3rd year

General Pharmacology

By Medical World
3rd year
1.1 Pharmacology- An Introduction
The word pharmacology is derived from two Greek words, pharmacon meaning a drug, and logos
meaning an opinion or reason. It can be defined as

“The science which deals with the history, source, physical properties, chemical properties, compounding,
biochemical effects, physiological effects, mechanism of action, absorption, distribution,
biotransformation, excretion, therapeutic and other uses of drugs, is called pharmacology.”

“The study of a substance that interacts with the living system through chemical processes especially by
binding to regulatory molecules and activates or inhibits normal body processes”

“The science of substances used to prevent, diagnose and treat disease.”

Drug:
The word drug comes from Drogue meaning a dry herb. A drug can be defined as:

“A substance, material or product used for the purpose of diagnosis, prevention and relief of symptoms or
cure of disease.”

WHO defines drug as:

“A substance, material or product used or intended to be used to modify or explore the physiological
processes or pathological states for the benefit of the recipient.”

General Features of a Drug:

• Variability in molecular size

• Variability in shape

• Variability in chemical nature

• Variability in lipid/water partition coefficient

• Variability in degree of ionization

• Physical Properties

• Variability in molecular size

Smaller sized molecules are easily absorbed than larger molecules. Normally the molecular
weight is between 100-1000 but may be higher or lower. Streptokinase is an example of large
molecular weight drug while lithium or nitric oxides are of small molecular weight.

• Variability in shape
 Drugs may be globular or linear in structure. Their shape is modified according to the receptor on
which they act.

• Variability in chemical nature

Tertiary compounds are lipid soluble while the quaternary compounds are water soluble. Tertiary
compounds can cross the membranes easily as compared to the quaternary compounds. This is
because of the fact that the quaternary compounds are ionized.

• Variability in lipid/water partition coefficient

Lipid soluble drugs (having higher lipid water partition coefficient) are more retained in the body
while water soluble drugs are easily excreted out.

• Variability in degree of ionization

Polar or ionized forms of drugs are lipid insoluble. Non polar drugs are water insoluble or lipid
soluble. Ionized forms of drugs can pass through the specific places i.e. through channels like
Na+ and K+ channels.

• Physical Properties

Drugs may be solids, liquids or gases. Examples include halothane and nitrous oxide, both of
which are gases.

Solubility of gases is greater than that of liquids, while solubility of liquids is greater than that of
solids.

Rational Drug Therapy

Administration of the right drug indicated for the disease in right dose through an appropriate route for
the right duration.

Rational drug therapy applies to the doctor.

Drug Abuse

Drug when used for non medical purposes is known as drug abuse. It is the wrong use of a drug other
than for the disease e.g. addiction of certain drugs, like morphine, nicotine.

Misuse of Drug:

Drug that is not required by the patient i.e. drug therapy that is not justified. If violate the quantity or
duration of the required drug, it is known as misuse.

History of Drug Development

Drug Development in Ancient Civilizations:

Egyptian- Medical Papyrus 1600 B.C

Ebers Papyrus 1550 B.C

China- Shen Nung

India- Ayurvedic medicine

Ancient Greek Culture- Hippocrates 460-377 B.C

Galen 130-201 A.D

Roman- Theophrastus 372-287 B.C

Dioscorides 57 A.D

Persians

Drug Development during the Middle Ages

Paracelsus (1493) is known as grandfather of science of pharmacology. According to him:

• Most body reactions are chemical in nature

• One must never use a combination of drugs.

• Every drug is a poison; it is the dose that matters.

Development in chemistry

Development in botany

• Opium poppy

• Cinchona bark- for malaria

• Digitoxin from Digitalis purpura- for edema due to cardiac failure

• Castor oil- for constipation

• Atropa belladonna- source of atropine and thiosine

• Hyoscyamus Niger- source of thiosine

Morphine was isolated as a pure compound in 1805.

Claude Bernard in 1856 found Curare

Fleming in 1928 found Benzyl penicillin which became the first antibiotic.

Modern Drug Development

 • Salicylic acid- anti-inflammatory, synthesized from phenol in 1800 by Kolbe and Lautemann.

• Acetyl salicylic acid (aspirin) was synthesized from salicylic acid in 1899 by Dreser.

• Prontosil, therapeutically inactive dye is transformed in the body to an antibacterial sulfonamide,

was developed by Domagk in 1935.

• Acetazolamide and thiazide are diuretics

• Sulfonyl ureas are anti diabetic.

• H1 antihistamines were developed by Bovet in 1944

• Beta adrenoreceptors were discovered by James Black in 1960

• H2 antagonists (Cimetidine for peptic ulcer) were developed in 1970,

• Immunoglobulins and gene therapy

1.2 Branches and Divisions of Pharmacology

Pharmacology is the science of drugs. It is the study of chemical substances that interact with the living
things by chemical processes, especially by binding to regulatory molecules, i.e. receptors.

In 1847, Rudolph established the first institute of pharmacology.

Drug:

The word drug comes from a French word ‘Drogue’ meaning a dry herb. It can be defined as:

“Substance or material that is used or intended to be used to modify or explore physiological processes or
pathological states, for the benefit of the recipient.”

Branches of Pharmacology:
Following are the important branches of Pharmacology:

• Pharmacokinetics
• Pharmacodynamics
• Therapeutics
• Chemotherapy
• Toxicology
• Clinical Pharmacology
• Pharmacy
• Pharmacognesy
• Pharmacogenetics
 • Pharmacogenomics
• Pharmacoepidemiology
• Comparative Pharmacology
• Animal Pharmacology
• Pharmacoeconomics
• Posology

1. Pharmacokinetics:

The word Pharmacokinetics is derived from two words, Pharmacon meaning drug and kinetics meaning
putting in motion. It can be defined as:

“The branch of pharmacology that deals with the absorption, distribution, metabolism and excretion of
drugs and their relationship with the onset, duration and intensity of the drug effect.”

What the body does to the drug is pharmacokinetics. For example, the absorption, distribution,
metabolism and excretion of Paracetamol is included in Pharmacokinetics.

2. Pharmacodynamics:

Pharmacodynamics is the branch of Pharmacology that deals with the mechanism of action of drug and
the relation between the drug concentration and its effect.

It is the study of physical and chemical effects of drugs on body, parasites and microorganisms.

What the drug does to the body is pharmacodynamics. For example, adrenaline acts on adrenal receptors,
stimulates adenyl cyclase system producing effects such as cardiac stimulation and hyperglycemia is
studied in Pharmacodynamics.

3. Therapeutics:

The branch of pharmacology that deals with the art and science of treatment of disease. It is the
application of pharmacological information together with the knowledge of disease, for the prevention
and cure of the disease.

4. Chemotherapy:

Chemotherapy refers to the treatment of diseases by chemicals that kill the cells, especially those of
microorganisms and neoplastic cells. It is classified into two divisions:

• Antibiotics
Includes the choice of drugs most potent against the organism or least toxic. Examples include
Erythromycin given for gram positive organisms and Aminoglycans for gram negative organisms.

• Antineoplastics
Examples include:
 Methotrexate, which is an anticancer drug. It inhibits the dihydrofolate reductase and interferes with
the DNA synthesis and repair.

Vinca alkaloids, which bind tubulin of microtubules, and arrest mitosis in metaphase.

5. Toxicology:

Toxicology is the branch of pharmacology which includes the study of adverse effects of drugs on the
body. It deals with the symptoms, mechanisms, treatment and detection of poisoning caused by different
chemical substances.

The main criterion is the dose. Essential medicines are poisons in high doses and some poisons are
essential medicines in low doses.

6. Clinical Pharmacology:

Clinical pharmacology is the scientific study of drugs in man. It includes pharmacokinetic and
pharmacodynamic investigations in healthy or diseased individuals. It also includes the comparison with
placebos, drugs in the market and surveillance programmes.

The main objectives are:

• Maximize the effect of drug

• Minimize the adverse effects
• Promote safety of prescription
Aims include:

• Generate optimum data for use of drug.

• Promote usage of evidence based medicine.

7. Pharmacy:

Pharmacy is the branch of Pharmacology and is the art and science of compounding by dispensing drugs,
preparing suitable dosage form for administration to man and animals. The health profession blends
health science with chemical science and effective use of drugs.

8. Pharmacognosy:

Pharmacognosy is the identification of drugs by just seeing or smelling them. It is a crude method no
longer used. Basically it deals with the drugs in crude or unprepared form and study of properties of drugs
from natural sources or identification of new drugs obtained from natural sources.

9. Pharmacoeconomics:

Pharmacoeconomics deals with the cost of drugs. In this discipline the cost of one drug is compared with
another for same use. The cheap drugs are preferred.
10. Pharmacogenetics:

Branch of pharmacology dealing with the genetic variations that cause difference in drug response among
individuals or population.

Example includes succinyl choline which is a skeletal muscle relaxant used in general anesthesia. It is
metabolized by pseudocholine esterase and has short duration of action. The presence of enzyme is
determined by the gene and lack of this is recessively inherited. This may lead to respiratory paralysis,
apnea and death. Halothane in some patients may lead to malignant hyperpyrexia. G6PD deficiency may
lead to hemolysis on administration of antimalarial drugs.

11. Pharamcogenomics:

Pharmacogenomics is the broader application of genomic technologies to new drug discovery and further
characterization of older drugs.

Recombinant DNA technology involves the artificial joining of DNA of one specie to another. E. coli is
mostly used. In this way we can get huge amounts of drug in purified form which is less antigenic.

Examples include GH, interferon and vaccines.

12. Pharmacoepidemiology:

Pharmacoepidemiology deals with the effects of drugs on a large population. The effects may be good or
harmful. It is conducted in three ways:

• Observational cohort studies

• Case control studies
• Phase trials
a. Cohort studies:

Patients receiving drugs are collected and followed up to determine the outcomes. It is prospective
(forward looking) research, however, is time consuming and lengthy.

b. Case Control Studies:

These are retrospective studies. They reverse the direction of scientific logic from forward looking to
backward looking.

c. Phase Trials:

These include different phases:

• Human pharmacology (20 to 50 subjects), pharmacokinetics and pharmacodynamics of the drug

are observed in either healthy volunteers or diseased subjects. These studies are carried out by
experienced staff and in such premises where facilities are available.
• Therapeutic exploration (50 to 300 subjects), drugs are compared with placebos
• Therapeutic confirmation (250 to 1000 subjects), safety, efficacy of drugs is compared with the
drugs already present
 • Therapeutic use (2000 to 10000 subjects), the opinion of physicians prescribing the drugs is
collected regarding dosage and efficacy. Surveillance programmes are lengthy when conducted
outside hospitals.

13. Comparative Pharmacology:

Branch of pharmacology dealing with the comparison of one drug to another belonging to the same or
another group.

14. Posology:

Posology deals with the dosage of drugs. Example includes paracetamol given as one tablet of 500mg
thrice a day.

15. Animal Pharmacology:

Animal pharmacology deals with the different properties of drugs in animals. A vast variety of animals
are utilized including rabbits, mice guinea pigs, etc. Drugs are given to the animals and all parameters
(their behavior, activities, vital signs, etc.) are recorded. Any change is noted down. If found to be useful
in animals, then the drug is tested on humans.

1.3 Scientific Sources of Drug Information

The scientific sources of drug information include:

• Textbooks

• Medial publications

• Pharmacopoeia

• Monographs (writings on one topic, single document)

• Professional seminars (USP conventional and European council meetings)

• Databases, CDs

Miscellaneous Sources:

• Mail brochures

• Library catalogues

• Advertisements

• Displays

• Pharmaceutical representatives
 Pharmacopoeia:
Pharmacopoeia is an official book published legally in a country for the manufacturing of drugs. A
pharmacopoeia describes:

• Standard of drugs

• Physical properties

• Tests for identity/purity/potency/efficacy

Common pharmacopoeias include:

• USP (Unites States pharmacopoeia)

• BP (British pharmacopoeia)

• European pharmacopoeia

• International pharmacopoeia

• Martin Dale extra pharmacopoeia

Compendium:

Compendium is the comprehensive collection of knowledge in a field.

Essential Drugs:

Drugs which satisfy health care needs of a large population and are available readily all the time in
that particular area, are known as essential drugs.

WHO has provided a model list of essential drugs which includes 300 items and is updated every two
years.

Formularies:

Formularies are the lists of licensed medicines containing information about formulas for
manufacturing as well as information regarding compounding and testing of drugs.

1.4 Routes of Drug Administration

The path taken by the drug to get into the body is known as the route of drug administration. A drug may
be in ionized or unionized form.

Classification:
 • Enteral

• Parenteral

• Inhalation

• Topical

• Enteral Route:
Enteral route is through the alimentary canal. It might be:

• Oral

• Sublingual

• Per rectum

• Oral Route:

Oral route is the most common route of drug administration. It is mostly used for the neutral
drugs. It may be in the form of tablets, capsules, syrup, emulsions or powders.

Advantages:

• It is convenient

• It is the cheapest available route

• It is easy to use

• It is safe and acceptable.

Disadvantages:

• Less amount of drug reaches the target tissue.

• Some of the drug is destroyed by gastric juices e.g. adrenaline, insulin, oxytocin

• Absorption has to take place which is slow, so is not preferred during emergency.

• It might cause gastric irritation

• It might be objectionable in taste.

• It might cause discoloration of teeth e.g. iron causes staining, tetracyclines below 14 cause brown
discoloration so are not advisable during pregnancy.

First Pass Effect:

First pass effect is the term used for hepatic metabolism of drug when absorbed and delivered through
portal blood. Greater the first pass effect, less amounts of the drug reach the systemic circulation.

• Sublingual Route:

Sublingual route involves tablets placed under the tongue or between cheeks or Gingiva. The
drug should be lipid soluble and small.

Advantages:

• Rapid absorption takes place.

• Drug is dissolved easily

• Drug enters the blood directly

• Less first pass effect.

• Spitting out of the drug removes its effect

Disadvantages:

• This method is inconvenient.

• Irritation of the mucous membrane might occur

• Person may swallow the drug

• Might be unpleasant in taste.

Examples of drugs given by this route include nitroglycerin, isoprenaline and oxytocin Nifedipine
used for the treatment of hypertension in emergency is given by sublingual route.

• Rectal Route:

Drugs in solid forms such as suppositories or in liquid forms such as enema are given by this
route. This route is mostly used in old patients. Drugs may have local or systemic actions after
absorption.

Advantages:

• This route is preferred in unconscious or uncooperative patients.

• This route avoids nausea or vomiting

• Drug cannot be destroyed by enzymes.

• This route is preferred if drug is irritant.

Disadvantages:
 This route is generally not acceptable by the patients.

Locally acting drugs include glycerin and Bisacodyl suppository

Systemic acting drugs include Indomethacin (anti inflammatory) and aminophyllin

(bronchodilator)

Retention enema is diagnostic and is used for finding the pathology of lower intestines.

Drugs given by rectal route have 50% first pass metabolism.

• Parenteral Route:
Parenteral route includes:

Injections:

• Intra muscular

• Intra venous

• Intra-arterial

• Intra-cardiac

• Intra-thecal

• Intraosseous- into bone marrow

• Intrapleural

• Intraperitoneal

• Intra-articular

• Intradermal (Intracutaneous)

• Subcutaneous route (Hypodermic)

Hypospray or jet injections

Advantages:

• Parenteral route is rapid.

• It is useful for uncooperative patients

• It is useful for unconscious patients

• Inactivation by GIT enzymes is avoided

• First pass effect is avoided

• Bioavailability is 100%

Disadvantages:

• Skill is required

• It is painful

• This method is expensive

• It is less safe.

Classification:
• Site of Release:

Site of release may be intradermal, intraperitoneal, intrapleural, intracardiac, intra-arterial,

intrathecal (into meninges of spinal cord), intra-articular (into joint cavity).

• Subcutaneous:

Subcutaneous route might be used for the arm, forearm, thigh and subscapular space.

The volume used is 2ml. Insoluble suspensions like insulin and solids might be applied
by this route.

Advantages:

• Absorption is slow and constant

• It is hygienic

Disadvantages:

• It might lead to abscess formation

• Absorption is limited by blood flow

Examples of drugs given by subcutaneous route include insulin, adrenaline and norplant.

• Intramuscular route:

Intramuscular route might be applied to the buttock, thigh and deltoid. The volume used
is 3 ml.

Advantages:
 • Absorption is rapid than subcutaneous route.

• Oily preparations can be used.

• Irritative substances might be given

• Slow releasing drugs can be given by this route.

Disadvantages

Using this route might cause nerve or vein damage.

• Intravenous injections:

Intravenous injections might be applied to the cubital, basilic and cephalic veins.

Advantages:

• Immediate action takes place

• This route is preferred in emergency situations

• This route is preferred for unconscious patients.

• Titration of dose is possible.

• Large volume of fluids might be injected by this route

• Diluted irritant might be injected

• Absorption is not required

• No first pass effect takes place.

• Blood plasma or fluids might be injected.

Disadvantages:

• There is no retreat

• This method is more risky

• Sepsis-Infection might occur

• Phlebitis(Inflammation of the blood vessel) might occur

• Infiltration of surrounding tissues might result.

• This method is not suitable for oily preparations

• This method is not suitable for insoluble preparations

 • Intraarterial route:

This method is used for chemotherapy in cases of malignant tumors and in angiography.

• Intradermal route:

This route is mostly used for diagnostic purposes and is involved in:

Schick test for Diphtheria

Dick test for Scarlet fever

Vaccines include DBT, BCG and polio

Sensitivity is to penicillin

• Intracardiac route

Injection can be applied to the left ventricle in case of cardiac arrest.

• Intrathecal route:

Intrathecal route involves the subarachnoid space. Injection may be applied for the
lumbar puncture, for spinal anesthesia and for diagnostic purposes. This technique
requires special precautions.

• Intra-articular route:

Intra-articular route involves injection into the joint cavity. Corticosteroids may be
injected by this route in acute arthritis.

• Intraperitoneal route:

Intraperitoneal route may be used for peritoneal dialysis.

• Intrapleural route:

Penicillin may be injected in cases of lung empyma by intrapleural route.

• Injection into bone marrow

This route may be used for diagnostic or therapeutic purposes.

Hypospray/Jet Injection:

This method is needleless and is subcutaneous done by applying pressure over the skin. The drug solution
is retained under pressure in a container called ‘gun’. It is held with nozzle against the skin. Pressure on
the nozzle allows a fine jet of solution to emerge with great force. The solution can penetrate the skin and
subcutaneous tissue to a variable depth as determined by the pressure. Mass inoculation is possible but the
method is expensive, definite skills are required and cuts might result.
• Inhalation:
Inhalation may be the route of choice to avoid the systemic effects. In this way drugs
can pass directly to the lungs. Drugs used involve volatile drugs and gases. Examples
include aerosols like salbutamol; steam inhalations include tincture and Benzoin

Advantages:

• Rapid absorption takes place.

