Pharmacology can be defined as the study of the effects of drugs on the functions of living

systems. Pharmacology includes the knowledge of the pharmacokinetics and pharmacodynamics

properties of a drug. Pharmacokinetic include the study of the effect of the body on the drug. That
is, how the body affects a specific drug after administration through the mechanism of; absorption,
distribution, metabolism and excretion. All of these determine the effective concentration of
drug at it site of action. While, pharmacodynamics studies the biochemical and physiological
effects of drugs and their mechanism of actions. It describes how a drug affects the body, including;
mechanism of action, therapeutic effects and side effects.
While, a drug can be defined as a chemical substance of known structure, other than a nutrient
or an essential dietary ingredient, which, when administered to a living organism, produces a
biological effect.
Source of drugs
They are natural, semisynthetic and synthetic.
a. Natural sources are plants, animals, minerals, microorganisms, etc.
Plants:
• Alkaloids are nitrogen containing compounds, e.g. morphine, atropine, quinine, reserpine,
ephedrine
• Glycosides contain sugar group in combination with non-sugar through ether linkage, e.g.
digoxin, digitoxin.
• Volatile oils have aroma. They are useful for relieving pain (clove oil), as carminative
(eucalyptus oil), flavoring agent (peppermint oil), etc.
• Resins are sticky organic compounds obtained from plants as exudate, e.g. tincture benzoin
(antiseptic).
• Terpenes and Terpenoids—Ginkgo, ginseng, valerian, Melissa officinalis, sage; azadirachtin,
(Neem tree), artemisinin, present in Artemisia annua Chinese worm wood and
tetrahydrocannabinol, present in Cannabis sp
Animals:
• Urine: conjugated estrogen (Premarin) from pregnant mare’s urine
• Venom: antiplatelet echistatin from Echis carinatus (viper)
• Serum: Botulism antitoxin from horses and sheep serum
• skin extracts of the Ecuadorian poison frog Ameeregabilinguis (potent analgesic compound
epibatidine),
• pancreas of cow and pork (insulin, hormone)
Minerals:
• ferrous sulfate in iron deficiency anemia; magnesium sulfate as purgative; magnesium
trisilicate, aluminum hydroxide and sodium bicarbonate as antacids;
• zinc oxide ointment as skin protectant, in wounds and eczema; gold salts (solganal,
auranofin) as anti-inflammatory and in rheumatoid arthritis; selenium as anti-dandruff
shampoos
 • Kaolin (aluminium silicate) is used as an adsorbent in antidiarrheal mixtures; Mercurial
salts are used in syphilis and iodine is used as antiseptic.
Microorganisms:
Aquatic:
• Halichondrin B (anticancer) from the japanese marine sponge Halichondria okadai
• Curacin A, lipid constituent, from a marine cyanobacterium Lyngbya majuscule shows
potent anti-tumor activity
• cephalostatinsa, a broad class of bactericidal antibiotics from Cephalosporium acremonium
fungus.
Terrestrial:
• Gentamicin from micromonospora purpurea
• chloramphenicol from Streptomyces venezuelace,
• anti-fungal drug grisofulvin from Penicillium griseofullivum
• neomycin from Streptomyces fradiae and streptomycin from actinobacterium Streptomyces
griseus

b. Semisynthetic:
In semi-synthetic drugs, the nucleus of drug obtained from natural source is retained but the
chemical structure is altered. Sometimes semi-synthetic processes are used to prepare drugs when
the natural sources may yield impure compounds or when the synthesis of drugs (complex
molecules) may be difficult, expensive, and commercially unviable.
Some examples are prepared by chemically modifying substances that are available from natural
source to improve its potency, efficacy and also reduce side effects.
Semisynthetic drugs from plant sources include;
• Heroine from morphine
• bromoscopolamine from scopolamine
• homoatropine from atropine,
From animal sources are
• animal insulin changed to be like human insulin and
• 6-aminopenicillanic acid derivatives.

c. Synthetic:
In synthetic drugs, the nucleus of the drug from natural source as well as its chemical structure is
altered. At present, majority of drugs used in clinical practice are prepared synthetically, such as
aspirin, oral antidiabetics, antihistamines, amphetamine, chloroquine, chlorpromazine, general and
local anesthetics, paracetamol, phenytoin, synthetic corticosteroids, sulphonamides, and thiazide
diuretics. Most of the synthetic drugs are prepared synthetically, i.e., by chemical process
(reaction) with the help of the knowledge of phytochemical investigation.
Advantages of synthetic drugs include their chemical purity, simple and cost-effective method of
preparation and high quality. Since the pharmacological activity of a drug depends on its chemical
structure and physical properties, more effective and safer drugs can be prepared by modifying the
chemical structure of the prototype drug.

