1186/s12916-017-0845.

Gunatilake, R., Patil, A.S. (2013) Drugs in pregnancy. Merck Manual

Online for Health Care Professionals.
www.merckmanuals.com/professional/gynecology_and_obstetrics
/drugs_in_pregnancy/drugs_in_pregnancy.html?qt=drugspregnan
cy&alt=sh. (Accessed May 15, 2020).

Hansen, W.F., Peacock, A.E. & Yankowitz, J. (2002). Safe prescribing

practices in pregnancy and lactation. J Midwifery Womens Health.
47:409–421.

Mosley, A.T., Amy, P. & Witte, A.P. (2013). Drug. Fan Pregnancy. Do
the Benefits Outweigh the Risks?US Pharmacist 38(9):43-46.

Sachdeva, P., Patel, B.G. & Patel, B.K. (2009). Drug Use in Pregnancy; a
Point to Ponder!Indian J Pharm Sci, 71(1): 1–7.

Sannerstedt, R. et al. (1996). Drugs during Pregnancy. An Issue of Risk

Classification and Information to Prescribers. Drug Safety 14 (2):
69-77.

Shaikh, A.K. et al. (2013). Drugs in pregnancy and lactation. Int J Basic
Clin Pharmacol, 2(2):130-135.

Bajcar, J.M. et al. (2008). Medication reconciliation at hospital discharge:

evaluating discrepancies. Ann Pharmacother, 42(10):1373-9. doi:
10.1345/aph.1L190.

The American Geriatrics Society, (2015). Beers Criteria Update Expert

Panel: American Geriatrics Society updated Beers Criteria for
potentially inappropriate medication use in older adults.
63(11):2227-46, http:// doi: 10.1111/jgs.13702.

Hanlon,J, T. et al. (2015). Alternative medications for medications in the

use of high-risk medications in the elderly and potentially harmful
drug-disease interactions in the elderly quality measures. J Am
Geriatr Soc 63(12): e8-e18, http:// doi: 10.1111/jgs.13807.

http://en.wikipedia.org/wiki/Instruments_used_in_obstetrics_and_gynec
ology.

Rashmi. R., Gynaecological and obstetrics Instruments. Manmohan

Memorial Institute of Health Sciences.

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Antidiabetics., (31st May 2020). Retrieved from.

http://www2.harpercollege.edu/ls-
hs/nur/120/jcordts/web/Pharm8_ files/Slide0013 .gif.

AMBOSS., (6th June 2020). Retrieved

from.https://www.amboss.com/us/knowledge/Non-opioid
analgesics.

Piper, J.M., Ray, W.A., Daugherty, J.R.& Griffin, M, R. (1991).

Corticosteroid use and peptic ulcer disease: role of nonsteroidal
anti-inflammatory drugs. Ann Intern Med 114(9), 735–740. paid:
2012355.

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MODULE 3 PHARMACOTHERAPEUTICS IN PUBLIC

HEALTH

Unit 1 Taking Drug History & Evidence Based Medicine

Unit.2 Pharmacovigilance/Pharmacovigilance in Public Health
Programmes
Unit 3 Rational Use of Medicines/Drug Dependence and
Substance Abuse

UNIT 1 TAKING DRUG HISTORY AND EVIDENCE

BASED MEDICINE

CONTENTS

1.0 Introduction
2.0 Objectives
3.0 Main Content
3.1 Definition of Terms
3.2 Taking Drug History
3.2.1 Importance of accurate drug history
3.2.2 Informant (Information Sources)
3.2.3 Challenges with Difficult Clients
3.2.4 Interviewing the client: Introduce yourself
3.2.5 Issues Regarding manner
3.2.6 Questions to Ask
3.2.7 Medication History Taking TIPS
3.2.8 Additional Questions to Explore
(Effectiveness/Compliance)
3.3 Client Education
3.4 Reconciliation and Documentation
3.5 Adherence Problems
3.6 Documenting Medication Histories=9
3.7 Wrapping Up
3.8 Evidence Based Medicine
3.9 Sources of Information
3.10 Concepts of Evidence-Based Medicine
3.11 The Five Step EBM Model
3.11.1 Step 1: Formulating answerable clinical questions
3.11.2 Step 2: Finding the evidence
3.11.3 Step 3: Appraising the evidence
3.11.4 Step 4: Applying the evidence
3.11.5 Step 5. Evaluating performance
3.12 Anatomy of a good clinical question: PICO
3.13 Benefits: Why Evidence Based Medicine?
3.14 Limitations of Evidence Based Medicine
3.14.1 Value

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3.14 2 Older Professionals

3.14.3 Costs
3.14.4 A Lack of Evidence
3.14.5 The Personal Touch
3.14.6 Lack of Skills
4.0 Conclusion
5.0 Summary
6.0 Tutor- Marked Assignment
7.0 References/Further Reading

1.0 INTRODUCTION

A medication history taking is a detailed, accurate and complete account

of all prescribed and non-prescribed medications that a patient had taken
or is currently taking prior to current admission or medical care. It
provides valuable insights in to patient’s allergic tendencies, adherence to
pharmacological and non-pharmacological treatments and self-medication
with complementary and alternative medicines etc. Interviewing a patient
in collecting the data medical history is called medication history
interview.

Without an accurate medication history, prescribers may inadvertently

make incorrect decisions about a patient’s treatment, causing harm if
previously discontinued medicines are restarted, or if current medicines
are omitted or prescribed at the wrong dose for the patient. In 2010, the
National Patient Safety Agency issued a rapid response report about the
importance of avoiding missed doses of medicines [1], highlighting the
need to identify a list of critical medicines (including some long-term
medicines such as anticonvulsants and anti-Parkinsonian treatments),
although this list does not exclusively apply to medication histories.

A study had reported that up to 67% of patients admitted to a general

medical ward had at least one error associated with their medication
history; the most common being an omission, medicines added that the
patient did not take, and incorrect frequency and dosage. In a systematic
review by Tam et al. (Tam et al 2005) demonstrated that 41% of
medication history errors were clinically important, with 22% having the
potential to cause harm, and the EQUIP study demonstrated that 30% of
prescribing errors were due to medicines missing on admission. Some of
these errors may be attributed to the limitations of the sources used to
obtain the history.

Health care professionals are increasingly required to base clinical

decisions on the best available evidence. Evidence based medicine (EBM)
is a systematic approach to clinical problem solving which allows the

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integration of the best available research evidence with clinical expertise

and patient values.
An early critique of statistical methods in medicine was published in 1835.
However, until recently, the process by which research results were
incorporated in medical decisions was highly subjective. Called "clinical
judgment" and "the art of medicine", the traditional approach to making
decisions about individual patients depended on having each individual
physician determine what research evidence, if any, to consider, and how
to merge that evidence with personal beliefs and other factors.

In the case of decisions that applied to groups of patients or populations,

the guidelines and policies would usually be developed by committees of
experts, but there was no formal process for determining the extent to
which research evidence should be considered or how it should be merged
with the beliefs of the committee members. There was an implicit
assumption that decision makers and policy makers would incorporate
evidence in their thinking appropriately, based on their education,
experience, and ongoing study of the applicable literature.

2.0 OBJECTIVES

By the end of this unit, you will be able to:

 identify the significance of history taking

 describe how to take medication history
 explain the approach to patient while taking medication history
 define evidence-based practice as it is used in physical therapy
 recognise the 5-step processes in Evidence-Based Practice
 compare and contrast arguments for and against evidence-based
practice
 state the key research methods needed to locate medical
evidence
 identify and describe the steps included in supporting evidence-
based practice
 define and describe types of studies in evidence-based practice
 describe strategies to apply evidence-based practice to clinical
cases

3.0 MAIN CONTENT

3.1 Definition of Terms

Medication; a chemical substance or other form of medicine that is used

to treat or prevent disease.

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Hospital admission; admission of a Covered Person to a Hospital as an

Inpatient for Medically Necessary and Appropriate care and treatment of
an Illness or Injury.

Medical Care; the provision of what is necessary for a person's health and
wellbeing by a doctor, nurse, or other healthcare professional.

Medical treatment; the management and care of a patient to fight disease

or disorder.

Short-term treatment; involves a treatment duration of approximately

one month.

Long-term treatment; a treatment which helps meet both the medical

and non-medical needs of people with a chronic illness or disability who
cannot care for themselves for long periods.

3.2 Taking Drug History

In patient’s drug history, care should be taken to write clearly and

explicitly, all entries should be signed and dated. Technician complying
the drug history should be able to identify any drug omissions, errors on
the drug chart or potential problems for discharge. These should be
highlighted to the relevant clinical pharmacist who will be able to detect
the clinical significance and take the necessary action.

3.2.1 Importance of accurate drug history

The goal of medication history interview is to obtain information on

aspects of drug use that may assist in overall care of patient. The
information obtain can be utilised to: Compare medication profile with the
medication administration record and investigate the discrepancies or
verify medication history taken by other staffs and provide additional
information where appropriate.

Although doctors usually obtain medication histories during their initial

patient interview, there is evidence that those obtained cannot be accurate.
When doctors review a patient on admission, the patient may not be able
to provide an accurate list of medicines, especially if they are confused or
particularly distressed by the cause of their admission.

i Preventing prescription errors and consequent risk to patients.

ii Useful in detecting drug –related pathology or changes in
clinical signs that may be the result of drug therapy.

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iii It should encompass all currently and recently prescribed drugs,

previous adverse drug reactions including herbal or alternative
medicines and adherence to therapy for better care plan.

3.2.2 Informant (Information Sources)

i Patient
ii Family or Caregiver
iii Medication Vials / Bubble packs
iv Medication List
v Community Pharmacy
vi Medication Profile from other facility

Patients should always be consulted unless if it is not physically possible

(e.g. they are unconscious or confused). If appropriate, the patient’s
parent, partner or career may be consulted instead of, or in addition to, the
patient. Direct discussion with the patient may also highlight issues with
medicines adherence and identify other medicines that the patient uses
(e.g. over the counter medicines, herbal medicines or medicines from
specialist clinics). Patients should also be consulted to confirm any
previous allergies or intolerances to medicines.

3.2.3 Challenges with Difficult Clients

i Belief – physician has information

ii Unfamiliar with medications and names
iii Difficulty recalling
iv Medicated clients (sedated, confused)
v Disease affects mental status
vi Language barrier
vii Hearing impairment
viii Elderly clients
ix Caregiver administers or sets up medications
x Medication vials or list unavailable

3.2.3 Interviewing the client

i. Introduce yourself
ii. Inform client of reason for you being there
iii. Inform client of importance of maintaining a current medication list
in chart

It is vital that the interviewer clearly introduce himself (in line with the
‘Hello my name is’ campaign Dr/Pharm. Bassi, and explain the purpose
of their consultation with the patient. Careful questioning techniques must

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be used as some patients may not consider non-oral medications (e.g.

inhalers, eye drops, creams or patches) as medicines or they may fail to
mention medicines that they do not consider important, such as oral
contraceptives or hormone replacement therapy, or other products they
may be regularly taking, such as herbal medicines or dietary supplements.

Patients are encouraged to bring their medicines into hospital to aid

medicines reconciliation, prevent missed doses and reduce undue costs.
The patient should always be consulted when assessing their own
medicines and pharmacy practitioners should always consider:

i that some medicines may have been left at home if the patient
stores some separately (e.g. eye drops stored in the refrigerator,
patients with most of their medicines dispensed in a multi-
compartmental compliance aid [MCCA]);
ii the doses that the patient takes may not be those stated on the
dispensed label because of deliberate action by the patient, advice
from the prescriber (e.g. phosphate binder dose adjusted
according to their serum phosphate), or a dispensing error;
iii medicines brought in may not belong to the patient — he or she
may have brought in the wrong medicines or “borrowed”
medicines from a relative;
iv the patient may not be taking the medicine at all. The date of
dispensing may indicate an adherence issue.

3.2.5 Issues Regarding manner

i Use language that the patient understands

ii Present facts and concepts in simple words logical order
iii Use open ended questions

3.2.6 Questions to Ask

Which community pharmacy do you use?

Any allergies to medications and what was the reaction?

Which medications are you currently taking:

i The name of the medication

ii The dosage forms
iii The amount (specifically the dose)
iv How are they taking it (by which route)?
v How many times a day
vi Any specific times
vii For what reason (if not known or obvious)

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What prescription medications are you taking on a regular or as needed

basis? How many do you take at a time? Do you have to cut the tablet?
What over-the-counter (non-prescription) medications are you taking on a
regular or as needed basis?

What herbal or natural medicines are you taking on a regular or as needed

basis?

What vitamins or other supplements are you taking?

Have you recently started any new medicines?
Did a doctor change the dose or stop any of your medications recently?
Are any of the medications causing side effects?
Have you change the dose or stopped any medications because of
unwanted effects? Do you sometimes stop taking your medicine whenever
you feel better?
Do you stop taking your medicine if it makes you feel worse?
Have you recently started any new medications?
Did a doctor change the dose or stop any of your medications recently?
Did you change the dose or stopped any of your medications recently?

3.2.7 Medication History Taking TIPS

Balance open-ended questions (what, how, why, when) with yes/no

questions

i Ask non-biased questions

ii Avoid leading questions
iii Explore vague responses (non-compliance)
iv Avoid medical jargon – Keep it simple
v Avoid judgmental comments
vi Various approaches can be used:
- 24 hours’ survey (morning, lunch, supper, bedtime)
- Review of Systems (head to toe review)
- Link to prescribers (family physician, specialists)

Prompt for questions for: Pain medications, Stomach medications,

Medications for bowels, sleeping aids and ask for Samples. E.g. Eye or
ear drops, nose sprays, Patches, creams & ointments, Inhalers (puffers) or
Injections (needles).

Use non-biased questions that do not lead the patient into answering
something that may not be true. E.g. Fosamax must be taken on an empty
stomach first thing in the morning and you must remain upright for 30
minutes. That is how you are taking it, right? Avoid judgmental
comments such as: I see that you have been on lorazepam for quite some
time, you’re likely addicted to them.

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If medication vials available: Review each medication vials with patient,

confirm content of bottle and Confirm instructions on prescription vials
are current.
If bubble packs available: Review each medication with patient, confirm
patient is taking entire contents.

3.2.8Additional Questions to Explore (Effectiveness/Compliance)

Are any of the medications causing side effects?

Have you changed the dose or stopped any medications because of
unwanted effects? Do you sometimes stop taking your medicine whenever
you feel better?
Do you sometimes stop taking your medicine if it makes you feel worse?

Table 40: Cards for Medication History Script

Medication History script Additional questions
Allergies Do you have any:
 Do you have any allergy to or  Eye or ear drops, nose
avoid any medications due to side sprays
effects?  Patches, creams &
 what type of reactions do you ointments
have?  Inhalers (puffers)
 When do you take them  Injections (needles)
Prescription Medication: Do you receive any:
 What prescription medications  Needle (Injections)
are you taking on a regular or as  Sample from the
needed basis? doctors consulting room
 When do you take them  Study medication?
non-prescription Medication Do you frequently take
 What over-the-counter  Pain medications
medications are you taking on a  Stomach medications
regular or as needed basis  Medications for bowels
 When do you take them  Sleeping aids
Herbal, supplements, Vitamins: Did you or your doctors
 What herbal or natural change any of your
medicines are you taking on a regular medications
or as needed basis?
 What vitamins or other
supplements are you taking?
 When do you take them

3.3 Client Education

Encourage ownership
Educate client to bring medications from home at each appointment

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Educate client to carry a list of current medications (prescription and

OTC)
Encourage family members/ caregivers to become involved
Encourage one pharmacy

3.4 Reconciliation and Documentation

Upon discovering a discrepancy

i Update the list if minor (e.g. OTC taken as needed)

ii Include medications prescribed by other physicians (e.g. specialist)
iii Inform physician if client is not taking as prescribed

Medication histories have traditionally been documented in the ‘Drug

history’ section of a doctor’s clerking; if the interviewer identified any
errors with this list, they would usually document these in the subsequent
progress notes. To avoid having information scattered across multiple
sections, and to facilitate improved documentation of changes made to a
patient’s pre-existing medicines, some hospitals or National health
insurance scheme (NHS) trusts have implemented specific proformas for
recording medication histories. To view a sample medicines reconciliation
form. These proformas can be designed to prompt the recording of details
concerning the sources used to confirm the medication history and any
additional relevant information about the patient’s medicines, including:

3.5 Adherence Problems

details, for patients taking warfarin, of the indication, target INR, most
recent INR and dose; details of a patient’s MCCA (e.g. the name of the
community pharmacy that dispensed them, how many weeks at a time
they’re supplied with them, and how many they have left at home);
restrictions on supplies issued in primary care (e.g. patients issued a
maximum of seven days because of risk of overdose).

Maintaining and using an accurate medication history

Once an accurate medication history has been obtained, this information

should be documented in the patient’s medical notes. The medical team
should be informed if any changes to the inpatient prescription are
required, ensuring a patient’s medicines prescribed on admission
correspond to what the patient was taking before admission, unless there
are any deliberate changes. Any changes, deletions or additions to the
patient’s regular medicine should be clearly documented to facilitate the
provision of accurate information about changes made to a patient’s
medicines during their admission for GPs.

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3.6 Documenting Medication Histories

Medication histories have traditionally been documented in the ‘Drug
history’ section of a doctor’s clerking; if pharmacists identified any errors
with this list, they would usually document these in the subsequent
progress notes. To avoid having information scattered across multiple
sections, and to facilitate improved documentation of changes made to a
patient’s pre-existing medicines, some NHS trusts have implemented
specific proformas for recording medication histories. To view a sample
medicine reconciliation form, click here. These proformas can be designed
to prompt the recording of details concerning the sources used to confirm
the medication history and any additional relevant information about the
patient’s medicines.

3.7 Wrapping Up

i. Thank the patient for their time and information.

ii. Ask them if they have any other questions.
iii. Remind them that if questions do come up, they tell their nurse
that they would like to talk to the pharmacist and we will stop
back in.
iv. Remind patient that we will be in to discuss any changes to
medications and provided updated list prior to discharge.

3.8 Evidence Based Medicine

3.8.1 Introduction Evidence-based medicine is the application of the

scientific method into healthcare decision-making. It is the conscientious,
explicit, and judicious use of current best evidence in making decisions
about the care of individual patients. Medicine has a long tradition of both
basic and clinical research that dates back at least to Avicenna.

The term "evidence-based medicine", as it is currently used, has two main

tributaries. Chronologically, the first is the insistence on explicit
evaluation of evidence of effectiveness when issuing clinical practice
guidelines and other population-level policies. The second is the
introduction of epidemiological methods into medical education and
individual patient-level decision-making.

“Evidence-based medicine” was first introduced in the mainstream

medical literature in a 1992 article, “Evidence-based medicine: A new
approach to teaching the practice of medicine,” which presented EBM as
“a fundamentally new approach” emphasising “question formulation,
search and retrieval of the best available evidence, and critical appraisal
of the study methods to ascertain the validity of results”.