• Rapid onset of action takes place.

• This route has minimum side effects.

• No first pass effect takes place.

• This method is easy.

• Fewer doses are required.

Disadvantages:

• Special apparatus is required.

• Irritation of the respiratory tract may take place.

• Cooperation of the patient is required.

• Airway must be patent.

• Topical route:
Drugs may be applied to the external surfaces, the skin and the mucous membranes.
Topical route includes:

• Enepidermic route

When the drug is applied to the outer skin, it is called enepidermic route of drug
administration. Examples include poultices, plasters, creams and ointments.

• Epidermic route (Innunition):

When the drug is rubbed into the skin, it is known as epidermic route. Examples
include different oils.

• Insufflations:
 When drug in finely powdered form is blown into the body cavities or spaces with
special nebulizer, the method is known as insufflations.

• Instillation

Liquids may be poured into the body by a dropper into the conjunctival sac, ear,
nose and wounds. Solids may also be administered.

• Irrigation or Douching

This method is used for washing a cavity e.g. urinary bladder, uterus, vagina and
urethra. It is also used for application of antiseptic drugs.

• Painting/Swabbing

Drugs are simply applied in the form of lotion on cutaneous or mucosal surfaces
of buccal, nasal cavity and other internal organs.

Time of Action using Different Routes of Administration

Drugs take different time durations after injection using different routes to perform their actions. Some of
the approximate time intervals are given below:

Route of Drug Administration Delay time for Action

Intravenous route 30-60 seconds
Intraosseous route 30-60 seconds
Endotracheal inhalation 2-3 minutes
Sublingual route 3-5 minutes
Intramuscular route 10-20 minutes
Rectal route 5-30 minutes
Ingestion 30-90 minutes

This time delay is important, oral route has controlled release time, thus depot or reservoir preparation
may be made e.g. penicillin for rheumatic fever.

Usage of drug depends on its physical properties, chemical properties, speed of action, need and bypass
effect.

1.5 Dosage Forms

Dosage Forms given Orally

• Liquid preparations- mixtures, suspensions, emulsions, linctuses, elixirs, syrups, tinctures,

spirits, aromatic water

• Solid preparations

Dosage Forms given Rectally

 Suppositories, enemas

Dosage Forms given Parentally

Injections (ampoules, vials, infusions)

Through respiratory passages

Gases, vapors, steam inhalations, aerosols, sprays, nebulizers

Topically given (External application, skin, mucous membranes)

Creams, ointments, liniments, lotions, pastes, poultices, dusting powders, lozenges, eye, ear and
nasal drops, mouth washes, glycerin, paints, gargles, solutions, vaginal douches, pessaries

Oral Route:
Mixtures:

It is a liquid preparation consisting of one or more drugs dissolved in aqueous vehicle, usually flavored,
meant for internal administration. E.g. carminative mixture

Suspension:

Mixtures of insoluble or sparingly soluble drugs in water or other vehicle, in which particles of insoluble
drugs are kept in suspended state, with the help of a suitable suspending agent. E.g. kaolin suspension,
dijex suspension

Emulsions:

Mixtures containing two immiscible liquids made miscible with the help of emulsifying agents. E.g.
castor oil emulsion.

Linctuses:

Thick viscous liquid preparations containing sucrose and medicines with demulcent, expectorant and
sedative properties. They are used for cough. E.g. codeine linctuses

Elixirs:

Pleasantly flavored and sweetened liquid preparation containing high proportion of alcohol or glycerin or
propylene glycol. E.g. paracetamol elixir

Syrups:

Concentrated aqueous solution of sucrose or other sugars to which medicines or flavoring agents may be
added. E.g. codeine phosphate syrup

Tinctures:
Alcoholic or hydrochloric solutions containing comparatively low concentration of active principles of
crude drugs. They are generally prepared by percolation or maceration. E.g. tincture cardamom
compound.

Tablets:

Compact products containing medicines in compressed form, discoid in shape but may be round or long,
cylindrical or triangular. E.g. aspirin tablet, co trimoxazole

Capsules:

Capsules consist of a medicine enclosed in a shell. Shell is made of gelatin. This is convenient for
medicines having unpleasant taste. Capsules are usually cylindrical. E.g. capsule amoxil.

Pills:

Spherical or ovoid masses containing one or more medicaments (medicines). They are smaller in size and
contain smaller quantity of drug.

Powders:

Mixtures of two or more medicines in finely divided forms. Minimum weight is 120 mg. e.g. atropine
powder, ORS.

Granules:

Preparations of medicines usually in the form of small irregular particles 2-4 mm in diameter. E.g. eno
granules.

Rectal Route
Suppositories

Solid preparations meant for rectal route administration. E.g. glycerin suppository.

Enemas:

Aqueous, liquid, oily solutions or suspensions for rectal route. They are anti inflammatory, having
anthelmintic, purgative and sedative effect. They are also used for x-ray examination of the large gut. E.g.
pregnisolone

Parenteral Route:
Injections:

Sterile solutions intended for parenteral administration given for those drugs that cannot be given orally
or are inactivated in the body. They produce rapid and prolonged effect. E.g. hydrocortisone injections.

Inhalation Route
Aerosol Inhalation:

Aerosol inhalation consists of solution of medicine in a mixture of inert propellants held under pressure in
aerosol dispenser, consisting of metering valve. E.g. salbutamol aerosol inhalation

Inhalations:

Liquid preparations composed of volatile ingredients when vaporized are brought into contact with the
lining of the respiratory tract. E.g. benzoic inhalation.

Sprays:

Preparations of medicines in aqueous, alcohol or glycerol containing media applied through nose or throat
by atomizer. E.g. lignocaine spray.

Topical Route
Lotions:

Liquid preparations used for external application to skin but not rubbed into skin. Usually contain alcohol
or glycerin. E.g. calamine lotion.

Creams:

Viscous emulsions of semisolid consistency. Creams may be of oil in water (aqueous creams) or water in
oil (oily cream) type. E.g. betamethasone cream.

Ointments:

Liquid/semi liquid preparation meant for external use containing substances possessing analgesic,
soothing or stimulating properties. E.g. sulphur ointments.

Liniments:

Liquid or semi liquid preparation meant for external application e.g. turpentine liniment.

Paste:

Semisolid preparation for external application consisting of medicine mixed with soft paraffin or liquid
paraffin or with non greasy base made with glycerol, mucilage or soap. It has antiseptic properties,
soothing effect and is protective. E.g. zinc, coal tar paste.

Poultices:

Thick pasty preparation used externally for reducing inflammation and pain. E.g. kaolin poultice.

Dusting powder:

Mixture of two or more substances in finely powdered form. It is applied externally but not on open
wound. E.g. boric, zinc, starch, dusting powder.
Eye Drops:

Sterile solutions or suspensions for instillation into eyes. They contain substances with antiseptic,
anesthetic, anti inflammatory, anti microbial, mydriatic or micotic properties. E.g. chloramphenicol eye
drops, pilocarpine.

Eye Lotions:

Solutions for washing or bathing eye. E.g. sodium bicarbonate eye lotion.

Eye Ointment:

Semisolid soft preparation for application to conjunctival sac or lid margin.

Ear Drops:

Liquid preparations instilled into the ear. E.g. chloramphenicol.

Lozenges:

Solid dosage forms of medicines for slow dissolution in mouth. They consist of medicines mostly in
flavored bases. E.g. strepsils.

Paints:

Liquid preparations meant for skin, mucous membranes containing volatile solvent which evaporates
quickly to leave a dry film of medicine. They contain glycerin which prolongs their effect. E.g. gum paint,
throat paint.

Gargles:

Aqueous solutions usually in concentrated form, used after diluted for prevention or treatment of throat
infections. They are usually thrown out of mouth but aspirin gargles and saline gargles can be swallowed.

Mouth Washes:

Aqueous solutions in concentrated form with deodorant, antiseptic, local analgesic, astringent properties.
They are thrown out of mouth after rinsing. E.g. Listerine mouth wash.

Pessaries:

Solid bodies for vaginal administration containing drugs for local actions. E.g. nystatin pessaries.

1.6 Sources of Drugs

Drugs are obtained from six major sources:

• Plant sources
• Animal sources
• Mineral/ Earth sources
• Microbiological sources
• Semi synthetic sources/ Synthetic sources
• Recombinant DNA technology

• Plant Source:
Plant source is the oldest source of drugs. Most of the drugs in ancient times were derived from
plants. Almost all parts of the plants are used i.e. leaves, stem, bark, fruits and roots.

Leaves:

a. The leaves of Digitalis Purpurea are the source of Digitoxin and Digoxin, which are cardiac
glycosides.

b. Leaves of Eucalyptus give oil of Eucalyptus, which is important component of cough syrup.

c. Tobacco leaves give nicotine.

d. Atropa belladonna gives atropine.

Flowers:

• Poppy papaver somniferum gives morphine (opoid)

• Vinca rosea gives vincristine and vinblastine
• Rose gives rose water used as tonic.
Fruits:

• Senna pod gives anthracine, which is a purgative (used in constipation)

• Calabar beans give physostigmine, which is cholinomimetic agent.
Seeds:

• Seeds of Nux Vomica give strychnine, which is a CNS stimulant.

• Castor oil seeds give castor oil.
• Calabar beans give Physostigmine, which is a cholinomimetic drug.
Roots:

• Ipecacuanha root gives Emetine, used to induce vomiting as in accidental poisoning. It also has
amoebicidal properties.
• Rauwolfia serpentina gives reserpine, a hypotensive agent.
Reserpine was used for hypertension treatment.
Bark:

• Cinchona bark gives quinine and quinidine, which are antimalarial drugs. Quinidine also has
antiarrythmic properties.
• Atropa belladonna gives atropine, which is anticholinergic.
• Hyoscyamus Niger gives Hyosine, which is also anticholinergic.
Stem:
 Chondrodendron tomentosum gives tuboqurarine, which is skeletal muscle relaxant used in general
anesthesia.

2. Animal Source:
• Pancreas is a source of Insulin, used in treatment of Diabetes.
• Urine of pregnant women gives human chorionic gonadotropin (hCG) used for the treatment of
infertility.
• Sheep thyroid is a source of thyroxin, used in hypertension.
• Cod liver is used as a source of vitamin A and D.
• Anterior pituitary is a source of pituitary gonadotropins, used in treatment of infertility.
• Blood of animals is used in preparation of vaccines.
• Stomach tissue contains pepsin and trypsin, which are digestive juices used in treatment of peptic
diseases in the past. Nowadays better drugs have replaced them.

3. Mineral Sources:
i. Metallic and Non metallic sources:

• Iron is used in treatment of iron deficiency anemia.

• Mercurial salts are used in Syphilis.
• Zinc is used as zinc supplement. Zinc oxide paste is used in wounds and in eczema.
• Iodine is antiseptic. Iodine supplements are also used.
• Gold salts are used in the treatment of rheumatoid arthritis.

ii. Miscellaneous Sources:

• Fluorine has antiseptic properties.

• Borax has antiseptic properties as well.
• Selenium as selenium sulphide is used in anti dandruff shampoos.
• Petroleum is used in preparation of liquid paraffin.

4. Synthetic/ Semi synthetic Sources:

i. Synthetic Sources:

When the nucleus of the drug from natural source as well as its chemical structure is altered, we call it
synthetic.

Examples include Emetine Bismuth Iodide

ii. Semi Synthetic Source:

When the nucleus of drug obtained from natural source is retained but the chemical structure is altered,
we call it semi-synthetic.
Examples include Apomorphine, Diacetyl morphine, Ethinyl Estradiol, Homatropine, Ampicillin and
Methyl testosterone.

Most of the drugs used nowadays (such as antianxiety drugs, anti convulsants) are synthetic forms.

5. Microbiological Sources:
• Penicillium notatum is a fungus which gives penicillin.
• Actinobacteria give Streptomycin.
• Aminoglycosides such as gentamicin and tobramycin are obtained from streptomycis and
micromonosporas.

6. Recombinant DNA technologies:

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.

Advantages:

• Huge amounts of drugs can be produced.

• Drug can be obtained in pure form.
• It is less antigenic.
Disadvantages:

• Well equipped lab is required.

• Highly trained staff is required.
• It is a complex and complicated technique.

1.7 Active Principles of Crude Drugs

Active Principal:

Chemical constituents present in crude animal or vegetable preparations responsible for biological activity
are called active principles.

Important active principles include:

• Alkaloids
• Glycosides
• Saponins
• Fixed and volatile oils
• Fats
• Waxes
• Gums
• Resins
 • Oleoresins
• Gum resins
• Balsams
• Tannins
• Neutral principles

• Alkaloids:
Alkaloids are the nitrogenous compounds having complex structure.

Source:

They are obtained from plants.

Taste:

They are bitter in taste.

Biological activity:

Alkaloids are biologically very active compounds.

Nature:

Alkaloids are basic in nature.

Reaction with acids:

With acids, alkaloids form salts.

Solubility:

Alkaloids are not soluble in water but are soluble in alcohol. Their salts are water soluble.

Physical State:

Alkaloids are mostly solids and rarely liquids.

Name:

English name ends in “ine”.

Examples:

Examples include :

a. Solids :

Atropine, hyosine, quinine, strychnine, codeine and theobaine.

b. Liquids :
Nicotine, lobeline and pilocarpine.

• Glycosides :
Glycosides are non-nitrogenous compounds having complex structure similar to the alkaloids.

Source:

Glycosides are obtained from plants

Biological activity:

Glycosides are biologically very active.

Portions:

Glycosides are hydrolyzed by enzymes and acids into two portions:

• Sugar portion- Glycone ( has pharmacokinetic properties)

• Non sugar portion- Aglycone (has pharmacodynamic properties).
If sugar portion is glucose, glycosides are known as glucosides.

Name:

English name ends in “in”.

Examples:

Examples include cardiac glycosides such as digitoxin and digoxin, gitoxin and gitalin.

3. Fixed/ Volatile Oils:

a. Fixed Oils:

Fixed oils are the esters of higher fatty acids.

Source:

Fixed oils are obtained from plant as well as animal sources.

Solubility:

They are not soluble in water but are soluble in alcohol, chloroform and ether.

Fixed oils are bland and non-irritating.

They leave a greasy mark on paper.

Distillation:

Fixed oils decompose on distillation.

Chemical Reactions:
With alkalies, they form soaps.

Pharmacological Actions:

They serve as nutrients and emolients (soften the skin).

b. Volatile Oils:

Volatile oils contain liquid hydrocarbons. Chemically they are phenols, alcohols or ketones.

Solubility:

They are slightly soluble in water.

They impart smell and taste to water.

They are highly aromatic compounds.

Pharmacological Actions:

They have many pharmacological actions like:

• Carminatives- Cardamom oil

• Diuretics- Sandalwood oil
• Expectorants- Balsam of tolu
• Counter irritants- turpentine oil
• Antiseptics- clove oil
Physical State:

They are usually solids like camphor, thymol and menthol, but may be liquids as well, like oil of
Eucalyptus (Eucalyptol).

Differences Between Volatile and Fixed Acids

Fixed Oil Volatile Oil

Source: Plant and animal Plants only
Volatility: Non volatile Volatile
Distillation: Decompose Can be distilled
Nature: Greasy and thick in consistency Thin and non greasy
Solubility in water: Completely insoluble Slightly soluble
Action: Non irritant, soothing when applied to Mild irritant to skin and mucosa
skin and mucosa
Activeness: Not much active Quite active
Rancidity: Get rancid with time Do not get rancid
Nutritional value: Have nutritional value No nutritive value
Examples: castor oil, cod liver oil, olive oil ANISE, camphor, eugenol, methanol

4. Fats:
Fats are the fixed oils. These include the triglycerides.

Physical State:

They are solids at room temperature.

Sources:

Fats are obtained from plants as well as animal source.

Examples:

Examples include theobroma, lard and wool fat.

5. Saponins:

Saponins resemble glycosides and are the emulsifying agents.

Sources:

These are obtained from the plants.

Reaction:

Saponins are neutral in reaction.

Toxicity:

Saponins are toxic and cause hemolysis of RBC’s.

With water:

With water, saponins form a clear solution which makes soap like foam on shaking.

Examples:

Examples include Senegin and Quillaia Sapotoxin.

6. Waxes:

Waxes are the esters of fatty acids with monohydric alcohol. They are the complex mixtures and are used
in the formation of ointments, topical preparations.

Examples include bees wax (Cera alba).

7. Gums:

Gums are the exudates of plants. They are carbohydrates, amorphous and transparent compounds which
form viscous solution with water. This viscous solution is known as mucilage.

Examples include gum acacia and gum tragacanth.

8. Resins:

Resins are the solid and brittle oxidized volatile oils which form soaps with alkalies. They are soluble in
alcohol.

Examples include colophonium and podophyllum.

9. Oleoresins:

Oleoresins are the resins dissolved in volatile oils. E.g. Copaiba.

10. Gum Resins:

Gum resins are the combination of gums and resins and are the exudates of plants. Examples include
Myrrh and Asafetida.

11. Balsams:

Balsams are the resins in combination with benzoic acid with or without cinnamic acid. Examples include
Benzoin, Peru and Tolu.

12. Tannins:

Tannins are the non nitrogenous compounds which are precipitated by metallic salts and alkalies. They
are mucous and leave a blue inky color with iron. They are hydrolyzed to tannic acid. They act as
astringents which harden the mucous membrane by coagulation of proteins.

13. Neutral Principles:

Neutral principles do not confer to any special group and include Santonin and Aloin.

1.8 Absorption of Drugs

Absorption:

Absorption is the process by which drug molecules cross biological membranes. Absorption is the process
usually associated with oral drugs and their absorption through the GIT. It also occurs by subcutaneous,
intra muscular and transdermal routes of administration of drugs. However, the absorptive process does
not occur during direct injection of drug by intravenous or intra arterial injection.

Biological Membrane:

Biological membranes consist of a lipid bilayer separating different compartments, with protein
molecules acting as enzymes, channels or carrier proteins.

Drugs have to cross the biological membranes to get absorbed.

Processes Determining Absorption:

Absorption, distribution and excretion of drugs overlap in the processes determining them. These
processes include:

• Passive Transport
• Simple diffusion
• Filtration/ Aqueous diffusion
• Bulk flow
• Active Transport
• Primary active transport
• Secondary active transport
• Pinocytosis
• Phagocytosis
• Specialized Transport involving facilitated diffusion

Simple Diffusion:

Most of the drugs are absorbed by simple diffusion, which is the movement of molecules down the
concentration gradient i.e. from higher concentration to lower concentration. This type of transport occurs
mostly for the lipid soluble drugs.

Non-specific:

This type of transport is non-specific i.e. no carrier proteins are required.

Energy Expenditure:

No energy is required for this type of transport.

Factors:
1. Concentration Gradient Across Membrane:

Fick’s law of diffusion explains the concentration gradient across the membrane. It is stated as the
flux of molecules per unit time is equal to the concentration gradient times the area times the
permeability coefficient divided by the thickness.