d. Biosynthetic sources (genetically engineered drugs)

This is relatively a new field which is being developed by mixing discoveries from molecular
biology, recombinant DNA technology, DNA alteration, gene splicing, immunology, and immune
pharmacology. Recombinant DNA technology involves cleavage of DNA by enzyme restriction
endonucleases. The desired gene is coupled to rapidly replicating DNA (viral, bacterial, or
plasmid). The new genetic combination is inserted into the bacterial cultures which allow
production of vast amount of genetic material.
In this process, huge number of drugs can be produced, drug can be obtained in pure form, and it
is less antigenic. Well-equipped laboratory and highly trained staffs are required, and moreover, it
is a complex and complicated technique.
Some of the recent developments are genetically engineered novel vaccines
• Recombivax HB—a hepatitis-B vaccine,
• recombinant DNA engineered insulin (Humulin–human insulin) for diabetes and
• Interferon-alpha-2a and interferon-alpha-2b for hairy cell leukemia.

note
Understanding the origins of drugs is crucial for healthcare professionals such as nurses. This
knowledge helps ensure patient safety, effective medication administration, and patient education.
• Patient Safety: Knowing a drug’s source can help anticipate potential side effects or
interactions with other medications.
• Patient Education: Explaining a drug’s origin can empower patients to understand their
treatment better.
• Advocacy: Nurses can advocate for sustainable sourcing practices to protect the
environment and ensure a steady supply of natural drug sources
Classification of Drugs
Drugs can be classified in various ways based on different criteria such as the:
1. Chemical structure
2. Therapeutic effects/uses
3. Pharmacological effects
4. Legal description
it is important to note that many drugs may fall into multiple categories depending on their
properties and usage.
Chemical Structure of Drugs
Drugs can be classified based on their chemical structure, which is the arrangement of atoms within
a molecule. The chemical structure of a drug directly affects its pharmacological properties by
determining its interaction with biological targets such as receptors, enzymes, or ion channels.
Small changes in the chemical structure can lead to significant alterations in the pharmacokinetics,
efficacy, potency, and side effects of the drug. This leads to a concept known as Structure-activity
relationship (SAR). This classification can provide insights into a drug’s properties, such as its
solubility, Some common chemical classes of drugs include: absorption, and metabolism

• Alcohols: Drugs containing the hydroxyl functional group (-OH), such as ethanol and
methanol.
• Alkaloids: Naturally occurring nitrogen-containing compounds with pharmacological
effects, such as morphine and caffeine.
• Steroids: Compounds with a characteristic structure containing four fused rings, such as
corticosteroids (dexamethasone) and sex hormones (estradiol, progesterone, and
testosterone).
• Amines: Compounds containing the amino functional group (-NH2), such as
amphetamines and antihistamines.
• Amides: Compounds containing the carbonyl group (C=O) linked to a nitrogen atom, such
as acetaminophen and lidocaine.
• Benzodiazepines: Drugs with a benzene ring fused to a diazepine ring, such as diazepam
and alprazolam.
• Catecholamines: Compounds containing a catechol (benzene with 2 hydroxyl groups)
moiety, such as dopamine and epinephrine.
• Proteins and peptides: Large molecules of amino acids, such as insulin and growth
hormone.
Therapeutic Effects/Uses
Drugs can also be classified based on their therapeutic effects, which are the desired outcomes of
drug use. This classification is often used by healthcare providers to select appropriate medications
for patients.
Some common therapeutic classes of drugs include:

• Analgesics: Drugs used to relieve pain, such as acetaminophen and ibuprofen.

• Antipyretics: Drugs used to reduce fever, such as aspirin and paracetamol (acetaminophen).
• Antineoplastics: Drugs used to treat cancer, such as chemotherapy agents (paclitaxel) and
targeted therapies (Erlotinib).
• Anticoagulants: Drugs used to prevent blood clot formation, such as warfarin and heparin.
• Antihypertensives: Drugs used to lower blood pressure, such as amlodipine and losartan.
• Antibiotics: Drugs that inhibit the growth of or kill bacteria, such as penicillin and
erythromycin.
• Antivirals: Drugs that inhibit the replication of viruses, such as acyclovir and oseltamivir.
Pharmacological Effects
Drugs can be classified based on their pharmacological effects, such as their mechanism of action,
physiological effects, and interaction with specific receptors or biochemical pathways. This
classification can help healthcare providers understand how drugs work and predict potential side
Some common pharmacological classes of drugs include:

• Beta-blockers: Drugs that block the effects of adrenaline (epinephrine) and noradrenaline
(norepinephrine) on beta receptors, commonly used to treat hypertension and cardiac
arrhythmias by lowering blood pressure. Examples include propranolol and timolol.
• Selective serotonin reuptake inhibitors (SSRIs): Drugs that inhibit the reuptake of serotonin
in the brain, used primarily as antidepressants, such as fluoxetine and sertraline.
• Nonsteroidal anti-inflammatory drugs (NSAIDs): Drugs that inhibit the enzyme
cyclooxygenase (COX), thereby reducing inflammation, pain, and fever, such as ibuprofen
and aspirin.
• Angiotensin-converting enzyme (ACE) inhibitors: Drugs that inhibit the enzyme ACE,
leading to vasodilation and decreased blood pressure, commonly used to treat hypertension
and heart failure, such as captopril and enalapril.
Legal Description
Drugs can also be classified based on their legal status, which is determined by government
regulations. This classification is important for understanding the restrictions on drug use and
distribution.
Some common legal classifications of drugs include:

• Prescription drugs: Drugs that require a prescription from a healthcare professional for
legal acquisition, such as antibiotics and antidepressants.
• Over-the-counter (OTC) drugs: Drugs that can be purchased without a prescription, such
as pain relievers and antacids.
• Controlled substances: Drugs regulated by government authorities due to their potential for
abuse and addiction. They are categorised into different schedules (e.g., Schedule I, II, III,
IV, V in the United States).
o Schedule i: highest potential to be abused, No medical use due to safety, MDMA,
mescaline, LSD
o Schedule ii: high potential for abuse but ˂ I, Serious consequences can occur. Eg,
amphetamines, codeine, fentanyl
o Schedule iii: less abuse potential than I and II, Moderate-low physical dependence or
high psychological dependence. Eg., anabolic steroids, dronabinol, buprenorphine
o Schedule iv: less potential abused than I, II, or III, used for treating anxiety and
seizures. Eg., benzodiazepines, phenobarbital
 o Schedule v: least potential for abuse, limited physical or psychological dependence.
Eg, diphenoxylate, guaifenesin
Drug Names
There are three (3) types of drug names;
• Chemical name: chemical make-up of compound: usually too complex for people to remember
• Generic name: assigned by the “United States Adopted Names Council”. Only one generic
name/compound (nonproprietary name)
• Trade name: proprietary (brand) name. Name by which drug is marketed

Names

Chemical Non-proprietary Proprietary

Acetylsalicylic acid Aspirin Disprin

Acetaminophen Paracetamol Panadol

Routes of drug administration

The route of administration is the way through which the dosage form of a drug is administered
into the body for treatment of various diseases and disorders. Various routes of administrations
play a marked role in the bioavailability of the active drug in the body
The various routes of administrations are classified into following categories:
1. Local route: In this route the drug is applied on the skin and mucous membrane for the
local action
• Topical
• Intra-arterial route
• Administration of the drug into deep tissues by injection
2. Systemic Route: In Systemic route the drug reaches to the systemic circulation (Blood).
So that it is called systemic route. Systemic route can be further classified into
Enteral route Parenteral route
1 Oral Intravascular
2 Sublingual Intramuscular
3 Rectum Subcutaneous
4 Inhalation
Local route
Local routes are the simplest mode of administration of a drug at the site where the desired action
is required.
a) Topical: Drug is applied to the skin or mucous membrane at various sites for localized action.
• Oral cavity: As
o troche, e.g. clotrimazole (for oral candidiasis);
o cream, e.g. acyclovir (for herpes labialis);
o ointment, e.g. 5% lignocaine hydrochloride (for topical anaesthesia);
o spray, e.g. 10% lignocaine hydrochloride (for topical anaesthesia).
• GI tract: As tablet which is not absorbed, e.g. neomycin (for sterilization of gut before
surgery)
• Eye, ear and nose: As drops, ointment and spray (for infection, allergic conditions
• Skin: As ointment, cream, lotion, powder, e.g. clotrimazole (antifungal) for cutaneous
candidiasis.
b) Intra-arterial route: This route is rarely employed. It is mainly used during diagnostic studies,
such as coronary angiography and for the administration of some anticancer drugs, e.g. for
treatment of malignancy involving limbs.
c) Administration of the drug into deep tissues by injection, e.g. administration of triamcinolone
directly into the joint space in rheumatoid arthritis.