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3.8 Sources of Information

As EBM gained prominence in the late 1990s and beyond, three streams
of evidence dissemination developed:

i Systematic reviews gained increasing prominence in the medical

literature,
ii Knowledge search engines (including internet engines such as
Google, and Medline interfaces such as Ovid) became standard
tools for medical literature searching, and
iii Knowledge distillation and “push” services developed as a way to
compile and disseminate concise reviews of evidence on specific
topics or questions (e.g., ACP Journal Club, Info Poems, etc.).

In order to decide what to do in practice, we also need to know how we’ll

know when we are there – that is, what kind of outcomes do we
seek?

Medical outcomes can be broadly grouped into 3 categories.

i Surrogate markers of disease - Some outcomes (e.g. Hb A1c

blood pressure or cholesterol levels) are merely surrogate markers
of disease. We measure these surrogate markers because we think
they tell us something prognostic about the expected course of a
person’s disease process, but they do not directly impact on how a
patient feels from day to day.
ii Stage or extent of disease - Others measure actual stage or extent
of disease (e.g. the stage of a diabetic ulcer, or the angiographic
extent of disease). These may have a more direct bearing on a
patient’s quality of life or extent of suffering, but still do not
provide direct measures of long-term quality of life.
iii Patient-oriented outcomes - The most important outcomes for
guiding medical decisions are those that affect how patients feel
and the quality of their lives – that is, patient-oriented outcomes
such as mobility, suffering, longevity, and other considerations
that bear directly on how a patient experiences his or her
quality of life. In short, patient-oriented outcomes have primarily
to do with long-term morbidity or mortality

An even simpler way to break down the types of outcomes that may be
considered is into “disease oriented” outcomes such as blood sugar, blood
pressure, flow rate, coronary plaque thickness, or “patient oriented
outcomes” such as reduced morbidity, reduced mortality, symptom
improvement, improved quality of life, or lower cost.

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3.10 Concepts of Evidence-Based Medicine

“Evidenced-based medicine is the concept of formalising the scientific

approach to the practice of medicine for identification of “evidence” to
support our clinical decisions. It requires an understanding of critical
appraisal and the basic epidemiologic principles of study design, point
estimates, relative risk, odds ratios, confidence intervals, bias, and
confounding. By using this information, clinicians can categorise
evidence, assess causality, and make evidence-based recommendations.
Evidence-based medicine allows analysis of complicated material so that
we can make the best possible clinical decisions for the populations we
serve.”

The concept of evidence-based medicine (EBM), defined as the

‘‘integration of best research evidence with clinical expertise and patient
values’’ is based on,

i A process of Life-long self-directed learning in which caring for

patients creates the need for important information about clinical
and other health care issues.
ii EBM recognises that the research literature is constantly changing.
What the evidence point to as the best method of practice today
may change next month or next year. The task of staying current,
although never easy, is made much simpler by incorporating the
tools of EBM such as the ability to track down and critically
appraise evidence, and incorporate it into everyday clinical
practice. The work of people in the field of Paediatric and child
health centres on the problems of children and their families and
care givers. Questions about diagnosis, prognosis, and treatment
often arise and sometimes the answers to these questions need to
be sought. EBM allows the integration of good quality published
evidence with clinical expertise and the opinions and values of the
patients and their families or care givers.

Deciding on how to treat patients should not be based solely on the

available evidence. Other factors such as personal experience, judgement,
skills, and more importantly patient values and preferences must be
considered. The practice of EBM should therefore aim to deliver optimal
patient care through the integration of current best evidence and patient
preferences, and should also incorporate expertise in performing clinical
history and physical examination.

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Figure 36: Theories and Methods

3.11 The Five Steps Ebm Model

The practice of EBM involves five essential Steps. First, converting

information needs into answerable questions; second, finding the best
evidence with which to answer the questions; third, critically appraising
the evidence for its validity and usefulness; fourth, applying the results of
the appraisal into clinical practice; and fifth, evaluating performance.

3.11.1 Step 1: Formulating answerable clinical questions

One of the difficult steps in practicing EBM may be the translation of a

clinical problem into an answerable question. When we come across a
patient with a particular problem, various questions may arise for which
we would like answers.

These questions are frequently unstructured and complex, and may not be
clear in our minds. The practice of EBM should begin with a well
formulated clinical question.

This means that we should develop the skill to convert our information
needs into answerable questions. Good clinical questions should be clear,
directly focused on the problem at hand, and answerable by searching the
medical literature. A useful framework for making clinical questions more
focused and relevant has been suggested by Sackett et al. They proposed
that a good clinical question should have four (or sometimes three)
essential components: the patient or problem in question; the intervention,
test, or exposure of interest; comparison interventions (if relevant); and
the outcome, or outcomes of interest. Thus, an answerable clinical
question should be structured in the PICO (Patient or Problem,
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Intervention, Comparison, Outcome/s) or PIO (Patient or Problem,

Intervention, Outcome/s) format.

To illustrate the concept of PICO/PIO,

Imagine that you have a 45-year-old male with hypertension presents to

your clinic for follow up. At a prior visit he was screened for diabetes. His
haemoglobin A1C has been 7.0% on two occasions, which is a new
diagnosis of diabetes.

His blood pressure is well controlled at 125/80. He has no evidence of

microalbuminuria or kidney disease.
You recall from medical school that ACEI are good for preventing
diabetic kidney disease, but you’re not sure if this fact applies to this
patient.

You want to find this answer.

We will walk you through the process of developing a clinical question!

You decide to use ‘‘clinical score’’ as a measure of improvement. The
PICO format consists of 4 basic components to keep in mind. The key
components of your clinical question would be:

i Problem and Population: What is the disease or condition?

What are the important characteristics of my patient?
ii Intervention: What is the intervention I am looking for? Is it
realistic (availability, cost, convenience, etc.)? Is this different
from how I currently practice?
iii Comparison: What is the alternative to the intervention?
iv Outcome: Is it something patients care about? Or is it something
only physiologists/pharmacists care about?
So, how do I develop a clinical question? Focusing the PICO
question
v Population: Starting with your patient, ask "How would I
describe a group of patients similar to mine?" Be precise but
brief. —target the appropriate specificity (DM/HTN patients who
are normotensive on medication without microalbumuria is too
specific, etc.). “In adult patients with diabetes mellitus II and
hypertension”
vi Intervention/Comparison: Ask “What is the main intervention I
am considering?”and “What is the main comparison/control?” Be
specific, but consider feasible alternatives.

Ask “What is the main intervention I am considering?”and “What is the

main comparison/control?”
In this Patient: “An ACEI”

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Outcomes: Ask "What can I hope to accomplish?" or "What could this

exposure really affect? “Select patient-oriented outcomes instead of “the
numbers.”

Ask "What can I hope to accomplish?" or "What could this exposure really
affect? “
Are these outcomes our patient cares about?

“Prevent development of microalbumuria?” OR “Prevent

worsening of eGFR?”

Ask yourself patient oriented question: Are these outcomes our patient
cares about?

The Patient Is What Matters

There two outcomes our patient cares about?

i Disease-Oriented Evidence (DOE): Measures outcomes that are

markers for disease, the “Silent numbers”
ii Patient-Oriented Evidence That Matters (POEMs): Measure
outcomes that our patients care about. They have the potential to
change the way we practice!

Physicians may be focused on a number (e.g., GFR, A1C, LDL, BP, etc.)
of disease-oriented evidence and overlook the broad goal in mind. What
matters is if it changes the patient’s overall morbidity, morality, or quality
of life (patient-oriented evidence). For example, no one ever dies of high
blood cholesterol. They die from the effects of high cholesterol, like a fatal
heart attack or a stroke. We often get side-tracked into tracking the
numbers when the patient is what truly matters. We need to look at the
evidence in the context of the patient and make sure we are doing things
that make them live longer or live better!

Characteristics of DOEs and POEMs

i Disease-Oriented Evidence (DOE): Pathophysiological

parameters such as Laboratory values or Biochemical markers,
Pharmacology e.g. size of tumour, Blood pressure and Aetiology
ii Patient-Oriented Evidence That Matters (POEMs): this includes;
Morbidity e.g. Symptoms or Daily function, Mortality and Quality
of Life (as perceived by the patient)

Another way of looking at this is that the disease-oriented evidence

focuses on the mechanism of action (the internal gears, dials, or “settings”
that a patient has).

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Instead of looking at the patient-oriented outcomes that the patient is able

to see, feel and detect (the external effects of it on their life, like symptoms,
their daily functioning or their quality of life.)

3.11.2 Step 2: Finding the evidence

Once you have formulated your clinical question, the next step is to seek
relevant evidence that will help you answer the question. There are several
sources of information that may be of help.

i Traditional sources of information such as textbooks and journals

are often too disorganized or out of date.
ii You may resort to asking colleagues or ‘‘experts’’ but the quality
of information obtained from this source is variable.
Secondary sources of reliable summarised evidence which may
help provide quick evidence-based answers to specific clinical
questions include Archimedes. Other important sources of
evidence include the online electronic bibliographic databases,
which allow thousands of articles to be searched in a relatively
short period of time in an increasing number of journals. The ability
to search these databases effectively is an important aspect of
EBM. Effective searches aim to maximise the potential of
retrieving relevant articles within the shortest possible time.
Studies have shown that, even in countries where hospitals have
facilities for internet access allowing health care personnel access
to a number of electronic databases, many people are not familiar
with the process of carrying out efficient searches and often
conduct searches which result in too few or too many articles. It is
therefore important for health care professionals to undergo basic
training in search skills, either through their local library services
or through the attendance at formal courses.

iii basic search principles

Convert the clinical problem into an answerable question.

The key to successful searching is to convert your clinical problem into a
clear answerable question, which should ideally be framed in the
PICO/PIO format as discussed above.
Generate appropriate keywords

A word list can be generated, based on keywords from the clinical

question. For example, from the clinical question above, the following
keywords could be used for the search:

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“In adult patients with diabetes mellitus II and hypertension” such would
include words like; ACEI, Blood Glucose (A1c), Blood Pressure,
Microalbumuria and Morbidity, mortality

Choose a bibliographic database: Numerous online databases are

available. These include the Cochrane Library databases, MEDLINE,
EMBASE, and CINAHL.

i.Conduct the search

Once the key words and databases have been identified, the next
thing is to run the search. You can limit your search by publication
type (for example, randomized controlled trials or review articles);
by date of publication; by language, by study population, and so
on. Example of a basic search strategy to try to find evidence to
answer the clinical question I formulated earlier, we can use the
keywords generated to search the Cochrane database of systematic
reviews and PUBMED, using the following search strategy:
When this search strategy was used to search the Cochrane
database of systematic reviews in 2014, four articles were
retrieved, but only one of these was relevant. Other strategies that
may be used to improve the sensitivity and specificity of literature
searches have been described by Sackett et al.

Table 41: Some compare and contrast examples of DOEs and

POEMs.
Disease oriented evidence Patients oriented evidence that
(DOE) matters
Intensive treatment can lower Intensive treatment in patients
blood glucose levels in patients with type 2 diabetes does not
with type 2 diabetes decrease Mortality
Beta – carotene and Vitamin E Neither beta – carotene or Vitamin
are good-antioxidants E prevent Cardiovascular disease
or cancer

Your literature revealed, there is no evidence that driving an A1c below

9% decreases mortality and the outcomes that the UKPDS study shows
only microvascular outcomes like less diabetic retinopathy and the
ACCORD study shows that driving the A1c<6% is associated with
increased mortality.
Similarly, antioxidants have not panned out to demonstrate effects to
prevent heart disease or cancer. (for more information, see the
accompanying reference).

The question is, do patients care enough about their eyes that they are
willing to risk dying earlier than they would otherwise?

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Table 42: Here are some more examples.

Disease oriented evidence (DOE) Patients oriented
evidence that matters
The drug varenicline can help smokers Varenicline increases the
stop smoking (which should lead to a risk of cardiovascular
decrease in cardiovascular events). events.
Older antiarrhythmic medications can Medical treatment of
decrease irregular heartbeats in asymptomatic arrhythmias
patients with asymptomatic arrhythmias. increases mortality by
10%.

The drug Varenicline (Chantix) can help smokers quit, but has been shown
to itself, increase the risk of CV events.
Older antiarrhythmics that were commonly used to prevent arrhythmias
(according to the methods you may recall learning about in medical school
with class IA-c) turned out to actually increase mortality.

3.11.3 Step 3: Appraising the evidence

After you have obtained relevant articles on a subject, the next step is to
appraise the evidence for its validity and clinical usefulness. Although
there is a wealth of research articles available, the quality of these is
variable. Putting unreliable evidence into practice could lead to harm
being caused or limited resources being wasted. Research evidence may
be appraised with regard to three main areas: validity, importance, and
applicability to the patient or patients of interest. Critical appraisal
provides a structured but simple method for assessing research evidence
in all three areas. A detailed discussion of the critical appraisal of
randomised controlled trials and systematic reviews will be provided in
the two articles of the series.

3.11.4 Step 4: Applying the evidence

When we decide after critical appraisal that a piece of evidence is valid

and important, we then have to decide whether that evidence can be
applied to our individual patient or population. In deciding this we have to
take into account the patient’s own personal values and circumstances.
The evidence regarding both efficacy and risks should be fully discussed
with the patient or parents, or both, in order to allow them to make an
informed decision. This approach allows a ‘‘therapeutic alliance’’ to be
formed with the patient and the parents and is consistent with the
fundamental principle of EBM: the integration of good evidence with
clinical expertise and patient values. The decision to apply evidence
should also take account of costs and the availability of that particular
treatment in your hospital or practice. A practical illustration of issues to

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consider before applying research evidence will be provided in the fourth

article of the series.

Reviewing the Patient with the evidence, “In adult patients with diabetes
mellitus II and hypertension”

Intervention: “ACEi”
Comparison: “Placebo”
Outcome: “Prevent worsening of eGFR?”
Is eGFR an outcome
our patient cares about?

So, let’s go back to one of our PICO questions. “in adult patient with
DM/HTN, does an ACEi when compared to placebo prevent worsening of
eGFR?” Is eGFR an outcome our patient cares about?
The outcome measured “eGFR” is a disease-oriented outcome (DOE).
eGFR is an intermediary marker. It is not something patients care about if
it does not help them live longer or better
Can you think of a way to rephrase the question to make the outcome
patient-oriented evidence that matters (POEM)?

i. Possible POEM Alternatives:“In patients with diabetes, are ACEi

associated with lower mortality rates?” Or “In patients with
diabetes, do ACEi delay progression toward end-stage kidney
disease requiring dialysis?” Or “In patients with diabetes, do ACEi
delay progression toward end-stage kidney disease requiring a
kidney transplant?”

ii. You now search If the audience wants to know the answer,
Cochrane 2012: Antihypertensive agents for preventing diabetic
kidney disease.

Related to our clinical questions,

ACEi reduced the risk of death (all-cause mortality) when compared to

placebo (POEM)
ACEi reduced the risk of new onset of microalbuminuria,
macroalbuminuria or both when compared to placebo, with similar
benefits in people with and without hypertension, and when
compared to calcium channel blockers (DOE)
ACEi were found to prevent new onset DKD and death even in
normoalbuminuric people with diabetes, and therefore can be used
for our patient.

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iii. Alternate Clinical Queries

After developing a “best” case-based PICO question, the next step
is exploring other searchable clinical queries. These are a list of
flexible alternative questions since the answer to your precise
question may not match the current scientific literature. Typically,
the alternatives involve reasonable variations of your
interventions/comparison or alternative outcomes.

For example, for the DMII/HTN introductory case, a 2012 Cochrane study
shows the following variants of what was ACTUALLY STUDIED:

i I & C: ACEi versus placebo, ACEi versus ARB, ACEi versus

“other active agents” (BB, CCB), combination ACEi+ARB vs
ACEi alone
ii O: POEM: all-cause mortality
iii O: DOEs: microalbuminuria, macroalbuminuria, blood pressure,
doubling of Cr/progression to ESKD
iv O: time to dialysis/kidney transplant (while a great patient-
oriented measure, was not a measure because follow-up only
ranged from 6–72 months.)

3.11.4 Step 5. Evaluating performance

As we incorporate EBM into routine clinical practice, we need to evaluate

our approach at frequent intervals and to decide whether we need to
improve on any of the four steps discussed above. As Strauss and Sackett
have suggested, we need to ask whether we are formulating answerable
questions, finding good evidence quickly, effectively appraising the
evidence, and integrating clinical expertise and patient’s values with the
evidence in a way that leads to a rational, acceptable management strategy.
Formal auditing of performance may be needed to show whether the EBM
approach is improving patient care.

3.12 Anatomy of a good clinical question: PICO

PICO is a mnemonic that helps one remember the key components of a

well-Focused question. The question needs to identify the key problem of
the patient, what treatment you are considering for the patient, what
alternative treatment is being considered (if any) and what is the outcome
you want to avoid or promote.

i P = Patient or problem: How would you describe a group of

patients similar to yours? What are the most important
characteristics of the patient? This may include the primary
problem, disease, or co-existing conditions. Sometimes the sex,

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age or race of a patient might be relevant to the diagnosis or

treatment of a disease.

ii I = Intervention, prognostic factor, or exposure: Which main

intervention, prognostic factor, or exposure are you considering?
What do you want to do for the patient? Prescribe a drug? Order a
test? Order surgery? What factor may influence the prognosis of
the patient? Age? Co-existing problems? Has the patient been
exposed to something? Asbestos? Cigarette smoke?

iii C = Comparison: What is the main alternative to compare with

the intervention? Are you trying to decide between two drugs, a
drug and no medication or placebo, or two diagnostic tests? Your
clinical question does not always need a specific comparison.

iv = Outcomes: What can you hope to accomplish, measure,

improve or affect? What are you trying to do for the patient?
Relieve or eliminate the symptoms? Reduce the number of
adverse events? Improve function or test scores?

Table 43: Constructing A Clinical Question

P = Patient I = C= O= Outcome
Intervention Comparison
Who? What? Alternative Outcomes
Intervention
“How would I ” Which “Compared to What is the
describe a group treatment, test what other patient-oriented
of patients or other treatment, test, outcome – better
similar to this intervention?” or perhaps prognosis? Higher
particular compared to rate of cure? Etc.?”
patient?” doing nothing”

3.13 Benefits: Why Evidence Based Medicine?

The most important reason for practicing EBM is to improve quality of

care through the identification and promotion of practices that work, and
the elimination of those that are ineffective or harmful. EBM promotes
critical thinking. It demands that the effectiveness of clinical
interventions, the accuracy and precision of diagnostic tests, and the power
of prognostic markers should be scrutinised and their usefulness proven.
It requires clinicians to be open minded and look for and try new methods
that are scientifically proven to be effective and to discard methods shown
to be ineffective or harmful.