Flux (molecules/unit time) = (C1- C2) x Area x Permeability coefficient

-----------------------------------------------------

Thickness

Where permeability coefficient is the motion of drug molecules across the membrane.

Thus Flick’s law indicates that the movement of molecules is directly proportional to the
concentration gradient, area and the permeability coefficient and is inversely proportional to the
thickness of the membrane.

• Molecular/ Particle Size:

Molecular size is the size of a single molecule. The particle size is different for different preparations
of the same drug. More the particle size, slow is the diffusion and absorption.

Therefore, if we want to have slower time of absorption, we can make the particle size larger.

• Membrane Surface Area:

More the surface area of the membrane, more is the absorption. Stomach and intestinal lining is the
main area of absorption for the oral drugs. Thus the absorption is greater in the small intestine due to
the large surface area.

• Lipid Water Particle Coefficient:

Membranes have a thin water layer on them. Therefore, part of the drug must dissolve in the water
film, while most of the remaining portion is lipid soluble. If the lipid water particle coefficient is
large, more diffusion will occur due to greater lipid solubility. In cases of small lipid water particle
coefficient, less diffusion will occur due to the less lipid solubility.

• Ionization of Drugs:
Most of the drugs are either weak acids or weak bases. Therefore they are part ionized and part
unionized. The ionized portion is charged, which attracts water molecules, thus forming large
complexes. These complexes cannot cross the membranes because they are less lipid soluble. This is
why the ionized part of the drugs cannot cross the membrane. Drugs are better absorbed in unionized
form.

Decreasing pH by one unit, 91% of acid would become unionized and 91% of base would become
ionized. Decreasing pH by two units, 99% of acid would become unionized.

Acidic drugs

AH ↔ A- + H+ (eq 1)

Acidic drugs on dissociation give anion and proton.

Basic drugs

B + H+ ↔ BH+ (eq 2)

Basic drugs on combining with a proton become an anion.

The existence of drugs as neutral or charged particles depends on the pH.

Acidic Medium

In acidic medium, lots of protons are present. Therefore, greater amount of acidic drug is unionized
(shift towards left of eq 1). Thus in acidic medium acidic drug is present more in unionized form,
which increases its absorption. This is why acidic drugs are better absorbed from the stomach.

Basic drugs get ionized in acidic medium (right shift of eq 2), thus this form is poorly absorbed.
Aspirin, an acidic drug is unionized in acidic medium of stomach, so is easily absorbed.
Basic Medium:

The opposite is true in case of basic medium. Acidic drugs are poorly absorbed while the basic drugs
are well absorbed. Quinidine and pyrimethamine are antimalarials and basic, so are ionized in
stomach and unionized in intestines, from where they are absorbed.

• Protonated/Unprotonated form:
Protonated form of acidic drugs is well absorbed while the protonated form of basic drugs is poorly
absorbed, due to the reasons given above.

• Ionization Coefficient:
Ionization coefficient is the pH at which the drug is 50% ionized and 50 % unionized. For acidic
drugs, pKa is lower, while that for basic drugs is higher.

• Henderson Hasselbalch Equation:

This can be stated as:

pKa – pH = log [P/UP]

where P is the protonated form while UP is the unprotonated form

If pH is lower than pKa the value will be positive indicating that the protonated form is more than the
unprotonated form.

For acidic drugs,

pKa – pH = log [AH/A-]

If pH is lower than pKa, AH will be more.

For basic drugs,

pKa – pH = log [BH+/B]

If pH is lower than pKa, BH+ will be more.

Drugs in Intestines:

For acidic drugs A- is more, so the drugs are present in ionized form in the intestines, thus are less
absorbed. But as the surface area of the stomach is small while that of intestines is very large, even
acidic drugs are more absorbed from the upper part of the intestine.

For basic drugs, B is more, thus are present in unionized form in the intestines and are absorbed in a
much greater quantity.

In short we can say that acidic drugs are better absorbed in the acidic medium while basic drugs are
better absorbed in the basic medium.

Ion trapping:
Most of the drugs are reabsorbed from the proximal tubules of kidneys. Acidic drugs are better
reabsorbed from acidic urine. This is an important fact, which can be manipulated to get desired
results, as is the case of poisoning with acidic drugs. If we make the urine alkaline (by administering
sodium bicarbonate), decreased reabsorption of acidic drugs take place, a phenomenon known as ion
trapping.

In case of poisoning with basic drug, urine can be made more acidic (by administering ammonium
chloride), by virtue of which the basic drug becomes ionized and is not reabsorbed, with the result
that more of it is excreted out.

Filtration:

Filtration involves the aqueous channels or pores through which hydrophilic drugs can pass. Filtration
occurs in the jejunum and proximal tubules of kidneys. It is absent in the stomach and the lining of
the urinary bladder.

Only certain ions like Na+ and drugs of low molecular weight, like ethanol and glycerol can undergo
filtration.

Bulk Flow:

The drug in this process passes through the pores between capillary endothelial cells. The passage is
independent of water and lipid solubility. Bulk flow is the phenomenon mostly seen with the intra
muscular and subcutaneous injections. Drug is injected in bulk form into the muscle. Drug molecules
along with the aqueous medium pass through the pores of endothelium, and diffuse into the blood.
This type of transport is independent of pH and pKa. Bulk flow does not occur in brain because of
absence of pores.

However, bulk flow is dependent on the blood flow, more the blood flow, more rapid is the
absorption. This is why the area is rubbed after intra muscular injections to increase the blood flow.

Active Membrane Transport:

Active membrane transport is for the drugs which cannot cross the lipid membrane and require
transport proteins. Their structure is similar to the endogenous substances undergoing active transport
like amino acids, sugars, neurotransmitters, which have the transport proteins. Active transport is the
carrier mediated transport.

The drug moves against the concentration gradient. Energy in the form of ATP is required for the
process to occur. Different drugs bind different proteins, thus their absorption is selective from
different areas, as well as their distribution.

Some drugs directly affect the brain like the Levo Dopa which utilize amino acid transporting
mechanism. Other examples include methyl dopa for hypertension and fluorouracil which is
anticancer drug.

Active transport mechanism is saturable and can be inhibited by competing drugs.

 Primary Active Transport:

When the substance moves against the concentration gradient by the expenditure of energy, the
process is called primary active transport.

Secondary Active Transport:

When the substance moves against the concentration gradient by the energy stored by a substance
moving down the concentration gradient, the process is called secondary active transport.

Phagocytosis:

Phagocytosis is also known as cell eating. This type of transport is utilized by large molecular weight
drugs. This may be a two way process.

• Endocytosis- e.g. uptake of vitamin B12 along with intrinsic factor

• Exocytosis- e.g. anticancer drugs

Pinocytosis:
Pinocytosis, or cell drinking, requires expenditure of energy. Fat soluble vitamins, protein
molecules and folic acid enter the cells by this process.

Facilitated Transport:

Facilitated transport involves the drug moving down the concentration gradient by the help of
transport proteins. No energy expenditure is required. This type of transport is also specific and
saturable. The main objective is that lipid insoluble drugs become lipid soluble by combining with the
carrier. E.g. iron binds with apoferritin and certain catecholamines enter the nerve cells by this
process.

Simple Diffusion Facilitated Diffusion Active Transport

Down concentration gradient
No energy required
No carrier protein involved
Non-specific
Non-saturable
Lipid soluble drugs
Down concentration gradient Against concentration gradient
No energy required Energy required
Carrier proteins involved Carrier proteins involved
Specific Specific
Saturable Saturable
Non-diffusible drugs Lipid insoluble drugs

1.9 Factors affecting Absorption

Related to Drugs:
• Lipid water solubility

Lipid water solubility coefficient is the ratio of dissolution of drug in lipid as compared to
water. Greater the lipid water solubility coefficient, more is the lipid solubility of the drug and
greater is the absorption. Less the coefficient, less is the lipid solubility and less is the absorption.
 Water film exists on the membranes so part of the drugs must be water soluble to cross this water
film

Drugs with benzene ring, hydrocarbon chain, steroid nucleus and halogen groups in their
structures are lipid soluble.

• Molecular size

Smaller the molecular size of the drug, rapid is the absorption. There exist different processes
involved in absorption for different molecular sizes. Thos e with a large molecular size undergo
endocytosis or facilitated diffusion, while those with smaller molecular sizes utilize aqueous
diffusion or lipid channels.

• Particle size

Particle may be composed either of a single molecule or more than hundred molecules. Larger is
the particle size, slower will be the diffusion and absorption and vice versa.

• Degree of Ionization

Different drugs are either acidic or basic and are present in ionized or unionized form, which is
given by their pKa values. In the body, the ratio of the ionized and unionized forms depend on the
pH of the medium. Acidic drugs are unionized in the acidic medium and basic drugs are
unionized in the basic medium. Acidic drugs are better absorbed from the acidic compartment.

• Physical Forms

Drugs may exist as solids, liquids or gases. Gases are rapidly absorbed than the liquids, while the
liquids are rapidly absorbed than the solids. Thus the drugs in syrup or suspension form are
rapidly absorbed than the tablets or capsules. Volatile gases used in general anesthesia are quickly
absorbed through the pulmonary route.

• Chemical Nature

Chemical nature is responsible for the selection of the route of administration of drug. Drugs that
cannot be absorbed through the intestines are given by the parenteral route. Examples include
heparin which is large molecular weight, and cannot be given orally. Simililarly, benzyl penicillin
is degraded in the GIT, so is given parenterally.

Salt forms of drugs are better absorbed than the organic compounds when given orally. The
organic compounds are given by routes other than the oral or enteral route.

Drugs in inorganic form are better absorbed than organic forms e.g. iron in Fe+2 is better
absorbed than Fe+3, d-tubocurarine exists in ionized form and is a quaternary ammonium
compound. Neostigmine is also a quaternary ammonium compound.

• Dosage Forms
 Dosage forms affect the rate and extent of absorption. A drug can be given in the form of tablets,
capsules or transdermal packets. Injections may be aqueous or oily. This changes the rate of
absorption. Examples include nitroglycerin which when given by sublingual route, disintegrates
rapidly but stays for a shorter duration. When it is given orally, it disintegrates slowly and stays
for longer duration. When given by transdermal route, the drug can cover an even longer
duration.

• Disintegration:

Disintegration is the breaking up of the dosage form into smaller particles. When rapid is the
disintegration, rapid will be the absorption.

• Dissolution:

After disintegration, the drug dissolves in the gastric juices, which is called dissolution. It is
only then that the drug can be absorbed.

When these two processes occur rapidly, the rate of absorption increases.

• Formulation

When the drugs are formed, apart from the active form some inert substances are included. These
are the diluents, excipients and the binders. Normally they are inert, but if they interact, they can
change the bioavailability. Examples include Na+ which can interact to decrease the absorption.

Atropine is required by some patients only in amounts of 0.2 to 0.6 mg.

• Concentration

According to Fick’s law, higher the concentration more flux occurs across the membrane. The
rate is less affected than the extent of absorption.

Related to Body
• Area of Absorptive Surface

Area of absorptive surface affects oral as well as other routes. Most of the drugs are given orally
because of the large area of absorptive surface, so that greater absorption occurs. Intestinal
resection decreases the surface area leading to a decreased absorption. Similarly, when the
topically acting drugs are applied on a large surface area, they are better absorbed.

Organophosphate compounds are highly lipid soluble and poisoning can occur even by absorption
through skin.

• Vascularity

More the vascularity, more is the rate and extent of absorption and vice versa. In shock, blood
supply to the GIT is less so the oral route of drug administration is affected. The blood flow to the
 peripheries is decreased, so absorption in those areas is diminished as well. Therefore,
intravenous route is preferred in case of shock.

Vasoconstrictors decrease the blood supply of an area, thus are useful to restrict the local
anesthesias so that they remain for a longer duration. Their wash away as well as their toxic
effects are decreased in this way.

Massage in intramuscular injections improves vascular supply to enhance absorption.

• pH

Acidic pH favors acidic drug absorption while basic pH is better for basic drugs.

• Presence of other Substances

Foods or drugs may interact with the drugs to alter their rate of absorption. Especially for the
drugs given orally, food can increase or decrease the absorption.

Antihyperlipidemic drugs like the statins are better absorbed when taken with the food.

Iron when given with milk has decreased absorption.

Vitamin C enhances the absorption of iron.

Phytates decrease iron absorption.

Milk decreases the absorption of tetracyclines.

Epinephrine when given with local anesthetics decreases their absorption.

Calcium salts when given with iron salts or tetracyclines interfere with their absorption

Aspirin is given with food while antibiotics are given in empty stomach. Liquid paraffin may
affect drug absorption. Some acidic drugs bind with cholestyramine to from a complex which is
not absorbed in GIT.

• GI Mobility

GI mobility must be optimal for absorption of oral drugs. It should be neither increased nor
decreased which may affect the rate or extent of absorption.

Different diseases or drugs may alter the mobility. Diarrhea causes rapid peristalsis, decreasing
contact time and thus the extent of absorption is affected more. Constipation affects disintegration
and dissolution so decreases motility.

• Functional Integrity of Absorptive Surface

Flattening and edema of mucosa decreaes absorption. Dysfunctional breach in the skin affects the
absorption of topical drugs.
 Parasympathomimetic drugs can decrease drug absorption and parasympatholytic drugs can
increase absorption. Metodopramide prevents vomiting and accelerates gastric emptying. It
increases gastric emptying increasing drug absorption.

• Diseases

• Diarrhea

Already discussed.

• Malabsorptive syndrome

Decreases absorption

• Achlorhydria

Acidic medium for acidic drugs is affected.

• Cirrhosis

Cirrhosis affects portal circulation. Thus affecting metabolism of drugs.

• Emphysema

Emphysema affects the absorption of volatile gases through the pulmonary route.

• Lipodystrophy

Lipodystrophy decreases absorption. In diabetics, insulin might lose its affect.

Methods for Delaying Absorption

• Vasoconstrictors

When the drug is given by parenteral route, vasoconstrictors are added.

• Formulation

Clonidine is given by transdermal route. Drugs are also given in oily preparations. Slow releasing
(SR) preparations are also prepared.

Methods for Enhancing Absorption

• Formulation

Sublingually given drugs are rapidly absorbed. Aspirin is rapidly absorbed when water dissolved.

• Massage
1.10 Distribution of Drugs:
Drug enters the body by absorption. Inside the body, drugs move in the blood to different parts of the
body. Distribution of drugs can be defined as:

“The process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular
fluid) and/or the cells or tissues.”

The drugs are present in free or bound form and different processes or mechanisms affect their
distribution.

Compartments for Distribution:

• Plasma

• Interstitial fluid

• Intracellular fluid

• Transcellular fluid

Factors Affecting Distribution:

Factors affecting distribution of drugs include those related to the drug and those related to the body.

Factors Related to the Drug:

• Lipid Solubility

Greater the lipid solubility, more is the distribution and vice versa.

• Molecular size

Larger the size, less is the distribution. Smaller sized drugs are more extensively distributed.

• Degree of Ionization

Drugs exist as weak acids or weak bases when being distributed. Drugs are trapped when present
in the ionized form, depending upon the pH of the medium. This fact can be used to make the
drug concentrated in specific compartments.

• Cellular binding

Drugs may exist in free or bound form. Bound form of drugs exists as reservoirs. The free and
bound forms co-exist in equilibrium. Cellular binding depends on the plasma binding proteins.

Tissue binding:

Different drugs have different affinity for different cells. All cells do not bind the same drugs.
• Duration of Action

The duration of action of drugs is prolonged by the presence of bound form while the free form is
released. This leads to a longer half life and duration of action of drug.

• Therapeutic Effects:

Bisphosphonate compounds bind with the bone matrix cells and strengthen them. They are used
in the treatment of osteoporosis.

• Toxic Effects:

Chloroquinine can be deposited in the retina.

Tetracycline can bind the bone material. It may also get bound to the enamel of the teeth.

Factors Related to the Body:

• Vascularity

Most of the blood passes through the highly profused organs (75%) while the remaining (25%)
passes through the less profused areas. Therefore, most of the drugs go first to the highly profused
areas. They may get bound to these organs. They are then redistributed to the less profused areas
like the skin and the skeletal muscles. This phenomenon is common among the lipid soluble
drugs.

Example includes thiopentone sodium which is used as general anesthetic. When given, it goes to
the brain producing its effects. It is then redistributed to the less profused organs. Because of high
lipid solubility, it is accumulated in the fatty tissue for longer duration. Thus the clearance of the
drug is slow, producing prolonged period of drowsiness (up to 24 hours).

• Transport Mechanism

Different drugs are taken up by different compartments of the body differently. Lipid soluble
drug move by passive transport which is non specific. Active transport occurs only where carrier
proteins are present.

• Blood Barriers

Different blood barriers exist. Blood brain barrier is present because of the delicacy of nervous
tissue to avoid chemical insult to the brain.

Structure:

Endothelial cells, pericytes and glial cells form the barrier through which drugs cannot pass
easily. Only selective passage takes place.

Transporters:
 Certain efflux pumps or transporters exist through which drug can be effluxed as well. Example
includes p-glycoprotein.

Disruption:

• Disruption of barrier may occur, e.g. by inflamed meningitis. Drugs may pass which might be
toxic as well as beneficial i.e. during meningitis penicillin can pass which has beneficial effects.

• Placental Barriers

Trophoblastic tissue separates maternal blood from fetal blood. Different transporters are present.
Efflux transporters cause efflux back of the drugs from the fetus to the mother.

• Plasma Binding Proteins

Many proteins exist in the plasma. Plasma binding proteins include:

• Albumin

Albumin is the most abundant plasma protein. It has higher affinity for acidic drugs but the
capacity is low. Only two sites are present for binding drug molecules.

However, albumin can bind a large number of basic drugs but has lower attractive forces. Its
capacity for binding basic drugs is more but the affinity is less.

• Globulins

Globulins can bind hormones, vitamins, etc.

• Glycoproteins

Alpha glycoproteins mainly bind basic drugs. Their levels are increased during stress, trauma
and surgery. It is during these times that their more amounts are required.

• Lipoproteins

Lipoproteins also bind some drugs.

Free and Bound Forms of Drugs

When drug enters the body, it exists in:

• Free form

• Bound form

These two forms have certain effects on the pharmacokinetics and pharmacodynamics. Free forms are
metabolized and excreted because they can cross the glomerular membrane. Free forms of drugs are
therapeutically active.
Bound forms of drugs act as a reservoir. They are not metabolized or excreted and do not have therapeutic
or toxic effect. When the free form is used up, drug is released from the reservoirs. Thus both forms exist
in equilibrium.

Significance:

• Bound form acts as a reservoir, providing free form when required

• Drugs having higher plasma protein binding if given in normal doses, are only used in binding
plasma proteins, with the result that less free form is available for therapeutic effect. Thus drugs
having higher plasma protein binding are given in larger doses at the start. This is known as
loading dose. This is to ensure that enough free form of the drug is available. Higher plasma
protein binding drugs include warfarin and phenytoin while those having negligible plasma
protein binding include lithium, metronidazole and myxothiazol.