Systemic route
I. Oral Route
It is the most common and acceptable route for drug administration. In this route the drug is placed
in the mouth and swallowed. Dosage forms are tablet, capsule, powder, syrup, linctus, mixture,
suspension.
Forms: Tablets, capsules, liquids, elixirs.
Advantages:
• Non-invasive and Painless
• convenient for repeated and prolonged use
• Cost-effective when compared with other route
• Easy to self-administer.
• Wide variety of formulations.
Disadvantages: It is not suitable for/in:
• unpalatable and highly irritant drugs
• unabsorbable drugs (e.g. aminoglycosides)
• drugs that are destroyed by digestive juices (e.g. insulin)
• drugs with extensive first-pass metabolism in the liver can reduce drug bioavailability (e.g.
lignocaine)
• patients who are vomiting, unconscious, or unable to swallow
• emergency as onset of action of orally administrated drugs is slow
 II. Sublingual and Buccal Route
The drug preparation is kept under the tongue (sublingual) or between the gums and cheek
(buccal), where it is absorbed through the buccal mucous membrane and enters systemic
circulation directly.
Examples: Nitroglycerin (sublingual for angina), and buprenorphine (buccal).
Advantages:
• Rapid absorption and onset of action due to rich blood supply.
• Bypasses first-pass metabolism
• Self-administration is possible
Disadvantages:
• Limited to potent drugs with small doses.
• May irritate the mucous membranes.
• It is not suitable for irritant and lipid-insoluble drugs
• It is not suitable for drugs with bad taste

III. Rectal Route

Many drugs that are administered orally can also be administered rectally. In this form, a drug is
mixed with a waxy substance that dissolves or liquefies after it is inserted into the rectum. Since
the rectum's wall is thin and rich in blood supply, the drug is readily absorbed. A suppository is
prescribed for patient who cannot take a drug orally because they have nausea, cannot swallow, or
have restrictions on eating, as is required after many surgical operations.
Examples
As an enema: administration of drug into the rectum in liquid form
• Evacuant enema (for evacuation of bowel): For example, soap water enema where soap
acts as a lubricant and water stimulates rectum.
• Retention enema: For example, methylprednisolone in ulcerative colitis.
As a suppository: administration of the drug in a solid form into the rectum, e.g. bisacodyl
suppository for evacuation of bowel.
Advantages
• Unconscious patients and children:
• If patient is having nauseous or vomiting
Disadvantages
• May cause irritation
• Others???????????? Self-assignment

IV. Intravenous (i.v.) Route

Drugs are injected directly into the blood stream through a vein. Drugs are administered as a.
Bolus: Single, relatively large dose of a drug injected rapidly or slowly into a vein, e.g. i.v.
ranitidine in bleeding peptic ulcer.
Slow intravenous injection: For example, i.v. morphine in myocardial infarction.
Intravenous infusion: For example, mannitol infusion in cerebral oedema; fluids infused
intravenously in dehydration.
Advantages
• Bioavailability is 100%.
• Quick onset of action, so it is the route of choice in emergency, e.g. intravenous diazepam
to control convulsions in status epilepticus.
• Large volume of fluid can be administered (1-100+ mL), e.g. intravenous fluids in patients
with severe dehydration.
• Highly irritant drugs, e.g. anticancer drugs can be given because they get diluted in blood.
• Hypertonic solution can be infused by intravenous route, e.g. 20% mannitol in cerebral
oedema.
• By i.v. infusion, a constant plasma level of the drug can be maintained, e.g. dopamine
infusion in cardiogenic shock
Disadvantages
• Local irritation may cause phlebitis.
• Self-administration is usually not possible.
• Strict aseptic conditions are needed.
• Extravasation of some drugs (e.g. noradrenaline) can cause injury, necrosis and sloughing
of tissues.
• Depot preparations cannot be given by i.v. route

V. intramuscular (i.m.) Route

Drugs are injected into large muscles, such as deltoid, gluteus maximus and vastus lateralis, e.g.
paracetamol, diclofenac, etc. A volume of 5–10 mL can be given at a time.
Advantages
• Absorption is more rapid as compared to oral route.
• Mild irritants, depot injections, soluble substances and suspensions can be given by this
route.
Disadvantages
• Aseptic conditions are needed.
• Intramuscular (i.m.) injections are painful and may cause abscess.
• Self-administration is not possible.
• There may be injury to nerves.