It is important that health care professionals develop key EBM skills

including the ability to find, critically appraise, and incorporate sound

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scientific evidence into their own practice. EBM advocates the use of up-
to-date "best" scientific evidence from health care research as the basis for
making medical decisions.

For supporters, EBM has three main advantages:

i It offers the surest and most objective way to determine and

maintain consistently high quality and safety standards in medical
practice;
ii It can help speed up the process of transferring clinical research
findings into practice;
iii It has the potential to reduce health-care costs significantly.
The approach, however, is not without its opponents. These
consider that EBM risks downplaying the importance of clinical
experience and expert opinion, and that the conditions under
which clinical trials used to define best practice take place are
hard to replicate in routine practice.

3.14 LIMITATIONS OF EVIDENCE BASED MEDICINE

Although evidence-based medicine is regarded as the gold standard of

clinical practice. There is however, a number of limitations to its use.
According to Strauss and McAllister, the limitations are basically 3
namely:

i limitations universal to the practice of medicine

ii limitations unique to evidence-based medicine and
iii misperceptions of evidence-based-medicine

Popular limitations include;

EBM produces quantitative research, especially from randomized
controlled trials (RCTs). Accordingly, results may not be relevant for all
treatment situations.

Because RCTs are expensive, the priority assigned to research topics is

inevitably influenced by the sponsors' interests.

There is a lag between when the RCT is conducted and when its results
are published.

There is a lag between when results are published and when these are
properly applied. Certain population segments have been historically
under-researched (racial minorities and people with co-morbid diseases),
and thus the RCT restricts generalising.

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Not all evidence from an RCT is made accessible. Treatment effectiveness

reported from RCTs may be different than that achieved in routine clinical
practice.

Published studies may not be representative of all studies completed on a

given topic (published and unpublished) or may be unreliable due to the
different study conditions and variables.

Research tends to focus on populations, but individual persons can vary

substantially from population norms, meaning that extrapolation of
lessons learned may founder. Thus, EBM applies to groups of people, but
this should not preclude clinicians from using their personal experience in
deciding how to treat each patient.

3.14.1 Values: while patient values are considered in the original

definition of EBM, the importance of values is not commonly emphasised
in EBM training, a potential problem under current study.

3.14.2Older Professionals: As with any concept, there are disadvantages

as well as advantages of applying evidence-based medicine to modern
healthcare; despite the integration of evidence-based medicine in the
curriculum for university medical studies courses, as a relatively new
practice the number of healthcare professionals not familiar with such a
routine is still fairly high. Furthermore, many of those who practiced long
before the implementation of evidence-based medicine feel it undermines
their clinical expertise and the value of their experience to a degree.

3.14.3 Costs: Short term cost is an obvious limitation but can be justified
to some extent when considering the long-term cost-effectiveness of using
evidence-based medicine. The decision related to which research program
to fund raise ethical as well as economic issues but it is obviously not
possible to fund research into every known illness.

3.14.4A Lack of Evidence: Critics of the evidence-based medicine

system have stated that most commonly a lack of funding for research
means there is a lack of sufficient evidence for treatments associated with
many different illnesses, particularly those that are relatively uncommon.
If no money is committed to researching certain illnesses then it is possible
that no progress will ever be made concerning the treatment of that
particular illness, despite advances in technology and scientific research
possibilities. In addition to this, research suggests that not all data is made
available for all to see, with negative trials often not published; this infers
a degree of selectivity and bias.

3.14.5The Personal Touch: Whilst the evidence supporting the benefits

of evidence based medicine is abundant in terms of determining effective

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treatments, this concept does not account for issues such as how an
individual patient feels from one day to the next; even if a drug is proven
scientifically to be effective it will still affect each individual in a different
way and therefore some patients may not follow the predicted course of
recovery.

3.14.6Lack of Skills: Critics have expressed concern that those healthcare

professionals who have not previously been specifically trained to
interpret the data they receive do not have the necessary skills to do so and
are therefore struggling to act in accordance with new guidelines.

Amidst these limitations and criticism, there are some advantages to its
use. These include

i Patients satisfaction
ii Improved efficiency
iii With the explosion of scientific knowledge being published, it’s
difficult for clinicians to stay current on the latest best medical
practices.
iv Improved technology enables healthcare workers to have better
access to data and knowledge.
v Payers, employers, and patients are all driving the need for the
healthcare industry to show transparency, accountability, and
value.

4.0 CONCLUSION

In this unit, you have learnt the importance of history taking. This includes
the approach to patient while taking medication history and proper
documentation and possible limitation to expect in taking medication
history. The second part of this unit deals with evidence-based practice as
it is used in physical therapy. Students have been exposed to how to
recognise the 5-step process in Evidence-Based Practice, compare and
contrast arguments for and against evidence-based practice, understand
the key research methods needed to locate medical evidence and have
learnt how to describe strategies to apply evidence-based practice to
clinical cases

5.0 SUMMARY

This unit introduces you to the importance taking detail, accurate and
complete account of all prescribed and non-prescribed medications that a
patient had taken or is currently taking prior to current admission or
medical care. Its emphasis that without an accurate medication history,
prescribers may inadvertently make incorrect decisions about a patient’s
treatment, causing harm if previously discontinued medicines are

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restarted, or if current medicines are omitted or prescribed at the wrong

dose for the patient.

Medication history help in preventing prescription errors and consequent

risk to patients. It is useful in detecting drug –related pathology or changes
in clinical signs that may be the result of drug therapy and it should
encompass all currently and recently prescribed drugs, previous adverse
drug reactions including herbal or alternative medicines and adherence to
therapy for better care plan.

The need to approach the patients properly introducing yourself and

purpose of interview as well as the content and tips of history taking was
outlined.

Elements of client education such as encouraging patient to take

ownership, educate client to bring medications from home at each
appointment, and educate client to carry a list of current medications
(prescription and OTC) were outlined. The Unit conclude with tips on how
to wrap up medication. For example, the need to conclude with thanking
the patient for their time and information and asking them if they have any
other questions etc.

EBM aims to improve quality of care through the integration of best

research evidence with clinical expertise and patient’s and parents’
preferences. In this, it has explained the five essential steps for practicing
EBM, which are: formulating answerable clinical questions; searching for
evidence; making a critical appraisal; assessing the applicability of the
evidence; and evaluating performance.

We have discussed The Five “A” and identify each component of the
PICO pneumonic:

P = patient, problem, population

I = intervention
C = comparison
O = outcome

How to ask and identify and develop a well-articulated question about

either patient care issues or research issues using the PICO Worksheet.
Then determine the study question category as either diagnosis,
therapy/prevention, prognosis, or aetiology.

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SELF ASSESSED EXERCISES

i. Explain the anatomy of a good clinical question.

ii. Discuss the limitations of Evidence Based Medicine.

6.0 TUTOR- MARKED ASSIGNMENT

1. You are asked to take a medication history. Why is it important

for you to obtain a complete description of the patient’s
medication history?
2. Outline steps in medications
3. Tabulate a sample of Cards for Medication History Script
4. Define EBM, outline the five steps of evidence-based Model
5. what PICO? Discuss it role in patients’ evidence
6. discuss the benefit and limitation evidence Based medicine

7.0 REFERENCES/FURTHER READING

Lau, H.S., Florax, C., Porsius, A.J., & De Boe, R.A. (2000). The
completeness of medication histories in hospital medical records of
patients admitted to general internal medicine wards. Br J. Clin
Pharmacol, 49(6):597‐603. doi:10.1046/j.1365-2125.2000.00204.
National Patient Safety Agency. (2010) Reducing harm from omitted and
delayed medicines in hospital. Rapid Response Report. Retrieved
January 2016.
http://www.nrls.npsa.nhs.uk/alerts/?entryid45=66720.

Tam V.C., Knowles, S.R., Cornish, P.L., Fine, N., Marchesano, R. &
Etchells, E.E. (2005). Frequency, type and clinical importance of
medication history errors at admission to hospital: a systematic
review.CMAJ, 173(5):510‐515. doi:10.1503/cmaj.045311.

Dornan, T., Darren, A., Heather, H., Penny, L., Jon, Miles., David,
Taylor., Mary,Tully. & Wass V. (2009). An in-depth investigation
into causes of prescribing errors by foundation trainees in relation
to their medical education. EQUIP study final report December
2009. Available at: http://www.gmc-
uk.org/about/research/25056.asp (accessed January 2016).

Parveen K.C. (2020). Obtaining the Best Possible Medication History

Medication Reconciliation Initiative Winnipeg Regional Health.
Retrieved 7th May 2020 from,
Authority.inhttps://www.slideshare.net/ParveenKumarChadha1/m
edication-history.

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Kanchan V. K. (2020). Medication History Interview. Slide Presentations.

ttps://www.slideshare.net/rafibhatttt/medication-history-interview.
(access 7th June 2020).

Gareth, N., &Rhys, D. (2016). How to take an accurate and detailed

medication history.Pharm J, 296 (7886) online. Http:// DOI:
10.1211/PJ.2016.20200476.https://www.pharmaceutical-
journal.com/cpd-and-learning/learning-article/how-to-take-an-
accurate-and-detailed-medication-
history/20200476.article.(access7th April 2020).

Sackett, D. (1997). Evidence Based Medicine. London: Churchill

Livingstone. University of Oxford Evidence based medicine
tools,2013.

Grimshaw, J., Eccles, M., Thomas, R., MacLennan, G., Ramsay, C.,
Fraser, C. & Vale, L. (2006). Toward evidence-based quality
improvement. Evidence (and its limitations) of the effectiveness of
guideline dissemination and implementation strategies 1966-1998.
J Gen Intern Med, Suppl 2 (Suppl 2): S14-20. Http: // doi:
10.1111/j.1525-1497.2006.00357. x.

.David, S., Rosenberg, W., Muir, Gray., Brian, H.& Scott, R. (1996).
Evidence based medicine: what it is and what it isn’t.BMJ, 312
(71). https://doi.org/10.1136/bmj.312.7023.71.

Imogen, E., Hazel, T.& Iain, C. (2011). Testing Treatments: Better

research for better healthcare (2nd ed.).London: Printer and
Martin Ltd.

.Eccles, M.P. Armstrong, D., Baker, R., Cleary, K., Davies, H., Davies,
S., Glasziou, P., Ilott, I., Kinmonth, A., Leng, G., Logan, S.,
Marteau, T., Michie, S., Rogers, H., Malone, J. & Sibbald, B.
(2009). An implementation research agendaImplementation Sci, 4
(18).

Every-Palmer, S. & Howick, J. (2014). "How evidence‐based medicine is

failing due to biased trials and selective publication". J Evalu
ClinPrac, 20(6), 908-914. https://doi.org/10.1111/jep.12147.

Gate, C. (2006). Drug history taking-avoiding the common pitfalls.

Hospital Pharmacist, 13, 98-100.

Law, J. & Martin, E. (2020). Course medical dictionary (oxford quick

reference). OUP Oxford.

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UNIT2 PHARMACOVIGILANCE/PHARMACOVIGILANCE
IN PUBLIC HEALTH PROGRAMMES

CONTENTS

1.0 Introduction
2.0 Objectives
3.0 Main Content
3.1 Definition of terms
3.2 Pharmacovigilance
3.2.1 Origins of pharmacovigilance: Era of safety
monitoring,
3.1.1 How Medicine Safety Is Assured,
3.1.2 Detection of Adverse Drug Reactions
3.1.3 ADR Reporting
3.1.4 Causality Assessment
3.3 Pharmacovigilance in Public Health Programmes
3.3.1 Goal of Public Health Programmes,
3.3.2 Types of Public Health Programmes.
3.3.3 Characteristics of Public Health Programmes,
3.3.4 Current situation in Public Health Programmes.
3.3.5 Why PV should be integrated into PHPs,
3.3.6 Challenges of pharmacotherapy in PHPs.
3.3.7 Strengths and Weaknesses of PHPs,
3.3.8 Opportunities, Public Health Programmes
3.3.9 Threat to Pharmacovigilance Public Health
Programmes
4.0 Conclusion
5.0 Summary
6.0 Tutor- Marked Assignment
7.0 References/Further Reading

1.0 INTRODUCTION

Modern medicines/drugs have brought significant benefits to our lives,

offering reduction in morbidity and mortality. The improving health status
of increasing number of the population can be attributed to drugs.
However, even though medicines are generally seen as beneficial, all
medications including the excipients in medicines are capable of
producing adverse or unwanted effects. Governments in several countries
consider the need to ensure quality, safety, and efficacy of all medicines
and health products used in their country as an important public health
function. Pharmacovigilance activities relating to the detection,
assessment, understanding and prevention of adverse effects or any
other possible drug-related problems become an integral part of health
care in recent times.

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Ensuring Pharmacovigilance in Public Health Programmes become

necessary because, many Public Health Programmes (PHPs) are involved
in direct administration of medicines to large populations and
communities for the prophylaxis, treatment and/or eradication of diseases
The large number of patients who will receive the drugs in a systematic
manner in these programmes generates the possibility of harm if
unmonitored and, at the same time, an opportunity to develop systems for
generating valid and valuable data that will assist in decision making.
Therefore, PHPs and Pharmacovigilance (PV) can derive mutual benefits
from each other; PV and adverse drug reactions monitoring in PHPs can
detect rare adverse events and risk factors in patients and can have a
tremendous positive impact on the implementation and success of these
programmes; PHPs on the other hand can provide an opportunity to
introduce PV in countries that lack a system for drug safety monitoring.
Safety issues that are specific to various disease-control programmes
(Chagas, HIV/AIDS, Malaria, Tuberculosis, etc.) are being addressed
through different Projects.

Registers and databases are being created and used as a foundation for
statistics that allow medical care providers to oversee potential risks and
minimise them. The success or failure of any pharmacovigilance activity
depends on the reporting of suspected adverse reactions. WHO has played
a vital role in promoting the safety of medicinal products as a clinical and
public health issue? Duly, the data collected through spontaneous
reporting, national pharmacovigilance centres, and the WHO Programme
for International Drug Monitoring has led to changes in the labelling of
medicines. It has become an essential tool in providing the necessary
infrastructure for drugs programmes. Furthermore, the cost of an effective
pharmacovigilance system is notably smaller when compared to the
national expenditure on medicines or the cost of managing ADRs.

2.0 OBJECTIVES

By the end of this, you will be able to:

 identify what is and why we Need Pharmacovigilance

 outline the goals, need and importance of pharmacovigilance
 explain origin of modern PV: Era of Safety and Efficacy
 identify working knowledge of the guides & tools for reporting
 describe tools used for causality assessment and able to
 assess severity and causality of ADRs
 describe the importance of Pharmacovigilance in Public Health
Programme (PHP).
 State why PV should be integrated into PHPs
 describe practices to improve ADR reporting in PHP.
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 describe strategies to strengthen functioning of the Expert Advisory

Committee.

3.0 MAIN CONTENT

3.1 Definition of Terms

i. Organisations involved

WHO - World Health Organisation

CIOMS - Council of International Organisations of Medical Sciences
ICH – International Conference on Harmonisation

ii. Pharmacovigilance: Is define as the science and activities

relating to the detection, assessment, understanding and
prevention of adverse effects or any other possible drug-
related problems.
iii. Spontaneous Report: An unsolicited communication by MAHs,
healthcare professionals, or consumers that describes one or
more adverse drug reactions in a patient who was given one or
more medicinal products and that does not derive from a study or
any organised data collection scheme.
iv. Serious Adverse Event or Reaction: Any untoward medical
occurrence that, at any dose, results in death; is life
threatening; requires inpatient hospitalisation or prolongs current
hospitalisation; results in persistent or significant disability,
incapacity, or congenital abnormality
v. Serious Adverse Event Or Reaction : Any untoward medical
occurrence that at any dose
a. results in death
b. is life-threatening
c. requires inpatient hospitalisation or
d. prolongation of existing hospitalisation
e. results in persistent or significant disability or incapacity
f. results in a congenital abnormality
note on Serious adverse event or reaction

To ensure no confusion or misunderstanding of the difference between the

terms 'serious' and 'severe', the following note of clarification is provided:

The term 'severe' is not synonymous with serious. In the English language,
'severe' is used to describe the intensity (severity) of a specific event (as
in mild, moderate or severe); the event itself, however, may be of
relatively minor medical significance (such as severe headache).

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Seriousness (not severity) which is based on patient/event outcome or

action criteria serves as guide for defining regulatory reporting
obligations.

Table 44:Frequency Of Adverse Drug Reactions (Cioms):

Very common ≥1/10
Common (frequent) < 1/10 but ≥ 1/100
Uncommon (infrequent) < 1/100 but ≥ 1/1000
Rare < 1/1000 but ≥ 1/10000
Very rare < 1/10000 but

vi. Signal:Possible causal relationship between adverse event and

drugs previously unknown or incompletely documented. More
than one report is needed depending on; Quality of the
information or Seriousness of the event

vii. Causality Assessment: The process of assessing the likelihood

that the reported adverse reaction is actually due to the suspected
medicine using pre-determined criteria such as the WHO causality
assessment criteria.

viii. Spontaneous Report: A system whereby case reports of adverse

drug events are voluntarily submitted by health professionals and
MAHs to the National Pharmacovigilance Centre.

ix. Health Product: Any product, substance or a mixture of

substances used or purported to be suitable for use that is
manufactured or sold for use in the diagnosis, treatment, mitigation,
modification or prevention of a disease, abnormal physical or
mental state, or the symptoms thereof, in humans or animals; or for
restoring, correcting or modifying any somatic, psychic or organic
function in humans or animals. A health product can include
medicines, herbal products, vaccines, antisera, biological and blood
products.

x. Health Products Regulation: All the processes involved in the

pre-marketing evaluation, marketing authorisation, and post-
marketing review of medicines, vaccines, devices, and other
health products to ensure compliance with established standards
of quality, safety, and efficacy.

xi. Marketing Authorisation Holder (MAH): The holder (an

individual, institute, manufacturer, company, importer,
distributor, development partner/donor agency) of a marketing
authorisation to market a medicinal product. For the purpose of this

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policy document, the MAHs will have full responsibility and liability for
their product on the market and full responsibility for ensuring that
appropriate action can be taken when necessary.

xii. Medication Errors: Any unintended preventable events that may

cause or lead to inappropriate medication use or patient harm
while the medication is in the control of the healthcare
professional, patient or consumer. Such events may be related to
professional practice, healthcare products, procedures and systems
including prescribing, order communication, product labelling,
packaging and nomenclature, compounding, dispensing,
distribution, administration, education, monitoring and use.
Cosmetics, chemicals/detergents medical devices and all drinks
including packaged water.

xiii. Periodic Safety Update Report (PSUR): A report produced by

an MAH intended to provide an update of a worldwide safety
experience (with some focus on Nigeria) of a medicinal product to
the competent authorities at defined times post authorisation.