• Drug Interactions

If a number of drugs are simultaneously given, or drugs interact with endogenous substances, one
drug can be displaced by another.

Example includes interaction of sulphonamide with bilirubin, with the result that bilirubin is
displaced which may cause kernicterus in babies.

Drug interactions occur if both drugs bind to same protein and depend on:

• Affinity

Higher the affinity of the drug, more easily can it displace the other drug.

• Concentration

Higher concentration drug can displace the lower concentration drugs.

This phenomenon might be of consequence in the following situations:

• Volume of Distribution:

The volume into which the drug is distributed is known as the volume of distribution. If
drug can be distributed to different body compartments, it is diluted when goes to the
different compartment. If the drug has a small volume of distribution, it stays in the same
compartment producing toxic effects. (Explained separately)

Toxic effects are produced when more drug is present in free form than usual.

• Therapeutic Index

Therapeutic index is the safety margin, the range in which the drug is safe. If drug has a
large therapeutic index, then large concentrations of the drug are safe. If it has a small
 therapeutic index, it may move out of the safe range and cause toxic effects. Thus the
drug displacement phenomenon is significant in low therapeutic index drugs.

• Disease States

Different diseases affect the distribution of drugs. Renal diseases cause hypoalbuminemia. Due to
less proteins, toxic levels of free drugs may be present. Uremic by-products are also produced
which compete with drugs.

Hepatic diseases cause decreased synthesis of proteins causing hypoalbuminemia. Free drugs may
be present in toxic levels and bilirubin by products increase as well.

Thus drug, whose doses have to be adjusted to produced desired effects (may be reduced even to
half).

• Drug Reservoirs

Drugs are stored and are released slowly which affects their pharmacokinetics and
pharmacodynamics. Drug reservoirs include:

• Plasma proteins

• Liver

• Adipose

• Bone

• Placenta

• Breast milk

• Transcellular fluid reserves

• Other body tissues- eye, kidneys, skeletal muscles, skin

• Volume of Distribution

The apparent or hypothetical volume in the body into which a drug distributes.

Compartments:

First of all the drug enters the plasma which is approximately 4 liters. Heparin is a large
molecular drug, it does not cross blood vessel lining, thus volume of distribution is less.

Gentamicin, an antibiotic leaves the plasma to enter the interstitial fluid, its volume of distribution
is approximately 14 liters.

Some drugs like ethanol pass from the interstitial fluid to the intracellular fluid and enter the fluid
of the cells, thus have the volume of fluid approximately 42 liters.
 We cannot measure the volume of distribution beyond the intracellular fluid. Drug does not stay
here but binds cell membranes, enzymes, nuclear proteins and transporting proteins. All of this
volume cannot be measured by any means.

Thus we say that the volume of distribution is the apparent volume. Each drug has different
plasma binding and cellular binding values.

Volume of distribution can be calculated as:

Vd = D/C

Where D is the dose while C is the concentration. Dose is the total amount of drug being given
while concentration is found from the plasma.

Significance:

• If we know Vf and the concentration required, we can calculate the appropriate dose.

• Drugs having large volume of distribution have to given in large loading doses, so that
binding proteins can be saturated first. Example includes chloroquinine, 4 tablets of which are
given at the start, then smaller doses are used subsequently.

• Relation with half life and duration of action.

Half life is prolonged when drug stays for a longer duration in different compartments.
Chloroquinine has a half life of 45 days, while that of gold is 1 year. Thus the duration of
action is prolonged.

Redistribution of Drugs:

The movement of drug from more perfused organs to less perfused organs is known as redistribution of
drugs. Initially the heart, liver, kidneys, brain and other highly perfused organs receive most of the drug,
during the first few minutes after absorption.

1.11 Bioavailability
Fraction of the dose of a drug contained in any dosage form that reaches the systemic circulation in
unchanged or active form administered through any route is known as bioavailability.

Drugs injected using intravenous route of administration have 100% bioavailability, while others have
much less bioavailability, because:

• All of the drug may not be adsorbed

• Metabolism of the drug might occur before reaching the site of action
Drugs not absorbed by the oral route are highly polar drugs, thus have low bioavailability.

Bioavailability = AUC (oral)/ AUC (I/V) x 100

Where AUC is the area under the curve

X-axis represents time, while y-axis represents the plasma concentration.

Bioavailability is the ratio of the area calculated for oral route of administration to the intravenous route
of administration. It is determined by comparing the plasma levels of a drug after administration with
plasma drug level achieved by I/V injection.

Factors Affecting Bioavailability:

• Route of administration

Drugs given by intravenous route have 100% bioavailability. Exception includes prostaglandins,
which are inactivated/metabolized in the lungs, therefore, their bioavailability may be zero after
I/V injection. Those given by intramuscular route have bioavailability less than I/V route but
more than subcutaneous route, while subcutaneous route has bioavailability more than the oral
route. Only 10% of the dose of digoxin reaches systemic circulation after oral administration
because of lack of absorption and bacterial metabolism within intestines. Even some of the drugs
given by oral route may have 100% bioavailability but this is rare.

By rectal route, half of the drug undergoes first pass metabolism.

Chloramphenicol, an antibiotic, administered by intravenous route has bioavailability less than

oral route because it is present in pro form and has to be activated in the intestines.

Route Bioavailability Characteristics

Intravenous 100% Most rapid
Intramuscular 75≤100% Large volume may be injected
but painful method
Subcutaneous 75≤100% Smaller volume than IM, may
be painful
Oral 5≤100% Convenient, first pass
metabolism occurs
Rectal 30<100% Less first pass metabolism
than oral route
Inhalation 5<100% Rapid onset
Transdermal 80≤100% Usually slow absorption, lack
of first pass metabolism and
prolonged duration of action

• Factors affecting absorption

 Factors affecting absorption may be classified as those related to the drug and those related to the
body. They have been discussed separately. If absorbance is decreased, bioavailability is
decreased and vice versa. For a drug to be readily absorbed, it must be hydrophobic yet have
some solubility in aqueous solution.

• First pass metabolism

Pre systemic metabolism en-route from the route of administration to the site of action is known
as the first pass metabolism. Most common site of first pass metabolism is the liver because after
absorption the drug administered by oral route enters the portal circulation to reach the liver. First
pass metabolism may also occur in the intestines, lungs adrenals or any other organ.

Significance:

• Drug undergoing first pass metabolism has low bioavailability, the dose must be adjusted
keeping this in mind.

• If a person is undergoing a liver disease, bioavailability may be increased, because most

drugs then enter systemic circulation in unchanged form. The dose must be decreased
otherwise toxic effects might result.

Drugs undergoing first pass metabolism and sites:

• Bronchial mucosa:

Prostaglandins, nicotine and isoprenaline

• Intestinal mucosa:

Chlorpromazine, levo dopa, tyramine, alpha methyl dopa, testosterone and progesterone

• Liver:

Glyceryltrinitrate, amitriptyaline, nortriptyaline, imipiramine, pentazocine, lignocaine,

propanolol, labetalol, cimetidine and pethidine.

Glyceryltrinitrate is administered sublingually, by oral route it has almost 0% bioavailability.

Lignocaine is a local anesthetic and antiarythmic drug, its bioavailability by oral route is also
0%.

Highly polar drugs also have 0% bioavailability. They are not absorbed from the intestine.
Examples include streptomycin and gentamicin.

Extraction Ratio:

The effect of first pass metabolism on bioavailability is measured by extraction ratio.

Extraction ratio = Clearance by liver/Hepatic blood flow

 Where clearance is the amount of drug cleared from the unit plasma in unit time by liver.

Systemic bioavailability = Absorption x (1- Extraction ratio)

• Chemical Instability

Drug may be destroyed by the HCl or enzymes present in the GIT. Benzyl penicillin is not given
orally because it is destroyed by HCl. Parenteral route is generally preferred.

• Quality control

Quality control is related mainly to different brands. One drug might be manufactured by
different companies. These brands have different bioavailability although the drug is same. The
difference lies in the manufacturing process.

• Particle size:

Greater the size, smaller is the absorption. Size is inversely proportional to bioavailability.
Small particle size is important for absorption of corticosteroids, chloramphenicol and
griseofulvin.

• Diluents/Excipients

Inactive ingredients which do not have pharmacological action. These are important when the
drug is given in solid forms (tablets, capsules, pills). Drug before absorption must disintegrate
and dissolute. Disintegration and dissolution may differ with different brands. If dissolution
time is more, bioavailability will be less and vice versa.

These are added to:

• Increase bulk when dose is very low e.g. digoxin

• Adding stability, making drug resistant to environmental conditions

• Mask objectionable taste of drug

Excipients

Excipients are the inert substances added to the tablets or pills to increase their bulk because
sometimes the dosage is very small.

Diluents

Diluents are inert substances used in case of liquids. Commonly used diluents include lactate,
lactose, starch, sucrose, calcium phosphate.

Diluents and excipients may affect bioavailability of different brands. They may bind with
the active principle. Sometimes when the patient is taking one brand for a very long time,
suddenly bioavailability may change by changing the company.
 • Compression pressure

If tablets or pills are more tightly bound, the bioavailability is decreased.

• Moisture content/Binding agents

Moisture content may act in two ways:

• If the moisture content is more, disintegration time is less

ii. Sometimes some drugs when have more moisture, form lumps in the stomach, which
decreases their absorbance.

Thus moisture content may act both ways.

• Polymorphism

When the drug is chemically same but different in arrangement of molecules, the
phenomenon is known as polymorphism. Arrangement of molecules may be different with
different brands.

Disintegration time:

The time in which a solid dosage from administered orally releases the active drug for absorption is called
disintegration time.

Clinical Significance:
Bioavailability differs with the dosage forms. Drug in liquid form have more bioavailability than those of
solids, while gases have the highest bioavailability. This is why inhalation is used in bronchial asthma.

With the same brand, dosage form manufactured by different companies may differ in bioavailability.

Three terms are generally used:

• Bioequivalent:

If two similar drugs have the same bioavailability, they are called bioequivalent. If the two
similar drugs do not have the same bioavailability, they are called non-bioequivalent.

• Therapeutic equivalent

If two similar drugs perform the same effect, have same efficacy and toxicity, then they are called
therapeutically equivalent.

• Chemical Equivalent

If two drugs are manufactured according to the same principles and criterion layed down in
pharmacopoeia (official book published by country to manufacture drugs in that country), then
they are called chemically equivalent.
Two brands may be chemically equivalent but may not be bioequivalent and therapeutically
equivalent because they might differ in the factors mentioned above.

Sensitive Drugs:

• Antimicrobials

• Anticonvulsants

• Corticosteroids

• Cardio active drugs

• Oral antidiabetics

• Chemotherapeutic agents for cancer

If patient is stabilized on one brand, it should not be changed, because if the bioavailability is
decreased the drug will have less effect or if the bioavailability is increased, it might lead to
toxicity.

Antimicrobials:

Anti tuberculosis drugs have to be continued for six to nine months. Recurrence of disease might
occur on changing to brand with less bioavailability, although symptoms disappear after four
weeks. Bacteria may also become resistant.

Anticonvulsants:

Anticonvulsant dose is adjusted by starting from a lower dose to reach the state where patient is
free from fits. Drugs have to be continued for the whole life. If the brand is changed reappearance
of convulsions might occur due to decreased bioavailability. Phenytoin is a drug of low
therapeutic index. There exists small difference between toxic and therapeutic effects which must
be taken care of.

Cardio active drugs:

Cardio active drugs like digoxin have low therapeutic index. Small changes in plasma levels may
lead to toxicity.

Oral antidiabetic drugs:

Oral anti diabetic drugs have to be continued for the whole life. If bioavailability is increased, it
may lead to hypoglycemia and fainting. Decreased bioavailability may cause hyperglycemia and
diabetic complications.

Chemotherapeutics have low therapeutic index too. Plasma levels of corticosteroids matter as
well.

We have to adjust the dose so that therapeutic failure does not occur.
 Therapeutic Index:

Therapeutic index represents the safety of a drug. Drugs having large therapeutic index and safer
and vice versa.

Therapeutic index = LD50/ED50 = TD50/ED50*

Where, LD50 is a dose which can kill 50% of the animals administered

ED50 is a dose which can save 50% of the animals

TD50 is the median toxic dose

ED50* is the median effective dose

Drugs having low therapeutic index include:

Anticonvulsants, lithium, anticoagulents, corticosteroids and cardio active drugs.\

Therapeutic Window:

Therapeutic window is the range between the high therapeutic index and low therapeutic index. Drugs
with low therapeutic index have a narrow therapeutic window.

Drugs having 100% bioavailability

Drugs having 100% bioavailability include chlordiazepoxide, diazepam, lithium, metronidazole,

phenobarbitol, salicylic acid, trimethoprin and valproic acid.

1.12 Plasma Half Life

Onset, duration and intensity of effect of drug depends on the rate of absorption, distribution and
elimination (biotransformation, excretion). In case of oral route, plasma concentration gradually rises and
reaches its peak value, then it begins to fall down. Drug requires a minimum effective plasma
concentration for the effects to start appearing. Once the level falls below the minimum effective plasma
concentration, the effect is over.

“Time required for the concentration of a drug to fall to half of its initial concentration after reaching its
peak.” For example, after intravenous administration, if maximum concentration is 16 mg and the half life
is 2 hours, after 2 hours 8 mg will be left, and so on.

Half life of a drug is directly proportional to the volume of the distribution and inversely proportional to
the clearance.

Half life = 0.693 x Vd/ total body clearance

Alpha half life = plasma / distribution half life

Beta half life = tissue / elimination half life

Most of the drugs have alpha half life and remain in the plasma. Drugs having beta half life have two half
lives, one in the plasma and one in the tissues. They are highly distributed drugs. Their total time of
elimination Is more.

When the drug is absorbed and reaches the plasma, it is distributed to the tissues. Some drugs have high
volume of distribution and are distributed to various tissues, mostly adipose tissue. More time is required
for their elimination, thus have greater half life. More the clearance of a drug, shorter is the half life.

Thiopentone sodium is used as a general anesthetic. It is administered through intravenous route and has
very short duration of action (about 5 to 10 min). After administration, the drug immediately goes to the
brain, produces its effects, then leaves plasma to get deposited in the tissues. It is slowly released from
here. Once it leaves the brain, person regains consciousness but because it is deposited in the tissues,
person keeps on feeling drowsy. Elimination half life is about 7 to 10 hours. Alpha half life is about 2 to
5 minutes.

Plasma half life of some drugs:

Drug Half Life

Acetylcholine, GABA, catecholamines Milliseconds

Adenosine 10 seconds

Aspirin 15 minutes

Propanolol 4 hours

Digoxin 39 hours

Digitoxin 168 hours

Amiodarone more than 100 days

Factors affecting Half Life:

• Plasma protein binding:

Protein bound drug produces no effect and is not excreted because proteins are not filtered by
glomeruli. It is thus slowly released. Drugs having plasma protein binding have longer half life (
directly proportional). Acidic drugs bind albumin while basic drugs mostly bind globulins.

Example includes warfarin, an anticoagulant, having very long half life due to extensive protein
binding.

The bound drug:

 • Is not distributed to tissues (stays in plasma)

• Has no pharmacological activity

• Is not metabolized (no biotransformation)

• Pharmacokinetic pattern

The rate of absorption, metabolism. Biotransformation and excretion are considered in

pharmacokinetic pattern. Most important pattern is the pattern of elimination of drug, consisting
of:

• Biotransformation

• Excretion

Pharmacokinetic pattern of drug elimination can be divided into:

• First order kinetics:

In first order kinetics, fixed fraction of drug is eliminated in unit time. If plasma
concentration of a drug is 100 mg and fixed fraction is 10%, after first hour 10 mg will be
eliminated, after second hour 9 mg will be eliminated, and so on.

• Zero order kinetics

In zero order kinetics, fixed amount is excreted in unit time. If plasma concentration of a drug
is 100 mg and fixed amount is 10 mg, after first hour 10 mg will be eliminated, after second
hour 10 mg, and so on. The capacity of body to eliminate drug is saturable, so also called
saturation kinetics.

Elimination is proportional to plasma concentration in first order kinetics, but not in zero
order kinetics. Half life is achieved early in zero order kinetics. Half life of drugs following
first order kinetics is not affected by dose of the drug, which is not the case with zero order
kinetics.

Most of the drugs follow the first order kinetics in therapeutic doses. When the dose is
increased, ultimately a point is reached where systems of metabolisms become saturated, then
only a fixed amount of the drug is excreted in unit time.

Significance:

Drugs which follow the first order kinetics have a constant half life. Drugs following zero order
kinetics do not have a constant half life. Their increased dose increases plasma concentration
which increases half life.

In toxic doses, drugs follow the zero order kinetics. Certain drugs follow zero order kinetics in
therapeutics after a small increase in dose. These include:
 • Alcohol

• Phenytoin

• Salicylates

Doctor needs to be extra careful with these drugs and monitor their plasma levels. Alcohol stays
in blood because of zero order kinetics. Thus a dose of alcohol taken at night is still present in the
blood in the morning.

• Renal/hepatic diseases

Half life Is increased in kidney diseases because the elimination is less. Half life is also increased
in hepatic diseases because the metabolism is not taking place. Aminoglycosides get accumulated
in renal diseases as they are excreted through glomerular filtration.

• Active metabolites:

Some of the drugs when taken need to be converted to active metabolites. Thus they have longer
half life. Example includes diazepam, which is a sedative hypnotic. It has 72 hours long half life.
Aspirin has a half life of 15 minutes but salicylic acid has half life of 2 hours.

• Enterohepatic circulation

Some drugs are metabolized in the liver. They are conjugated with glucuronic acid and excreted
into the bile. In the intestines, the conjugate is broken down by the bacteria and enzymes. The
active drug is released and is reabsorbed. These drugs have a longer half life. Examples include
rifampicin, doxycycline, spironolactone and digitoxin.

Oral contraceptives undergo enterohepatic circulation, thus their dose must be adjusted. When
interference with the enterohepatic circulation occurs (gastritis or diarrhea), decreased
reabsorption and decreased half life is observed leading to therapeutic failure

• Volume of Distribution

Greater the volume of distribution, more is the half life.

Clinical Significance:
• Rate of elimination

Rate of elimination is the rate at which drug is eliminated from the body. Certain minimum
plasma levels of a drug have to be maintained for the effect to occur. Drugs having shorter half
lives are given in frequent doses. Drugs which are eliminated slowly, are given with less
frequency. About 90-95% of the drug is eliminated after four half lives.

• Duration of Action
 Drugs having longer half life have more duration of action and vice versa. Ranitidine has a half
life of only 2 hours, but duration of action is about 12 hours. Although its concentration falls in
the plasma but binding to site of action is tight.