VI. Inhalation Route

Description: Drugs administered through the respiratory tract, reaching the systemic circulation
allowing absorption into the blood via the alveoli, or local effect within the lungs.
Forms: Aerosols, nebulizers, dry powder inhalers.
Advantages:
• Rapid absorption due to the large surface area of the lungs.
 • Avoidance of first-pass metabolism
• Targeted therapy/suitable for respiratory therapies (e.g., asthma, COPD).
Disadvantages:
• Requires proper technique for effective delivery.
• May not be suitable for patients with severe respiratory issues.
• Variability in dosing
• Local effect (deposition in the oropharyngeal area; corticosteroid ADR)
• Need for specialized equipment

VII. Subcutaneous (s.c.) Route

The drug is injected into the subcutaneous tissue (the fatty layer of the thigh, abdomen, arm, e.g.
adrenaline, insulin, etc.
Advantages
• Self-administration of drug is possible, e.g. insulin.
• Depot preparations can be inserted into the subcutaneous tissue, e.g. norplant for
contraception.
Disadvantages
• It is suitable only for nonirritant drugs.
• Drug absorption is slow, hence not suitable for emergency

VIII. Transdermal Route

Description: Delivery of drugs through the skin for systemic effects, typically via adhesive
patches.
Examples: Fentanyl patches (pain management), and nicotine patches.
Advantages:
• Provides continuous delivery of medication.
• Bypass first-pass metabolism.
• Convenient for long-term therapy.
Disadvantages:
• Limited to drugs with suitable molecular size and lipid solubility.
• Potential for skin irritation.

IX. Intrathecal and Epidural Route

Description: Injection of drugs into the cerebrospinal fluid (intrathecal) or epidural space for
central nervous system effects.
Advantages:
• Effective for pain management and treatment of central nervous system conditions.
Disadvantages:
• Invasive and carries risks of infection or complication.
• Requires specialized training for administration.

Factors determining the route of drug administration

Characteristics of the drug: characteristics of a drug such as solubility, stability, pH, molecular
size, lipid solubility influence the route of administration. For example:
• Oxygen-sensitive drugs like nitroglycerin are administered sublingually to avoid
degradation;
• Insulin is administered via subcutaneous injection due to its protein structure and need for
precise dosing.
Emergency/routine use: Emergency situations require rapid action, and drugs with routine use
should be administered via a route that allows for more flexibility. For example:
• Morphine is administered intravenously (IV) in emergency situations, but orally or
epidurally for chronic pain management
Condition of the patient (unconscious, vomiting and diarrhea): Unconscious patients require
alternative routes rather than the conventional route of administration of that drug. That is; either
from oral to intramuscular or intravenous route. Also vomiting or diarrhea may preclude oral
administration as administration of drug via oral route may induce more emesis. For example:
• Unconscious patients may receive IV or IM medications.
• Patients with severe vomiting may receive rectal or parenteral medications.
• Patients with diarrhea may receive IV to avoid gastrointestinal upset.
Associated diseases: Renal or hepatic impairment may require adjusted routes, while respiratory
diseases may require inhalational therapy. For example:
• Asthma patients often receive inhalational medications
Patient’s/doctor’s choice (sometimes): the route of drug administration may be influence by
patient preference and the need for compliance. Same also is doctor’s experience and familiarity
with the route. For example:
• Patients who fear needles may opt for oral medications.
• Doctors may prefer IM injections for vaccines due to ease of administration.
• Patients with chronic conditions may prefer transdermal patches for convenience.
 Pharmacokinetics
Pharmacokinetics is derived from two words: Pharmacon meaning drug and kinesis meaning
movement. In short, it is ‘what the body does to the drug’. It includes absorption (A), distribution
(D), metabolism (M) and excretion (E). All these processes involve movement of the drug
molecule through various biological membranes.

Drug absorption
Movement of a drug from the site of administration into the blood stream is known as absorption