3.2 Pharmacovigilance

Pharmacovigilance is defined as the science and activities relating to the

detection, assessment, understanding and prevention of adverse effects
or any other possible drug-related problems.
Recently, its concerns have been widened to include herbals, traditional
and complementary medicines, blood products, biologicals, medical
devices and vaccines etc. Other issues relevant to this science include

i. Substandard medicines
ii. Medication errors
iii. Lack of efficacy reports
iv. Use of medicines for indications that are not approved and for
which there is inadequate scientific basis
v. Case reports of acute and chronic poisoning
vi. Assessment of drug-related mortality
vii. Abuse and misuse of medicines
viii. Adverse interactions of medicines with chemicals, other
medicines and food’.

Pharmacovigilance is an arm of patient care. It aims at getting the best

outcome of treatment with medicines. No one wants to harm patients, but
unfortunately, because of many different factors, any medicine will
sometimes do this.

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3.2.1Origins of Pharmacovigilance: Era of Safety Monitoring

The 1st reported case of ADR occurred over 150 years ago, in 1848, a 15-
year-old girl from Winlaton, north-east England, had a routine general
anaesthetic while undergoing a surgical procedure for an ingrown toenail.
The anaesthetic agent, chloroform, had only been introduced into clinical
practice a year earlier, since it produces less nausea and vomiting than
Ether. The girl died during the anaesthesia from what was probably an
episode of ventricular fibrillation. The Lancet set up a commission, which
invited doctors in Britain and its colonies to report anaesthesia-related
deaths. Their findings were subsequently published in medical journal in
1893. Thus, the forerunner of a Spontaneous reporting system for
suspected adverse drug reactions (ADRs) was established, at least for a
time.

Another early incident of harmful effects of drug was recorded in 1937,

where a formulation defect in elixir of sulphonamide resulted in
poisoning. DEG; US 105 deaths in 1937 Federal Food, Drug and Cosmetic
Act (1938) with the premarket notification requirement. Though, the
sulphonamide incidence led to improvement in pharmaceutical
regulations, there was no define monitoring system for drug safety until
Thalidomide: 1956 – 1962 about 10,000 children were born with severe
malformations, including phocomelia. In 1960 report of 2 grossly
deformed infants in Germany (thalidomide disaster). By 1961 477 cases
of phocomelia in paediatric clinics, and withdrawal recommended.
However, a delay of one month, lead to another 50 - 100 new cases and
by the time regulation was put in place, - More than 4000 cases.

Thurs in 1962 the World Health Assembly (Kefauver-Harris Drug

Amendment (1962) required proof of effectiveness and safety before
marketing) requested the WHO Director General to study ways to make
drugs safer including ‘securing prompt transmission to national health
authorities of new information
on serious side effects of pharmaceutical preparations. As a result, an
international system for monitoring adverse reactions to drugs (ADRs) –
Pharmacovigilance, based on data from national centres was proposed.
Voluntary notification scheme (1961962: Kefauver-Harris Drug
Amendments
Figure 37: A child with Phocomelia. Due to thalidomide disaster
(@Wikipedia
en.wikipedia.org )

passed to ensure drug efficacy and safety; first time Pharma were required
to prove effectiveness before market entry After a pilot project was carried
out in the USA, an international database was established at WHO
headquarters in Geneva in 1971 and moved to Uppsala, Sweden in 1978.

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3.2.2 How medicine safety is assured

All drugs undergo a significant amount of testing and evaluation before

marketing to ensure their effectiveness as well as safety. Marketed
medicines undergo trials in animals (preclinical testing) and humans
(clinical trials) to establish their efficacy, safety, and quality.

i. Pre-marketing evaluation

Pre-marketing evaluation involves animal studies and clinical trials in

humans. Studies in two or more animal species are conducted to test
whether the drugs are harmful and whether they may for instance induce
cancer, damage an unborn child; etc. Once scientists are sure that the drug
is safe, they start studies in human beings and these studies are known as
Clinical Trials.

Each phase involves increasing number of patients and by the end of full
pre- marketing clinical trials about 5000 patients would have taken the
drug. However, when the drug is marketed millions of people will take the
medicine. There is therefore the question of whether the clinical trials
involving just about 5000 people will provide enough information to
extrapolate the safety of a new drug to millions of people. Pre- marketing
safety evaluations have two significant drawbacks:
Under – identification of adverse drug reactions: ADRs which occur
infrequently are difficult to identify. Statistically, reactions with an
incidence of less than 1% are frequently not identified.

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Over- identification of ADRs: Many adverse drug reactions that are

identified in pre- clinical studies are not proven to be related to the drug,
but are nevertheless listed in the product literature as potentially causing
the ADR. This provides some measure of legal protection for
pharmaceutical company but is misleading to practitioners and patients, as
many of these reactions are not definitely proven.

ii. Post-marketing surveillance (PMS)

It is not possible to identify all of the safety- related problems that may
exist with a new drug during pre- market testing and evaluation. After
drugs have been released on the market, NAFDAC, the
manufacturers/importers and health care professionals are responsible for
post-marketing surveillance of these products. Drugs released to the
market will be used not only by more people, but also by different
categories of people other than those in whom the drug was tested. The
marketed drug will be used by older people, those with more serious
illness, and those from different ethnic groups, pregnant women and also
by children in whom drugs are rarely tested.

The medicines may also be used under many different dose regimens (not
necessarily the correct and approved dose) and they could also be
deliberately misused. These circumstances inevitably lead to a potential
for more adverse drug reactions. For these reasons, it is obvious that the
safety of a drug requires long-term surveillance after marketing.
Regulations Around the world

USA – 1962 FDA required both safety and efficacy data

UK – 1963 committee on safety of drugs, and yellow card system
1965 – Committee on safety of medicine (CSM). Medicine Act (safety,
quality, efficacy requirements)
EU – 1965 EC Directives 6565
WHO – 1968 Program for international Drug monitoring?

3.6 History of Withdrawals

i. Therapeutic mishaps have catalysed medicines regulation

ii. DEG poisoning from 1937-2008, about 600 deaths in11 countries
iii. Heparin ― 131 heparin-related deaths reported to FDA 1 Jan 2007
and 13 April 2008
iv. 125 products withdrawn for safety reasons over past 40 years
v. FDA Amendment Act (2007)
vi. Enhanced statutory authority regarding post-market safety of
drugs

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Table 45: Number of deaths in different countries

Year Country # of deaths reported
1937 United states 105
1985 Spain 5
1986 India 14
1987 South Africa 7
1990 Bangladesh 51
1990 Nigeria 47
1992 Argentina 7
1995/96 Haiti 88
1998 India 33
2006 Panama 123
2008 Nigeria 84
2009 Bangladesh 25

3.7 Detection of Adverse Drug Reactions

3.7.1 Mode of Reporting

In Nigeria there are two modes of reporting suspected adverse drug

reaction. Voluntary and Mandatory.

i. Voluntary: is when a healthcare practitioner identifies suspected

adverse drug reaction and report it to the National
Pharmacovigilance Centre (NPC). It is voluntary for health
providers & traditional herbal medicine practitioners. Although it
is voluntary it is a professional duty.
ii. Mandatory: It is mandatory for all Marketing Authorisation
Holders (MAHs). These include Manufactures and their local
agents in Nigeria including public health programs to report ADR
related to their product.

It should be noted that reporting does not suggest culpability. Adverse

drug reaction reports shall not be tendered as evidence in a legal dispute.
NAFDAC does not regulate medical practice.
The strategic methods for detection of ADR consist of the following:

3.7.2 Passive pharmacovigilance (Spontaneous reporting of ADRs)

Spontaneous reporting of adverse events identified during the use of any

health product is mandatory for the manufacturer or marketing
authorisation holder (MAH) of that product. Serious adverse events
occurring during clinical trials conducted in Nigeria should also be
mandatorily reported. Spontaneous reporting of adverse events suspected
to be related to the use of a health product is an ethical responsibility for
all healthcare providers. No claims of medical malpractice can be based
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solely on a submitted report. Reports received by the Centre as part of

spontaneous reporting shall not be made available to support any legal,
administrative or any other action that may be detrimental to the reporting
health professional or the patient.

3.7.3. Active pharmacovigilance.

Reporting of medication errors.

Reporting of suspected cases of substandard and counterfeit medicines
and other health products.
Detection of lack of effectiveness.

Collaboration with public health programmes.

Due to the inherent limitations of passive pharmacovigilance

(spontaneous reporting), the NPC shall undertake either solely or in
collaboration with relevant stakeholders’ active forms of
pharmacovigilance when necessary. Active pharmacovigilance could
be in the form of Cohort Event Monitoring, Prescription Event
Monitoring, Intensive Medicines Monitoring Programme, Record
Linkages, and Pregnancy Registers etc. as maybe necessary. NPC shall
also put in place a process for the detection of signals of public health
importance that require further evaluation through active surveillance.

3.8 Adr Reporting

3.8.1 Reporting of medication errors

The generation of information on medication errors and its dissemination

minimises similar occurrence in clinical practice.

To achieve this goal, the National Pharmacovigilance Centre shall ensure:

That healthcare providers report any case of medication error to the
nearest pharmacovigilance centre/NPC.

The maintenance of a database for medication errors.

The carrying out of an appropriate root cause analysis on the reported
medication errors.
The dissemination of information on medication errors to prevent future
occurrence.

Sources of ADR and other medicine related problems shall include:

Individuals: doctors, pharmacists, nurses, traditional herbal/alternative
medicine practitioners or other healthcare providers in the public or
private sector who, on their own initiative, send reports of adverse drug

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reactions and other medicine related problems to the nearest

pharmacovigilance centre/NPC.

Institutions: healthcare institutions, including hospitals, clinics,

medical Centres, research institutes and Public Health Programmes
operating in the public or private sectors.

Traditional/herbal medicinal institutions/Centres/associations.

Other units of NAFDAC such as the Drug Quality Control

Laboratories, Drug Information Centres and the Consumer Affairs
Division.
Manufacturers or importers/distributors (MAHs) of products covered
by this policy. Any other relevant sources.

3.8.2 Who is to report?

i. Doctors, pharmacists, nurses, medical laboratory scientists and

traditional herbal medicine practitioners or health care
practitioners or healthcare providers working in the public,
private and Non-Governmental sectors shall report adverse drug
reactions and other medicine related problems to the nearest
pharmacovigilance centre/NPC.
ii. Patients/ consumers are strongly encouraged to report all ADRs
and medicine related problems to their healthcare providers who
will in turn forward the report to the nearest pharmacovigilance
centre/NPC.
iii. Importers/distributers, retailers, Marketing Authorisation
Holders of pharmaceutical products, traditional/herbal medicinal
products and other related products.

3.8.3 What is to be reported

All response to medicines used in humans which are harmful and

unintended

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i. No improvement after treatment

ii. Medication error
iii. Overdose
iv. Misuse and/or abuse of a medicine
v. Counterfeit or substandard medicine
vi. Case reports of acute and chronic poisoning
vii. Assessment of drug-related mortality
viii. Abuse and misuse of medicines
ix. Adverse interactions of medicines with chemicals, other
medicines and food

3.8.4. When Do I Report?

At the stage of Pharmacovigilance development that Nigeria is in, we need

to report all safety issues of concern. By the time we would have
developed our capacity in detecting, reporting and assessing of adverse
effects of medicines then we would be in a position to report only serious
ADR’s.

3.8.5 How to Report

Report Serious adverse event or reaction

i. A serious ADE or ADR is any untoward medical occurrence that

at any dose:
ii. Results in death;
iii. Results in inpatient hospitalisation or prolongation of existing
hospitalisation;
iv. Results in persistent or significant disability or incapacity;
v. Is life-threatening;
vi. Is a congenital anomaly/birth defect.

NB: The term “SEVERE” is not synonymous with “SERIOUS”. While

severe is used to describe the intensity (severity) of a specific event (as in
mild, moderate or severe); the event itself, however, may be of relatively
minor medical significance (such as severe headache). Seriousness (not
severity) which is based on the outcome of the event on the patient or
action criteria serves as the guide for defining regulatory reporting
obligations.

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Figure 38: How to report adverse drug reaction (@NAFDAC Nigeria

PhV training slides)

3.9 Causality Assessment and Signal Generation

Causality assessment is the assessment of relationship between a drug

treatment and the occurrence of an adverse event. It is also used to
evaluate and to check that the particular treatment is the cause of an
observed adverse event or not. It is an essential part of ADR report and
important task, conducted by National Pharmacovigilance Programme
in each country.

3.9.1Objectives of Causality Assessment are to

i. Provide relationship between the drug and events.

ii. Signal detection (“a possible causal relationship between an
adverse event and a drug, the relationship being unknown or
incompletely documented previously".)
iii. Provide better evaluation of the benefit/harm profiles of drugs.
iv. Play as an essential part of evaluating ADR reports in early
warning systems and for regulatory purpose

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In order to assess the likelihood that the suspected adverse reaction is

actually due to the medicine, a list of causality assessment criteria for
deciding on the contribution of the medicine towards the adverse event.

3.9.2 How the Causality Assessment is performed

Many researchers developed various methods of causality assessment

by using different criteria like

v. Chronological relationship between the administration of the

drug and the occurrence of the ADR,
vi. Screening for drug and non-drug related causes,
vii. Confirmation of the reaction by in vivo or in vitro test,
viii. Previous information on similar events etc.

But there is no universally accepted method for assessing causality of

ADRs

3.9.3 Methods of causality

Causality is broadly classified under three broad categories

i.Expert Judgement/ Global Introspection

 Swedish method by Wilholm et al.

 World Health Organisation (WHO) - Uppsala Monitoring
 Centre (UMC) causality Assessment criteria.

i. Algorithms: It consists of a problem-specific flow chart with step-

by-step instruction on how to arrive at an answer. Actually, its
form contains some questionnaire, whose answers provide the
causality of particular ADR. It gives structured and standardized
methods of assessment in a systematic approach. Assessment of
ADRs based on parameters such as time to onset of the ADR or
temporal sequence, Previous drug/adverse reaction history,
Dechallenge and Rechallenge

Types of Algorithms Method

There are many algorithmic methods of causality assessment but no single

algorithm is accepted as the “gold standard‟, because of many
shortcomings. Important Algorithmic Methods are-

i. Dangaumou’s French method

ii. Kramer et al. method
iii. Method Naranjo scale (Naranjo et al (9181)

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iv. Balanced assessment method (Lagier et al.1983)

v. Summary time plot (Castle et al.1984)
vi. Ciba geigy method (Venulet et al. 1980)
vii. Roussel Uclaf causality assessment method (RUCAM)
viii. Maria and Victorino (M and V) scale
ix. Drug Interaction Probability Scale (DIPS)

Naranjo Algorithms -Naranjo et al. method (Naranjo scale)

Widely accepted method. The method used to determine the causal link
between drug and clinical event. Likelihood of whether an adverse drug
reaction is actually due to the drug rather than the result of other factors.
It is a systematic causality assessment consists of ten questions that are
answered as “yes‟, “no‟, “unknown” (don’t know)
These answers are assigned via a score termed Definite, Probable, Possible
or Doubtful. Definite- when a total score of ≥ 9. Probable- when a total
score of 5–8. Possible- when a total score of 1–4. Doubtful- when a total
score of ≤ 0.

Table 46: The Naranjo ADR Probability Scale

Questions Yes No Don’t
Know
1) Are there previous conclusive reports on +1 0 0
this reaction?
2) Did the ADR appear after the suspected +2 -1 0
drug was administered?
3) Did the ADR improve when the drug was +1 0 0
discontinued?
4) Did the ADR appear with re-challenge? +2 -1 0
5) Are there alternative causes for the ADR? -1 +2 0
6) Did the reaction appear when placebo was -1 +1 0
given?
8) Was the reaction more severe when the +1 0 0
dose was increased, or less severe when the
dose was decreased?
9) Did the patient have a similar reaction to +1 0 0
the same or similar drug in any previous
exposure?
10) Was the ADR confirmed by any objective +1 0 0
evidence?

The Naranjo Probability Scale

The score: -
> 8 = highly (Definite) probable
5-8 = probable
1-4 = possible

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0 = doubtful
Limitation-:

- Method only explains the causality of one individual drug

- Not explains the causality occur due to drug interactions

Probabilistic or Bayesian Approaches

i. Australian method
ii. Bayesian Adverse Reactions Diagnostic Instrument (BARDI)
iii. MacBARDI spreadsheet
Causality assessment based on study of prior probability and
posterior probability. i. The prior probability is calculated from
epidemiological information.
ii.The posterior probability combines this pedological background
information with the evidence in the individual case.
This method allows the simultaneous assessment of multiple
causes.
iii.Bayesian Adverse Reactions Diagnostic Instrument (BARDI)
iv.BARDI is used to calculate the odds in favour of a particular drug
causing an adverse event compared with an alternative cause
(posterior odds)
v.The posterior odds factor is calculated by considering six assessment
subsets: one deals with background epidemiologic or clinical trials
information (the prior odds) and the other five deal with case specific
information (the likelihood ratios).

PsO = PrO × LR(Hi) × LR(Ti) × LR(Ch) × LR(De) × LR(Re)

i. Pro (the prior odds) - epidemiologic or clinical trials information

ii. The five likelihood ratios (LRs) deal with any information of
differential diagnostic value under
iii. patient history (Hi)
iv. timing of the adverse event with respect to drug administration
(Ti)
v. characteristics of the adverse event (Ch)
vi. drug dechallenge (De)
vii. drug rechallenge (Re)

3.9.4 Causality Assessment of Vaccine Related Adverse Events

i. Vaccines are administered on large scale to healthy individuals,

children, infants and neonates. So, vaccines must meet with high
degree of safety.
ii. Method developed by the Advisory Committee on Causality
Assessment (ACCA) in Canada.

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iii. ACCA is composed of specialist in paediatrics, epidemiology,

infectious diseases, immunology, neurology, pathology, adverse
event surveillance, and microbiology
iv. They review individual cases in a systematic stepwise manner to
categorize them on a specially designed causality assessment
form.
v. This causality assessment form consists of seven sections. Section
one, Section two, Section three, Section four, Section five,
Section six and Section seven

Section one-: Section one relates to the reason for reporting and whether
the committee agreed with both the diagnosis that was made and the
statement of severity.

Section two-: Section two takes the evaluators through several important
factors like frequency of occurrence of adverse events, similar events
known to occur with other diseases, vaccine-event interval compatible
with event, similar symptoms in past, concomitant drugs or other
conditions; for assessment of causality.

Section three-: Section three relates to causality assessment by using

WHO-UMC criteria.

Section four-: Section four permits brief summary of case with important
elements and discussion which contributed to the final assessment of
causality.

Section five-: Section five permits recommendations for improving

immunization or case reporting procedures to be written.

Section six-: Section six considers whether the case could be useful for
Educational purpose

Section seven-: Section seven considers whether the case could be useful
for publication.

