UNIT-ONE

GENERAL PHARMACOLOGY

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Specific Objectives:

At the end of this lesson students will be able to :

 Define: Pharmacology ,drugs
 Identify branches of pharmacology
 List out sources of drugs
 Identify routes of drug administration
 Describe pharmacokinetic and pharmacodynamic
processes of drugs
 Discuss steps in new drug development process

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 I. Introduction

 The term ‘pharmacology’ is derived from two Greek

words:

’Pharmacon’ -which means ‘a drug/poison’ and

‘Logos’ - meaning ‘a reasonable’ or ‘rational

discussion’
 Can be defined as the study of substances that
interact with living systems through chemical
processes, especially by binding to regulatory
molecules and activating or inhibiting normal body
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 Medical pharmacology, is often defined as the
science of substances used to prevent, diagnose,
and treat disease.
 Is a discipline devoted to patient therapy through
the use of drugs.
 Is a science that draws on information from
multiple disciplines, among them anatomy,
physiology, psychology, chemistry, and
microbiology.

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 Fig. Major areas of study in
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 History of Pharmacology

 Pharmacology is one of the oldest form of healthcare,

practiced in virtually every culture dating to antiquity.
 Prehistoric people undoubtedly recognized the
beneficial or toxic effects of many plant and animal
materials

(Applying products to relieve suffering has been

recorded throughout history) ,
 Around the end of the 17th century, reliance on
observation and experimentation began to replace
theorizing in medicine.
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 Materia medica= the science of drug preparation
and the medical use of drugs began to develop as
the precursor to pharmacology.
 However, any real understanding of the mechanisms
of action of drugs was prevented by the absence of
methods for purifying active agents from the crude
materials that were available.
 Modern pharmacology began in the early 19th
century through the isolation of specific active
agents from their complex mixtures.
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 Claudius Galen (129–200 A.D.)
 First attempted to consider the theoretical
background of pharmacology.
 He said “both theory and practical experience
were to contribute equally to the rational use of
medicines through interpretation of observed
and experienced results.”

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Theophrastus von Hohenheim (1493– 1541 A.D.)
 Called Paracelsus, began to question doctrines handed
down from antiquity, demanding knowledge of the active
ingredient(s) in prescribed remedies, while rejecting the
irrational concoctions and mixtures of medieval medicine.
 He prescribed chemically defined substances with such
success that professional enemies had him prosecuted
as a poisoner.
 Against such accusations, he defended himself with the
thesis that has become an axiom of pharmacology:

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“ If you want to explain any poison properly, what
then isn‘t a poison?
All things are poison, nothing is without poison;
the dose alone causes a thing not to be poison.”

Johann Jakob Wepfer (1620–1695)

 Was the first to verify by animal experimentation

assertions about pharmacological or toxicological

actions.

“ I pondered at length. Finally I resolved to clarify

the matter by experiments.”
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 Rudolf Buchheim (1820–1879)-

 Founded the first institute of pharmacology at the University

of Dorpat (Tartu, Estonia) in 1847,

 Leading in pharmacology as an independent scientific

discipline.

 In addition to a description of effects, he strove to explain the

chemical properties of drugs.

“ The science of medicines is a theoretical, i.e.,

explanatory one.

It is to provide us with knowledge by which our judgment

about the utility of medicines can be validated at the

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Oswal Schmiedeberg (1838–1921)-
 Helped to establish the high reputation of
pharmacology.
 Fundamental concepts such as structure-activity
relationship, drug receptor, and selective toxicity
emerged from the work of, respectively,
 Together with the internist, Bernhard Naunyn
(1839–1925),
Founded the first journal of pharmacology, which
has
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since been published without interruption.
John J. Abel (1857–1938)

 The “Father of American Pharmacology”,

 Was among the first Americans to train in

Schmiedeberg‘s

laboratory and was founder of the Journal of

Pharmacology and Experimental Therapeutics

(published from 1909 until the present).

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 Subdivision/Branches of pharmacology

1. Pharmacodynamics:
 The study of the biological and therapeutic effects of
drugs and molecular mechanism of action
(what the drug does to the body”)
2. Pharmacokinetics:
 Study of drug movement in and alteration of drug by
the body
It deals with drug disposition
(absorption, distribution, metabolism and
excretion
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3. Pharmaco-therapeutics:
 It deals with the proper selection and use of drugs for

the prevention and treatment of disease, drug adverse

and toxic effects contraindications , precautions as well

as drug interactions .

[Link] dynamics:
 It is the study of poisonous effect of drugs and other

chemicals with emphasis on detection ,prevention ,and

treatment of poisonings.

N.B. Many drugs in larger doses may act as poisons

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5. Clinical Pharmacology:
 It is scientific study of drugs in man.
 Includes :
 Pharmacokinetics,
 Pharmacodynamics ,
 Evaluation of efficacy and safety of
drugs as well as
 Comparative trials with other forms
of treatment

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6. Pharmacogenetics:

 Is the study of the genetic variations that cause

individual differences in drug response

(concerned with unusual i.e. idiosyncratic drug

responses that have hereditary basis)

 Genetic variation in any of subcellural steps

involved in pharmacokinetics could lead to

idiosyncratic drug responses.

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 Drug

 The term drug is derived from the French

word ‘drogue’ which means ‘a dry herb’.

 Are chemical substances which change the

function of biological system by interacting at

molecular level;

 May be chemicals administered to achieve a

beneficial therapeutic effect on some process

within the patient

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 For their toxic effects on regulatory processes in
parasites infecting the patient.
 Can also be defined as any substance that is used for
the prevention, diagnosis or treatment of disease.
 A medicine is a chemical preparation, which usually but
not necessarily contains one or more drugs, administered
with the intention of producing a therapeutic effect.
 To count as a drug, the substance must be administered
as such, rather than released by physiological
mechanisms.

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Sources of Drugs:

Drugs are obtained from:

1. Minerals: Liquid paraffin, magnesium sulfate,

magnesium trisilicate, kaolin, etc.

2. Animals: Insulin, thyroid extract, heparin and

antitoxin sera, etc.

3. Plants: Morphine, digoxin, atropine, castor

oil,

etc.
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4. Synthetic source: Aspirin, sulfonamides,

Paracetamol, zidovudine, etc.

5. Semi –synthetic forms: Ampicillin, Cloxacillin,...

6. Micro organisms: Penicillin, streptomycin and

many other antibiotics

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 Properties of an Ideal Drug

 The ideal medication exists in theory only:

In reality, there's no such thing as a perfect drug.

 The three most important characteristics that any
drug can have are: Effectiveness, Safety, and
Selectivity.

Effectiveness
 An effective drug is one that elicits the responses for

which it is given.
 Effectiveness is the most important property a drug

can have.
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 Safety

 A safe drug is defined as one that cannot

produce harmful effects even if administered in

very high doses and for a very long time.

There is no such thing as a safe drug.

 All drugs have the ability to cause injury,

especially with high doses and prolonged use.

 The chances of producing adverse effects can be

reduced by proper drug selection and proper

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 Selectivity
 A selective drug is defined as one that elicits only
the response for which it is given.
 A selective drug would not produce side effects.
 There is no such thing as a selective drug:

All medications cause side effects.