Factors influencing drug absorption

A. Physicochemical properties of the drug:
• Physical state: Liquid form of the drug is better absorbed than solid formulations.
• Lipid-soluble and unionized form of the drug is better absorbed than water-soluble and
ionized form.
• Particle size: Drugs with smaller particle size are absorbed better than larger ones, e.g.
microfine aspirin, digoxin and griseofulvin are well absorbed from the gut and produce
better effects. Some of the anthelmintics have larger particle size. They are poorly absorbed
through gastrointestinal (GI) tract, hence they produce better effect on gut helminths.
• Disintegration time: It is the time taken for the formulation (tablet or capsule) to break up
into small particles and its variation may affect the bioavailability.
• Dissolution time: It is the time taken for the particles to go into solution. The shorter the
time, the better is the absorption.
B. Route of drug administration:
IV administered drug bypasses the process of absorption as it directly enters the circulation. This
route is important for compounds that are highly polar compounds, ionize in solution and are not
absorbed through GI tract. e.g. gentamicin.
C. pH and ionization:
Strongly acidic (heparin) and strongly basic (aminoglycosides) drugs usually remain ionized at all
pH, hence they are poorly absorbed.
D. Food:
Food decreases the absorption of rifampicin, levodopa, etc., hence they should be taken on an
empty stomach for better effect. Milk and milk products decrease the absorption of tetracyclines.
Fatty meal increases the absorption of griseofulvin.
E. Presence of other drugs:
Concurrent administration of two or more drugs may affect their absorption, e.g. ascorbic acid
increases the absorption of oral iron. Antacids reduce the absorption of tetracyclines
F. Area of the absorbing surface:
Normally, drugs are better absorbed in small intestine because of a larger surface area. Resection
of the gut decreases absorption of drugs due to a reduced surface area.
G. Gastrointestinal and other diseases:
In gastroenteritis, there is increased peristaltic movement that decreases drug absorption. In
achlorhydria, absorption of iron from the gut is reduced.

Bioavailability
It is the fraction of a drug that reaches systemic circulation after a given dose. Intravenous route
of drug administration gives 100% bioavailability as it directly enters the circulation. The term
bioavailability is used commonly for drugs given by oral route. If two formulations of the same
drug produce equal bioavailability, they are said to be bioequivalent. If formulations differ in their
bioavailability, they are said to be bioinequivalent.

Factors Affecting Bioavailability

a) The factors which affect drug absorption also affect bioavailability
b) First-pass metabolism (First-pass effect, presystemic elimination): When drugs are
administered orally, they have to pass via gut wall to the portal vein then to the liver and finally
into systemic circulation. During this passage, certain drugs get metabolized and are removed
or inactivated before they reach the systemic circulation. This process is known as first-pass
metabolism. The net result is a decreased bioavailability of the drug and diminished therapeutic
response, e.g. drugs like lignocaine (liver), isoprenaline (gut wall), etc. Consequences of high
first-pass metabolism include
• Drugs which undergo extensive first-pass metabolism are administered parenterally, e.g.
lignocaine is administered intravenously in ventricular arrhythmias.
• Dose of a drug required for oral administration is more than that given by other systemic
routes, e.g. nitroglycerin.
c) Hepatic diseases: They result in a decrease in drug metabolism, thus increasing the
bioavailability of drugs that undergo high first-pass metabolism, e.g. propranolol and
lignocaine.
d) Enterohepatic cycling: Some drugs are excreted via bile but after reaching the intestine they
are reabsorbed, transported to the liver, then bile and back to the intestine and the cycle is
repeated. Such recycling is called enterohepatic circulation and it increases bioavailability as
well as the duration of action of the drug, e.g. morphine and doxycycline.

Drug distribution
Drug distribution is defined as the reversible transfer of drugs between body-fluid compartments.
It is the penetration of a drug to the sites of action through the walls of blood vessels from the
administered site after absorption. Drugs distribute through various body fluid compartments such
as
• Plasma
• Interstitial fluid compartment
• Trans-cellular compartment
Apparent Volume of distribution (VD): The volume into which the total amount of a drug in the
body would have to be uniformly distributed to provide the concentration of the drug actually
measured in the plasma. It is an apparent rather than real volume.
Once a drug has entered the blood compartment, the rate at which it penetrates tissues and other
body fluids depends on several factors. These include

A. Capillary permeability
Drug delivery and eventual drug equilibration with intercellular tissue spaces are largely
determined by the extent of organ blood flow. The higher the blood supply, the higher the
organ/tissue drug distribution. Thus, a drug will appear in the interstitial fluid of liver, kidney, and
brain more rapidly than it will in muscle and skin
The renal and hepatic capillaries are especially permeable to the movement of most molecules,
except those of particularly large size. The rate of passage of drugs across capillary walls can be
influenced by agents that affect capillary permeability (e.g., histamine) or capillary blood flow rate
(e.g., norepinephrine)