3.9.5 Expert Judgement/Global Introspection

It is a process in which an expert expresses judgement about possible drug

causation by considering all available data relevant to a suspected ADR.

i. Assessment of ADR is either done by single expert evaluator or

by a group of expert evaluators.

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ii. As evaluation and assessment of ADR by these experts is purely

based on their respective knowledge and experience about the
subject of interest.

Two methods based on expert opinion or global introspection.

i. Swedish method by Wilholm et al.

ii. World Health Organisation (WHO) - Uppsala Monitoring Centre
(UMC) causality assessment criteria

World Health Organisation (WHO) - Uppsala Monitoring Centre (UMC)

causality assessment criteria. Widely and globally accepted method.
WHO-UMC system provides practical tool for assessment of case reports
for International drug monitoring and ssystem is used to detect unknown
and unexpected adverse drug reaction.

Assessment is based on following four criteria-:

iii. Time relationships between the drug use and the adverse event.
iv. Absence of other competing causes (medications, disease process
itself).
v. Response to drug withdrawal or dose reduction (de-challenge).
vi. Response to drug re-administration (re-challenge).

The level of causal association is grouped into four categories which are
based on a number of the above criteria being met.

3.9.6 WHO Causality Categories

i. C1 – Certain
ii. C2 – Probable
iii .C3 – Possible
iv C4 – Unlikely
v. C5 – Unclassifiable

WHO Causality Categories

Certain causality: a clinical event (including laboratory test abnormality)

occurs in a plausible time relationship to drug administration and cannot
be explained by concurrent disease or other drugs or chemicals; re-
administration of the drugs causes a similar reaction

Probable or likely causality: a clinical event occurs within a reasonable

time sequence to drug administration and is unlikely to be due to any
concurrent disease or other drug administration

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Possible causality: a clinical event occurs within a reasonable time

sequence to drug administration, but could be explained by concurrent
disease or another drug administration

Unlikely: a clinical event, including laboratory test abnormality, occurs

with no temporal relationship to drug administration and which makes a
causal relationship improbable, and in which other drugs, chemicals or
underlying disease provide plausible explanations
Conditional/unclassified: a clinical event, including laboratory test
abnormality, reported as an adverse reaction in which more data is
essential for a proper assessment, or the additional data is under
examination.

Unassessable/unclassifiable: a report suggesting an adverse reaction that

cannot be judged because information is insufficient or contradictory and
cannot be supplemented or verified

3.9.7 Assessment of Relationship and Causality

Assessment of each event 1

Initially, what we are really doing is assessing the strength of the

relationship between the drug and the event.

We can seldom say without any doubt that a specific drug caused a specific
reaction
We work with imperfect data and our conclusions are those of probability.

Assessment of each event 2

Relationship assessment is an essential discipline. It ensures:

i. careful review of report details
ii. standardised assessment
iii. an in-depth understanding of the data
iv. standardised data for later evaluation
v. the ability to sort reports by quality

Relationship Categories

1. Certain
vi. Event with plausible time relationship
vii. No other explanation -disease or drugs
viii. Event definitive -specific problem
ix. Positive dechallenge
x. Response to withdrawal plausible
Key feature: Positive rechallenge

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2. Probable

i. Event with plausible time relationship to drug intake

ii. No other explanation
iii. Response to withdrawal (dechallenge) clinically reasonable
iv. No rechallenge, or result unknown

Key feature: Positive dechallenge

3. Possible

v. Event with plausible time relationship to drug intake

vi. Could also be explained by disease or other medicines
vii. Information on drug withdrawal lacking or unclear

Key feature: other explanations for the event are possible

4. Unlikely

viii. Event with a duration to onset that makes a relationship improbable

ix. Diseases or other drugs provide plausible explanations
x. Event does not improve after dechallenge

Key feature: several factors indicate strongly that the event is not a
reaction.

3.9.8 Uses and Limitation of Causality Assessment.

What it can do:

xi. Decrease disagreement between accessor.

xii. Classify uncertainty
xiii. Mark individual case reports
xiv. Improve the scientific basis of assessment

What it cannot do;

xv. Give and accurate quantitative measurement of the likelihood of a
relationship.
xvi. Distinguish valid from invalid cases
xvii. Quantify the contribution of a drug to the development of an
adverse event
xviii. Change uncertainty to certainty

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3.10 Pharmacovigilance In Public Health Programmes

3.6.1 Goals and objectives of pharmacovigilance in Public health

Programmes
xix. the rationale and safe use of drugs
xx. to contribute to the assessment and communication of benefit,
harm, effectiveness and risk of medicines,
i.identification of risk factors and possible mechanisms underlying
ADRs
ii.educating and informing patients

Specific objectives

i. early detection of hitherto unknown ADRs

ii. detection of increases in frequency of known ADRs
iii. estimation of benefit/risk
iv. dissemination of information
v. to improve patient care and safety
vi. to improve public health and safety
vii. to promote education and clinical training
viii. to promote effective communication to the public
ix. to promote rational and safe use of medicines

3.10.2 Types of Public Health Programmes

Education, Lifestyle and behavioural changes, Environmental

modifications, Nutritional interventions and Drug administration
programmes (Mass control programmes, case control programmes and
individual treatment programmes)

3.10.3 Characteristics of Public Health Programmes

1. Vertical and intensive programmes

x. Vaccination, préventive treatment (Ivermectine, Albendazole,
antibiotic and antiparasitic prophylaxis…)
xi. Artémisinine dérivatives against malaria, ARVs, Tuberculoses,
Schistosomiasis.
xii. Lymphatic filariasis, Trachomatis, Leprosy, poliomyelitis
elimination programmes…Involve - Drug and vaccines.
xiii. Procurement agency
xiv. In 2009 delivered over 2.4 million patients’ treatment
xv. In 2011 brought up to 60,000 additional MDR-TB patients’
treatment.

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3.10.4 Current situation in Public Health Programmes

Pharmacovigilance in Public health Programme and
medicinal products

i. Accelerated access the use of new drugs in new environment,

which are mostly devoid of pharmacovigilance activities for
priority disease
ii. Faster large-scale ups of public health programmes due to available
new funding’s from major donors such as Global fund, World
Bank, PEPFAR, PMI etc.
iii. Mass distribution of medicines with often presumptive treatment
iv. New drug is reaching developing countries in greater numbers and
more quickly because of new funding’s from several donors
including Bill and Melinda gates foundations
v. Often there is rarely records adverse drug reactions
vi. In most in setting pharmacovigilance and public health
programmes operate in isolation, as independent vertical
programmes.

3.10.6 Why PV should be integrated into PHPs

PHPs definition range and changed over time to include disease

prevention, and health promotion through organized efforts amongst the
population as a whole. It focusses on entire population not individuals and
disease and involves healthy as well as sick people, with the goal to reduce
morbidity and mortality due to major and common disease.
Pharmacovigilance into Public Health Programme because;

vii. Old medinas in different populations combination and indication

viii. Integration can increase public trust in programme are being
dispense
ix. Infection collected can be provided to the public increasing
compliance
x. Integration can help take appropriate measures and communicate
effectively in a crisis.
xi. Integration can help strengthen existing national
pharmacovigilance or provide leverage for setting up a
pharmacovigilance where it does not exist.

3.10.7Challenges of pharmacotherapy in PHPs

One key challenge that has emerged is the issue of monitoring the safe use
of medicines in countries with no active regulatory or safety monitoring
system in place. In this scenario, the use of medicines in specific
communities, such as the treatment of diseases like malaria, leishmaniasis

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and schistosomiasis, or HIV/AIDS and tuberculosis, becomes a matter of

great concern and the subject of coordinated efforts to reduce the risks.

xii. may use agencies and staff with a wide variety of skills and patients
may not be seen by a physician insufficient diagnosis and follow
up large numbers exposed, may include special populations i.e.
pregnant & breast-feeding mothers
xiii. use of new drugs with limited experience, i.e. ARVs, ACTs; use of
substandard drugs; incorrect use of drugs; counterfeit drugs
xiv. weak health care systems, often poor drug control/legislation

3.10.3 Strengths of PHPs

xv. Well established programmes using a limited number of drugs or

vaccines
xvi. Operate according to standard guidelines
xvii. Well-funded with international support
xviii. Monitoring and evaluation procedures
xix. Quality of product can be assured
xx. Good databases
xxi. Expertise in assessment of drug safety
xxii. training in benefit/risk assessment
xxiii. Good international support, WHO, UMC

Public health programmes (PHP) are well established and organised. PHP
use limited number of medicines as 1st& 2nd lines, this may not be same
with other health conditions where choice of medicines may be less
restricted. Ensuring the quality of those limited products is an issue of
public health importance, hence the WHO has the prequalification scheme
for such products. Large, defined populations are involved in PHP,
example ART/TB/Malaria/Immunisation, etc. and data is more readily
available. There is stricter use of STGs in PHP. There is extensive
international support in PHP programmes through PEPFAR, Global funds
and others.

3.10.9 Weaknesses of PHPs

xxiv. No direct contact with a Physician

xxv. Diagnosis may not be well diagnosed/presumptive
xxvi. lack experience in drug safety monitoring, insufficient follow -up
xxvii. drugs used in PHPs considered safe
xxviii. lack of coordination between PHPs, duplication
xxix. may cover special populations
xxx. relatively new concept
xxxi. role not well recognised
xxxii. poorly funded, considered a luxury

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xxxiii. not seen as a component of PHPs

Ensuring rational use of medicines can be very challenging in PHP. In

PHP, it may not always be possible to tailor medicines to individual
patient needs to reflect co-morbid conditions, nutritional status or for
pregnant women, nursing mothers, Paediatrics, and elderly. Even with the
attention to quality, widespread use of generics and multisource products
still makes it challenging to ensure quality. Drug resistance may quickly
manifest as in HIV/AIDS/TB/Malaria, at times aided by drug interactions
and poor adherence.

3.10.10 Opportunities

Together, PV and PHPs may greatly benefit each other.

I. PV will assist in the early identification and prevention of ADRs

and product quality problem.
ii. Improve compliance thereby reduce drug resistance
iii. PHPs may provide resources, reliable
iv. PV can improve knowledge and there improve patients care
v. Databases, M and E tools leading to …….

The importance of PhV to PHP is reflected in the fact that both are
mutually beneficial to each other. PHP can serve as pathfinders for PhV
in RLS particularly in introducing or strengthening spontaneous reporting,
and the initiation of active surveillance activities. PHP also have large
cohorts of patients which is very beneficial in the conduct of PhV studies.
PhV can support PHP in providing important outcome data on toxicity and
safety of PHP medicines. Such data can be used to address safety scares
or spurious claims when they arise and improve acceptability of the
programs. PhV also ensures rational use since safety risk factors identified
through PhV studies can be used to inform better patient management.

3.10.11 Threat to Pharmacovigilance Public Health Programmes

i. Lack of political/public support

ii. funding shortfalls
iii. misunderstanding of each other’s roles
iv. The malaria PV project – an update

4.0 CONCLUSION

This unit exposes the you to the understand what is and why we Need
Pharmacovigilance as a science and activity relating to assessment,
detection and reporting adverse drug reactions. It describes the goals,
need and importance of pharmacovigilance and how the origin of modern

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PV (Era of medicine safety and efficacy) developed. The course discussed

thetools used for causality assessment and able to assess severity and
causality of ADRs. The importance of Pharmacovigilance in Public
Health Programme (PHP) and why PV should be integrated into PHPs
including the strategies to strengthen functioning PV in PHP.

5.0 SUMMARY

Pharmacovigilance (PV): Is a science and activities relating to the

detection, assessment, understanding and prevention of adverse effects
or any other possible drug-related problems. The origins of
pharmacovigilance dates back to the 1st reported case of ADR occurred
over 150 years ago, in 1848, when a 15-year-old girl, had a routine general
anaesthetic while undergoing a surgical procedure for an ingrown toenail.
The anaesthetic agent, chloroform, had only been introduced into clinical
practice a year earlier. That become, the forerunner of a spontaneous
reporting system for suspected adverse drug reactions (ADRs) was
established, at least for a time. There was no define monitoring system for
drug safety until Thalidomide in 1960 report of 2 grossly deformed infants
in Germany (thalidomide disaster). By 1961 477 cases of phocomelia in
paediatric clinics, and withdrawal recommended.

There exist strategic methods for detection of ADR consist of the

following: 1. Passive pharmacovigilance (spontaneous reporting of
ADRs), Active pharmacovigilance. Active pharmacovigilance could be
in the form of (Cohort Event Monitoring, Prescription Event Monitoring,
Intensive Medicines Monitoring Programme, Record Linkages, and
Pregnancy Registers etc. as maybe necessary), Reporting of medication
errors, Reporting of suspected cases of substandard and counterfeit
medicines and other health products, and Detection of lack of
effectiveness.

Causality assessment is the assessment of relationship between a drug

treatment and the occurrence of an adverse event. Many researchers
developed various methods of causality assessment by using different
criteria like

1. Chronological relationship between the administration of the

drug and the occurrence of the ADR, 2. Screening for drug and
non-drug related causes, 3 Confirmation of the reaction by in
vivo or in vitro test, 4Previous information on similar events
etc. But there is No universally accepted method for assessing
causality of ADRs
Causality is broadly classified under three broad categories 1.
Algorithms, 2. Probabilistic Methods and 3. Expert Judgement/ Global
Introspection. The level of causal association is grouped into four

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categories which are based on a number of the above criteria being met.
WHO Causality Categories C1 – Certain, C2 – Probable, C3 – Possible,
C4 – Unlikely and C5 – Unclassifiable?

Good progress made in early implementation with key personnel in place

and active. Need: to scale up activities with stimulation of reporting and
data collection

The potential benefits of a public health programme aimed at reducing or

eliminating a specific condition will depend on the health burden due to
that condition, which is a function of the seriousness of the condition and
its frequency, as well as the likely efficacy of the programme in reaching
its goals. The present article has outlined an approach to
pharmacovigilance for such a donor-funded programme, using
pharmacovigilance in leishmaniasis as an example.

SELF ASSESSED EXERCISES

Justify the importance of pharmacovigilance in Public Health Practice.

What is the role of pre-marketing evaluation and post marketing
surveillance in Determining drug safety?

6.0 TUTOR MARKED ASSIGNMENT

1. Exercise: Using WHO Criteria determine the causality

relationship of the events

i. An event with:
 a plausible time to onset
 no dechallenge information
 other medicines could have caused the event
 Relationship =.....................................

ii. An event with:

 a plausible time to onset
 no other obvious causes of the event
 positive dechallenge & rechallenge
 Relationship =.....................................

iii. An event with:

 a plausible time to onset
 no other obvious causes of the event
 event resolved on dechallenge
 a rechallenge was undertaken, but the result is not known
 Relationship =.....................................

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iv. An event with:

 unknown duration to onset
 positive dechallenge
 rechallenge not stated
 no other obvious cause
 Relationship =.....................................

vi. An event with:

 a plausible time to onset
 no other obvious cause
 event outcome ‘death’
 cause of death was a known reaction to the medicine
 Relationship =.....................................

vii. An event with:

 a plausible time to onset

 no other obvious causes of the event
 a dechallenge was undertaken, but the event did not resolve
 Relationship =.....................................

2. A 24years pregnant woman with normal LFTs was commenced

on lamivudine, zidovudine, and nelfinavir at 16 weeks gestation.
event -jaundice leading to liver failure
• onset after 13 weeks (29weeks Gestation)
• outcome: recovered completely after drug stopped and
• commenced on: Efavirenz, Emtricitabine, tenofovir
• well at 12 months

What is the Causality Relationship =

……………………………………….?

i.Discuss advantages, opportunities and of Pharmacovigilance integrated

in Public Health Programmes

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7.0 REFERENCES/FURTHER READING

Edwards, I.R. (2001). The importance of pharmacovigilance safety

monitoring of medicinal plants. Drug Safety, 22(6):416-423.

Uppsala Monitoring Centre (UMC), the WHO Collaborating Centre for

International Drug Monitoring. Glossary of terms used in
pharmacovigilance. Available under http://www.who-
umc.org/graphics/8321.pdf.

CIOMS Working Group VIII. Practical aspects of signal detection in

pharmacovigilance. Geneva: Council for International
Organizations of Medical Sciences. 2010.

Nigerian National Pharmacovigilance Policy and Implementation

Framework. 2012. Federal Ministry of Health.

National Agency for Food and Drug Administration and Control

(NAFDAC)2010. Safety of Medicines in Nigeria: National
Pharmacovigilance Training Curriculum Trainers Manual.
Federal Ministry of Health, Abuja, Nigeria.

Naranjo, C.A., Busto, U., Sellers, E. M., Sandor, P., Ruiz, I., Roberts, E.
A., Janecet, E., Domecq, C., Greenblatt, D.J. (1981). "A method
for estimating the probability of adverse drug reactions". Clin.
Pharm Therap, 30 (2), 239–245. Http: //
doi:10.1038/clpt.1981.154.

Castle, W.M. (1984). Assessment of causality in industrial settings. Drug

Inf J 18 (3-4), 297-
302.https://doi.org/10.1177/009286158401800317.

Venulet, J., Ciucci, A. & Berneker, G.C. (1980). Standardised assessment

of drug-adverse reaction associations: rationale and experience. Int
J Clin Pharmacol Ther Toxicol, 18(38)1-8.

Lagier, G., Vincens, M., &Castot, A. (1983). Imputability in drug

monitoring. Principles of the balanced drug reaction assessment
method and principal errors to avoid. Therapie,38(3), 303-318.

Gbabiaka, T.B., Savović, J. & Ernst, E. (2008). Methods for

CausalityAssessment of Adverse Drug Reactions. Drug-Safety, 31,
21–37. https://doi.org/10.2165/00002018-200831010-00003.

NAFDACGood Pharmacovigilance Practice Guidelines 2016.

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World Health Organisation (WHO), Uppsala Monitoring Centre. The use

of the WHO-UMC system for standardized case causality
assessment. WHO [online]. Available from URL:
http://www.whoumc.org/graphics/4409.pdf.[ Accessed 29 April
2020].

Safety of medicine in Public health

Programmehttps://www.who.int/medicines/areas/quality_safety/s
afety_efficacy/Pharmacovigilance_B.pdf?ua=1.

Shanti, P. (2013). Pharmacovigilance in Public Health Programmes

WHO essential medicines and health Products.