• Interval between doses

Drugs having short half life, the interval between the doses is kept short and are given frequently
to maintain minimum effective plasma levels.

• Time for steady state

When the drug is given by constant intravenous infusion or given repeatedly in fixed doses at
fixed intervals, plasma concentration of drug rises gradually, and if patient is still taking the drug
at fixed intervals and doses, it reaches a peak value and then plateau is reached.

This is because the amount of drug being administered is equal to the amount of the drug being
eliminated, which is called the steady state.

The amount of the dug in plasma becomes constant. This can only be reached when fixed doses
of drugs are given after regular intervals. At steady state, elimination kinetics = assimilation
kinetics.

After about five plasma half lives the steady state is achieved. Drugs having longer half lives take
longer time to reach the steady state. Drugs having longer half lives have no immediate effect.

For the drugs which need to be monitored, first sample is taken after the steady state has been
reached.

Lithium for bipolar disorder is an example. Plasma levels are maintained by repeated
examinations because the drug can be toxic. Its half life is about 24 hours, so the plasma levels
are checked after 5 days.

• Time for complete elimination

Drugs having short half lives have shorter time for complete elimination. 90-95% of the drug is
eliminated after four half lives.

Clinical Situations involving Increased Half Life

• Decreased renal plasma flow, e.g. heart failure, cardiogenic shock, hemorrhage.

• Increased volume of distribution

• Decreased excretion ratio as in renal diseases

 • Decreased metabolism e.g. cirrhosis of liver.

Drugs having half life less than two hours:

Aspirin, ACTH, cephalosporins, chlorthiazide, heparin, lignocaine, methyl dopa, naloxone,

penicillin G (30min), dobutamine (I min), esmolol

Drugs having half life between two to five hours

Atropine, cimetidine, indomethacin, paracetamol

Drugs having half life between ten to twenty four hours

Amitriptyline, imipramine, practolol, theophylline

Drugs having half life greater than thirty six hours

Diazepam, digoxin, phenobarbitone, thyroxin, warfarin, piroxicam (48 hrs).

1.13 Biotransformation of Xenobiotics

“Enzymatic modification of the drug occurring within the living organisms or chemical transformation a
drug goes through in living organisms or biological fluids is known as biotransformation”.

Biotransformation occurs in those foreign agents to whom the body is exposed, which may be for
therapeutic, intentional, unintentional or recreational purposes. Once these agents gain entry, they
undergo chemical reactions or remain inert. Whenever these drug molecules are administered,
pharmacokinetic process occurs, first absorption sets into play, then distribution, metabolism and finally
elimination takes place.

Drug at site of administration

Absorption Distribution

Drug in plasma Metabolism

Drug metabolites Elimination

Biotransformation occurs only for the agents at physiological pH, having low molecular weight and less
complex. Highly lipophilic, non-ionized, high molecular weight, or agents complexed with tissue or
plasma proteins are not biotransformed easily.

Biotransformation is a process specifically to make agents more polar and excretable. If biotransformation
does not occur, drugs may have longer duration of action, and undesired effects are observed along with
desired ones. Biotransformation, in fact, is the inactivation of pharmacological action of drugs.
Biotransformation may convert drugs to active metabolites or inactive sometimes toxic metabolized
products.

Prodrugs:

Prodrugs contain parent drug compounds in inactive form. Active specie is required to be carried to the
site of action. Prodrugs carry maximum amount of specie to site of action. These prodrugs have minimum
biological activity, longer half life and low toxic activity. They undergo biotransformation to bring about
desired results.

Advantages of Prodrugs:

• More stable

• Better bioavailability

• Low side effects

• Less toxic

• Desirable pharmacokinetic profile.

• Increase concentration of drug at site of action.

• Increase duration of action of drug

Examples include:

• Chloral hydrate converted into trichloroethanol

• Phenacetin converted into paracetamol

• 6-metacaptoprine

• Cortisone converted into hydrocortisone

• Prednisone converted into prednisolone

• Clorazepate

• Dipivefrin

• Enalapril converted into enalaprilat

First pass Effect:

Presystemic metabolism of drug compounds, more commonly seen with oral drugs. Drugs are absorbed
from gut, enter portal blood, reach liver, are metabolized and delivered to general circulation.

Drugs undergoing first pass effect have low bioavailability, hence first pass metabolism contributes to
termination of activity of drug, along with biotransformation.
Drug Biotransformation:
Sites:

Liver is the main organ. Others include GIT, lungs, kidneys, skin, adrenals and blood (plasma).

Some of the drugs biotransformed at these sites include:

• Liver:

Meperidine, pentazocine, morphine, nitroglycerine, lidocaine, propanolol, paracetamol, prazosin.

• GIT:

Insulin, catecholamines, clonazepam, chlorpromazine, tyramine, salbutamol

• Lung:

Prostanoids

• Plasma:

Suxamethonium

Types of Biotransformation:
• Enzymatic

• Microsomal

• Non-microsomal

• Non-enzymatic (Hofmann Elimination)

Non Enzymatic Elimination:

Spontaneous, non-catalyzed and non-enzymatic type of biotransformation for highly active, unstable
compounds taking place at physiological pH. Very few drugs undergo non-enzymatic elimination. Some
of these include:

• Mustin HCl converted into Ethyleneimonium

• Atracurium converted into Laudanosine and Quartenary acid

• Hexamine converted into Formaldehyde

• Chlorazepate converted into Desmethyl diazepam

Enzymatic Elimination:
Biotransformation taking place due to different enzymes present in the body/cells is known as enzymatic
elimination.

Non-Microsomal Biotransformation:

The type of biotransformation in which the enzymes taking part are soluble and present within the
mitochondria. Examples include:

• Xanthine oxidase converting hypoxanthine into xanthine.

• Cytotoxic agent 6-mercaptocurine

• Monoamine oxidase involved in non-microsomal metabolism of catecholamines and

noradrenaline.

• Alcohol dehydrogenase responsible for metabolism of ethanol into acetaldehyde

• Tyrosine hydrolases enzymes

Microsomal Biotransformation:

Enzymes responsible are present within the lipophilic membranes of endoplasmic reticulum. After
isolation and putting through homogenization and fractionation, small vesicles are obtained, known as
microsomes. They possess all functional, morphological properties of endoplasmic reticulum i.e. smooth
and rough. Smooth ER is concerned with biotransformation and contains enzyme components while the
rough ER is mainly concerned with protein synthesis.

Enzymes isolated from ER possess enzymatic activity termed as microsomal mixed function oxidase
system.

Components:

• Cytochrome P450 (ferric, ferrous forms)

• NADPH (flavoprotein)

• Molecular oxygen

• Membrane lipids

Cytochrome P450:

Cytochromes are the heme proteins, present abundantly within the living kingdom. They have about
thousand known kinds. Only 50 of these heme proteins are found within the humans, which are divided
into 17 families and sub-families. Name is derived because it is a heme protein (abbreviation cyp) and
450 because it reacts with carbon monoxide and during the reaction absorbs light at 450 nm.

NADPH

NADPH is a flavoprotein, less abundant than cyp 450.

For every 10 molecules of cytochrome P450, only one NADPH cytochrome reductase is present.

Cytochrome P450 cycle, RH is parent drug, ROH is oxidized metabolite, e- is electron.

Biochemical Reactions:
• Phase I reactions

• Phase II reactions

Phase I reactions:

Phase I reactions are non-synthetic catabolic type of chemical reactions occurring mainly within the ER.
They are the reactions in which the parent drug is converted into more soluble excretable agents by
introduction or unmasking of functional component.
Example includes phenobarbitone, aromatic hydroxylation of which abolishes its hypnotic activity.
Similarly, metabolism of azathioprine produces 6-mercaptopurine.

Drug products, which are water soluble are excreted by the kidneys. Sometimes this is not true and phase
I compounds do not result in true inactivation and may act as functional components of phase II reactions.

Phase I reactions include:

Oxidation

Reduction

Hydrolysis

Oxidation:

Hydroxylation

• Hydroxylation of aromatic ring

e.g. phenobarbitone is converted into p-hydroxy phenobarbitone

• Aliphatic hydroxylation

e.g. Meprobamate is converted into hydroxymeprobamate

Dealkylation

Conversion of mephobarbitone into phenobarbitone

O-Dealkylation

Conversion of codeine into morphine.

N-oxidation:

Conversion of aniline into nitrobenzene

Sulfoxidation

Conversion of chlorpromazine into chlorpromazine sulfoxide

Deamination

Conversion of amphetamine into phenylactate.

Desulfuration

Conversion of parathion into paraoxon

Reduction
Chloramphenicol, dantrolene, clonazepam

Hydrolysis

Esters: procaine, suxamethonium and aspirin

Amides: procainamide, lidocaine

Consequences of Phase I reactions:

• Active drug may be converted into inactive metabolite. Active parent drug inactivation may
terminate biological activity.

• Active drug may be converted into active metabolite. E.g. morphine is converted into more active
metabolite.

• Prodrug may be converted into active metabolite

• Active drug may be converted into toxic metabolite

e.g. halothane used in general anesthesia, is converted into trifluoroacetylated compound or

trifluoroacetic acid, leading to hepatic toxicity.

5. Biotransformation of xenobiotics to mutagenic or carcinogenic agents.

6. Conversion of xenobiotics into harmless compound.

Phase II reactions:

Phase I metabolites if not readily excretable or contain component ends, combine with endogenous
substrates like glucuronic acid, sulphuric acid, amino acid or acetic acid, to undergo conjugation
reactions, yielding more excretable drug conjugates which are excreted by the kidneys. Phase II reactions
are said to by synthetic, occurring within cytosol, while some occur within mitochondria.

Phase II reactions lead to :

• Usually inactivation of drug

• Production of water soluble metabolites, which is the main aim of biotransformation.

• Usually detoxification reaction for xenobiotics (as some substances might be carcinogenic)

• There are some important exception, toxic metabolites may be produced by their activation, e.g.
methanol is converted into formaldehyde, which is toxic.

• Certain conjugation reactions may lead to the formation of reactive species responsible for the
hepatotoxicity of drugs.

• Products produced might be more potent e.g. M-6-P.

 Reactions are mainly conjugate reactions. Normally phase I reactions are followed by phase II
reactions but in case of isoniazid (antituberculous drug), phase II reactions occur before phase I
reactions because N-acetyl moiety acts as an endogenous substrate for the conjugation reaction. This
is followed by phase I hydrolysis to isonicotinic acid.

Effects of Phase II reactions on drugs

• Lipid solubility is totally converted into solubility.

• Drugs are generally inactivated

• Sometimes drugs are activated e.g. minoxidil is activated to minoxidil-o-sulphate (a vasodilator).

Morphine is activated to morphine-6-glucuronide.

Type of Endogenous Transferrase Types of Examples

Conjugation Reactant (Location) Substrates
Glucuronidatio UDP glucuronic UDP Phenols, Nitrophenol,
n acid glucuronosyl alcohols, morphine,
transferrase carboxylic acetaminophen,
(microsomes) acids, diazepam, N-
hydroxylamines hydroxydapsone
, sulfonamides , sulfathiazole,
meprobamate,
digitoxin,
digoxin
Acetylation Acetyl-coA N-acetyl Amines Sulfonamides,
transferrase isoniazid,
(cytosol) clonazepam,
dapsone,
mescaline
Glutathione Glutathione (GSH) GSH-S- Epoxides, arene Acetaminophin,
conjugation transferrase oxides, nitro ethacrynic acid,
(cytosol, groups, bromobenzene
microsomes) hydroxylamines
Glycine Glycine Acyl-coA Acyl-coA Salicylic acid,
conjugation glycinetransferas derivatives of benzoic acid,
e (mitochondria) carboxylic acids nicotinic acid,
cinnamic acid,
cholic acid,
deoxycholic acid
Sulfation Phosphoasenosyl Sulfotransferrase Phenols, Estrone, aniline,
phosphosulfate (cytosol) alcohols, phenol, 3-
aromatic amines hydroxy-
coumarin,
acetaminophen,
methyl dopa
Methylation S- Transmethylases Catecholamines, Dopamine,
adenosylmethionin (cytosol) phenols, amines epinephrine,
e pyridine,
histamine,
 thiouracil
Water Water Epoxide Arene oxides, Benzopyrene
conjugation hydrolase cis-disubstituted 7,8-epoxide,
(microsomes) and mono- styrene 1,2-
subsituted oxide,
oxiranes carbamazepine
epoxide
(cytosol) Alkene oxides, Leukotriene A4
fatty acid
epoxides

Phase III reactions:

Some reactions coupled with excretory pumps in the cell membranes are known as phase III reactions.
Drugs undergoing these reactions, is still the subject of extensive research even today.

1.14 Factors affecting Biotransformation

1. Enzyme Induction:

When drugs given over prolonged period of time, upregulation of enzymes takes place. Most of the time
cytochrome P450 is involved leading to increased synthesis of new enzymes. The rate of metabolism
increases as enzyme induction takes place. The drugs which bring about these changes are known as
enzyme inducers. Some examples include anticonvulsants like phenytoin, carbomycin and chronic
alcoholism. Others include various sedatives, hypnotics, tranquilizers and insecticides.

When drugs are taken together, sometimes drugs acting as enzyme inducers for others cause increased
metabolism of themselves, which is known as autometabolism. Example includes artemether and
carbamazepine when taken together.

Enzyme induction is brought about by gene transcription, which is enhanced. Enzyme induction leads to a
decreased levels of the parent dug and increased levels of metabolites. Sometimes toxic metabolites are
also produced. The rate of reaction increases and more quicker conversion of parent drug takes place.

Drugs following first pass metabolism, have decreased bioavailability.

Significance:

Care should be taken when enzyme inducers are given, Especially when two drugs are given together,
drug-drug interaction might occur, leading to therapeutic failure.

• Rifampicin is an enzyme inducer. If it is taken by female patients taking contraceptives,

decreased therapeutic effect might occur, leading to pregnancy. Therefore, the dose should be
increased.
 • Phenobarbitone is used in seizures and epilepsy. It is also an enzyme inducer. If it is administered
to patients taking warfarin, therapeutic failure might occur, leading to increased bleeding
tendency.

Some enzyme inducers include:

• Ethchlorvynol enhances metabolites of warfarin

• Phenytoin enhances metabolism of cortisol and digitoxin

• Rifampicin increases metabolism of digitoxin

• Barbiturates

• Chloral hydrate

• Erythromycin

Drugs which are significantly affected by enzyme induction include:

• Phenytoin

• Warfarin

• Tolbutamide

• Imipramine

• Oral contraceptives

• Chloramphenicol

• Doxycycline

• Theophylline

• Griseofulvin

• Phenylbutazone

Consequencs of Microsomal Enzyme Induction

• Decreased intensity and duration of action of drugs e.g. failure of contraceptives

• Increased intensity of action of drugs activated by metabolism. E.g. acute paracetamol toxicity is
due to one of its metabolites.

• If drug induces its own metabolism e.g. cicobarbitone it develops tolerance so effects are not
produced.
 • Precipitation of acute intermittent porphyria. Enzyme induction might increase porphyrin
synthesis.

• Intermittent use of an inducer might interfere adjustment of dose of another drug e.g. oral anti
coagulants, oral hypoglycemic, antiepileptics and antihypertensives.

Auto induction

The phenomenon in which a drug induces metabolism of other drugs as well as its own. E.g.
carbamazepine-antiepileptic.

2. Enzyme Inhibition

The process in which drug metabolizing capacity of cyp is decreased is known as enzyme inhibition. The
rate of metabolism is decreased. Drugs bringing about these changes are known as enzyme inhibitors.
Examples include ketoconazole- antifungal drug, cimetidine and verapamil- calcium channel blockers.

Enzyme inhibition is a rapidly occurring process, most critical for the drugs having a large therapeutic
index. Competition for the active sites takes place between the enzymes and the given drugs. When
enzyme inhibitor attaches, less metabolism occurs. As rate of metabolism is decreased, plasma levels of
parent drug are increased while that of metabolites are low. Serious drug-drug interactions might occur, as
the plasma half life is also increased.

Sulfonamides decrease the metabolism of phenytoin so that its blood levels become toxic. Cimetidine
decreases the metabolism of propanolol leading to enhanced bradycardia. Metabolism of tolbutamide is
inhibited by phenylbutazone or coumarins, leading to prolonged hypoglycemia. Oral contraceptives
inhibit metabolism of antipyrine.

3. Presystemic Metabolism/First pass effect/Route of Administration

Drugs following first pass metabolism have decreased bioavailability. Most of the drugs are metabolized
within the liver. Changing the route of administration might change the first pass metabolism.

Propanolol is 80% metabolized before reaching systemic circulation.

4. Genetic Variations:

Inter individual variations might occur, as drugs behave differently in different individuals due to genetic
variations resulting in absent or malformed enzymes due to absent or malformed genes. Mostly non
microsomal enzyme show genetic variations. Examples include succinyl choline, which is a skeletal
muscle relaxant. It is metabolized by pseudocholine esterase. Some people lack this enzyme, due to which
lack of metabolism of succinyl choline might occur. When administered in those individuals, prolonged
apnea might result. Different groups of populations might be classified as fast metabolizers and poor
metabolizers of drugs. For certain drugs, like isoniazid, fast acetylators as well as slow acetylators are
present. Fast acetylators cause rapid acetylation, while poor metabolizers metabolize less. Hepatic acetyl
transferrase catalyzes acetylation. Slow acetylation might occur due to genetic malformation leading to
decreased production.
Fast metabolism may lead to hepatotoxicity while poor metabolism might result in peripheral neuropathy.
Absence of catalase may lead to achalasia, while G6PD deficiency predisposes erythrocytes to hemolysis
as a result of oxidative stress imposed by some commonly used drugs.

5. Species Differences

Species differences are most established in animals. Some metabolize drugs rapidly. Rats and rabbits
metabolize drugs more efficiently than humans. Certain species of rabbits feed on Belladonna, and have
atropinase to tolerate the effects of atropine. Research on humans is still going on. Asians, Orientals,
blacks and whites might have different drug metabolizing capacity. Examples include difference in drug
metabolizing capacity of certain anti malarial, amongst the Eskimos and the Asians. Eskimos may
metabolize drugs more efficiently than the Asians.

6. Exposure to Pollutants from Environment or Industry

Cigarette smokers might act as enzyme inducers. Chronic alcoholism might lead to enzyme induction as
well. Similarly, pesticides or insecticides may act as enzyme inducers.

In hot and humid climate biotransformation is decreased and vice versa. At high altitude, decreased
biotransformation occurs due to decreased oxygen leading to decreased oxidation of drugs.

7. Age

Age plays a very important role. Extreme age groups (very young and very old) behave almost the same.
Drug metabolizing enzyme develop early but their capacity is low. Thus the rate of metabolism is infants
is very low. Care should be taken in administering drugs in younger patients. True development of
enzyme occurs in one to two months.