b. Extent of plasma protein and specific organ binding

Many drugs bind to plasma proteins like albumin, α1 acid glycoprotein, etc

Clinical importance of plasma protein binding

• Drugs that are highly bound to plasma proteins have a low volume of distribution because they
remain trapped in the peripheral vasculature, since the plasma proteins themselves cannot
traverse into the extravascular space. However, if the affinity of a drug for tissues (e.g., fat,
muscle) is greater than the affinity for plasma proteins, widespread distribution can occur
despite a high degree of plasma protein binding
• Plasma protein binding delays the metabolism of drugs.
• Bound form is not available for filtration at the glomeruli. Hence, excretion of highly plasma
protein bound drugs by filtration is delayed.
• Highly protein bound drugs have a longer duration of action, e.g. sulphadiazine is less plasma
protein bound and has a duration of action of 6 hours, whereas sulphadoxine is highly plasma
protein bound and has a duration of action of 1 week.
• In case of poisoning, highly plasma protein bound drugs are difficult to be removed by
haemodialysis.
• In disease states like anaemia, renal failure, chronic liver diseases, etc. plasma albumin levels
are low (hypoalbuminaemia). So, there will be a decrease in bound form and an increase in
free form of the drug, which can lead to drug toxicity.
• Plasma protein binding can cause displacement interactions. More than one drug can bind to
the same site on plasma protein. The drug with higher affinity will displace the one having
lower affinity and may result in a sudden increase in the free concentration of the drug with
lower affinity.

c. Transport mechanisms available and permeability characteristics of specific tissue

membranes
Drugs are not always uniformly distributed to and retained by body tissues thus, either higher or
lower in particular tissues. The transports of these drugs into these tissues are regulated by some
cell associated selective permeability. These include;
Blood-Brain Barrier
The transfer of drugs into the brain is regulated by the blood-brain barrier. Only drugs that have a
high lipid–water partition coefficient can penetrate the tightly apposed capillary endothelial cells
of the brain.

Placental Barrier
The blood vessels of the fetus and mother are separated by a number of tissue layers that
collectively constitute the placental barrier. Drugs that traverse this barrier will reach the fetal
circulation. Also, factors that regulate passage of drugs through any membrane (e.g., pKa, lipid
solubility, protein binding) are applicable here.

Drug biotransformation (Drug Metabolism)

The metabolism of a drug usually converts lipid-soluble and unionized compounds into water-
soluble and ionized compounds which are not reabsorbed in the renal tubules and are excreted. If
the parent drug is highly polar (ionized), then it may not get metabolized and is excreted as such.
The end result of drug metabolism is inactivation, but sometimes a compound with
pharmacological activity may be formed as a result of metabolism.
Below are examples of product that may arise as a result of drug metabolism
1) Active drug to inactive metabolite: This is the most common type of metabolic
transformation. Eg. Phenobarbitone conversion to Hydroxyphenobarbitone
2) Active drug to active metabolite: Codeine conversion to Morphine
3) Inactive drug (prodrug) to active metabolite: Levodopa conversion to Dopamine
Sites of drug metabolism: liver, GI tract, kidney, lungs, brain, skin and placenta.
Drug-Metabolizing Enzymes
They are broadly divided into two groups;
• microsomal enzyme systems and
• non-microsomal enzyme systems
 Microsomal enzymes Non-microsomal enzymes
Location Smooth endoplasmic reticulum of Cytoplasm, mitochondria, plasma, e.g.
cells, liver, kidney, lungs, e.g. conjugases, esterases, amidases,
cytochrome P450, flavoprotein oxidases
monooxygenase, glucuronyl
transferase
Reactions Most of the phase I reactions, Oxidation, reduction (few), hydrolysis. All
Glucuronide conjugation conjugations except glucuronide
conjugation
Inducible Not inducible – may show genetic
polymorphism

Pathway of drug metabolism

Drug metabolic reactions are grouped into two phases. They are;
• Phase I or nonsynthetic reactions and
• Phase II or synthetic reactions.

Phase I reactions
Oxidation Addition of oxygen/removal of Phenytoin, phenobarbitone,
hydrogen pentobarbitone, propranolol
Reduction Removal of oxygen/addition of Chloramphenicol, methadone
hydrogen
Hydrolysis Break down of compound by addition Esters – procaine, succinylcholine
of water Amides – lignocaine,
procainamide
Cyclization Conversion of straight chain compound Proguanil
into ring structure
Decyclization Breaking up of the ring structure of the Phenobarbitone, phenytoin
drug