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UNIT 3 RATIONAL USE OF MEDICINES/DRUG

DEPENDENCE AND SUBSTANCE ABUSE

CONTENTS

1.0 Introduction
2.0 Objectives
3.0 Main Content
3.1 Definition of Terms
3.2 Rational Use of Medicines
3.3 Irrational Use of Medicines
3.3.1 Examples of Common Inappropriate Prescribing
Practices
3.3.2 Example of Over the Counter (OTC) Drugs
3.3.3 Examples of Irrational Drug Combinations
3.3.4 Obstacles/Reasons Irrational Use Continue
3.3.5 Factors Underlying Irrational Use of Drugs
3.3.6 Impact of Inappropriate Use of Drugs
3.4 The Role of Hcps in Promoting Rational Drug Use
Objectives
3.5 Changing A Drug Use Problem: An Overview of The
Process
3.5.1 Steps in rational drug use
3.6 Strategies to Improve Use of Drugs
3.6.1 Educational Strategies
3.6.2 Training for prescribers
3.6.3 Managerial strategies
3.6.4 Economic strategies
3.6.5 Avoid perverse financial incentives
3.6.6 Regulatory strategies: Goal: to restrict or limit
decisions
3.7 Drug Dependence and Substance Abuse
3.7.1 Introduction:
3.7.2 Causes of Substance Use Disorders
3.7.3 Classification of Drug Dependence/Substance Abuse
3.7.4 Diagnosis of Drug Dependence / Substance Abuse
3.7.5 Principles of Effective Treatment
3.7.6 Management of Substance Abuse/Dependence
4.0 Conclusion
5.0 Summary
6.0 Tutor- Marked Assignment
7.0 References/Further Reading

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1.0 INTRODUCTION

Rational use of medicines requires that patients receive medications appr

opriate to their clinical needs, in doses that meet their requirements, for a
n adequate period of time, and at the lowest cost to them and their comm
unity. Unfortunately, more than 50% of all medicines are prescribed, dis
pensed, or sold inappropriately on a global basis and 50% of patients fail
to take their medicines correctly according to estimates based on various
ad hoc reviews. Common types of inappropriate medicines use include,
Polypharmacy (the use of too many medicines per patient), overuse
ofinjections, inappropriate use of antimicrobials, failure to prescribe in a
ccordance withclinical guidelines, and inappropriate self‐medication,
often with prescription‐only medicines. Inappropriate use of medicines
is harmful for patients in terms of poorpatientclinical outcomes and avoi
dable adverse drug reactions. Overuse of antimicrobialsexerts pressure to
increase rates of antimicrobial resistance. Non‐sterile injections
contribute to the transmission of hepatitis, HIV/AIDS and other blood
borne diseases. Inappropriate medicines use wastes scarce economic
resources that could be used for food or other necessities. Unnecessary
overuse of medicines can stimulate inappropriate patient demand and lead
to medicine stockouts and loss of patient confidence in the health
system.

About 275 million people worldwide, which is roughly 5.6 per cent of the
global population aged 15-64 years, used drugs at least once during 2016.
Some 31 million of people who use drugs suffer from drug use disorders,
meaning that their drug use is harmful to the point where they may need
treatment. Initial estimations suggest that, globally, 13.8 million young
people aged 15-16 years used cannabis in the past year, equivalent to a
rate of 5.6 per cent. Roughly 450,000 people died as a result of drug use
in 2015, according to WHO. Of those deaths, 167,750 were directly
associated with drug use disorders (mainly overdoses). The rest were
indirectly attributable to drug use and included deaths related to HIV and
hepatitis C acquired through unsafe injecting practices.

Opioids continued to cause the most harm, accounting for 76 per cent of
deaths where drug use disorders were implicated. PWID - some 10.6
million worldwide in 2016 - endure the greatest health risks. More than
half of them live with hepatitis C, and one in eight live with HIV.

The headline figures for drug users have changed little in recent years, but
this stability masks the striking ongoing changes in drug markets. Drugs
such as heroin and cocaine that have been available for a long time
increasingly coexist with NPS and there has been an increase in the non-
medical use of prescription drugs (either diverted from licit channels or
illicitly manufactured). The use of substances of unclear origin supplied

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through illicit channels that are sold as purported medicines but are
destined for non-medical use is also on the increase. The range of
substances and combinations available to users has never been wider.

Psychoactive drugs are substances that, when taken in or administered into

one's system, affect mental processes, e.g. perception, consciousness,
cognition or mood and emotions. Psychoactive drugs belong to a broader
category of psychoactive substances that include also alcohol and nicotine.
“Psychoactive” does not necessarily imply dependence-producing, and in
common parlance, the term is often left unstated, as in “drug use”,
“substance use” or “substance abuse”.

Production, distribution, sale or non-medical use of many psychoactive

drugs is either controlled or prohibited outside legally sanctioned channels
by law. Psychoactive drugs have different degrees of restriction of
availability, depending on their risks to health and therapeutic usefulness,
and classified according to a hierarchy of schedules at both national and
international levels. At the international level, there are international drug
conventions concerned with the control of production and distribution of
psychoactive drugs: the 1961 Single Convention on Narcotic Drugs,
amended by a 1972 Protocol; the 1971 Convention on Psychotropic
Substances; the 1988 Convention Against Illicit Traffic in Narcotic Drugs
and Psychotropic Substances.

Note: Public health practitioners have attempted to look at substance use

from a broader perspective than the individual, emphasizing the role of
society, culture, and availability. Some health professionals choose to
avoid the terms alcohol or drug "abuse" in favour of language they
consider more objective, such as "substance and alcohol type problems"
or "harmful/problematic use" of drugs.

2.0 OBJECTIVES

By the end of this unit, you will to be able to:

 define rational use of medicines and identify the magnitude of the

problem
 state the problems of irrational drug use
 outline the reasons underlying irrational use
 identify factors which influence the behavior of prescribers and
patients
 explain the role of HCPs in promoting rational drug use
 describe strategies and interventions to promote rational use of
medicines
 define of various terms used in substance abuse
 classify drug of abuse and its management
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 list factors responsible for substance abuse

 analyse pharmacological and harmful effects of substance abuse.

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3.0 MAIM CONTENT

3.1 Definition of Terms

i. Rational Use of Medicines: The rational use of drugs requires

that patients receive medications appropriate to their clinical
needs, in doses that meet their own individual requirements for an
adequate period of time, and at the lowest cost to them and their
community. (WHO conference of experts Nairobi 1985)

ii. Irrational Use of Medicines

Irrational (inappropriate, improper, incorrect) use of medicines is
when one or more of these conditions is not met. The use of drugs
when no drug therapy is indicated, the use of wrong drugs for a
specific condition requiring drug therapy, the use of drugs with
doubtful or unproven efficacy, the use of drugs of uncertain safety
status, failure to prescribe available, safe, & effective drugs or
incorrect administration, dosages, or duration

iii. Meaning of Appropriate Use: The term "appropriate drug use"

means different things to different people. When a patient received
correctly prescribed, dispensed or sold medicines and take their
medication as prescribed or dispensed. This is opposite irrational
use which may take many different forms, for example,
polypharmacy, over-use of antibiotics and injections, failure to
prescribe in accordance with clinical guidelines and inappropriate
self-medication.

iv. Medical definition of Abuse is defined by the WHO Expert

Committee on Drug Dependence as “persistent or sporadic
excessive drug use inconsistent with or unrelated to acceptable
medical practice”. The term “abuse” is sometimes used
disapprovingly to refer to any drug use at all, particularly of illicit
drugs.
v. Analgesic is a medicine that reduces pain.

vi. Controlled medicines are medicines containing controlled

substances.

vii. Drug includes any substance or mixture of substances

manufactured, sold or advertised for use in the diagnosis, treatment,
mitigation or prevention of any diseases or disorder, abnormal
physical state or symptoms thereof, in man or in animals; restoring,
correcting or modifying organic functions in man or animal’s
disinfection or the control of vermin, insects, pests or
contraception.

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viii. Drug abuse is an intense desire to obtain increasing amounts of a

particular substance.

ix. Drug dependence is the body's physical need, or addiction, to a

specific agent. Over the long term, this dependence results in
physical harm and behavior problems which causes tolerance and
cross tolerance. Thus, it creates a vicious cycle.

x. Dependence is defined by the WHO Expert Committee on Drug

Dependence as “A cluster of physiological, behavioural and
cognitive phenomena of variable intensity, in which the use of a
psychoactive drug takes on a high priority. The necessary
descriptive characteristics are preoccupation with a desire to
obtain and take the drug and persistent drug-seeking behaviour.

xi. Hard drug (lead to severe physical addiction): – Drug that is

generally considered to be more dangerous, with a higher risk of
dependence that soft drugs. E.g.: Heroin, methamphetamine,
cocaine.

xii. Medicine: Any substance in a pharmaceutical product that is used

to modify or explore physiological systems or pathological states
for the benefit of the recipient.

xiii. Misuse (of a controlled substance) for the purposes of these

guidelines, is defined as the nonmedical and non-scientific use of
substances controlled under the international drug control treaties
or under national law.

xiv. Narcotics are derived from the opium and its derivatives which
include morphine and codeine. They are also derived from cannabis
and coca leaf plants. Also included are synthetic Narcotics, such as
Pethidine, Fentanyl, and Methadone. Legally they are substances
contained in Schedule I, II, III and IV of the UN Single Convention
on Narcotics as amended 1961. The differences in the scheduling
relate only to the control measures to be applied. The medicines are
indispensable for the relief of pain and the convention seeks to
make them adequately available for medical and scientific purposes
only.

xv. Opioids means literally “opium-like substance”. It can be used in

different contexts with different but overlapping meanings:
Opioids Substitution Therapy refers to treatment Opioids
Substitution Therapy refers to treatment of opioids dependence
with relatively stable doses of the long acting agonists (usually
methadone or buprenorphine) prescribed over prolonged periods of

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time (usually more than six months), which allows stabilisation of

brain functions and prevention of craving and withdrawal.
xvi. Precursors are raw materials which when used in the production
of a drug become part of a finished product. Reagent and Solvents
are also listed as precursors but usually not a part of the finished
product. They are however used in the manufacture and processing
of some Narcotic drugs and psychotropic substances. Examples are
ephedrine used in the manufacture of methamphetamine; sulphuric
acid is a reagent and acetone are a solvent.

xvii. Psychotropic Substances are drugs that alter the central nervous
system such as sedatives, hypnotics, hallucinogens and stimulants.
Under the UN Convention on Psychotropic Substances of 1971,
these substances are listed under Schedules I, II, III, and IV. Some
of these medicines are employed in anaesthesia for surgical
procedures (such as thipopentone and midazolam), essential in
emergency obstetrics (ergometrine) or used as anxiolytics and
hypnotics (benzodiazepines) or as antiepileptics (phenobarbital and
benzodiazepines).

xviii. Rational drug use requires that patients receive medications

appropriate to their clinical needs, in doses that meet their own
individual requirements for an adequate period of time and at the
lowest cost to them and their community. This implies rational
prescribing; good this implies rational prescribing, good dispensing
practices and concordance.

xix. Soft drug (do not cause physical addiction): – While they do not
cause physical addiction, some of them may still lead to
psychological dependency. Psychological dependency is a
dependency of the mind. This means that people feel better when
they have the drug. E.g.: lysergic acid diethylamide (LSD),
Cannabis.

xx. Street drug: Drug that is taken for non-medicinal reasons (usually
for mind-altering effects); drug abuse can lead to physical and
mental damage and (with some substances) dependence and
addiction. e.g.: Alcohol, heroin, methamphetamine, crack, cocaine
and marijuana (Cannabis).

xxi. Tolerance is defined as a person’s diminished response to a drug

that is the result of repeated use. People can develop tolerance to
both illicit drugs and prescription medications. As stated above,
tolerance is a physical effect of repeated use of a drug, not
necessarily a sign of addiction. For example, patients with chronic

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pain frequently develop tolerance to some effects of prescription

pain medications without developing an addiction to them.

3.2 Rational Use of Medicines

The rational use of drugs requires that patients receive medications

appropriate to their clinical needs, in doses that meet their own individual
requirements for an adequate period of time, and at the lowest cost to them
and their community. (WHO conference of experts Nairobi 1985)

Criteria’ for Using Medicine

i. correct drug
ii. appropriate indication
iii. appropriate drug considering efficacy, safety, suitability for the
patient, and cost
iv. appropriate dosage, administration, duration
v. no contraindications
vi. correct dispensing, including appropriate information for patients
vii. patient adherence to treatment.

3.3 Irrational Use of Medicines

Irrational drug use consists of poly pharmacy, use of drugs that are not
related to diagnosis, or unnecessarily expensive, inappropriate use and
irrational self-medication, with many insufficient quantities’ consumption
of drugs.

3.3.1 Examples of Common Inappropriate Prescribing Practices

i. The overuse of antibiotics and antidiarrhoeals for nonspecific

childhood diarrhea
ii. Indiscriminate use of injections
iii. Multiple or over-prescription
iv. Wrong Diagnosis
v. Use of antibiotics for mild, non-bacterial infection, e.g., common
cold URI
vi. Tonics and multivitamins for malnutrition
vii. Unnecessary use of expensive antihypertensives
viii. Adequacy of diagnostic process

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Inappropriate antibiotic use

Overuse and misuse of antibiotics is a particularly serious global problem.

Established and newly emerging infectious diseases are increasingly
threatening the health of populations. If antibiotics become ineffective,
these diseases will lead to increased morbidity, health-care use and
eventually premature mortality. Furthermore, antibiotics are required for
other treatments (taken for granted in developed countries), such as
surgery and cancer chemotherapy, which would become unavailable with
the disappearance of effective antibiotics. Unfortunately, while resistance
to older antibiotics is increasing, the development of new generations of
antibiotic medicines is stalling. Therefore, efficient use of existing
antibiotics is needed to ensure the availability in the long term of effective
treatment of bacterial infections. Efficient use includes both restrictive and
appropriate use. However inappropriate and incorrect use of antibiotics
occurs in both developing and developed countries. Doctors prescribe
antibiotics to patients who do not need them, while patients do not adhere
to their treatment causing the risk of antibiotic resistance. Two thirds of
all antibiotics are sold without prescription, through unregulated private
sectors. Even in those European countries where over-the-counter delivery
of antibiotics is not allowed, patients use antibiotics without prescription.
Low adherence levels by patients are common, many patients taking
antibiotics in under-dose or for shortened duration — 3 instead of 5 days.

Since there is very little information on medicines use for chronic diseases
or on the use of over-the-counter (OTC) medicines in developing
countries, the focus of this discussion would mainly on use of prescription-
only medicines in acute disease, particularly antibiotics, although mention
will be made of treatment of chronic diseases, especially in terms of
adherence to medication.

Absolutely Irrational Use

i. Injudicious use of antimicrobials: Antibiotics in Viral fever and

diarrhoea
ii. Unnecessary combinations
iii. Use of drugs not related to diagnosis
iv. Incorrect route
v. Incorrect dosing – under or overdose
vi. Incorrect duration – prolong or short-term use
vii. Unnecessary use of expensive medicines
viii. Unsafe use of corticosteroids
ix. Polypharmacy

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3.3.2 Example of Over the Counter (OTC) Drugs

i. Topical anti-bacterial, anti-fungal OTC drugs: - Bacitracin,

Clotrimazole (vaginal, topical use) Miconazole 2% ointment etc.
ii. Pain reliever OTC drugs: Acetaminophen, Aspirin, NSAIDs,
Ibuprofen, Naproxen etc.
iii. Smoking cessation OTC drugs: Nicotine patch
iv. Topical Dermatological (skin, scalp) OTC drugs: Capsaicin,
Doak tar distillate oil, Hydrocortisone, Permethrin, Pyrethrin, Zinc
oxide ointment.
v. Diabetes OTC drugs: Insulin OTC vials (Humulin 50/50 vial,
Humulin N, Humulin R, Novolin 70/30 vial, Novolin R vial etc)
Glucose chewable tablet.
vi. Digestion OTC Drugs Anti-diarrheal drug: - Loperamide
vii. Anti-ulcer drugs: Cimetidine, Famotidine, Ranitidine Nizatidine.
viii. Proton pump inhibitors: -Omeprazole Laxatives &Cathartics: -
Bisacodyl, Docusate, Glycerine, Psyllium, Sorbitol.
ix. Other digestion drugs: -Aluminium hydroxide gel, Antacid liquid
suspension, Calcium antacid tablets, Simethicone drops etc.
x. OTC Vitamins: - Calciferol, Ergocalciferol drops, Calcium
carbonate, Calcium carbonate 600mg+vit. D, Calcium citrate,
Ferrous fumarate, Ferrous gluconate, Ferrous sulfate, Magnesium
oxide, Multivitamins etc.
xi. Eye care OTC drugs: -Artificial tears, Refresh tears, liquate (15ml
or 30ml bottle only), Sodium chloride 5% drops, ointment, Systane
etc.
xii. Cough/Cold/allergy OTC drugs Anti –histamine: Cetirizine tab,
Cetirizine-D tab, Cetirizine sol., Diphenhydramine, Loratadine,
Loratadine-D,
xiii. Anti-histamine/DecongestantCombinations: -
Brompheniramine- Pseudoephedrine elixir.
xiv. Other drugs: - Nasal spray, Pseudoephedrine

3.3.2 Examples of Irrational Drug Combinations

i. If the combination of drugs is illogical in terms of plasma half-life

and pharmacokinetics of the drug, the combination should be
termed as irrational drug combination. Large numbers of such
irrational drug combinations are available in the market which
unnecessarily increase the cost of medication and add to the side
effects of the therapy.

ii. Ampicillin + Cloxacillin Ampicillin is effective against Gram

negative bacilli but Cloxacillin is an Anti-staphylococcal penicillin
and not effective against Gram negative bacilli. Mixed Gram
negative and Staphylococcal (Gram positive) infection rarely

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coexists. So, in a patient with a single infection, one of the drugs of

the combination would be useless. In addition to the cost of therapy
it would add to adverse side effects and resistance of bacteria to the
drug. On the other hand, the combination would reduce the dose of
effective drug to the half and the patient would need longer course
of therapy.

iii. Antibacterial + Antiamoebic Combinations: Ciprofloxacin +

Metronidazole, Norfloxacin + Tinidazole and Ofloxacin +
Ornidazole are such commonly available fixed dose drug
combinations. In bacterial diarrhoea only anti-bacterial drug is
effective and antiamoebic drug is useless. Similarly, in intestinal
amoebiasis only antiamoebic drug is effective while antibacterial
drug is useless. Amoebiasis and bacterial diarrhoea rarely coexist.
The therapy should be based on the diagnosis to reduce the cost of
treatment since in a given case, only one drug of the combination
would be effective and the other one would be useless.

iv. NSAIDs Combinations: Nimesulide, diclofenec, ibuprofen and

Paracetamol are some non-steroidal anti-inflammatory drugs
(NSAIDs). There is no justification in combining one NSAID
(nimesulide, diclofenec, ibuprofen) with another NSAID
(paracetamol) having same pharmacological actions. The increased
risk of hepatotoxicity has been reported due to the use of
combination of nimesulide with paracetamol. There is increased
risk of nephrotoxicity with NSAIDs combinations.
v. H2 Blocker + Domperidone: Ranitidine and Famotidine are H2
blockers. H2
blockers reduce gastric acid production in peptic diseases and give
symptomatic relief. The combination of these drugs with
antiemetic drug (Domperidone) is an irrational drug combination
as peptic ulcer is not always associated with vomiting. Even in
gastro-oesophageal reflux disease (GERD), the domperidone is less
effective as compared to metoclopramide, so combining H2
blockers with domperidone seems to be an irrational choice.

vi. H2 Blocker (Ranitidine) + Antispasmodic Drug (Dicyclomine):

The pain of peptic ulcer is due to high level of gastric acid but not
due to spasm of smooth muscles and will subside only with
reduction in gastric acid in stomach by use of H2 blocker
(Ranitidine) or proton pump inhibitor drugs (Omeprazole,
Pantoprazole or Lansoprazole). So, there is no justification in
combining H2 blocker (Ranitidine) with antispasmodic drug
(Dicyclomine).