Chloramphenicol (antimicrobial drug) when administered in infant, does not have great efficacy. Toxic
effects in the form of grey baby syndrome might occur. The baby may be cyanosed, hypothermic, flaccid
and grey in color. Shock and even death might occur if toxic levels get accumulated.

Diazepam (sedative hypnotic) may result in floppy baby syndrome in which flaccidity of the baby is seen.

In elderly, most processes slow down which leads to decreased metabolism. Shrinkage of organs occurs
as well along with decreased liver functions and decreased blood flow through the liver. All these factors
decrease the metabolism. Old people are usually taking multiple drugs, so are more prone. The drug doses
should be decreased in the elderly.

8. Sex

Male have a higher BMR as compared to the females, thus can metabolize drugs more efficiently, e.g.
salicylates (others might include ethanol, propanolol, benzodiazepam). Females, during pregnancy, have
an increased rate of metabolism. Thus, the drug dose has to be increased. After the pregnancy is over, the
dosage is decreased back to normal levels. Example includes phenytoin, whose dose has to be increased
during pregnancy (specially second and third trimester).

9. Drug-Drug Interaction
Toxic effects might result when drug combinations act as enzyme inhibitors and inducers. The dose has to
be adjusted accordingly.

10. Nutrition

Malnutrition may also effect biotransformation. Depletion of amino acids and glycine may affect drug
metabolizing capacity, especially during the phase II, which depends on the food stores. Synthesis of
microsomal enzymes depend on nutritional status.

11. Pathological Conditions

Most of the drugs are metabolized in the liver, any disease of which (cirrhosis, viral hepatitis, drugs
induced hepatitis, hepatocarcinoma) may affect and slow down the metabolizing capacity. Jaundice
depresses glucuronic acid conjugation and oxidative function of liver microsomes.

Cardiovascular diseases, although have no direct effect, decrease the blood flow, which may slow down
biotransformation of drugs like isoniazid, morphine and propanolol. Similarly pulmonary conditions may
decrease biotransformation. Procaine and procainamide hydrolysis is impaired.

Hypothyroidism increases drug metabolizing capacity (increased half life of antipyrine, digoxin,
methimazole, practolol) while hyperthyroidism decreases it.

12. Circadian rhythm

The rate of hepatic metabolism of certain drugs follow diurnal rhythm in rats and mice. This may be true
in humans as well.

Elimination of a Drug

The irreversible shift of a drug from one part of the body to other part of system is known as elimination.
It is from the more perfused parts to the lesser perfused parts. Elimination may be by:

• Biotransformation
• Excretion
Rate of elimination (ER) = Q (Ca-Cv)

Where Q is the quantity of drug going to the organ (blood flow to organ), Ca is the arterial concentration
of the drug and Cv is the venous concentration of drug.

Factors affecting Elimination

 • Perfusion of Organ
If the drug is rapidly or completely eliminated, then the rate of blood flow does not effect
elimination. E.g. mannitol is almost completely eliminated from kidneys; therefore increasing the
blood flow to the kidneys has no effect on elimination of mannitol. In cases of drugs not
completely eliminated, increased blood flow increases the rate of elimination.

• Binding to proteins/ Bound and unbound forms

If a drug is in bound form, its elimination is less and vice versa.

• Metabolism
Increased metabolism means decreased plasma half life and increased elimination.

• Clearance
Dopamine and prostaglandins cause vasodilatation of renal vessels, increasing their elimination.
Adrenaline causes vasoconstriction, leading to decreased blood flow and decreased elimination.
Renin is another vasoconstrictor.

1.15 Excretion and Clearance of Drugs

What drugs are taken in, they should be eliminated as well, as we do not want their action to continue
indefinitely. If they remain in the body, they might produce undesirable results. Excretion and clearance
are two separate terms but are closely linked together.

Excretion:
Drugs can be excreted in two forms:

• Unchanged drugs

• Form of metabolites

The primary role of biotransformation is to convert lipophilic drugs into hydrophobic compounds or to
convert non-excretable drugs into excretable forms. Being lipophilic is a property desirable for absorption
and passage through the body, but not for excretion.

Sites for Excretion

Kidneys
Kidneys are not fully developed in newborns. They mature in the first few weeks and attain normalcy.
Throughout the adult life, 1% decline per year in kidney functions occurs. Therefore, in almost all the
elderly, some renal impairment has occurred. While prescribing drugs, one needs to be extra careful in the
extremes of ages.

There are three important processes in urine formation; filtration, tubular secretion and tubular
reabsorption. If a disease process occurs resulting in renal impairment, all these three processes are
affected.

• Glomerular Filtration

The basement membrane and capillaries have a special structure with pores and fenestrations to
make the filtration rather easy. Certain factors influence the filtration. These include:

• Size- larger the size, filtration becomes more difficult.

• Plasma protein bound- negligibly filtered

Proteins also line the fenestrations and have a negative charge. Plasma proteins also carry a
negative charge. These two charges repel each other and prevent filtration of plasma proteins at
the Bowman’s capsule.

Still some drugs are freely filtered. These include a group of antibiotics known as amino
glycosides (gentamicin)

• Tubular Reabsorption

Tubular reabsorption is quantitatively much more important than tubular secretion. It is mainly a
passive process in which simple diffusion takes place. Some active transport at distal convoluted
tubules occurs as well. Simple diffusion is dependent on concentration gradient. This gradient is
created by the salt and water being reabsorbed continuously. This leads to an increase in
concentration of drugs present in the lumen of renal tubules. Although the process is passive, it
can be interfered by ionization of drugs. Ionized drugs will not diffuse passively. Ionized drugs
are surrounded by water molecules, which increase their size, impeding their passage through the
semi-permeable membrane.

Lipid soluble drugs when taken orally and converted to polar molecules, they have reabsorption
impeded by ionization in the renal tubules. Drugs which are acids or bases can be manipulated for
desired results. According to Henderson-Hasselbalch equation, if urine is made alkaline, more
acid will be ionized, while in for basic drugs, medium can be made acidic to impede reabsorption
and to increase secretion in the urine.

This fact is made use of in cases of poisoning. In cases of aspirin poisoning, which is an acidic
drug, only available option is to make the urine alkaline (by bicarbonates). Thus the drug is
ionized and not absorbed. For basic drugs, ammonium chloride and ascorbic acid may be given
for making the medium more acidic. Giving these compounds only once will not change the pH
indefinitely. Instead, they are given repeatedly as long as the required time

• Secretion
Secretion occurs mostly in the proximal tubules, which are divided into S1, S2 and S3. Several
transporters are involved in the process of secretion. Transporters for acidic drugs are located
mostly in S2. This is an active process. This is why some drugs can be actively secreted because
of tubular secretion. Group of antibiotics called penicillin and cephalosporins are secreted by
tubular secretion.

Similar to acids, the process for bases occurs in S1 and S2 for which several transporters are
found. Procainamide, an antiarrhythmic uses this process for elimination.

As secretion is an active process, it has certain attributes:

• Processes are saturable because transporters are limited and ultimately all binding sites are
occupied.

• Transporter is non specific. Many drugs may be competing, which is the basis of drug
interaction.

Some diuretics are actively secreted by tubular secretion in S2. Uric acid, an inherent substance,
is also secreted by this. Due to this, competition occurs and secretion of uric acid is impaired.
Individuals predisposed to gout may develop the disease because of hyperuricemia. This is why
serum uric acid levels are checked and proper history is taken for gout.

Another example is of penicillin 90% of which uses tubular secretion. Probenecid was used in
combination with penicillin, at the time in history when penicillin was rare and expensive. This
drug helped to reduce the dose of penicillin. Now as penicillin is widely available, this drug is not
used any more.

Elimination by Liver

Liver is the major site for metabolism. It converts lipophilic compounds into hydrophilic
compounds by phase I and II reactions, which makes the drugs more excretable. In membranes of
canaliculi, transporters for active secretion of drugs or metabolites are present as well. Thus the
process of elimination in liver takes two forms:

• Metabolism

• Tubular secretion

Enterohepatic circulation delays elimination of drugs.

Drug (oral)

Bile

Gut Biotransformation
 Liver

Portal circulation

In certain situations, lower portion of gut bacteria produce glucuronidases, which split conjugated drugs
and are reabsorbed. This prolongs the duration of action of drugs unusually. When drugs are being taken
along with antibiotics like tetracyclines or ampicillin, the antibiotics destroy these gut bacteria. Drugs like
oral contraceptives, which are steroids and have known enterohepatic circulation, have shortened duration
of action. Therapeutic failure might result.

Lungs

Lungs constitute the most different route of drug elimination. This is the only route by which lipophilic
drugs are excreted because they are absorbed through the alveolar membrane. Examples include general
anesthetics, which are gases pumped through the endotracheal tubes and diffuse across the alveolar
membrane. When stop their administration, pure oxygen is supplied. The body acts as a reservoir and
transport occurs in reverse. Thus lipophilic compounds are lost through the lungs. Alcohol breath is
another example which can be tested by alcohol breath test, by which alcohol in the excreted air is
measured.

Intestines

Drugs are mostly absorbed in the small intestine. Anthracene purgatives, which act mainly on the large
bowel, are partly excreted in to that area from the blood stream after absorption from small intestine.
Heavy metals are also excreted through the intestine and can produce intestinal ulcerations.

Minor Sources

Breast milk is important because many drugs are excreted in it. Some effects of the drugs may be
transferred to the baby, which may prove harmful. It is important to know which drugs are not to be used
during breast feeding. Milk being slightly acidic than plasma, weak bases get ionized and have equal or
higher concentration in milk than in plasma. Non electrolytes like ethanol and urea readily enter the milk
independent of pH. 70% of plasma concentration of tetracyclines may enter milk, prolonged usage of
which might cause permanent staining of teeth and weak bones in the baby. Ampicillin may lead to
diarrhea and allergic sensitizations. Chloramphenicol might lead to aplastic anemia in baby, bone marrow
suppression and grey syndrome. Morphine, opoids and smoking may cause lethargic baby.

If the mother is taking drugs, she should lactate the baby a few hours after taking drugs or most
preferably half an hour before intake.

Following drugs given to mother appear in milk to effect the infant adversely:

• Penicillin causes allergy

• Diazepam cause sedation
 • Ethanol causes alcoholic effects
• Iodine causes thyroid suppression
• Phenobarbitone causes sedation
• Propyl thiouracil causes suppression of thyroid
• Isoniazid
Other sources include tears, saliva and other body secretions. These are not quantitatively
important. Examples include:

• Klaricid and Flagyll produce an awfully bad taste because they are excreted in the saliva.

• Metronidazole produces dark colored urine.

• Hair and skin have forensic importance e.g. arsenic poisoning

• Rifampicin used as anti tuberculosis drug, gives body secretions orange color.

• Metronidazole is also excreted in the saliva producing bad taste or metallic taste

• Iodides and metallic salts are also excreted in the saliva. Lead compounds deposited as lead
sulphide produce blue line on gums

The patient should be educated about these changes.

Clearance
Unit volume of blood which is cleared off a drug per unit time is known as clearance.

Clearance is not a measure of how much drug is being eliminated; it is only a measure of how much
plasma is cleared of it per minute. Units are ml/min, sometimes ml/min/kg body weight are used.

Clearance =Quantity or volume of urine measured (ml/min) X conc. substances in urine (mg/ml)

Clearance = ml/min x mg/ml

= mg/min

Rate of elimination of a substance in urine is denoted by ROE. Clearance is the rate of elimination of
substance in urine divided by the concentration in the plasma/blood.

Clearance = mg/min / mg/ml

= ml/min

Total clearance = CL kidney + CL liver + CL…..

Factors affecting Clearance:

• Inherent ability of the clearing organ to eliminate the drug. Any disease process might
interfere.
 • Blood flow to the organ- which sometimes is dependent on cardiac output. In severe cases
functions of excretory organs might be affected.

Importance of Clearance

CL = ROE/C

ROE = CL x C

Organs when not diseased and drugs within therapeutic limits, the clearance remains constant. Thus, the
rate of elimination is directly proportional to the concentration of the drug. This is in fact, first order
kinetics which most of the drugs follow.

Once the plateau is reached, the zero order kinetics is followed, which may not be in the therapeutic
range.

All drugs effect a person at certain concentrations. This concentration is known as target concentration.
It is achieved only after four to four and a half, half lives. This is also known as the steady state. In order
to achieve this, we determine the dosage rate.

Rate of administration = Rate of elimination

ROA = ROE

ROA = CL x C

Thus the dosage rate can be found. Most important parameter is the clearance. If clearance is affected,
diseased state may lead to toxicity.

Four things determine the pharmacokinetic parameters for dosage rate:

• Clearance- most important parameter which needs to be adjusted in diseases of kidneys, liver to
lower levels
• Volume of distribution
• Bioavailability
• Plasma half life
Two things can be said inexplicably

• Excretion is the excretory process

• Clearance is how efficient excretory processes are.
1.16 Mechanism of Drug Action
All drugs bring about complex interactions with molecules of living systems. These actions, either
physical or chemical, mainly act at four levels:

• Molecular- Receptor, ion channel, enzyme, carrier molecules.

• Cellular- Transduction e.g., G protein, ion channel, enzyme

 • Tissue- Contraction, secretion, metabolic activity, proliferation

• System- CNS, CVS

Transduction:

The target molecules where the drugs act are linked with various biochemical reactions in the cells,
resulting ultimately in response. These may be enzyme linked, Ca linked or g-protein linked.

Local Effect

When the drug effect occurs in immediate vicinity of application, this is known as local effect.

Systemic Effect

When the drug effect occurs away from the site of administration, this is known as systemic effect.

Primary effect:

Primary effect is the effect for which the drug is administered or the treatment of the disease for which the
drug is given.

Side effect:

All other effects occurring in addition are known as secondary effects. When the secondary effects are
undesirable by the patient, these are called adverse effects or side effects.

Most drugs act by altering the various body control systems, which may be receptors, enzymes or ion
channels. These various mechanisms include:

1. Physical mechanisms

2. Chemical mechanisms

3. Drug- receptor interactions

4. Drug- enzyme interactions

5. Drug- channel interactions

6. Miscellaneous mechanisms

1. Physical Mechanisms
When the drug does not produce any chemical reaction or change in the cells of the body and the effect is
only physical, the mechanisms involved are called physical mechanisms. These include:

• Local Application- Emollients, Counter irritants, Massagers, pastes

• Physically acting antacids- Milk, Mucin

 • Bulk forming purgatives- Bran, Ispaghula, Magnesium sulphate

• Mannitol

• Liquid paraffin

• Activated charcoal

• General Anesthetics

• Rubfacients

• Astringents

1. Local Application:

Drugs are applied topically on the external surfaces like the skin and the mucous membranes.

Emolients:

Emolients are the oily substances used to soften the skin especially dry skin.

Counter Irritants:

Counter irritants are the substances applied locally on intact skin to abolish deep musculoskeletal pain.
They mask the pain sensations.

2. Antacids

Antacids are the drugs which neutralize the acids in the stomach. They form a coating over the surface of
the stomach and adsorb HCl on their surface.

3. Bulk forming Purgatives

Purgatives are the drugs used to treat constipation. Bulk forming purgatives contain high fiber. This fiber
by adsorbing water swells, increasing the bulk of stools causing distention of the colon. This leads to an
increase in peristalsis and evacuation of the bowel.

4. Mannitol

Mannitol is an osmotic diuretic which increases urine formation. It is freely filtered, not reabsorbed and
produces osmotic effect.

5. Liquid Paraffin

Liquid paraffin is used to relieve constipation. It lubricates and softens the stools to facilitate removal.

6. Activated Charcoal

Activated charcoal is used to neutralize various poisons. It binds with the poisons in the stomach.
7. General Anesthetics

General anesthetics act by biophysical mechanisms acting mainly on the cell membrane and its
constituents (lipids, proteins, water). They cause disorganization of the molecules in the cell membranes.
Their effect may be reversed by increasing the atmospheric pressure, by which the disordered molecules
come into order.

8. Rubfacients irritate the surface on which they are applied causing hyperemia, so the area becomes
warm.

9. Astringents cause the sloughing off of superficial skin layer.

Chemical Mechanisms:
In chemical mechanisms, drugs act by producing chemical reactions in the body. These include:

• Chemically acting antacid- NaHCO3

• Chelating agents- Dimercaprol, penicillamine, desferrioxamine
• Pralidoxime
• Chemically acting antacids react chemically with HCl of stomach, causing neutralization.
Sodium bicarbonate chemically binds HCl forming NaCl and water.
• Chelating agents are the drugs used to treat poisoning with various metals. They incorporate or
chelate metal ions into inner ring structure and in this way inactivate or neutralize the effects of
metals.
• Pralidoxime is a choline esterase reactivator. Poisoning of drugs like acetyl choline esterase
inhibitors or organophosphate poisoning (insecticides, war gases) cause irreversible inactivation
of acetyl choline esterase enzyme. This drug reacts chemically with phosphate of
organophosphate compounds causing dephosphorylation. Thus acetyl choline esterase is released.
Drug Receptor Interactions
Receptor:

Macromolecules protein in nature which are target sites for drugs. Most drugs have to bind receptors to
produce effects. Receptors are located mostly on the cell membrane but certain intracellular receptors are
found as well.

There are three forms of binding to receptors:

• Agonists
• Antagonists
• Partial agonists
Ligands

Ligands are the endogenous substances, molecules or compounds which bind with receptors present in the
body e.g. acetyl choline, adrenaline, noradrenalin, neurotransmitters like glutamate, aspartate and GABA.
They produce various effects and interfere with the flow of ions through channels called ligand gated
channels. Their action may:

• Resemble with natural ligand

 • Block the natural ligand
Agonists

Agonists are the drugs which when bind receptors, cause activation of receptors. They have the capacity
to produce chain reactions in the receptors which ultimately bring about the effects. Agonists have two
properties:

• Affinity for receptor

• Capability to produce chain reactions in the cells having capability of intrinsic activity or efficacy
Coupling

Transduction process between occupancy of the receptor by agonist and response to occur is called
coupling. Most agonists when bind to receptors cause activation. Most of them alter the second messenger
systems in the cells.

There are three second messenger systems:

• Cyclic AMP
• Cyclic GMP
• Calcium and phosphoinositol second messenger system
The levels of these second messenger systems may increase or decrease. This may occur in three steps:

• Drug binds receptor

• Stimulation of g-regulatory protein occurs. G-regulatory protein exists in two forms; GS
(stimulatory g-protein) and GI (inhibitory g-protein).
• This causes change in the effector element-enzyme or ionic channel depending on GS or GI.

Drug Receptor Interaction

cAMP second messenger system

Beta 1, beta 2,alpha 2, and dopamine 1 are the receptors associated with cAMP second messenger system.

Ligands include ACTH, catecholamines (beta adrenoreceptors), hCG, FSH, glucagon, histamine (H2
receptors), LH, MSH, PTH, serotonin, etc.