Phase II Reactions: Phase II consists of conjugation reactions. If the phase I metabolite is polar,
it is excreted in urine or bile. However, many metabolites are lipophilic and undergo subsequent
conjugation with an endogenous substrate, such as glucuronic acid, sulphuric acid, acetic acid or
amino acid. These conjugates are polar, usually water-soluble and inactive.
Not all drugs undergo phase I and phase II reactions in that order. In case of isoniazid (INH), phase
II reaction precedes phase I reaction
Phase II reactions
Glucuronidation UDP glucuronosyl transferase Aspirin, Morphine
Acetylation N-acetyltransferase Isoniazid, Dapsone
Sulphation Sulphotransferase Paracetamol, Methyldopa
 Methylation Transmethylase Adrenaline, Dopamine
Glutathione conjugation Glutathione transferase Paracetamol
Glycine conjugation Acyl CoA glycine transferase Salicylates

Factors Affecting Drug Metabolism

1) Age: Neonates and elderly metabolize some drugs to a lesser extent than adults. In these cases,
it is due to diminished amount/activity of hepatic microsomal enzymes. Neonates conjugate
chloramphenicol more slowly, hence develop toxicity – grey baby syndrome. Increased
incidence of toxicity with propranolol and lignocaine in elderly is due to their decreased
hepatic metabolism
2) Diet: Poor nutrition can decrease enzyme function.
3) Diseases: Chronic diseases of liver may affect hepatic metabolism of some drugs, e.g.
increased duration of action of diazepam, in patients with cirrhosis, due to its impaired
metabolism.
4) Genetic factors (pharmacogenetics): These factors also influence drug metabolism. The study
of genetically determined variation in drug response is called pharmacogenetics
a. Slow and fast acetylators of isoniazid: There is an increased incidence of peripheral neuritis
with isoniazid in slow acetylators. The fast acetylators require a larger dose of the drug to
produce therapeutic effect.
b. Glucose-6-phosphate dehydrogenase (G6PD) deficiency and haemolytic anaemia: G6PD
activity is important to maintain the integrity of the RBCs. A person with G6PD deficiency
may develop haemolysis when exposed to certain drugs like sulphonamides, primaquine,
salicylates, dapsone, etc.
5) Simultaneous administration of drugs: This can result in increased or decreased metabolism of
drugs due to enzyme induction or enzyme inhibition.

Drug excretion
Removal of the drug and its metabolite from the body is known as drug excretion. The main
channel of excretion of drugs is the kidney; others include lungs, bile, faeces, sweat, saliva, tears,
milk, etc.
Kidney: The processes involved in the excretion of drugs via kidney are glomerular filtration,
passive tubular reabsorption and active tubular secretion. Glomerular filtration and active tubular
secretion facilitate drug excretion, whereas tubular reabsorption decreases drug excretion.

Rate of renal excretion = (Rate of filtration + Rate of secretion) – Rate of reabsorption

• Glomerular filtration: Drugs with small molecular size are more readily filtered. The extent of
filtration is directly proportional to the glomerular filtration rate (GFR) and to the fraction of
the unbound drug in plasma.
• Passive tubular reabsorption: The main factor affecting passive reabsorption is the pH of renal
tubular fluid and the degree of ionization. Strongly acidic and strongly basic drugs remain in
ionized form at any pH of urine, hence are excreted in urine.
a. Weakly acidic drugs (e.g. salicylates, barbiturates) in acidic urine remain mainly in
‘unionized’ form, so they are reabsorbed into the circulation. If the pH of urine is made
alkaline by sodium bicarbonate, the weakly acidic drugs get ‘ionized’ and are excreted
easily.
b. Similarly, weakly basic drugs (e.g. morphine, amphetamine, etc.) in alkaline urine
remain in ‘unionized’ form, hence are reabsorbed. If the pH of urine is made acidic by
vitamin C (ascorbic acid), these weakly basic drugs get ‘ionized’ and are excreted
easily.
• Active tubular secretion: It is a carrier-mediated active transport which requires energy. Active
secretion is unaffected by changes in the pH of urine and protein binding.
Lungs: Alcohol and volatile general anaesthetics, such as ether, halothane, isoflurane, sevoflurane
and ether are excreted via lungs
Faeces: Drugs like purgatives, e.g. senna, cascara, etc. are excreted in faeces
Bile: Some drugs are secreted in bile. They are reabsorbed in the gut while a small portion is
excreted in faeces, e.g. tetracyclines.
Skin: Metals like arsenic and mercury are excreted through skin.
Saliva: Certain drugs like potassium iodide, phenytoin, metronidazole and lithium are excreted in
saliva. Salivary estimation of lithium may be used for noninvasive monitoring of lithium therapy.
Milk: Drugs taken by lactating women may appear in milk. They may or may not adversely affect
the breast fed infant. Drugs like penicillins, erythromycin, etc. are safe for use but amiodarone is
to be avoided in mothers during breast feeding.