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 Additional Properties of an Ideal Drug

 Reversible Action

 Predictability

 Ease of Administration

 Freedom from Drug Interactions

 Low Cost

 Chemical Stability

 Possession of a Simple Generic Name

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No Drug Is Ideal … 25
 Drug Nomenclature (Naming System)

 Three basic drug names

1. Chemical Name-
– Helpful in predicting a substances
physical and chemical properties
– Often complicated and difficult to
remember or pronounce
E.g. Chemical name for diazepam:
7-chloro-1,3-dihydro-1-methyl-5-phenyl-
04/17/2025 2H-1,4-benzodiazepin-2-one 26
Chemical Name - N-acetyl-para-aminophenol
Generic (Nonproprietary) name - Acetaminophen

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Generic Name-

 Is assigned by the U.S. Adopted Names

Council

 Less complicated and easier to remember

 Only one generic name for each drug

 Less expensive

 Used internationally in pharmacopeias

Non- proprietary name

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Trade Names-
 Assigned by company marketing the drug
 Sometimes called proprietary, product or
brand name
 A single drug may have multiple names
 Selected to be short and easy to remember
 Shorter and easier than generic name

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 Example:

Generic substance Brand Name

 ASA Anacin, Bayer,

Excedrin

 Diphenhydramine- Benadryl, Caladryl, Allerdryl

 Ibuprofen- Advil, Motrin, Midol

 Digoxin Lanoxin

 Levothyroxine Sodium Synthroid

 Warfarin Coumadin
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 2. Pharmacokinetic principles
(drug disposition)

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 Pharmacokinetics -is currently defined as the study of
the time course of drug

Absorption, Distribution,Metabolism, and Excretion

 Examines the movement of a drug over time

through the body and metabolic alteration by enzymes.

 These fundamental pathways of drug movement and

modification in the body control

Speed of onset of drug action,
 The intensity of the drug's effect, and

 The duration of drug action

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 First, drug absorption from the site of
administration

permits entry of the therapeutic agent (either directly

or

indirectly) into circulatory system (Absorption).

 Second, the drug may then reversibly leave the

bloodstream and distribute into the interstitial and

intracellular fluids (Distribution)
 Third, the drug may be metabolized by the

liver, kidney, or other tissues (Metabolism)

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 Finally, the drug and its metabolites are
removed from the body in urine, bile, or feces
(Elimination)

 Pharmacokinetic processes determine how

rapidly and for how long the drug will
appear at the target organ.

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 Passage of Drugs Across Membrane

Structure of biological membrane

 The absorption, distribution, and excretion involve

passage of a drug across cell membranes

 The plasma membrane consists of a bilayer of

amphipathic lipids

 Membrane proteins embedded in the bilayer serve

as receptors, ion channels, and transporters to

transduce electrical or chemical signaling pathways

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   


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Fig. The four basic pharmacokinetic processes.
Dotted lines -represent membranes that must be
crossed as drugs move throughout the body.

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 Ways of drug passage across CM

1. Filtration [aqueous diffusion]

 Size should be less than size of pore

 Has to be water soluble E.g. Na+, Cl-, K+, Urea ...

2. Passive(Simple) Diffusion [Direct penetration]

 Transport from high to low concentration

 Deriving force is concentration gradient across CM

 Does not involve carriers,

 Not saturable and show low structural specificity.
 Majority of drugs are absorbed by this mechanism
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 But, the drug has to be lipid soluble
3. Carrier mediated absorption
a. Facilitated diffusion
 Passive diffusion but facilitated
 Does not require energy,

 Can be saturated, and may be inhibited

 E.g. Tetracycline, Pyrimidine, levodopa & amino acids into

brain

b. Active transport

 Use ATP & carrier proteins

 Saturable and structurally specific

 Against the concentration gradient, competitive inhibition

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E.g. Penicillin secretion, alpha methyldopa, 5-fluoro uracil
4. Endocytosis & pinocytosis
 Process by which large molecules are engulfed
by the
cell membrane & releases them intracellularlly.
E.g. Proteins, toxins(botulinum, diphtheria),
norepinephrine

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 A process of engulfing particles or dissolved materials by the cell.
 Transport large particles or fluid droplets through membrane in
vesicles using ATP
 Vesicular transport is the proposed process for the absorption of
vitamin A, D, E, and K, peptides and antibodies in new born
a) Exocytosis –transport out of cell
b) Endocytosis –transport into or across cell
1. phagocytosis – engulfing large particles
2. pinocytosis – taking in fluid droplets
3. transcytosis – transfer across the cell membrane
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04/17/2025 42
Fig.2a Mechanisms involved in the passage of drugs
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Fig.2b Mechanisms involved in the passage of drugs across CM

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 Fig.2c. Passage of drugs across membrane
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 Routes of Drug Administration

 Two major classes of routes of drug administration,

A. Enteral routes- Administering a drug through

alimentary tract [Oral, sublingual, and rectal routes]

Is the simplest and most common means of administering

drugs

B. Parentral routes- Administering a drug through

other sites or non alimentary [ i.e. Injection, or local

application on skin and mucus membrane

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 Eye/Ear
nose
lungs
urethra
vagina

Route of Administration
skin
mucous
Enteral Parenteral membrane
Oral Inhalational
Sublingual Injections Intravenous
Intramuscular
Buccal Subcutaneous
Transdermal Intra-arterial
Rectal Topical Intra-articular
Intrathecal
Nasogastric Intradermal

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 Fig.1 Route of drug
04/17/2025 administrations 49
Fig. 2. Enteral routes of drug administration

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 Fig.3 Parentral and other
routes of drug administration

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 The route of administration is determined

primarily by:

 Properties of the drug (water or lipid solubility,

ionization, etc.) ,

 Therapeutic objectives (the desirability of a

rapid onset of action or the need for long-term

administration or restriction to a local site)

 Patient characteristics (whether the patient is

conscious or not)
04/17/2025 52
 Enteral routes:

I. Oral:

Provides many advantages to the patient such as

 Oral drugs are easily self-administered and

 Safe, more convenient and economical

 Need no assistance for administration

 Limit the number of systemic infections that could

complicate treatment

 Toxicities or overdose by the oral route may be overcome

with antidotes such as activated charcoal

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 However ;the pathways involved in drug

absorption are the most complicated, and the

drug is exposed to harsh gastrointestinal (GI)

environments that may limit its absorption

 Some drugs undergo first-pass metabolism in the

liver,where they may be extensively metabolized

before entering the systemic circulation

E.g. Nitroglycerin
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 Ingestion of drugs with food, or in combination with
other drugs, can influence absorption
 Action slower and thus not suitable for emergencies
 Unpalatable drugs difficult to administer
 Not suitable for uncooperative /unconscious,
vomiting patients
 Certain drugs are not absorbed sufficiently (polar

drugs) from GIT

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 First pass metabolism (first pass effect, presystemic
elimination)
 Metabolism of drug (to inactive form) after administration
before reaching the systemic circulation
 Usually occur with orally administered drugs
 Orally administered drugs
 First pass effect in GIT
 Hepatic first pass metabolism
〜 during its first passage through liver
04/17/2025
Greater the first pass effect, lesser will be the bioavailability56
II. Sublingual
 Placement under the tongue allows a drug to

diffuse into the capillary network and, therefore,

to enter the systemic circulation directly.
 Has several advantages including:

 Rapid absorption,

 Convenience of administration,

 Low incidence of infection,

 Avoidance of the harsh GI environment,

and
 Avoidance of first-pass metabolism`
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III Rectal:
.