Calcium and Phospho-inositol system

Muscarinic and alpha 1 receptors are associated with calcium phospho-inositol system. Ligands include
acetylcholine (muscaranic receptors), angiotensin, serotonin, vasopressin (V1 receptors), and
catecholamines (alpha 1 adrenoreceptors).

Mechanism of Action of Nitrates

Nitric oxide receptors are associated with nitrates.

Types of Receptors:

There are four main types of receptors:

Type 1 Type 2 Type 3 Type 4

Ligand gated G-protein Kinase linked Nuclear

ion channels coupled receptors receptors
receptors

Location Membrane Membrane Membrane Intracellular

Effectors Ion channel Channel or Enzyme Gene

enzyme transcription

Coupling Direct G-protein Direct Via DNA

Examples Nicotinic Muscarinic Insulin, growth Steroid, thyroid

acetylcholine acetylcholine factor, cytokine hormone
receptor receptor receptors receptors
(nAchR), GABA (mAchR),
type A adrenoceptors

Structure Oligomeric Monomeric Single Monomeric

assembly of (occasionally transmembrane structure with
subunits dimeric) helix linking separate receptor
surrounding structure extracellular and DNA
central pore comprising seven receptor domain binding domains
transmembrane to intracellular
helices kinase domain

When drug binds the receptor, activation occurs, and the response gradually increases until it reaches the
peak, then the response decreases, although agonist still binds. This is due to desensitization of receptors,
which might be overcome by removing the agonists from the receptor. Example includes suxamethonium
(succinyl choline), which produces relaxation of skeletal muscles by:

• Activation of nicotinic receptors

• Desensitization of receptors in the neuromuscular junction
The reason for desensitization is not clear. In beta blockers (which act by cAMP), ultimately
phosphorylation of proteins and accumulation of phosphosilines occurs, which increases the binding of
beta receptors with proteins, known as beta arrestin. This beta arrestin interferes with the activity,
ultimately leading to inhibition of adenyl cyclase enzyme.

The binding of drug with receptor may by of two types:

 • Reversible binding
• Irreversible binding
In reversible binding, the bond between the drug and receptor is very weak ionic, hydrogen or van der
wall. This the effect is short lived.

In irreversible binding, very strong covalent bonds are present, which prolongs the effects of drug. The
effect continues until the drug is excreted or new receptor is generated.

Prolong contact of tissues with the agonists results in decreased number of receptors in the tissues called
down regulation of receptors. Example includes the patients suffering from bronchial asthma, in whom by
prolong usage of beta agonists down regulation occurs. This the effect is reduced.

Spare Receptors

Sometimes it is seen, especially in isolated tissues, that when various amounts of drugs are added e.g.
when in intestines of rabbits acetyl choline is added, this may lead to maximum effect. Only one percent
of receptors might be occupied but maximum response might be seen. This is due to the vast reserve.
There are spare receptors, only very small amounts of drugs are required for maximum effect.

Antagonists:

Binding of drug with receptor is the same. Most of the drugs binding receptors resemble the agonists but
they cannot activate the receptors, and also prevent agonist binding. Thus opposite effect occurs in case of
agonists and antagonists. They have two properties:

• Affinity
• Do not have efficacy or intrinsic activity
Examples include atropine, which is antagonist of acetyl choline. Propanolol is antagonist of beta
receptors.

The binding of antagonist with receptor is of two types:

• Reversible binding
• Irreversible binding
Reversible binding is also known as competitive antagonism. E.g. atropine.

Non competitive antagonism occurs when binding effect of antagonist is prolonged until drug is excreted
or new receptor is generated. Example includes phenoxy benzamine, which non-competitively blocks
action of catecholamines at beta receptors. Second generation H1 histamines are also non-competitive
blockers.

Prolonged contact of tissues with the antagonists results in up regulation of receptors or increase in the
number of receptors in the tissues. Example includes patients suffering from arrhythmias or angina taking
beta blockers, if we abruptly withdraw them, there will be reversing of the arrhythmia and angina. Up
regulation of catecholamines occurs which worsens the conditions.

Partial Agonists
Partial antagonists have intermediate levels of efficacy. They bind with the receptors but have very small
intrinsic activity and efficacy. It can be seen that even on 100 percent occupation of the receptors, the
response is sub maximal. Examples include beta blockers like pindolol and oxpranolol. They have ISA
property (intrinsic sympathomimetic property) and are used in patients suffering from diabetes mellitus,
peripheral vascular diseases and bronchial asthma.

Inverse Agonists

When inverse agonists bind receptors, they cause activation of receptors but produce effect opposite to the
agonists. Examples include benzodiazepines used as sedative hypnotics. They produce sedation, relieve
anxiety and relaxation of muscles. When beta carbolines are administered, they bind benzodiazepines
receptors causing the activation of receptors, producing stimulation, increase in tone, anxiety and
convulsions.

Drugs having agonist effect at receptors have positive efficacy.

Drugs having inverse agonist effect at receptors have negative efficacy.

Drugs having antagonist effect at receptors have zero efficacy.

Drug Enzyme Interaction

Drug enzyme interaction is similar to drug receptor interactions. The drugs resemble the natural
substrates, bind enzymes and cause change in their activity. This may take place by:

• Activation of enzymes
• Inhibition of enzymes
In therapeutic drugs causing inhibition on enzymes are generally used. This combination of drugs with the
enzyme may be:

• Competitive
• Non competitive
Non competitive response is irreversible until new enzyme is generated.

Examples of Competitive Inhibition

• ACE inhibitors e.g., captopril

• Carbidopa-------Levodopa
• Ethanol----------Methanol
• Reversible anticholinestrases e.g., Neostigmine, physostigmine
• Disulfiram------Alcohol
• Allopurinol

• ACE (angiotensin converting enzyme inhibitors) converts angiotensin I into angiotensin II, which
is a potent vasoconstrictor. ACE inhibitors are used in the treatment of hypertension.
• Levo dopa is metabolized by dopa decarboxylase in the periphery. Carbidopa competes with levo
dopa for the dopa decarboxylase enzyme. Thus peripheral metabolism of levo dopa is decreased,
more levo dopa enters brain producing more efficacy.
 • Ethanol (alcohol) undergoes metabolism in body in two steps:
a. Ethanol is converted into acetaldehyde by alcohol dehydrogenase

b. Acetaldehyde is converted into water and carbon dioxide by aldehdyde dehydrogenase.

4. Neostigmine acts as a reversible acetylcholine esterase inhibitor. Thus in treatment of myasthenia

gravis, acetyl choline levels are reversibly increased in the NMJ.

5. Disulfiram is used in alcohol aversion therapy. It inhibits aldehyde dehydrogenase enzyme. When
patient takes alcohol, increase in plasma levels of acetaldehyde cause bad symptoms like nausea,
vomiting and flushing.

6. Allopurinol is used in treatment of gout. Xanthine oxidase is inhibited which converts xanthine and
hypoxanthine into uric acid.

Non Competitive Inhibition

The effects of non competitive inhibition are prolonged. These include:

• Irreversible anticholinestrases e.g., Organophosphate compounds

• Aspirin
• MAO Inhibitors e.g., Iproniazid, Phenelzine
• Proton Pump Inhibitors e.g., Omeprazole, Esomeprazole
• Irreversible anticholinestrases include the insecticides and the war gases. These are toxic
compounds which can be absorbed through the skin.
• Aspirin is an analgesic used in headache, it inhibits cyclooxygenase enzyme in the platelets. It
inhibits the synthesis of prostaglandins especially thromboxane A2. Life of platelets is only seven
days. On maintenance therapy, aspirin is taken in low doses by cardiac patients.
• Monoamine oxidase inhibitors are used to treat depression. They inhibit the monoamino
oxidase enzyme which breaks down catecholamines. Thus decreased levels of noradrenalin and
serotonin are coped by MAO inhibitors and increased levels are achieved.
• Proton pump inhibitors inhibit the hydrogen potassium ATPase in parietal cells of stomach,
thus inhibit HCl secretion.
Drug Channel Interaction
In drug channel interaction, drug interfere with the flow of ions through the channels specific for these
ions. These include the Na+, K+,Ca++ and Cl- channels. Examples include:

• Sodium Channels:- Quindine Procainamide, Local anesthetics

• Calcium channels:- Nifedipine, Verapamil, Diltiazem
• Potassium Channels:- Amiodarone, sulfonylureas
• Chloride Channels:- Benzodiazepines
• Sodium Channel drugs are used in cardiac arrhythmias and act by blocking the sodium channels.
These include the local anesthetics which produce anesthesia in a localized area. Thus
depolarization does not take place and there is no nerve conduction in that localized area.
• Calcium channel drugs are used in the treatment of hypertension and arrhythmias. They block
the voltage gated calcium channels and release the vascular stiffness.
• Potassium channel drugs include amiodarone used in arrhythmias and block potassium channels.
Thus there is a prolonged refractory period. Sulfonylureas are antidiabetic and block the ADP
mediated potassium channels in the beta cells of pancreas.
 • Chloride channel drugs include benzodiazepines which produce sedation, used in epilepsy and
are muscle relaxants. They increase the entry of chloride ions through the chloride channels
causing hyper polarization.
Miscellaneous Interactions
Certain drugs act not through any of the mechanisms already mentioned, they are categorized as
miscellaneous. These include:

• Colchicines, vinca alkaloids

• Ionizing radiation
• Levamisole
• Immunosuppressive:- Cyclosporine
• Therapeutic antibodies
• Colchicines are used in the treatment of acute gout. The symptoms of gout are aggravated by the
migration of leukocytes causing phagocytosis of uric acid crystals producing lactic acidosis
leading to more inflammation and the cycle continues. Colchicines binds tubulin of microtubules
and prevents the migration of leukocytes.
Vinca alkaloids are used in cancer chemotherapy. They too bind tubulin of microtubules of
cancer cells, thus blocking mitosis.

• Ionizing radiations are used in cancer chemotherapy.

• Levamisole is anthelmintic used to expel worms and parasites to treat worm infestation. They
also cause stimulation of the immune system. When using immunosuppressive drugs, these are
taken as immunostimulant drugs.
• Immunosuppressive drugs act by binding cytosolic protein aminophilin and are used in
transplantation.
• Therapeutic antibodies are used for isolation of cytokines which are responsible for
inflammation.
1.17 Factors Modifying Action of Drugs
A multitude of host & environmental factors influence drug response. Understanding of these factors can
guide choice of appropriate drug & dose for individual patient.

Variation in response to the same dose of a drug between different patients and even in the same patient
on different occasions will occur. The range of variability may be marked or limited depending on the
pharmacokinetic & Pharmacodynamic characteristics of the drug. Drugs mostly disposed by metabolism
are most effected (e.g. propanolol) while those excreted by the kidneys are least effected (e.g. atenolol).

• Physiological Factors.

• Pathological Factors (Diseases)

• Genetic Factors

• Environmental Factors

• Interaction with other drugs

There exists no specific dose. The decision lies with the doctor. Giving optimum dose is mandatory for
desired results. Pharmacopoeia gives the guidelines and ranges. All factors affecting absorption and
biotransformation may influence the outcomes of drug actions.

1. Physiological Factors
a. Age

The adult dose is for people between 18 and 60 years of age. The tissues of an infant & child are highly
sensitive to large number of drugs. Children under 12 yrs require fraction of adult dose because:

• Drug metabolizing enzyme system is inefficient in them (Glucuronidation takes 3 months to

develop)

• Their barriers are not fully developed (BBB, blood aqueous barrier), thus are more sensitive to
CNS stimulants. All parts of the body are affected by the drug.

• Infants have an immature renal tubular transport system. Penicillin, streptomycin and amino
glycosides are not administered. After one year of age, elimination by kidneys is increased.

• Hepatic metabolizing capacity is also under developed. Chloramphenicol may cause grey baby
syndrome.

The dose for a child is calculated from the adult dose up to 8 yrs of age. The average adult dose is for an
individual of medium built. For very thin or obese individual the dose may be modified using either the
body surface area or body weight. i.e.

Surface area is found from height and weight, and is around 1.7-1.8/m2.

Dose to be prescribed = Body surface area (m2) x adult dose

1.7

Dose to be prescribed = Wt in kg x A.D

70

Child dose= Body surface area in m2 of child x A.D

1.7 (average body surface area in AD).

A.D = adult dose

Newborns

The drug dosage of newborn is decreased because:

• gastric acid secretion are not adequate e.g.

 GIT absorption of ampicillin and amoxicillin is greater in neonates due to decreased gastric
acidity

• liver microsomal enzymes (glucuronyl transferase) are deficient

Administration of Chloramphenicol may lead to Grey baby syndrome because of inadequate

glucouronidation of chloramphenicol resulting in drug accumulation

• Plasma protein binding is less

• GFR & tubular secretions are not adequate.

• There is immaturity of blood brain barriers in neonates.

Sulfonamides may lead to hyperbilirubinemia and kernicterus

Children

In children Tetracyclines may cause permanent teeth staining

Corticosteroids may lead to growth & development retardation

Antihistaminics may cause hyperactivity.

Geriatric age group (> 60yrs)

Patient requires special consideration because physiological changes occurig with age are to be kept in
mind such as:

• Reduced body weight

• Reduced body fat

• Reduced intestinal motility & mesenteric blood flow.

• Reduced renal & hepatic functions

• Altered mental functions

Elderly often require lesser doses than adults because they are prone to suffer from adverse drug
reactions. If liquid preparations are available, they should be preferred as are convenient for absorption.

Liver functions are impaired. Drugs like diazepam, theophylline having lower therapeutic index, may
have much larger half lives (2 hrs in normal 90 hrs in old)

Kidney functions are also impaired. Drugs like Digoxin, lithium and amino glycosides have decreased
excretion

Plasma protein binding is decreased leading to greater amounts of active drugs.

Increased sensitivity to CNS depressants like diazepam, morphine also occurs

b. Sex

Testosterone increases the rate of biotransformation of drugs.

Decreased metabolism of some drugs in female (Diazepam) occurs. Females are more susceptible to
autonomic drugs (estrogen inhibits choline esterase). Drugs used for ulcer treatment may cause increased
prolactin.

During menstruation, salicylates and strong purgatives should be avoided as they may increase bleeding.

c. Pregnancy

In pregnancy following are to be considered:

• Cardiac output

• GFR and renal elimination of drugs.

• Vd

• Metabolic rate of some drugs

Lipophilic drugs cross placental barrier & are slowly excreted. During pregnancy, uterine stimulants,
strong purgatives and drugs likely to have teratogenic effects should be avoided, especially during first
trimester no drug should be given unless absolutely necessary.

During labour, morphine should be avoided as it crosses placental barrier and depresses respiration in
newborn.

d. Plasma Protein Binding

Malnutrition causes decreased amino acids, decreased proteins leading to decreased binding sites for
drugs.

e. Body weight

Dose is given per kg body weight. Average muscular weight is between 50 and 100 kg, with 70 kg being
the average.

f. Lactation

During lactation, drugs may be excreted through milk and may affect the infant e.g. some purgatives,
penicillin, chloramphenicol and oral anticoagulants.

g. Food
Drugs are better absorbed in empty stomach. To prevent gastric irritation most drugs are taken after or
between foods, which affects the outcomes. Antimotion drugs are taken on empty stomach. Helminthes
(for evacuation of worms) are also taken on empty stomach.

h. Allergy

Allergy is the abnormal response of drug resulting from antigen-antibody reaction, leading to liberation of
histamine and histamine-like substances; therefore, there may be skin rashes, urticaria,
bronchoconstriction and fall of blood pressure. Allergic reactions may occur immediately or may be
delayed for many days.

Immediate and acute allergic reactions lead to acute anaphylactic shock which is dangerous for patient
and may even be fatal e.g. penicillin, sera, vaccines. Steps which can be taken include:

• History taking of previous allergic reactions

• Test dose should be given first

• Drugs required to deal with emergency should be kept ready

Sometimes skin rashes or urticaria along with fever and pain in joints and swelling of lymph nodes may
occur after a few days. This is delayed type of allergy called serum sickness type reaction.

i. Drug Dependence (Drug addiction)

Drug dependence is a state of periodic or chronic intoxication which is detrimental to person and society.
It becomes almost impossible to carry out normal physical functions without the drug.

Components of phenomenon of addiction include:

• Euphoria- sense of happiness and forgetfulness

• Tolerance- due to increased production of enzymes

• Psychic dependence (Habituation)- person desires but in absence of drug no harm occurs

• Physical dependence-

• Withdrawal symptoms (Abstinence syndrome)- symptoms opposite pharmacological actions of

drug develop in absence of drug

2. Pathological Factors
Diseases cause individual variation in drug response

(A) Liver Disease

In liver diseases, prolong duration of action occurs because of increased half life. Plasma protein binding
for warfarin, tolbutamide is decreased leading to adverse effects

If hepatic blood flow is reduced, clearance of morphine- propanolol may be affected.

Impaired liver microsomal enzymes may lead to toxic levels of Diazepam, rifampicin and theophylline

(B) Renal Disease

GFR, tabular function and plasma albumin may be affected leading to abnormal effects of digoxin,
lithium, gentamycin and penicillin

(C) Malnutrition

Plasma protein binding of drugs is reduced along with the amount of microsomal enzymes, leading to
increased portion of free, unbound drug e.g. Warfarin

3. Genetic Factors
Genetic abnormalities influence the dose of a drug and response to drugs. It affects the drug response in
individuals at 2 levels.

• At the level of receptors

• At the level of drugs metabolizing enzyme

Thus, interfering with the functions such as rate of plasma drug clearance.

Pharmacogenetics is the study of the relationship between genetic factors and drug response.

Idiosyncrasy

Idiosyncrasy is the abnormal drug reaction due to genetic disorder. It is the unpredictable response seen
on first dose of drug on hereditary basis. This may be due to

• Acetylation.

• Oxidation

• Succinylcholine apnea

• Glucose 6-phosphate dehydrogenase deficiency.

All individuals do not respond in similar way to same drug. Idiosyncrasy is used to describe abnormal
drug response on administration of first dose.

Genetic Polymorphism

The existence in a population of two or more phenotypes with respect to the effect of a drug. E.g.
Acetylation enzymes deficiency
Acetyl transferase (non-microsomal) affects Isoniazid, sulphonamides, etc.

Slow acetylator phenotype may show peripheral neuropathy .

Rapid acetylator phenotype may show hepatitis

Pseudocholinesterase deficiency

Succinyl choline is a skeletal muscle relaxant. Succinylcholine apnea may occur due to paralysis of
respiratory muscles.

Malignant hyperthermia

Occurs by succinyl choline due to inherited inability to chelate calcium by sarcoplasmic reticulum
resulting in Ca release, muscle spasm and rise in temperature.

Oxidation Polymorphism

In case of Debrisoquine

• Extensive metabolizers (EM) need larger dose.

• poor metabolizers (PM) - need smaller dose.