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vii. Mucolytic Agent + Antibacterial Ambroxol + Ciprofloxacin or

Cefadroxil or Roxithromycin.: Ambroxol is a mucolytic agent
used to liquefy thick respiratory secretions. There is no justification
in combining mucolytic agent with antibacterial, as thick secretions
in respiratory tract are always not due to respiratory infections.
Also, the antibacterial therapy always does not require an
associated dose of mucolytic agent.

ix. Metformin + Glimepiride + Pioglitazone: Metformin is

indicated drug in obese type -2 diabetes mellitus whereas
Sulfonylurea (Glimepiride) is indicated drug in non-obese type-2
diabetes mellitus. As per pharmacological principle, another drug
should be added only when monotherapy fails. Metformin
(biguanide) is to be administered after meal whereas Glimepiride
(sulfonylurea) drug is to be administered before meal, therefore
even when both the drugs are required, it would be better to
administer them separately. Pioglitazone is indicated in suspected
cases of insulin resistance. So, the combination of all these drugs
in one formulation is an irrational drug combination.

ix. Codeine+NSAID (paracetamol): This combination is used to

treat severe pain or to inhibit pain perception but these
combinations can cause excessive sedation which can be
dangerous. Needs further examination. Multi vitamin preparations
Multivitamin combination is considered to be irrational.
Excessive use may lead to several side effects.

x. Expectorant central cough suppressants: antihistaminics +

bronchodilator mucolytic agent Bromhexine Hydrochloride 8 mg
+ Terbutaline sulphate 2.5 mg + Guaiphenesin 100 mg + Menthol
5 mg, this combination of expectorants is a costlier way of helping
a condition which is often self- resolving. Expectorant given in
effective doses are often not tolerated and produce adverse drug
reaction.

3.3.4 Obstacles/Reasons Irrational Use Continue

Very few low- and middle-income countries regularly monitor drug use
and implement effective nation-wide interventions - because…

i. They have insufficient funds or personnel?

ii. Lack of objective information & of continuing education & training
in pharmacology.
iii. There is insufficient knowledge of concerning the cost-
effectiveness of interventions? They lack of awareness about the
funds wasted through irrational use?

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iv. Presence of large number of drugs in the market & the lucrative
methods of promotion of drugs employed by pharmaceutical
industries.
v. Lack of well-organised drug regulatory authority & supply of
drugs.
vi. The prevalent belief that “every ill has a pill.

3.3.5 Factors Underlying Irrational Use of Drugs

There is strong interrelationship of factors and as problems rarely have

single cause

i. Patients: drug misinformation, misleading beliefs and inability to

communicate problems
ii. Prescribers: lack of education and training, lack of drug
information, heavy patient load, pressure to prescribe,
generalisation of limited beliefs and misleading beliefs about
efficacy
iii. Drug Supply: inefficient management and non-availability of
required drugs
iv. Industry: promotion or misleading claims
v. Drug Regulation: availability of unsafe drugs, informal
prescribers etc.
vi. Adverse drug events are the 4-6th leading cause of death in the
USA, estimated costs from drug-related morbidity & mortality 30
million-130 billion US$ in the USA, 4-6% of hospitalisations in the
USA & Australia. commonest, costliest events include bleeding,
cardiac arrhythmia, confusion, diarrhoea, fever, hypotension,
itching, vomiting, rash, renal failure.

3.3.6 Impact of Inappropriate Use of Drugs

i. Reduced quality of therapy – Ineffective & unsafe treatment,

over-treatment of mild illness, inadequate treatment of serious
illness and exacerbation or prolongation of illness leading to
increase morbidity & mortality
ii. Waste of resources - Reduced availability & increased cost.
Irrational use is wasteful and can be harmful for both the individual
and the population.
iii. Risk of unwanted effects - adverse reactions & bacterial
resistance; Antimicrobial resistance is dramatically increasing
worldwide in response to antibiotic use much of its inappropriate
overuse (and is causing significant morbidity and mortality. It has
been estimated that antimicrobial resistance costs annually US$
4000–5000 million in the USA and €9000 million in Europe.
iv. Psycho-social impacts - patients rely on unnecessary drugs

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v. Adverse drug events –commonest, costliest consequences of

inappropriate use of medicines. These includes include bleeding,
cardiac arrhythmia, confusion, diarrhoea, fever, hypotension,
itching, vomiting, rash, renal failure. A 4-6th leading cause of death
in the USA, ADR is estimated costs from drug-related morbidity &
mortality 30 million-130 billion US$ in the USA. Adverse
medicines events cause significant morbidity and mortality and
rank among the top 10 causes of death in the United States of
America. They have been estimated to cost £466 million annually
in the United Kingdom of Great Britain and Northern Ireland and
up to US$ 5.6 million per hospital per year in the USA. (Source:
Review by White et al, Pharmacoeconomics, 1999, 15(5):445-458)
vi. The use of unsterile injections is associated with the spread of blood
borne infections, such as hepatitis B and C and HIV/AIDS.
Although evidence-based medicine has gained importance the use
of both diagnostic and treatment guidelines is sub-optimal and
could be greatly improved.

3.4 The Role of Hcps in Promoting Rational Drug Use Objectives

Thing to Ponder: Case Report - A 20yrs. female student, suffering from

tonsillitis, was seen by an OPD doctor in a 600-bed hospital. She obtained
a drug from the hospital pharmacy and took it as instructed. She felt very
weak after taking the drug. 3 days later she became severely comatose and
was admitted to the same hospital. She took chlorpropamide 250 mg four
times a day as dispensed to her at the Pharmacists. The OPD doctor
claimed that he prescribed chloromycetine 4x250 mg daily for her
tonsillitis. The patient eventually died two weeks after hospital admission.
Discuss possible cause of Death – Identify any system failure

3.5 Changing A Drug Use Problem: An Overview of The

Process

i. Examine: measure existing practice (Descriptive Quantitative

studies) improve diagnosis
ii. Diagnosis: Identify specific problems and causes (in-depth
qualitative and qualitative studies)
iii. Treat: Design and implement intervention (Data collect data to
measure outcome
iv. Follow up: measure changes in outcomes (qualitative and
evaluation)

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3.5.1 Steps of rational drug use

Step: - I Identify the patient’s problem based on symptoms & recognise

the need for action

Step: - II Diagnosis of the disease – define the diagnosis

Step: - III List possible intervention or treatment (drug or no drug) –

Identify the drug

Step: - IV Start the treatment by writing an accurate & complete

prescription e.g. name of drugs with dosage forms, dosage schedule &
total duration of the treatment.

Step: -V Give proper information, instruction & warning regarding the

treatment given e.g. side effects (ADR), dosage schedule & dangers/risk
of stopping the therapy suddenly

Step: -VI Monitor the treatment to check, if the particular treatment has
solved the patient’s problem.

i. Passive monitoring – done by the patient himself. Explain him

what to do if the treatment is not effective or if too many side
effects occurs
ii. Active monitoring - done by physician and he make an
appointment to check the response of the treatment

3.6 Strategies to Improve Use of Drugs

3.6.1. Educational Strategies: Goal: to inform or persuade

i. Training for Providers

Undergraduate education
Continuing in-service medical education (seminars, workshops)
Face-to-face persuasive outreach e.g. academic detailing
Clinical supervision or consultation

ii. Printed Materials

Clinical literature and newsletters

Formularies or therapeutics manuals
Persuasive print materials

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iii. Media-Based Approaches

Posters
Audio tapes, plays
Radio, television

3.6.2. Training for prescribers: The Guide to Good Prescribing

WHO has produced a Guide for Good Prescribing - a problem-based
method?

Developed by Groningen University in collaboration with 15 WHO

offices and professionals from 30 countries Field tested in 7 sites Suitable
for medical students, post grads, and nurses widely translated and
available on the WHO medicines website

3.6.3. Managerial strategies: Goal: to structure or guide decisions

i. Changes in selection, procurement, distribution to ensure

availability of essential drugs. - Essential Drug Lists, morbidity-
based quantification, kit systems
ii. Strategies aimed at prescribers - targeted face-to-face supervision
with audit, peer group monitoring, structured order forms,
evidence-based standard treatment guidelines
iii. Dispensing strategies - course of treatment packaging, labelling,
generic substitution

3.6.4. Economic strategies: Goal: to offer incentives to providers a

consumer
iv. Promotes positive financial incentives and also eliminating
perverse
v. incentives for prescribers.
vi. Implements significant changes in service providers’
reimbursement
vii. schemes or disallowing prescribers to sell medicines themselves
viii. Removes the financial motivation for over-prescribing are
economic
i. interventions that may be used.

3.6.5 Avoid perverse financial incentives

ix. prescribers’ salaries from drug sales
x. insurance policies that reimburse non-essential drugs or incorrect
doses
xi. flat prescription fees that encourage polypharmacy by charging the
same amount irrespective of number of drug items or quantity of
each item
xii. (reverse – Quebec, dispensing fee is given even if pharmacist does
not dispense for good reason)

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xiii. Reimburse without treatment guidelines (ceftriaxone as an OPD

medicine)

3.6.6 Regulatory strategies: Goal: to restrict or limit decisions

i. Drug registration
ii. Banning unsafe drugs - but beware unexpected results. Substitution
of a second inappropriate drug after banning a first inappropriate or
unsafe drug
iii. Regulating the use of different drugs to different levels of the health
sector e.g.
a. licensing prescribers and drug outlets
b. scheduling drugs into prescription-only & over-the-counter
iv. Regulating pharmaceutical promotional activities

Only work if the regulations are enforced

3.7 Drug Dependence and Substance Abuse

3.7.1Introduction:

Public health practitioners have attempted to look at substance use from a

broader perspective than the individual, emphasizing the role of society,
culture, and availability. Some health professionals choose to avoid the
terms alcohol or drug "abuse" in favour of language they consider more
objective, such as "substance and alcohol type problems" or
"harmful/problematic use" of drugs. The Health Officers Council of
British Columbia — in their 2005 policy discussion paper, A Public
Health Approach to Drug Control in Canada — has adopted a public
health model of psychoactive substance use that challenges the simplistic
black-and-white construction of the binary (or complementary) antonyms
"use" vs. "abuse”. This model explicitly recognizes a spectrum of use,
ranging from beneficial use to chronic dependence.

3.7.2 Causes of Substance Use Disorders

The cause of substance use disorders is still unknown, though genetics are
thought to account for 40% to 60% of a person’s risk. Substance use often
starts as a way to feel good or out of curiosity in childhood or early
adolescence. Repeated use of the substance and increased tolerance pave
the way to substance use disorder and addiction. Some adults who develop
a substance use disorder have a co-occurring mental illness, such as
depression, anxiety, or bi-polar disorder, and begin using drugs or alcohol
to cope with their symptoms. Other risk factors that may lead to a
substance use disorder include:

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i. Family history of addiction: Drug addiction is more common in

some families and likely involves genetic predisposition to mental
health disorder.
ii. Peer pressure: This is most common reason among young adults
and teenagers. They start to use drugs because they want to fit in.
Being rebellious as a teenager or young adult is very common. In a
lot of cases, young adults and teenagers don’t fully understand the
severity of drug use and addiction.
iii. Sleep problems & Chronic pain: In many cases, substances like
Alcohol, Marijuana and prescription painkillers act as a gateway to
drugs that have a more intense and mind-altering effect. Currently,
the Opioid epidemic is forcing people to turn to street drugs, like
Meth or Heroin, when their doctor stops writing refills for their
prescriptions.
iv. Experimenting: Mind-altering substance, like Cocaine and
Alcohol, promise to heighten experience and that experience is
worth exploring. Unfortunately, there are drugs like Heroin,
Ecstasy, and Meth that are so addictive that the person will begin a
pattern of abuse, which can eventually lead to an addiction.
v. Self- Medications: Self-medicating is the top reason people abuse
drugs and Alcohol. Stress, anxiety, reoccurring pain, undiagnosed
mental illnesses, severe depression, loneliness, trauma; these are all
reasons why people would self-medicate with mind-altering
substances to cope with what they are feeling or what they do not
want to feel.
vi. Also, Financial difficulties, Divorce or the loss of a loved one,
Tense home environment, Lack of parental attachment in
childhood, Relationship issues, Long-term tobacco habit etc.
vii. None of these risk factors guarantees that a person will develop a
substance abuse disorder, but a combination of factors plus
repeated substance use significantly increases the likelihood of
addiction.

3.7.3 Classification of Drug Dependence/Substance Abuse

The commonly types of drugs of abuse and dependence

viii. CNS Stimulants: methamphetamine (Desoxyn: meth, ice, crank,

chalk, crystal, fire, glass, go fast, speed), Amphetamines
(Biphetamine, Dexedrine: bennies, black beauties, crosses, hearts,
LA turnaround, speed, truck drivers, uppers), Cocaine (Cocaine
hydrochloride: blow, bump, C, candy, Charlie, coke, crack, flake,
rock, snow, toot), Methphenidate and Khat etc.
ix. CNS Depressant: Alcohol, Disulfiram, Naltrexone,
Benzodiazepines, Barbiturates

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x. Cannabinoids: Hashish (Boom, gangster, hash, hash oil, hemp),

Marijuana. (Blunt, ganja, grass, green, trees, weed etc.) 3. Bango.
xi. Opioids: Heroin (Diacetylmorphine: smack, horse, brown sugar,
dope, H, junk, skag, skunk, white horse, China white; cheese (with
OTC cold medicine and antihistamine)), Opium, (Laudanum,
paregoric: big O, black stuff, block, gum, hop), Morphine, Codeine
and Codeine-containing cough sedatives and Methadone,
Buphrpnorphine.
i.Hallucinogens: (Psychedelic); LSD, Anticholinergics and
Mescaline etc.
ii.Club Drugs:

MDMA (Methylenedioxymethamphetamine): Ecstasy, Adam, clarity,

Eve, lovers' speed, Molly, peace, uppers

Flunitrazepam: Rohypnol (date rape drug): forget-me pill, Mexican

Valium, R2, roach, Roche, roofies, roofinol, rope, rophies

GHB: Gamma-hydroxybutyrate: G, Georgia home boy, grievous bodily

harm, liquid ecstasy, soap, scoop, goop, liquid X
iii.
DISSOCIATIVE DRUGS;

Ketamine: Ketalar SV: cat Valium, K, Special K, vitamin K, PCP and

Analogs:Phencyclidine: angel dust, boat, hog, love boat, peace pill.

Salvia Divinorum: Salvia, Shepherdess’s Herb, Maria Pastora, magic

mint, Sally-D.
iv.Dextromethorphan (DXM): Found in some cough and cold medications:
Robot ripping, Robo, Triple C.

OTHER COMPOUNDS:

Anabolic Steroids: Anadrol, Oxandrin, Durabolin, Depo-Testosterone,

Equipoise: roids, juice, gym candy, pumpers

Inhalants: Solvents (paint thinners, gasoline, glues); gases (butane,

propane, aerosol propellants, nitrous oxide); nitrites (isoamyl, isobutyl,
cyclohexyl): laughing gas, poppers, snappers, whippets

Caffeine: Whether consuming caffeine in large amounts can increase

perinatal risk is unclear. Consuming caffeine in small amounts (e.g. 1 cup
of coffee/day) appears to pose little or no risk to the fetus. Some data,
which did not account for tobacco or alcohol use, suggest that consuming

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large amounts increases risk of stillbirths, preterm deliveries, low birth

weight & spontaneous abortions

Smoking: Carbon monoxide & nicotine - hypoxia & vasoconstriction,

increasing risk of spontaneous abortion, fetal growth restriction, abruptio
placentae, placenta previa, premature rupture of membranes, preterm
birth, chorioamnionitis & stillbirth, Anencephaly, congenital heart defects,
orofacial clefts, sudden infant death syndrome, deficiencies in physical
growth & intelligence & behavioral problems, Smoking during pregnancy
- childhood asthma

3.7.4 Diagnosis of Drug Dependence / Substance Abuse

Most of substances known to be amenable for abuse and dependence
(Addiction) can be grouped into the following classes

i. CNS Stimulants: Cocaine: An alkaloid derived from cocoa

leaves or synthesised from ecgonine or its derivative. Cocaine is
one of the most addictive of commonly abused substances and
one of the most dangerous. Various street names of cocaine, is
referred to as crack, snow, cock, girl and lady etc. It is a white
powder that is inhaled, smoked or injected.

Effect of cocaine on CNS: Cocaine is a psychoactive stimulant. Its

primary pharmacological action is related to its competitive blockade of
dopamine reuptake by dopamine transporters. This leads to marked
elevation of dopamine in synaptic clefts. Cocaine has powerful addictive
qualities. Psychological dependence on cocaine can develop after a single
use.

Withdrawal symptoms of cocaine: Withdrawal symptoms are mild

compared to those of opioids. They include depressed mood, dysphonia,
fatigue, hyper somnolence. Suicidal ideations may occur. Symptoms
persist for a few days up to one week. Craving is very strong.

Over dose of cocaine Intoxication by high doses is associated with

delirium, seizures, cerebrovascular diseases and myocardial infarction
which may lead to death.
Psychiatric disorders with cocaine abuse they include: psychotic
disorders, mood disorders, anxiety disorders, sexual dysfunction and sleep
disorder.

ii. CNS Depressant: Alcohol, Disulfiram, Naltrexone,

Benzodiazepines and Barbiturates.