 Has advantage of preventing the destruction

of the drug by intestinal enzymes or by low pH in the

stomach

 Also it is useful if the drug induces vomiting when given

orally,

 If the patient is already vomiting, or if the patient is

unconscious

 Is commonly used to administer antiemetic agents

however

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 Only fifty percent of the drainage of the rectal

region bypasses the portal circulation

 Absorption is slower, irregular, incomplete and

often unpredictable

 It is rather inconvenient and embarrassing

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 II. Parenteral
Parenteral:

 Par = beyond and enteral = intestine

 Drug directly introduced into tissue fluids or blood

without having to cross the intestinal mucosa

 Used for drugs that are poorly absorbed from the

GI tract ( heparin) and for agents that are unstable

in the GI tract ( insulin)

 Also used for treatment of unconscious patients under

circumstances that require a rapid onset of action

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❶ Parenteral Injections
 Intravascular(IV, IA)- placing a drug directly into blood stream
 Intramuscular(IM)- drug injected into the muscle
 Subcutaneous(SC)– injected into subcutaneous skin layer
 Intradermal(ID)- injection into skin dermal layer
 Intraperitoneal(IP)- into the peritoneum
 Intrathecal- into subarachnoid space (used for anesthesia)
 Intraarticular- into a joint
 Intra arterial-into arteries
 04/17/2025
Intravenous- into the vein 61
04/17/2025 62
 Have the highest bioavailability and

 Are not subject to first-pass metabolism or harsh GI

environments

 Provides the most control over the actual dose of drug delivered

to the body
 However, these routes are irreversible and may cause pain,

fever, and infections

 The three major Parentral routes are:
 Intravascular (intravenous[ IV] or intra-arterial

[ IA] ),
 Intramuscular[IM], and
63
1. Intravenous (IV):
 Is the most common Parentral route
 Permits a rapid effect and a maximal degree of
control over the circulating levels of the drug;
however
 It is the most risky route
 Injected drugs cannot be recalled by strategies
such as emesis or by binding to activated
charcoal
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 May also induce hemolysis or possibilities of
 Useful for compounds that are:
 Poorly or erratically absorbed,
 Extremely irritating to tissues, or
 Rapidly metabolized before or during their
absorption from other sites.
 The rate of injection should be slow enough to:
 Prevent excessively high local drug
concentrations
 Allow for termination of the injection if
undesired
04/17/2025 effects appear 65
2. Intramuscular (IM) :
 Drug is injected in one of the large skeletal muscles:

deltoid, triceps, gluteus maximus, rectus femoris

 Mild irritation can be applied and absorption is faster than SC

(high tissue blood flow)

 It can be given in diarrhea or vomiting

 By passes 1st pass effect

 Many vaccines are administered intramuscularly

N.B. The volume of injection should not exceed 10 ml

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3. Subcutaneous (SC):
 The drug is deposited in the loose subcutaneous

tissue( the layer of skin directly below the dermis and epidermis)

 Unsuitable for irritant drug administration and with

slow absorption rate

 Self injection is simple
 Oily solution or aqueous suspensions can be injected

for prolonged action

 Highly effective in administering vaccines and such
medications as insulin.
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 C. Others
1. Inhalation(Pulmonary administration)
 Provides rapid delivery of a drug ,producing an effect
almost as rapidly as IV injection
 Used for drugs that are gaseous (for example, some
anesthetics) or those that can be dispersed in an aerosol
 This route is particularly effective and convenient for
patients with respiratory complaints (such as asthma, or
COPD )
 Poor ability to regulate the dose
 04/17/2025
Irritation of the pulmonary mucosa 68
2. Intranasal:
 Involves administration of drugs directly into the

nose
 Nasal decongestants such as the anti-inflammatory

corticosteroid furoate
 Desmopressin is administered intranasally in the

treatment of diabetes insipidus;

 The abused drug, cocaine, is generally taken by

intranasal sniffing
04/17/2025 69
3. Topical:
 Topical application is used when a local effect of the

drug is

desired

 Application could be on mucous membranes, skin or the

eye

 For example, clotrimazole is applied as a cream directly

to the skin in the treatment of dermatophytosis

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 I. Drug Absorption

 It is a process by which the drug leaves

the site of administration to circulatory

system

 In case of IV or IA administration,

drug by passes absorption and enters

the circulation directly

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 Factors affecting drug absorption and bioavailability

1. PH of absorption area-

Most drugs are either weak acids or weak bases.

 Acidic drugs - E.g. Aspirin (pKa 3.5) are largely
unionized at acid gastric pH are absorbed better
at lower PH.
Basic drugs are absorbed better at higher PH and
E.g. Atropine (pKa 10) are largely ionized and are
absorbed only when they reach the
intestines.
04/17/2025 72
Fig.: Illustration of passive diffusion and filtration across the
lipoidal 73
biological membrane with aqueous pores
 2. Area of absorbing surface-
 Small intestine has microvillus;
 It has absorption surface 1000 times that of
stomach
3. Particle size of the drug and formulation

04/17/2025 74
4. Gut motility (contact time at absorption area)-

 Faster is the motility, lower is the absorption

E.g. Diarrhea, food in the stomach both

decrease drug absorption

5. Blood flow to GIT

 Blood flow to the intestine is higher and so

absorption is high from intestine

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 The efflux transporter P-gp located in the gut
epithelium.
E.g. digoxin and cyclosporine
 Inhibitors of P-gp like quinidine, verapamil,
erythromycin, etc. enhance, while
 P-gp inducers like rifampin and phenobarbitone
reduce the oral bioavailability of these drugs.

04/17/2025 76
6. Presence of other agents:

 Vitamin C enhances the absorption of iron from the GIT

 Calcium present in milk and in antacids forms insoluble

complex with some antibiotics( decrease its absorption)

7. Enterohepatic recycling:

8. First-pass hepatic metabolism

9. Pharmacogenetic factors:

10. Disease states:

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 The Enterohepatic Circulation
 Some drugs which excreted as glucuronides/glutathione conjuga
hydrolyzed by intestinal/ bacterial enzymes to the parent drugs wh
reabsorbed.
 Reabsorbed drugs are again carried to the liver for resecretion via
intestine.
 Drug cycling between the intestine & liver is called enterohepatic

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Bioavailability(F):
 Fraction of administered drug that reaches the systemic

circulation/site of action in chemically unchanged form

following non-vascular administration or
 Amount of drug available in the circulation/site of action

 It is expressed in percentage
N.B. When the drug is given IV/IA, the bioavailability is
100%

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 Plasma level (mg/Li)
A
MT
C
B

ME
C
C

Time (hr)

Fig.3 Plasma –drug level curves following administration of three

formulations (A, B, C) of the same drug.
Formulation A; has quick onset, short duration of action and has
toxic effects.
Formulation B; has longer duration of action and is non-toxic
Formulation C; in adequate plasma level and therapeutically
ineffective.

Note: MTC-Minimum toxic concentration.

MEC-Minimum effective concentration
04/17/2025 80
 II. Drug distribution

 Is the process by which a drug reversibly leaves

the blood stream & enters the interstitium and/or

cells of the tissues
 Cardiac output, regional blood flow, capillary

permeability, extent of plasma protein and specific

organ binding, regional differences in pH,
transport mechanisms available and tissue
volume determine the rate of delivery
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 Liver, kidney, brain, and other well-perffused

organs receive most of the drug [First phase] or

central compartment whereas
 Delivery to muscle, most viscera, skin, and fat is

slower [Second phase] or peripheral

compartments

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 Factors affecting rate of drug
distribution
A. Blood flow
 The rate of blood flow to the tissue capillaries varies widely as a result
of the unequal distribution of cardiac output to the various organs
 Blood flow to the brain, liver, and kidney is greater than that to the
skeletal muscles; adipose tissue, bone lower rate of blood flow

B. Plasma protein binding-

 Drug molecules may bound reversibly to plasma proteins such as

Albumin, Globulin, Lipoproteins, α1 Acid Glycoprotein's...

 Binding is relatively nonselective to chemical structure

 Bound drugs are pharmacologically inactive, while

free drugs leave plasma to the site of action ( are pharmacologically

active)
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 Acidic drugs bind principally to albumin, basic
 Drugs frequently bind to other plasma proteins,
such as lipoproteins and α1-acid glycoprotein
(α1-AGP),
Note- Protein binding acts as temporary store of
drugs(reservoir)

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Albumin:

 Is the most important contributor to drug

binding - Has a net negative charge at serum pH

 Basic, positively charged drugs are more weakly

bound
 Disease states (E.g., hyperalbuminemia,

hypoalbuminemia, uremia, hyperbilirubinemia) -►

change in plasma protein binding of drugs

04/17/2025 85
α1 Acid Glycoprotein:

 α1-AGP is a determinant of the plasma protein

binding of basic drugs, chlorpromazine,

imipramine, and nortriptyline

 There is evidence of increased plasma α1-AGP

levels in certain physiological and pathological

conditions, such as injury, stress, surgery
resulting in ______????

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 04/17/2025

Fig. Drug Distribution in the Body

87
A drug with a higher affinity may displace a drug with

weaker affinity

Increases in the non–protein-bound drug fraction

(i.e., free drug)

An increase in the drug’s intensity of pharmacological

response, side effects, and potential toxicity

(Only a limited number of drugs) , but

 Depends on the volume of distribution (Vd) and the

therapeutic index of the drug (TI)

04/17/2025 88
C . Capillary permeability
 Determined by capillary structure and by the chemical
nature of the drug
 In the brain, the capillary structure is continuous ►no
slit junctions
 Liver and spleen a large part of the basement
membrane is exposed due to large, discontinuous
capillaries►►►Large plasma proteins can pass
 Also ,can be influenced by agents that affect

capillary permeability (E.g., histamine) or

capillary blood flow rate (E.g., norepinephrine)
04/17/2025 89
04/17/2025 90
 Physiological Barriers
Blood-brain barrier[BBB]
 Ionized or polar drugs generally fail to enter the CNS

 While lipid-soluble drugs readily penetrate into the CNS

Placental Barrier
 Does not prevent transport of all drugs but is selective

Blood-Testis Barrier
 Found at the specialized Sertoli–Sertoli cell junction

 This barrier may prevent Cretan chemotherapeutic

agents from reaching specific areas of the testis

04/17/2025 91
Blood brain barrier
 Capillary endothelial cells in brain have

tight junctions and lack pores or gaps.

 Surrounding the tight and overlapping

endothelial layer is a continuous basement

membrane.
 These basement membranes in turn are

enveloped by “perivascular foot

processes” formed by astrocyte cells that
encircle about 85% of the surface areas of
brain capillaries.
 Together these layers add up to a

formidable non-polar barrier called the

blood-brain barrier (BBB).
04/17/2025 92
04/17/2025 93
Placenta barriers-
 Placenta is the membrane

separating Fetal blood from the

Maternal blood.
 Made of fetal trophoblast

basement membrane &

endothelium.
 Mean thickness in early pregnancy is

(25 µ) w/c reduces to (2 µ) at full term.

 Drugs having mol. wt. < 1000 Da and moderate to high

lipid solubility (ethanol, sulfonamides, barbiturates,
steroids, anticonvulsants and some antibiotics) cross the
barrier by simple diffusion quite rapidly .
04/17/2025 94
D. Drug structure:
 The chemical nature of a drug strongly influences its
ability to cross cell membranes

E. Affinity of drugs to certain organs:

 Drugs will not always be uniformly distributed to and
retained by body tissues

Eye: Chlorpromazine and other phenothiazines bind to

melanin and accumulate ►►► Retinotoxicity

Chloroquine concentration in the eye can be

approximately 100 times that found in the liver.

04/17/2025 95
 Adipose tissue (Fat): DDT, chlordane
 Bone: TTC, lead, and the antitumor agent
cisplatin
 Liver : Chloroquine,
 Thyroid gland :Iodine
 Lung: Basic amines E.g., antihistamines,
imipramine, amphetamine,methadone, and
chlorpromazine

04/17/2025 96
04/17/2025 97
F. Presence of back transporter proteins
 Like P- glycoprotein (Pgp), multidrug resistance–associated

protein (MDRP), and breast cancer resistance protein (BCRP);

 Are located in many tissues E.g. in the placenta

Function as efflux transporters, moving endogenous and

exogenous chemicals from the cells back to the systemic

circulation

Protect the fetus from exposure to unintended chemicals

04/17/2025 98
Miscellaneous Factors-

a) Age:-
 Difference in distribution pattern is mainly due to

 Total body water -(both ICF &ECF) greater in infants

 Fat content- higher in infants & elderly

 Skeletal muscle - lesser in infants & elderly

 Organ composition – BBB is poorly developed in

infant, myelin content is low & cerebral blood flow

is high, hence greater penetration of drug in brain
 Plasma protein content- low albumin in both infants

& elderly

04/17/2025 99
B) Pregnancy:-
 During pregnancy the growth of the uterus, placenta and

fetus increases the volume available for distribution of

drugs.
 Fetus have separate compartment for drug distribution,

plasma & ECF volume also increase but albumin content

is low.
C) Obesity:-
 In obese persons, high adipose (fatty acid) tissue so

high distribution of lipophilic drugs

D) Diet:- A diet high in fats will increases FFA levels in
circulation thereby affecting binding of acidic drugs
(NSAIDs
04/17/2025 to albumin) 100
 III. Biotransformation/Metabolism of drug

 Alteration of drug structure and/activity by

action of enzymes
 Main site of biotransformation: Liver
 Other tissues include the:
 Gastrointestinal tract,
 The lungs, the skin, and
 The kidneys

04/17/2025 101
 Site/Organs of Drug Metabolism with S. Cells

 Major site of drug metabolism is the liver

(microsomal enzyme systems of hepatocytes)
 Secondary organs of biotransformation
 Kidney (proximal tubule)
 Gastrointestinal tract
 Testes (sertoli cells)
 Skin (epithelial cells); blood (plasma)
 Nervous tissue (brain)

04/17/2025 102
Enzymes Responsible for Metabolism of Drugs

 Microsomal enzymes:
 Present in the smooth endoplasmic reticulum of the liver,
kidney and GIT

E.g. Glucuronyl transferase, dehydrogenases ,

hydroxylases and

cytochrome P450 enzymes

(primarily found in the liver and GI tract)