Alcohol: These are a large group of organic compounds derived from

hydrocarbons and containing one or more hydroxyl (OH) group. Ethanol

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is one of these class of compounds and it is the main psychoactive

ingredient in alcoholic beverages. Non-beverage alcohol includes
methanol, isopropyl alcohol and ethylene glycol are also occasionally
consumed alcohol e.g. Disu. 90% of USA population are using alcohol,
whereas only 12% or 18% have abuse or dependence problem,
respectively

Effects on Pregnancy: Causes vasoconstrictor leading to increased risk

of

i. spontaneous abortion with decrease birth weight by ~1 to 1.3 kg, if

regular drinking, Binge drinking in particular - fetal alcohol
syndrome
ii. Dysmorphic facial features (all 3 are required) - Small palpebral
fissures, thin vermilion border & smooth philtrum
iii. Prenatal and/or postnatal growth impairment 3. CNS abnormalities
(1 required)
iv. Structural: head size < 10th percentile, significant brain
abnormality on imaging
v. Neurological:

Effect of alcohol on the brain: Alcohol is a CNS suppressant. It exerts

this suppressant effect in a descending manner, where higher cortical
centres are inhibited first, resulting in euphoria and then disinhibition. In
larger doses, lower vital centres are inhibited, leading to hypotension and
respiratory depression. Also, functional such as global cognitive or
intellectual deficits, functional deficits in at least three domains

Effect of alcohol on neurotransmitters: It is found that ion channel

activities associated with acetyl choline, serotonin and GABA receptors
are enhanced by alcohol. Ion channel activities associated with glutamate
receptors are inhibited. Death is due to central respiratory depression or
inhalation of vomitus.

Alcohol-Related Disorders: Alcohol abuse and dependence, Alcohol

withdrawal, Alcohol induced dementia, Alcohol induced amnestic
disorders, Alcohol induced psychotic disorders and Alcohol related mood
disorders.

Alcohol withdrawal: the classic signs of alcohol withdrawal are due to

sympathetic over activity and tendency to develop epileptic convulsions.
Symptoms include tremulousness, sweating, restlessness and even
excitement. They may include psychotic symptoms (such as delusions and
hallucinations). Seizures and symptoms of delirium tremens may
eventually develop.

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Foetal alcohol syndrome: It occurs when foetuses are exposed in utero to

alcohol by their mothers' drinking alcohol. This syndrome is the leading
cause of mental retardation in the United States. Women with alcohol
related disorders have a 35 percent risk of having a child with deficits.

Cannabinoids: Hashish (Boom, gangster, hash, hash oil, hemp),

Marijuana. (Blunt, ganja, grass, green, trees, weed etc.), Bango.

iii.CANNABINOIDS (Cannabis): A generic term used to denote the

several psychoactive preparations of the marijuana (hemp) plant,
Cannabis Sativa. The psychoactive compound in cannabinoids is delta-
9tetrahydrocannabinol (THC). Cannabinoids are usually smoked, but may
be taken orally and are sometimes mixed with tea or food.
Common forms of Cannabinoids include marijuana leaf (in street jargon:
grass, pot, dope, weed or reefers), bhang (BHO), Hashish (derived from
the resins of the flowering heads of the plant) and hashish oil.

THC is lipid soluble and rapidly absorbed after inhalation. It is

redistributed from blood into other tissues. It is then released from its
adipose tissue stores into the blood stream. This explains the prolonged
effects of THC after acute intake

Effect of cannabinoids: Cannabinoids exert many of their actions by

influencing several neurotransmitter systems. These include
acetylcholine, dopamine, gammaamino-butyric acid (GABA), histamine,
serotonin, norepinephrine, opioid peptides, and prostaglandins.

Cannabis intoxication
Acute Effects: Euphoria; relaxation; slowed reaction time; distorted
sensory perception; impaired balance and coordination; increased heart
rate and appetite; impaired learning, memory; anxiety; panic attacks and
psychosis.
.
Cannabis withdrawals have been described in association with the use
of high doses in the form of: Irritable or anxious mood, Tremor,
Perspiration, Nausea and Sleep disturbances.
Health Risks: Cough; frequent respiratory infections; possible mental
health decline; addiction.

Hazards of cannabinoids - Chronic cannabinoids use is associated with

poor social and vocational functioning due to the development of
Amotivational Syndrome. A number of psychiatric disorders such as
bipolar mood disorder, anxiety, depersonalisation, and dissociative
episodes are reported as a consequence of cannabinoids abuse. Affective
disorders and paranoid symptoms may be exacerbated after cannabinoids
abuse.

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iv. Opioids: This generic term applies to alkaloids from opium

poppy (Paperver Somniferum) Opioids are highly addicting.

Natural Opioids alkaloids (Morphine and Codeine) and their semi

synthetic derivatives includes Semi synthetic opioids: hydromorphone, it
is also known as dihydromorphinone diacetyl morphine (diamorphine,
heroin), Hydrocodone is chemically altered codeine. Oxycodone which
derived from thebaine. Other examples are oxymorphone, ethyl morphine
and buprenorphine.

Fully synthetics opioids: fentanyl, pethidine, levorphanol, methadone,

tramadol, tapentadol and dextropropoxy.
Acute Effects: Euphoria; drowsiness; impaired coordination; dizziness;
confusion; nausea; sedation; feeling of heaviness in the body; slowed or
arrested breathing Health Risks: Constipation; endocarditis; hepatitis;
HIV; addiction; fatal overdose

Nervous system suppressants (endogenous opioids receptors). Their

effects include: Analgesia, Mood changes, "Mental clouding", Sedation,
Central nausea and vomiting, gastrointestinal effects, pupillary
constriction and Respiratory depression.

Over dose of opiates Severe intoxication is diagnosed by the triad of:

Coma, Pinpoint pupils and Respiratory depression. It is a medical
emergency that requires immediate attention.

Opioids Withdrawal Syndrome; Time of onset differs according to the

half-life of the drug used: e.g. 4-6 hours after the last use of heroin but up
to 36 hours after the last use of methadone. Severity varies with the dose
and duration of drug use. Early findings may include tachycardia,
hypertension, pupillary dilatation, and diffuse muscular-skeletal pain.
Central nervous system symptoms include restlessness, irritability
andinsomnia Gastrointestinal symptoms are anorexia, vomiting,
abdominal colics, and diarrhoea Cutaneous and mucocutaneous symptoms
includes lacrimation, rhinorrhoea and piloerection, also known as
"gooseflesh" Opioids Craving.

v. Hallucinogens: Agents that induce a state of marked perceptual

alterations. They are CNS stimulants. Examples are: lysergic acid
diethylamide (LSD) and amphetamines. They have both an
antagonist and an agonist effect on serotonergic system
vi. Lysergic acid diethylamide (LSD): LSD is synthetic derivative
of ergot fungus. It is extremely potent and is effective in
extremely low doses. It is ingested orally or through other mucous
membranes (sublingual, orally or corneal). Tolerance quickly

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develops, leading to ingestion of larger doses or increased

frequency of use. It is not highly addicting.

Hazards of hallucinogen use;

i. A drug precipitated psychosis may continue following the cessation

of hallucinogen use.
ii. Flashbacks are brief spontaneous recurrences of perceptual
changes, such as experienced while using hallucinogens. They have
been reported days, months or years after drug use.
i. Amphetamines is Pegnancy (Cat C). Causes Defects in Oral
clefts, Cardiovascular abnormalities: Phencyclidine (PCP, angel
dust) - Possible malformations & behavioral disturbances
ii. Benzodiazepines (BDZ): Benzodiazepines are psychoactive
depressant drugs that are used to control anxiety and epilepsy and
in induction of anaesthesia. Tolerance to benzodiazepines is
common. Benzodiazepines are widely used in combination with
heroin, cocaine, alcohol and stimulants.

Intoxication of BDZ, includes somnolence and behavioural disinhibition.

In higher doses, they cause hypotension and central respiratory
depression, particularly if taken with another depressant drug (e.g.,
alcohol)

Withdrawal of BDZ symptoms include rebound anxiety, restlessness,

agitation, hypertension, and d tachycardia. Epileptic seizure is a serious
emergency and may be fatal. Hospitalisation and gradual withdrawal of
benzodiazepines are the main lines of treatment of benzodiazepine
addiction. Prevention of seizures by antiepileptics may be needed

vi. Nicotine: Nicotine, in mild to moderate doses, is a central nervous

system stimulant. It enhances central cholinergic receptors
(activated by acetyl choline). The dependence-producing effects
of nicotine appear to be modulated by dopamine (nicotinic-
cholinergic receptors lie on dopamine neurons, nicotine increases
dopamine)

3.7.5 Principles of Effective Treatment

Addiction is a complex but treatable disease that affects brain function and
behaviour. No single treatment is appropriate for everyone.

i. Treatment needs to be readily available.

ii. Effective treatment attends to multiple needs of the individual, not
just his or her drug use or misuse.
iii. Remaining in treatment for an adequate period of time is critical.

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iv. Behavioural therapies—including individual, family, or group

counselling—are the most commonly used forms of drug use
disorder treatment.
v. Medications are an important element of treatment for many
patients, especially
vi. when combined with counselling and other behavioural therapies.
vii. An individual’s treatment and services plan must be assessed
continually and modified as necessary to ensure that it meets his or
her changing needs.
viii. Many drug-addicted individuals also have other mental disorders.
ix. Medically assisted detoxification is only the first stage of addiction
treatment and by itself does little to change long-term drug use and
misuse.
x. Treatment does not need to be voluntary to be effective.
xi. Drug use during treatment must be monitored continuously, as
lapses during treatment do occur.
xii. Treatment programs should test patients for the presence of
HIV/AIDS, Hepatitis B and C, tuberculosis, and other infectious
diseases, provide risk-reduction counselling, and link patients to
treatment if necessary.

3.7.6 Management of Substance Abuse/Dependence

Management of Substance Abuse/Dependence

Two major goals: the first is abstinence from the substance; the second is
physical, psychiatric, and psychosocial well-being of the patient.
Management of Substance Abuse/Dependence. Inpatient or outpatient
settings, Detoxification, and Rehabilitation.

Throughout treatment, individual, family, and group therapies (alcoholic

& narcotic anonymous) can be effective. Any underling psychiatric
disorder should be

xiii. Pharmacological Treatment of Substance Abuse: Because

substance abuse/dependence is in part a neuropharmacological
phenomenon, there is at present an aggressive search for agents that
may; decrease the reinforcing properties of substances (block the
drug euphoric effect), decrease craving associated with substances
or function as replacements for the drug of abuse.

xiv. Naltrexone (an opiate receptor blocking agent) decreases alcohol

consumption and relapse in alcoholic patients, also in opiate abuse.
xv. Nicotine replacement using nicotine gum, patch, spray and
inhalation have been used with successful results in nicotine
dependence.

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i.Methadone - an opiate receptor agonist proved to be highly effective

in abstinence from opiate use

4.0 CONCLUSION

In this section you have learnt about definitions of rational use of

medicines and identify the magnitude of the problemof irrational drug use.
Also, the reasons underlying irrational use and factors which influence the
behavior of prescribers and patients. The strategies and interventions to
promote rational use of medicines were also explained to you. In the
second part of the units the definition of drug of abuse/ substance abuse,
which is using chemicals for nontherapeutic effects on the body or mind
and that excessive use or misuse of drugs or alcohol for intoxicating or
mind-altering effects. Other various terms used in substance abuse was
defined, the factors responsible for substance abuse and classification of
drug of abuse and its management was discussed.

5.0 SUMMARY

Rational use of medicines requires that patients receive medications appr

opriate totheir clinical needs, in doses that meet their requirements,
for an adequate period oftime, and at the lowest cost to them and their
community. Unfortunately, more than 50% of all medicines are
prescribed, dispensed, or sold inappropriately on a global basis and
50% of patients fail to take their medicines correctly according to
estimates based on various ad hoc reviews. Common types of
inappropriate medicines use include, Polypharmacy (the use of too many
medicines per patient), overuse
ofinjections, inappropriate use of antimicrobials, failure to prescribe in a
ccordance withclinical guidelines, and inappropriate self‐
medication, often with prescription‐
onlymedicines. Inappropriate use of medicines is harmful for patients in t
erms of poorpatientclinical outcomes and avoidable adverse drug reactio
ns. Unnecessary overuse ofmedicines can stimulate inappropriate patient
demand and lead to medicinestockouts and loss of patient confidence in
the health system.

Examples of common inappropriate prescribing practices includes; the

overuse of antibiotics and antidiarrhoeals for nonspecific childhood
diarrhea, indiscriminate use of injections, multiple or over-prescription,
wrong Diagnosis, use of antibiotics for mild, non-bacterial infection, e.g.,
common cold URI, tonics and multivitamins for malnutrition, unnecessary
use of expensive antihypertensives and aadequacy of diagnostic process.
Examples of irrational drug combinations; Antibacterial + Antiamoebic
Combinations: Ciprofloxacin + Metronidazole, Norfloxacin + Tinidazole
and Ofloxacin + Ornidazole are such commonly available fixed dose drug

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combinations. In bacterial diarrhoea only anti-bacterial drug is effective

and antiamoebic drug is useless. Similarly, in intestinal amoebiasis only
antiamoebic drug is effective while antibacterial drug is useless.
Amoebiasis and bacterial diarrhoea rarely coexist. The therapy should be
based on the diagnosis to reduce the cost of treatment since in a given case,
only one drug of the combination would be effective and the other one
would be useless. NSAIDs Combinations: Nimesulide, diclofenec,
ibuprofen and Paracetamol are some non-steroidal anti-inflammatory
drugs (NSAIDs). There is no justification in combining one NSAID
(nimesulide, diclofenec, ibuprofen) with another NSAID (paracetamol)
having same pharmacological actions. The increased risk of
hepatotoxicity has been reported due to the use of combination of
nimesulide with paracetamol. There is increased risk of nephrotoxicity
with NSAIDs combination. Impact of inappropriate use of drugs includes,
reduced quality of therapy with exacerbation or prolongation of illness
leading to increase morbidity & mortality, Waste of resources - reduces
availability & increased cost. Adverse drug events –commonest, costliest
consequences of inappropriate use of medicines. These includes include
bleeding, cardiac arrhythmia, confusion, diarrhoea, fever, hypotension,
itching, vomiting, rash, renal failure.

The cause of substance use disorders is still unknown, though genetics are
thought to account for 40% to 60% of a person’s risk. Substance use often
starts as a way to feel good or out of curiosity in childhood or early
adolescence. Repeated use of the substance and increased tolerance pave
the way to substance use disorder and addiction. Some adults who develop
a substance use disorder have a co-occurring mental illness, such as
depression, anxiety, or bi-polar disorder, and begin using drugs or alcohol
to cope with their symptoms. Other risk factors that may lead to a
substance use disorder include; Family history of addiction, Peer pressure,
Sleep problems & Chronic pain, experimenting mind-altering substance,
like Cocaine and Alcohol, promise to heighten experience and that
experience is worth exploring, self- Medications to allay Stress, anxiety,
reoccurring pain, undiagnosed mental illnesses, severe depression,
loneliness, trauma; these are all reasons why people would self-medicate
with mind-altering substances to cope with what they are feeling or what
they do not want to feel. Financial difficulties, divorce or the loss of a
loved one, tense home environment, lack of parental attachment in
childhood, relationship issues and, long-term tobacco habit.

The commonly types of drugs of abuse and dependence are; 1. CNS

Stimulants e.g. Methamphetamine, Amphetamines 2. CNS Depressant
like Alcohol, disulfiram, Benzodiazepines, 3. Cannabinoids: 1. Hashish,
Marijuana.4. Opioids e.g. Morphine, Codeine and Codeine-containing
cough sedatives, 5. Hallucinogens Psychedelic); LSD, Anticholinergics
and Mescaline, Club Drugs like MDMA

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(Methylenedioxymethamphetamine, Flunitrazepamand 7. dissociative

drugs, ketamine, dextromethorphan (DXM), 8. other compounds such as
Anabolic Steroids, Inhalants: and Caffeine etc.

Addiction is a complex but treatable disease that affects brain function and
behaviour. No single treatment is appropriate for everyone. Effective
treatment attends to multiple needs of the individual, not just his or her
drug use or misuse etc.

Pharmacological management of Substance Abuse/Dependence is divided

into two major goals: the first is abstinence from the substance; the second
is physical, psychiatric, and psychosocial well-being of the patient.
Throughout treatment, individual, family, and group therapies (alcoholic
& narcotic anonymous) can be effective. Any underling psychiatric
disorder should be managed appropriately.

Common drugs use includes Naltrexone (an opiate receptor blocking

agent) decreases alcohol consumption and relapse in alcoholic patients,
also in opiate abuse, Nicotine replacement using nicotine gum, patch,
spray and inhalation have been used with successful results in nicotine
dependence and Methadone - an opiate receptor agonist proved to be
highly effective in abstinence from opiate use.

SELF ASSESSED EXERCISES

I. Explain the following terms: a) Dependence b) Pyschotropic

drugs
c) Narcotics d) Tolerance.
ii. What is the criteria for using medicines?

6.0 TUTOR -MARKED ASSIGNMENT

1. Identify the magnitude and nature inappropriate drug utilization in

your facility with life examples
2. Describe the reasons underlying irrational use by
prescribers/patients in your facilities
3. Outline the adverse impacts of inappropriate use of drugs
4. Discuss strategies and interventions to promote rational use of
medicines in Nigeria.
5. List the five most common substances of abused

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7.0 REFERENCES/FURTHER READING

The rational use of drugs. Report of the Conference of Experts. Geneva,

World Health Organization, 1985.

Builders, M.I. (2016). Rational and Irrational use of analgesics: A review.

World Journal of Pharmaceutical Sciences,4 (7), 55-
60.http://www.wjpsonline.org.

Promoting rational use of medicines: Core components. WHO Policy

Perspectives on Medicines, No.5. Geneva, World Health
Organization, (2002). Retrieved from:
http://apps.who.int/medicinedocs/pdf/h3011e/h3011e.pdf.

Ofori-Asenso, R. & Agyeman, A. A (2016). Irrational use of medicines-

A summary of key concepts. Pharmacy (Basel), 4 (4), 35. http:
//doi :10.3390/pharmacy4040035.

Medicines use in primary care in developing and transitional countries:

Fact book summarizing results from studies reported between
1990 and 2006. Geneva, World Health Organisation, 2009.
Retrieved.
http://www.who.int/medicines/publications/primary_care_8April0
9.pdf.

Sabaté, E. (2003). Adherence to long-term therapies. Evidence for action.

Geneva, World Health Organisation.

Using indicators to measure country pharmaceutical situations: Fact

book on WHO Level I and Level II monitoring indicators. Geneva,
World Health Organization,
2006.http://apps.who.int/medicinedocs/index/assoc/s14101e/s141
01e.pdf.

White TJ, Araekelian A, Rho JP. Counting the costs of drug related
adverse events. Pharmacoeconomics, 1999, 15(5):445–458.

Nigeria National Drug Policy, (2005). FMoH Abuja

Ensuring balance in national policies on controlled substances. Guidance

for Availability and Accessibility of Controlled Medicines. (WHO
2011).

The World Drug Report 2018 benefited from the expertise of and
invaluable contributions from UNODC colleagues in all divisions.

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National Institute on Drug Abuse. (2012). commonly abused drugs.

[Online]. Retrieved May 20, 2013
from http://www.drugabuse.gov/sites/default/files/cadchart_2.pdf

Street drugs:http://www.streetdrugs.org.

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