CYP3A4, CYP2D6, CYP2C9/10, CYP2C19, CYP2E1, and

CYP1A2
 Non-microsomal enzymes:
 Present
04/17/2025 in the cytoplasm, mitochondria of different organs 103
Therapeutic consequences of metabolism:
 Increase in solubility of drugs

 Activation of pro drugs (converted to active drug)

E.g. L-dopa (inactive) dopamine(active)

 Inactivation of active drugs

[Link](active)hydroxypentobarbital(inac
tive) Alteration of activity
E.g. [Codeine(Less active)  Morphine( more
active)
04/17/2025 104
Table – Prodrugs which activated to active forms in the
body

04/17/2025 105
 Decreseasing/increasing toxicity of the drug
E.g.- Metabolism of
acetaminophen

Fig. Metabolism of acetaminophen (AC) to hepatotoxic

metabolites. (GSH, glutathione; GS, glutathione
04/17/2025
moiety; Ac*,
Fig. Phase II activation of isoniazid (INH) to a hepatotoxic
metabolite.
04/17/2025 107
Reactions of Drug Metabolism:

1. Phase I biotransformation-
 Drug is changed to more polar metabolite by introducing or

unmasking polar functional groups like OH, NH2 etc..

 Increase, decrease, or leave unaltered the drug's

pharmacologic activity

 Consists of reactions:

 Oxidation - Introduction of an oxygen and/or the removal of

a hydrogen atom or hydroxylation, dealkylation or

demethylation of drug molecule

 Reduction - By the enzyme reductase

04/17/2025 108
 Hydrolysis -Splitting of drug molecule after adding water
Fig. Phase I and phase II reactions, and direct elimination, in drug
biodisposition.
04/17/2025 109
Note: Phase I metabolites are too lipophilic and can be

retained in the kidney tubules.

2. Phase II reaction/biosynthesis or [conjugation]

 Conjugation reaction with endogenous compounds

glucuronic acid, sulfuric acid, acetic acid, or an

amino acid

 Makes drugs most often therapeutically inactive, more

polar and water soluble and easily excreted .

04/17/2025 110
Examples of phase II reactions:
I. Glucuronide conjugation-
 It is the most common
E.g. Phenobarbitone, chloramphenicol,
Morphine, sulphonamide, ASA etc
Note: Neonates are deficient in this conjugating
system
II. Sulfate conjugation:
 Transfers sulfate group to the drug molecules

E.g. phenols, catechols, steroids etc

04/17/2025 111
III. Acetyl conjugation: INH, hydralazine,
dapsone,
IV. Glycine conjugation:
E.g. salicylic acid, isonicotinic acid, p-amino
salicylic acid
V. Methylation:
E.g. Adrenaline is methylated to
metanephrine by catechol-o-methyl transferase

04/17/2025 112
Fig. Examples of phase II conjugation reactions in drug
metabolism

04/17/2025 113
 Factors Affecting Drug
Biotransformation
 Genetic polymorphism
 Disease conditions especially of the major drug
metabolizing sites
 Age
 Predisposing factors to enzyme induction or
inhibition

04/17/2025 114
Regulation of the CYP Enzymes:
 CYP450 enzymes can be regulated by the presence of
other drugs or by disease states
Enzyme Inhibition:

 It is the primary mechanism for drug-drug

pharmacokinetic interactions

 The most common type of inhibition is simple

competitive inhibition

 A second type of CYP enzyme inhibition is mechanism

based inactivation (or suicide inactivation)

04/17/2025 115
Enzyme Induction:

 It can be due to:

 Synthesis of new enzyme protein or

 Decrease in the proteolysis degradation of the

enzyme

 The net result is the increased turnover

(metabolism) of substrate

 Most commonly associated with therapeutic failure

due to inability to achieve effective drug level in bld

04/17/2025 116
Table 1 Liver enzyme inhibitors and CYP isoforms
inhibited

04/17/2025 117
Table 2. Liver enzyme inducers and CYP isoforms
induced

04/17/2025 118
 IV. Drug Excretion
 Excretion is transport of unaltered or altered drug

out of the body

 Rate of excretion influences duration of drug action

Routes of Drug Excretion

 Minor route of excretion: Eye, breast, skin

 Intermediate route: Lung [volatile drugs like

inhalational anesthetics]

Bile [digoxin, rifampin]

04/17/2025 119
 Renal excretion- major route for most drugs &

involves

 Glomerular filtration

 Active tubular secretion

 Passive tubular reabsorption

Glomerular filtration:

 Depends on the:

 Concentration of drug in the plasma,

 Molecular size, shape and charge of drug, and120

04/17/2025
Fig. Renal excretion of drugs.
Filtration of small non–protein-bound drugs occurs through
glomerular
capillary pores.
Lipid-soluble
04/17/2025 and un-ionized drugs are passively reabsorbed 121
throughout the nephron. Active secretion of organic acids and
Active tubular secretion:

 Primarily occurs in the proximal tubules

I. For anions
II. For cations

 Each of these transport systems shows low specificity

and can transport many compounds; thus,

 Competition between drugs for these carriers can occu

within each transport system

E.g. Probenecid, and penicillins, Acetazolamide, benzyl

penicillin,
04/17/2025 122
Tubular re -absorption:
 Occurs either by simple diffusion or by active transport

 Manipulating the pH of the urine

 Increase the ionized form of the drug in the lumen

 Minimize the amount of back diffusion, and hence,

increase the clearance of an undesirable drug.

E.g. A patient presenting with phenobarbital (weak

acid), overdose can be given bicarbonate, which
alkalinizes the urine and keeps the drug ionized, thereby
decreasing its reabsorption
04/17/2025 123
 If overdose is with a weak base, such as cocaine,

acidification of the urine with NH4Cl leads to protonation of

the drug and an increase in its clearance

Hepatobiliary Excretion-
 Conjugated drugs are excreted by hepatocytes in to the bile

 Certain drugs may be reabsorbed back from intestine after

hepatic excretion and this is known as enterohepatic

cycling

E.g. CAF, oral estrogen

04/17/2025 124
Pulmonary excretion:
 Drugs that are readily vaporized, such as many
inhalation anaesthetics and alcohols are excreted
through lungs
 The rate of drug excretion through lung depends on

 The volume of air exchange,

 Depth of respiration,

 Rate of pulmonary blood flow and

 The drug concentration gradient

04/17/2025 125
Mammary excretion:
 Many drugs mostly weak basic drugs are

accumulated into the breast milk ???

 Therefore lactating mothers should be

cautious of furosemide, morphine,

streptomycin etc

04/17/2025 126
Summery Points:
 Route of drug administrations

 Pharmacokinetics –Def, Components ( in order)

 Factors affecting drug absorption

 Factors affecting drug distribution in the body

 Bioavailability

 Biotransformation, sites, enzymes , reaction phases ,

factors affecting
 Excretion , routes, steps

04/17/2025 127
 Pharmacokinetic Variables and Dose
Calculation

 Two models exist to study and describe

the movement of xenobiotics (Drugs) in
the body with mathematical equations
1. Classical compartmental models (one or
two compartments)
2. Physiologic models

04/17/2025 128
Purpose of Pharmacokinetic Models
 Predict plasma, tissue & urine drug levels with any
dosage regimen
 Calculate the optimum dosage regimen for each
patient individually
 Estimate the possible accumulation of drugs and/or
metabolites
 Correlate drug conc. with pharmacologic or toxicologic
activity
 Evaluate differences in the rate or extent of availability
between formulations (bioequivalence)
129
 Describe how changes in physiology or disease affect
Drug Product Performance Parameters:

1- Minimum effective concentration (MEC):

The minimum concentration of drug needed at the
receptors to produce the desired pharmacologic effect.
2- Minimum toxic concentration (MTC):
The drug concentration needed to just produce a toxic
effect.
3- Onset time:
The time required for the drug to reach the MEC.
4- Duration of action: The difference between the onset
time and the time for the drug to decline back to the
04/17/2025 130
5- The time of peak plasma level:

The time of maximum drug concentration in the plasma

and is proportional to the rate of drug absorption.

6- The peak plasma level:

The maximum drug concentration, usually related to the

dose and the rate constants for absorption and

elimination of the drug.

7- Area under the curve:

It is related to the amount of drug absorbed systemically.

04/17/2025 131
 Therapeutic Range or Window:

 Describes the dosage range between the MEC & MTC

(therapeutic threshold)

 Above the therapeutic threshold= toxicity

 Below the therapeutic threshold= no clinical effect

 Wider/larger range of therapeutic threshold = safer drug

 Narrower therapeutic threshold = more toxic drug (e.g.

Warfarin, Phenytoin)

 The objective of drug dosing is to maintain plasma drug

levels within the therapeutic range.

132
04/17/2025 133
 Pharmacokinetic Variables/Parameters
of Drug
 Absorption

 Bioavailability of drugs (F)

 Absorption rate constant (ka)

 Metabolism

 Disposition=Distribution + Elimination

 Volume of distribution (Vd)

 Clearance (CL)

 Half life ( t1/2 )

04/17/2025 134

1. Volume of distribution [Vd]:
 Hypothetical volume of body fluid in to which the
drug is
disseminated
 Correctly called the apparent volume of
distribution, because
 It has no direct physiologic meaning and does not
refer to a real biological volume

 Represents the extent of distribution of chemical

out of plasma and into other body tissues.

04/17/2025 135
 The real volume of distribution has
physiological meaning and is related to the
Body Water.

04/17/2025 136
 A drug's VD therefore reflects the extent to which it is
present in extra vascular tissues and not in the plasma.
 For a typical 70-kg man:

 The plasma volume is 4 L,

 Extracellular fluid volume outside the plasma is 10 L,

 InteraCelular volume is – 28 L

 The volume of total-body water is approximately 42 L.

 Many drugs exhibit volumes of distribution far in excess of

these values.

04/17/2025 137
 E.g. Apparent Vd of amiodarone is 400 lit
 Drugs that are extensively bound to plasma

proteins, but are not bound to tissue compartments,

- Vd approximately equals to plasma volume

 If the drug is highly lipid soluble, its volume of

distribution will be very high because it will

concentrate in the adipose and other lipid tissues

and its concentration in the plasma will be very low

04/17/2025 138
04/17/2025 139
 Vd relates the amount of the drug in the body to the
concentration of the drug (C) in the plasma
i.e. Vd = D /Co ; D-total amount of drug in the body
Co- plasma concentration of the drug at
zero time
 Described in units of liters or liters per kg of body weight

N.B. Maximum actual Vd= Total body water( 42 lit)

 Apparent Vd= The theoretical volume of body fluid in to

which a drug is distributed

 May not correspond to anatomical space

04/17/2025 140
 Effect of large Vd on half-life of a drug:

 If the Vd for a drug is large, most of the

drug is in the extraplasmic space and
unavailable to the excretory organs.
 Any factor that increases the volume of
distribution can lead to an increase in the
half-life and extend the duration of action
of the drug.
04/17/2025 141
Example:

A 23-year-old, 90-kg female is seen in the emergency

department 2 hours after the ingestion of 50 of her

brother's Theo-Dur (300 mg) tablets.

Her initial theophylline serum concentration is 40

mg/L.

Q. Estimate a peak serum concentration knowing that

theophylline has a Vd of 0.5 L/kg, F = .75 (75%

bioavailable).

04/17/2025 142
 Calculation:

Vd = Dose IV/C0 = Dose(other route)xF

Co

Where: F= fraction of drug available to systemic cir

C0= Initial peak plasma concentration

Thus C0= Dose X F / Vd

Co = 50 x 300 mg x 1 = 0.333 mg/ml
o.5 L/ Kg x 90 Kg

04/17/2025 143
 Importance of Vd
 Helpful in the context of drug monitoring.
 Predicts whether the practice of drug measurement in
blood will have any clinical value.
 Psychotropic drugs: tranquilizers, antidepressants,
antipsychotics, mood-altering agents, etc., create their
effects by binding at sites within the central nervous
system.
 Gives information on how the drug is distributed
in the body
 Used to calculate a loading dose
04/17/2025 144
Example -
Q, If 100 mg of drug X is administered intravenously
and the plasma concentration is determined to be 5
mg/L just after the dose is given, calculate volume of
distribution.
Solution
Vd = Dose/C0p = 100 mg/5mg/L = 20 Lit

04/17/2025 145
2. Clearance(CL):
 Is the volume of fluid body containing chemical that is
cleared off a drug per unit of time.
 Describes the rate of chemical elimination from the
body
 Has the units of flow (ml/min)

Example:
A clearance of 100 mL/min means that 100 mL of
blood or plasma containing xenobiotic is completely
cleared off in each minute.
04/17/2025 146
 Clearance characterizes the overall efficiency

of the removal of a chemical from the body i.e

High values of clearance indicate efficient and

rapid removal,

Low clearance values indicate slow and less

efficient removal.

04/17/2025 147
•
CL is an index of how well a drug is removed
irreversibly from the circulation.
 As a result it determines the dose-rate (dose per
unit time) required to maintain a Cp.

Dosing rate= CL×Css

04/17/2025 148
 Total body clearance is defined as the sum of clearances by
individual eliminating organs:
Cl = Clr + Clh + Cli . . .
Where- Clr-renal, Clh -hepatic, and Cli- intestinal clearances
respectively
 After IV , bolus administration, total body clearance is defined as

Cl = Dose IV/AUC0-∞

Where –Dose IV is the IV dose at time zero

AUC0-∞ is the area under the chemical concentration

versus time curve from time zero to infinity

04/17/2025 149
 Can be estimated by creratinien clearance

Cr cl= UxV/C
U -is the concentration of creatinine in urine
(mg/mL);
V - is the volume flow of urine (mL/min);
C - is the plasma concentration of creatinine
(mg/mL)
 If the volume of distribution and elimination rate
constants are known Cl can also be calculated.

Cl = Vd × kel - for a one-compartment model ,first

order process
04/17/2025 150
e.g. a drug eliminated entirely by glomerular

filtration will have a maximum CL of 120 ml/min

(i.e. GFR).
 If there is tubular secretion the drug CL may be
>120 mL/min, and if there is tubular
reabsorption, it may be <120 mL/min.
 Similarly the maximum CL from blood by
metabolism is equal to the liver blood flow (1500
mL/min).
04/17/2025 151
For flow dependent elimination

CL = Q.(Ca- Cv) = Q.E

Ca

Where Q- is blood flow,

Ca- is the concentration entering the organ, and

Cv -is the concentration leaving the organ,

E- is drug extraction by the organ

Note: Clearance is an exceedingly important

pharmaco
kinetic concept

04/17/2025 152
3. Half-Life( t1/2):

 Is the time required for the blood or plasma

concentration of a drug to decrease by one-half,

(50%).
t1-t2= Lnc1 –LnC2 = t1/2= Ln2 = 0.693
Ke Ke Ke
 t1/2 is influenced by both Vd for a chemical and

the rate by which the chemical is cleared from the

blood (Cl)
04/17/2025 153

 For a fixed Vd, T1/2 decreases as Cl increases,
 For a fixed Cl, as the Vd increases, T1/2
increases
Half life in minute

Fig.2 The dependence of T1/2 on Vd and Cl

N .B. Values for Vd of 3,18, 40 L represent approximate

volumes of
plasma water, extracellular fluid and total body water,
04/17/2025 154
respectively
Fig. Elimination of a hypothetical drug with a half-life of 5 hours.
The drug concentration decreases by 50% every 5 hours (i.e.,
t1/2 5 hrs).
 In general it takes five half lives‘ to either reach steady state for
The slope
repeated of the
dosing orline
for is theelimination
drug elimination once
rate (ke).
dosing is stopped.
155
4. Elimination:
 Includes biotransformation, exhalation, and excretion
•
 For one-compartment model occurs through a first-order

process; i.e
 Constant fraction of xenobiotics is eliminated per unit

time

( the amount of drug eliminated at any time is proportional

to the amount of the chemical in the body at that time);
 Only at chemical concentrations that are not sufficiently
high to saturate elimination processes.

04/17/2025 156
 The equation for a monoexponential model

C = C0 x e-Kel x t
•Transformed to a logarithmic equation that has the general
form of a straight line,
Log C= -Kel/2.303 X t + logC0

Where:

-Log C0 represents the y-intercept or initial concentration

-( kel/2.303) represents the slope of the line =Log(C1-C2)/(t2-

t1)

- The first-order elimination rate constants( Proportion of a drug

removed per unit time (kel = –2.303 × slope)

04/17/2025 157
 The fraction of dose remaining in the body over

time ( C/C0) is calculated using the elimination rate

• constant by rearranging the equation for the
C/C0 = Anti log [(–kel/2.303) × t]
Tab.1 Elimination of four different doses of a chemical
at 1 hour after administration
Dose mg Chemical Chem. Che.
remaining Eliminated Eliminated
( mg) (mg) (% of dose)

10 7.4 2.6 26
30 22 8 26
90 67 23 26
250 185 65 26
04/17/2025 158
Drug Accumulation:
 Accumulation is inversely proportional to the fraction of the dose

lost in each dosing interval.

 The fraction lost is 1 minus the fraction remaining just before the

next dose.

 The fraction remaining can be predicted from the dosing interval

and the half-life.

 A convenient index of accumulation is the accumulation factor(AF)

AF = 1______________ = __ 1__________
Fraction lost in one dosing interval 1 – Fraction
remaining

Q. For a drug given once every half-life, what is the

accumulation factor?
04/17/2025 159
Bioavailability:
 Bioavailability is the fraction of administered drug

that gains access to the systemic circulation in a

chemically unchanged form.
 Bioavailability of drugs given orally and some other

routes may not be 100% because of one of the

following reasons:
 Incomplete extent of absorption and

 First-pass elimination

04/17/2025 160
a) Absolute bioavailability- is fraction of the drug
absorbed through non-intravenous administration
compared with the corresponding intravenous
Plasma concentration (mcg/ml)

administration of the same drug.

AUC – area under the curve
F – bioavailability
AUC p.o. Dose iv
F = ------------- x ---------
( IV application)
AUC i.v. Dose po
( PO application)

0 5 10 15
Time (h)
04/17/2025 161
b)Relative bioavailability- measures the
bioavailability (estimated as area under the curve,
or AUC) of a certain drug when compared with
another formulation of the same drug, usually an
established standard, or through administration via
a different route.

04/17/2025 162
 The systemic bioavailability of the drug (F) can be

predicted from the extent of absorption (f) and the

extraction ratio (ER):

F= f (1-ER) Where

ER = Cl Liver/Q

Q- is hepatic blood flow, normally about 90 L/h in

a person weighing 70 kg

04/17/2025 163
Example: Morphine is almost completely
absorbed (f = 1), so that loss in the gut is
negligible.
 However, the hepatic extraction ratio for

morphine is 0.67,

Q. What is bioavailability of morphine?

04/17/2025 164
Clinical Implications of Altered Bioavailability
 Some drugs undergo near-complete presystemic

metabolism and thus cannot be administered orally.

E.g. Lidocaine, nitroglycerin

 Other drugs undergoing very extensive presystemic

metabolism but; can still be administered PO using

much higher doses than those required IV.

E.g. IV dose of verapamil would be 1 to 5 mg, compared

to

the usual single oral dose of 40 to 120 mg.

04/17/2025 165
Steady State Concentration(Css):
 Is plasma level of a drug where drug
elimination is in equilibrium with that
absorbed (rate in=rate out)
 It takes at least four to five half live’s to reach Css
Plasma level of the drug

C max

C min

Time (multiple of t ½)

Fig. Steady state plasma concentration after repeated

04/17/2025 166
administration
Dosage regimen:
 Is a systematic way of drug administration or
 The one in which the drug is administered:
 In suitable doses,
 By suitable route,
 With sufficient frequency that ensures
maintenance of plasma concentration within the
therapeutic window without excessive
fluctuation and drug accumulation for the entire
duration of therapy.)
04/17/2025 167
Two major parameters that can be adjusted in developing
a dosage regimen are:
1. The dose size:
 It is the quantity of the drug administered each time.

 The magnitude of therapeutic & toxic responses depend upon

dose size.
 Amount of drug absorbed after administration of each dose is
considered while calculating the dose size.
 Greater the dose size greater the fluctuation between Css,max

& Css,min (max. and min. steady state concentration) during

each dosing interval & greater chances of toxicity.
04/17/2025 168
2. Dose frequency:
 It is the time interval between doses.
 Dose interval is inverse of dosing frequency.
 Dose interval is calculated on the basis of half life
of the drug.
 When dose interval is increased with no change in

the dose size ,Cmin, Cmax & Cav decrease, but

 When dose interval is reduced, it results in greater

drug accumulation in the body and toxicity.
169
Note:
 By considering the pharmacokinetic factors
that determine the dose-concentration
relationship, it is possible to individualize the
dose regimen to achieve the target
concentration

04/17/2025 170
Fig. Temporal characteristics of drug effect and
relationship to the therapeutic window
(e.g., single dose, oral administration)

04/17/2025 171
There are two types of dosing:
 Constant ; and

 Variant dosing

Variant dosing includes;

1. A loading dose:
 Is one or a series of doses that may be given

at the onset of therapy with the aim of

achieving the target concentration rapidly.
04/17/2025 172
 2. Maintenance dose:
 Dose given at an adjusted rate to

maintain a chosen steady state

concentration .

 The amount is equivalent to daily

excreted dose

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Maintenance Dose:
 It is the amount of drug prescribed or administered on a
continuing basis.
 Thus, calculation of the appropriate maintenance dose is a
primary goal.
 At steady state, the dosing rate ("rate in") must equal the rate
of elimination ("rate out").
Dosing Rate ss = Rate elimination ss
Dosing Rate ss = CL x TC ; Where CL= Clearance
TC= Target concentration

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If intermittent doses are given, the maintenance dose is
calculated from:
Maintenance dose = Dosing rate x Dosing interval
Example;

1. A target plasma theophylline concentration of 10 mg/L

is desired to relieve acute bronchial asthma in a

patient.

If the patient is a nonsmoker and otherwise normal except

for asthma the mean clearance is 2.8 L/h/70 kg.

If the drug is given by intravenous infusion, F = 1.

Dosing rate = CL x TC
= 2.8L/h/70 Kg x 10 mg/L
04/17/2025 175
= 28 mg/h/70 Kg
 To maintain this plasma level using oral
theophylline, which might be given every 12
hours using an extended-release formulation
(Foral for theophylline is 0.96)

Q. When the dosing interval is 12 hours, what is

the size of each maintenance dose?

04/17/2025 176
Calculation:

Maintenance dose= Dosing rate x Dosing

interval
F
= 28 mg/h x 12
hrs
0.96
= 350 mg/70 kg
04/17/2025 177
Loading Dose:
 Is one or a series of doses that may be given at the onset of

therapy with the aim of achieving the target concentration

rapidly.

 The appropriate magnitude for the loading dose is

Loading dose = Target Cp x Vdss
F
Vd ss= Volume of distribution at steady state

 It is desirable if the time required to attain steady state by

the administration of drug at a constant rate is long relative

to the temporal demands of the condition being treated.

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Example.
 In administration of digitalis ("digitalization") to a patient

with Cp = 1.5 ng/ml and Vdss= 580 liter , F= 0.7

Loading dose = 1.5 ng/ml X 580 liter =1243 μg ~
1mg
0.7
 To avoid toxicity, this oral loading dose, which also could

be administered IV , would be given as an initial 0.5-mg

dose followed by a 0.25-mg doses 6 to 8 hours later, with
careful monitoring of the patient ...

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Disadvantages of Loading dose administration:
 Sensitive individuals may be exposed abruptly to a

toxic concentration of a drug.

 If the drug has long half-life►►► It takes long time

for the concentration to fall if the level achieved

was excessive
 Loading doses tend to be large, and they are often

given parentrally and rapidly; this can be

particularly dangerous if toxic effects occur as a
04/17/2025 180
result of action of the drug at sites that are in
 Drug Therapy During Pregnancy

 Drug treatment in pregnancy is complicated mainly

by two aspects:
 General concerns do exist regarding potentially
harmful effects of drugs on the embryo.
 Physiological changes occurring during pregnancy
may have an influence on pharmacokinetics or
pharmacodynamics and subsequently efficacy of
drugs

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 The Concept of Teratology

 One of the most important factors determining the

sensitivity of the embryo is the gestational age:
 During day 15 to 60 malformations may be induced,
depending on the exact date of exposure (organo-
genesis, embryogenesis).
 Sensitivity to drugs decreases during foetal period
(after 9 week), later exposure to xenobiotics may
induce functional defects or growth retardation.

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 Effects of Teratogens at Specific Stages of Fetal
Development

04/17/2025 183
04/17/2025 184
 Thalidomide (1957–1961)

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 USA: 17
babies

In 1962,
the United States Congress
enacted laws requiring tests
for safety during pregnancy
before a drug can receive
approval for sale in the U.S.
04/17/2025 186
 (S)-thalidomide (R)-thalidomide

 Thalidomide is racemic (contains left- & right-

handed isomers)
 (R) enantiomer is effective against morning
sickness while (S) is teratogenic and causes
birth defects (can interconvert in vivo).
 (S) enantiomer intercalates (inserts) into the DNA in
G–C (guanine – cytosine) rich regions.
04/17/2025 187
 Drugs With Documented Teratogenic or
Embryotoxic Effect

04/17/2025 188
 FDA Pregnancy Category
A - Controlled studies in women fail to demonstrate a risk to
the fetus in the first trimester, and the possibility of fetal
harm appears remote (only 8 drugs: folic acid, vit A, vit C,
vit D in physiol. D)
B - Animal studies do not indicate a risk to the fetus and
there is no controlled human studies, or animal studies
do show adverse effect on the fetus but well-controlled
studies in pregnant women have failed to
demonstrate a risk to the fetus (250 medicines;
penicillins, erythromycin, metthyldopa, lansoprazole).

04/17/2025 Cont.
189
C - Studies have shown that the drug exerts animal
teratogenic or embryocidal effects, but there is no
controlled studies in women, or no studies are available
in either animals or women. However, potential benefits
may overweight the potential risk (700 drugs; atenolol,
aminophylline).
D - Positive evidence of human fetal risk exists, but
benefits in certain situations (e.g., life-threatening
situations or serious diseases for which safer drugs cannot
be used or are ineffective) may make use of the drug
acceptable despite its risks (phenytoin, metotrexate,
doxycycline, enalapril, cyclophosphamide).
04/17/2025 Cont.
190
X - Studies in animals or humans have demonstrated
fetal abnormalities or there is evidence of fetal
risk based on human experience, or both, and the
risk clearly outweighs any possible benefit
(statins, dinoprost).

☞ Whereas categories A to C define the degree of

risk, categories D and X offer a risk-benefit
evaluation.

04/17/2025 191
 Some Recommended Drugs For Selected Indications During
Pregnancy

04/17/2025 192
 Drug Therapy During Breast Feeding
 Drugs get through breast milk and can effect infant
 Concentration of drugs differ in milk (lipid soluble drugs
are in higher concentration; milk is weakly acidic: weak
bases are concentrated).
 Generally most drugs are in too low a concentration to be
harmful to infant, while some drugs can lead to toxicity in
the child if enter the milk in pharmacological quantities.
 Some drugs are contraindicated because of known risk:
nicotine, amphetamines, lithium, marijuana, anticancer
drugs.

04/17/2025 193
 Some drugs to be avoided: Amiodarone, TTC,

quinolones, aspirin, benzodiazepines.

 The infant should be monitored if betalytics

(bradycardia), corticoids (infants´adrenal functions)

or lithium (intoxication) are prescribed to mother.

 Others: metronidazole gives milk an unpleasant

taste; bromocriptine and diuretics suppress

lactation.
04/17/2025 194
 Lactation Risk Categories (LRC)

L1 – Safest: paracetamol, ibuprofen, epinephrine.

L2 – Safer: diclofenac, fentanyl, cetirizine,
omeprazole,
cephalosporin
L3 – Moderately safe: acarbose, aspirin, indometacin,
codeine, morphine, midazolam, triazolam,
acebutоlol.
L4 – Hazardous: colchicine, lithium, ergobrevine,
ergotamine.
L504/17/2025
– Contraindicated: ACE inhibitors (enalapril etc.)
195
 PRCs LRCs

A: Controlled studies L1: Safest

show no risk L2: Safer
B: No evidence of risk in L3: Moderately safe
humans L4: Possibly
C: Risk cannot be ruled hazardous
out L5: Contraindicated
D: Positive evidence of
risk
X: Contraindicated in
pregnancy
04/17/2025 196