Porphyria

Deficiency of Glucose-6 phosphate dehydrogenase (G-6-PD)

G-6-PD Deficiency in RBCs leads to haemolytic anaemia upon exposure to some oxidizing agents like

• Antimalarial drug, primaquine

• Long acting sulphonamides

• Fava beans ( favism).

4. Environmental Factors
a. Route of Administration

Some drugs are incompletely absorbed after oral intake, when given intravenously; their dose has to be
reduced. Examples include morphine and magnesium sulphate. Magnesium sulphate when given orally is
osmotic purgative, but its 20% solution is injected intravenously to control the convulsions in ecclesia of
pregnancy.

Amonoglycosides like streptomycin when given intravenously cause neuromuscular blockage, which is
not observed after intramuscular injection.

b. Time of Administration
Hypnotics (producing sleep) act better when administered at night and smaller doses are required.

c. Effect of Climate

Metabolism is low in hot and humid climate. Purgatives act better in summer while diuretics act better in
winters. Oxidation of drugs is low at higher altitudes.

d. Racial Differences

Castor oil, a purgative, is ineffective in Chinese. The dilating effect of ephedrine in fair people on pupil is
absent in Negroes.

e. Preparation of Drug

Drugs in solid forms disintegrate slowly. Onset of action is rapid when drug is given in liquid form.

f. Age of Drug

Action may be modified if kept for longer durations. Outdated tetracyclines give rise to excretion of
amino acids in urine. Chloroform and carbon tetrachloride become toxic if kept for long durations.

g. Acidic or Basic Medium

If GIT has decreased acidity, acidic drugs like benzyl penicillin are not effective orally.

h. Effect of Disease

Certain drugs are only effective in disease conditions. These include antipyretics like aspirin and
paracetamol, which do not reduce temperature in case of healthy individuals.

Iron is better absorbed in iron deficiency anemia. As the anemia improves, it has less response.

Hyper susceptibility to Drugs

Variations in individuals leading to prolonged effects of drugs. Examples include diazepam, 2 mg of

which are used as antianxiety producing no hang overs. In hyper susceptible individuals, the drug has
prolonged action causing hangovers and hypnotic actions.

Opoids like morphine cause analgesia and sedation in 10 mg dose effective for 4-6 hours. In hyper
susceptible individuals, effect might be prolonged to 10-12 hours. These are individual based variations.

Hypersensitivity

Hypersensitivity is the quantitatively abnormal response with certain groups of drugs. Response is seen in
sub therapeutic doses not capable of producing pharmacological actions. This has immunological basis,
e.g. allergy. 25% of the drugs show hypersensitivity.

Hematological disorders can occur more pronounced in atopic individuals, who are already exposed to
antigens, e.g. ashthemics are more prone to allergic reactions.
Nearly all drugs show hypersensitivity in some category, which might be self limiting or even life
threatening. Penicillin when administered may cause anaphylactic shock. High molecular weight drugs
have a greater tendency to show hypersensitivity. History taking is helpful in predicting hypersensitivity.
Test dose can be given intradermally and localized reactions can be seen.

Tolerance

Resistance to normal therapeutic dose of drug, producing lesser response to normal therapeutic dose is
known as tolerance. This is acquired character. Examples include morphine, person is initially responsive,
if continued, changes occur at cellular and pharmacokinetic level, reducing the action. Thus one has to
increase the dose of drug to overcome.

Alcoholics do not respond to hypnotics and analgesics, dose of which has to be increased many folds. In
fact they may even tolerate toxic levels.

Cross Tolerance

A person tolerant to drugs resembling in chemical structure is known as cross tolerance. Those drugs
resembling in chemical structures show cross tolerance. If a person is tolerant to morphine, he also shows
tolerance to pathedine (synthetic derivative) and codeine.

Complete cross tolerance is observed in cases like diazepam and rizepam

Incomplete cross tolerance occurs with the drugs sharing the same pharmacological properties. Examples
include barbiturates and general anesthetics, site of action is CNS, incomplete cross tolerance may be
observed although they are not resembling chemically, but having same pharmacological properties.

Tachyphylaxis

Repeated administration of a drug at short intervals of time leads to a rapidly developing

tolerance. This occurs with indirectly acting drugs. On repeated administration, depletion of
endogenous receptors occurs. It is also known as acute tolerance. Example includes ephedrine,
which acts by releasing noradrenalin from adrenergic stores. After repeated administration, these
stores are exhausted and pharmacological action is not restored even on increasing the dose.

Tolerance Tachyphylaxis
Develops slowly Develops rapidly
Increase in dose manifests initial response Increase in dose does not manifest increase in
response

Cumulation

Drugs slowly metabolized or strongly bound to plasma proteins are eliminated slowly. They are liable to
accumulate especially when administered frequently. Amount of drug in body increases until equilibrium
is reached. Examples include:

• digitoxin
 • halogenated hydrocarbon type insecticides (DDT)

• Bromine, Iron, Silver

MAO inhibitors cause cumulative pharmacological effect but no cumulation of causative agent.

5. Interactions of Drugs
a. Synergism

Synergism is the facilitation/potentiation of pharmacological response by concomitant use of two drugs.

I. Potentiation

The total effect will be more than the sum of their individual effects. Examples are:

• Acetylcholine + physostigmine. Physostigmine inhibits the action of esterase prolonging the

effect of acetylcholine.

• Levodopa (Parkinsonism) + carbidopa/benserazide. Levo dopa is decarboxylated peripherally,

carbidopa inhibits the decarboxylase.

• Sulfonamide (effective against some microorganisms) when combined with trimethoprim is

effective against a wider range of microorganisms.

The action is more than the normal therapeutic effect.

II. Additive Effect (Summation)

In this case the total pharmacological action of two drugs will be equal to the sum of their individual
effect on simultaneous administration. The response is not more than their total algebraic sum. e.g.

• Aspirin + paracetamol as analgesic/ antipyretic

• Ephedrine + theophylline as bronchodilator

• Nitrous oxide + ether as general anesthetic

• Antihypertensive drugs

• Cardiac stimulants

b. Antagonism

When two drugs, administered simultaneously, oppose the action of each other on the same physiological
system, the phenomenon is called antagonism. It can be of following types.

• Chemical antagonism: involves reduction of the biological activity of a drug by a chemical

reaction with another agent e.g. between acids and alkalies: BAL and arsenic. Antacids, used for
 dyspepsia involve administration of sodium bicarbonate to react with hydrochloric acid. In cases
of heavy metal poisoning chelating agents are used like dimerzapam.

In iron poisoning deproxamine is given which binds sulphydral groups forming insoluble
complexes which can be easily detoxified.

• Pharmacological antagonism is of two types:

I. Competitive or reversible antagonism. In this type of antagonism the agonist and antagonist compete
with each other for the same receptors. The extent of antagonism will depend on the relative number of
receptors occupied by the two compounds. Other features are:

a. Antagonist has chemical resemblance with agonist.

b. Antagonism can be overcome by increasing the concentration of the agonist at receptor site. It
means the maximal response to agonist is not impaired.

c. Antagonist shifts the dose response curve to right

d. Emax of agonist is obtained with high concentration of agonist

e. Duration of action is short. It depends on drug clearance

Example is of acetyl choline and atropine antagonism on muscarinic receptors. In presence of antagonist,
log dose response curve of agonist shifts to right, indicating a higher concentration of agonist is required
for same response. Maximum height of the curve can be attained by overcoming the action of antagonist.
This leads to a parallel shift of log dose response curve towards right.

II. Non competitive antagonism: Here an antagonist inactivates the receptor in such a way so that the
effective complex with agonist cannot be formed irrespective of the concentration of the agonist. This can
happen by various ways:

• The antagonist might combine at the same site in such a way that even higher concentration of the
agonist can not displace it.

• The antagonist might combine at a different site of receptor in such a way that agonist is unable to
initiate characteristic biological response

• The antagonist might itself induce a certain change in receptor so that the reactivity of the
receptor site where agonist should interact is abolished.

Other features of this antagonism are:

• Antagonist has no chemical resemblance with agonist.

• Maximum response is suppressed

• Although antagonist shifts the dose response curve to right, the slope of the curve is reduced.
 • The extent of antagonism depends on the characteristics of antagonist itself and agonist has no
influence upon the degree of antagonism or its reversibility

• Emax of agonist is decreased even with high concentration of agonist

• Duration of action is long which depends upon new receptor synthesis.

Example is of phenoxybenzamine and adrenaline at alpha adrenergic receptors.

III. Physiological antagonism:

In this interaction of two drugs, both are agonists, so they act at different receptor sites. They antagonize
the action of each other because they produce opposite actions. Classical example of physiological
antagonism is adrenalin and histamine. Former causes bronchodilatation while later broncho Constriction.
So adrenalin is a life saving drug in anaphylaxis.

Clinical significance of drug antagonism

• It helps to correct adverse effects of a drug e.g. ephedrine and phenobarbitone.

• It is useful to treat drug poisoning e.g. morphine with naloxone

• It guides to avoid drug combinations with reduced drug efficacy such a as penicillin and
tetracycline combination

Factors Modifying Action/Dose of Drugs

• Age

• sex

• body weight

• body surface area

• genetic factor

• race

• species

• idiosyncrasy

• hyper susceptibility

• allergy

• presence of disease

• drug dependence
 • Route of administration

• time of administration

• tolerance

• synergism

• antagonism

• pharmacokinetic profile

• tachyphylaxis

• dosage form

• age of the drug

• cumulative effect

• metabolic disturbances

Some Specific Genetic Defects Which Lead To Discontinuous Variation in Drug Responses

Atypical pseudo cholinesterase – prolonged

Succinylcholine apnea.

G-6-PD deficiency- haemolysis with primaquine and other oxidizing drugs.

Acetylator polymorphism – isoniazid

neuropathy, procainamide and hydralazine induced lupus in slow acetylators.

Acute intermittent porphyria- precipitated by barbiturates due to genetic defect in repression of porphyrin
synthesis.

Malignant hyperthermia after halothane.

Inability to hydroxylate phenytoin- toxicity at usual doses.

Resistance to coumarin anticoagulants due to an abnormal enzyme (which regenerates the reduced form
of vitamin K) which has low affinity for the coumarins.

precipitation of an attack of angle closure, glaucoma by mydriatics in individuals with narrow

iridocorneal angle.

1.18 Adverse drug effects

Undesirable or harmful effects which can occur at therapeutic doses and need a reduction of dose or drug
withdrawal. Adverse drug effects include:

• Nausea and vomiting

• Deafness with gentamycin

• Death with penicillin

All drugs are poisons until used judicially. Every drug acts on all systems of the body, e.g. aspirin used
for headache also acts on GUT and blood producing side effects.

Types of adverse drug reactions

Adverse drug reactions are of five types; A, B, C, D and E

1) Type A reactions
Type A reactions are common and constitute 75 % of all adverse reactions. These are related to
pharmacological actions and are dose-dependent. Type A reactions are predictable and can be avoided by
adjusting the dosage regimen. Most of them are reversible upon stopping drug. Examples include

- Hypotension (antihypertensives)

- Hypoglycaemia (insulin)

a. Excessive therapeutic effect

Unwanted effects related to the main pharmacological actions of the drug that occur when the drug
produce greater therapeutic effect than is necessary.

e.g. Warfarin is an anticoagulant but may lead to bleeding tendency.

Insulin is used for normoglycemia but may produce hypoglycaemia

b. Side Effects

Unwanted effects unrelated to the main pharmacological actions of the drug but due to other normal
actions of the drug

e.g. morphine may cause constipation during its use as analgesic.

2) Type B reactions
Type B reactions are bizarre reactions, not related to the normal pharmacological actions of the drug.
They are unpredictable and not dose-related. They occur only in minority of patients. Test dose can be
given for judgement.

Types
a. Allergic reactions (Hypersensitivity)

b. Genetic disorders (Idiosyncrasy)

a) Hypersensitivity (allergic reactions)

Abnormal response to the drug due to antigen- antibody reactions e.g. Penicillin. These are the allergic
responses to a drug.

They include rashes, hypotension and bronchospasm (anaphylactic reaction).

b) Idiosyncrasy

Idiosyncrasy is abnormal response to the drug due to genetic disorders. E.g.

Succinylcholine apnea

Malignant hyperthermia

Favism

Porphria

Secondary Effects

Unwanted effects that occur secondary to the wanted actions of the drug. Examples include overgrowth of
microorganisms following use of broad spectrum antibiotics.

Type C reactions (Continuous reaction)

Type C reactions are due to long term use e.g. NSAIDs causing analgesic nephropathy due to long term
usage of drugs and changing doses.

Type D reactions (Delayed adverse reactions)

Teratogenesis Is congenital malformations occurring in the foetus due to exposure to drugs during
pregnancy e.g. Thalidomide may produce phocomelia (abnormal limbs)

Carcinogenesis is the ability of some substances to induce cancer. E.g. Stilbesterol may cause
adenocarcinoma of vagina in female off springs.

Mechanisms:

1. DNA alteration

Griesofulvin (antifungal) & alkylating cytotoxics (cancer), they are anti-mitotic, acting on spindle
formation

2. Immunosuppression
Immunosuppressant increase incidence of cancer e.g. organ transplantation & methotrexate in rheumatoid
arthritis

3. Hormonal

Long term use of estrogen replacement in post menopausal therapy may induce endometrial cancer

Type E reactions (Ending of drug)

Sudden discontinuation (abrupt withdrawal) may lead to rebound adrenal insufficiency
e.g. corticosteroids

Treatment should be started with smaller dose, which can be gradually increased. Patient compliance is
poor if adverse reactions occur.

Risk benefit ratio

Disease healing is important at the risk of side effects, especially in life threatening situations. This
depends on the expertise of the doctor.

1.19 Drug Dependence

Drug Use

Drug is used for therapeutic purposes

Drug Abuse

When the same drug used for therapeutic purposes for treatment of particular condition, because of
feeling of reward (e.g. pain relieving effect of analgesics) administered repeatedly is known as drug
abuse.

CNS drugs are psychoactive drugs, acting by mesolimbic dopaminergic pathway on ventral tegmental
areas, involved with behavior and emotion; show the phenomenon of drug dependence. When these drugs
are prescribed, in a few percentage of people, produce euphoria, the feeling of well being. This euphoria
compels them to take the drugs repeatedly due to which certain changes take place in the homeostasis by
virtue of presence of drug.

Definition

The WHO defines drug dependence as:

A state, psychic and sometimes physical resulting from taking a drug characterized by behavioral and
other responses that always include a compulsion to take a drug on a continuous or periodic basis in order
to experience its psychic effects, and some times to avoid discomfort of its absence
Body systems become adopted in a way that the person has to take the drug, leading to tolerance and
changes of toxicity e.g. morphine like drugs may cause respiratory depression.

Once the drug is stopped, since the body has adopted, it leads to withdrawal or abstinence symptoms,
opposite to therapeutic effects. Morphine, an analgesic, producing sedation and calming effects if not
provided, may cause pain, irritability and diarrhea. Thus leading to addiction.

Components:

• Euphoria
• Physical dependence- known now as dependence e.g. antihypertensive drugs have to be taken life
long by the patients, bronchodilators and nitrates (glyceryl trinitrate) are other examples. These
include non psychoactive drugs, individual is dependent but is not addiction
• Psychological dependence- known now as addiction, which is the compulsion to take the drug in
spite of negative effects. More relapses and compulsion to take drugs occur e.g. cocaine
addiction, but has no withdrawal symptoms, opoids have highly troublesome
• Abstinence/withdrawal syndrome
There are different symptoms and mechanisms of different drug abuse. The main problem is the denial by
the patient.

Development of dependence

The first use of a drug is in one of four contexts

• Therapeutics,
• Recreational
• Instrumental,
• Cultural
The outcomes of use of drugs depend on:

The drug – its availability form and its ability to induce reinforcement

The individual: curious rebellious unhappy, vulnerable types, pleasure seeking, motivation, also the
response to the drug

The culture: deprivation, constraints, peer groups, the age of instant gratification.

Common abused drugs

Common abused drugs/substances include

• Opiates and Narcotics

Heroin (diacetylmorphine, highly lipophilic and short lived), opium, codeine (used in cough
syrups), meperidine, hydromorphin
• Central Nervous System Stimulants
Amphetamines (sympathomimetic), cocaine, dextroamphetamine, Methamphetamine,
methylphenidate.
Most commonly used stimulants are caffeine and nicotine, for which craving develops
(psychological dependence)
 • Central Nervous System Depressants
Barbiturates: (amobarbital, Pento barbital, Secobarbital)
Benzodiazepines: (Valium, Ativan, Xanax)
Chloral hydrate (was used as sedative hypnotic in young children), paraldehyde
Benzodiazepines are sedatives and anti anxiety drugs, used on continuous basis, which leads to
dependence. Sleep cycle is disturbed and cause paradoxical problems in elderly

The most commonly used is alcohol, a social drink, which when taken within
limits presents no problems.

• Hallucinogens
LSD, Mescaline Psilocybin (Mushroom), Phencyclidine (Angel dust), Cannabis
Cannabis has medical importance and is anti cancer. They improve the quality of life but lead to
distorted perception.

Causes, Incidence and Risk Factors

Drug abuse can lead to drug dependence or addiction. Drug dependence may also follow the use of drugs
for physical pain relief. The exact cause of drug abuse and dependence is not known. However, the
genetic make-up of the individual (e.g. receptors for morphine), the pharmacology of the particular drug,
peer pressure, emotional distress, anxiety, depression, and environmental stress are all factor which seem
to be involved.

Consequences which can be severe

Drug abuse is simply excessive use of a drug or use of a drug for purposes for which it was not medically
intended. There are some substances that do not cause addiction but do cause physical dependence e.g.
(some blood pressure medications) and substances that cause addiction but not physical dependence
(Cocaine).

Symptoms
Opiates and Narcotics

Symptoms of use

• The first sign of addiction is denial

• Needle marks on the skin in some cases (because of release of histamine on scratching
• Scars from skin abscesses
• Rapid heart rate
• Constricted pupils (pin point) (dilated in cocaine)
• Relaxed and/or euphoric state
• Coma, respiratory depression leading to coma and death in high doses.
Symptoms of withdrawal

• Anxiety and difficulty sleeping

• Sweating
• Runny nose (rhinorrhea)
• Stomach cramps or diarrhea
• Dilated pupils
• Nausea and vomiting
• Excessive sweating
• Increase in blood pressure, pulse and temperature
Less potency drugs like methadone are given during withdrawal, otherwise patient may die.

Central Nervous System Stimulants

Symptoms of cocaine use

• Euphoria (exaggerated feeling of well being)

• Dilated pupils
• Rapid heart rate
• Restlessness and hyperactivity

Symptoms of cocaine withdrawals

• Fatigue and malaise

• Depression
• Vivid and unpleasant dreams

Central Nervous System Depressants

Symptoms of alcohols use

• Slurred speech
• Lack of coordination
• Decreased attention span
• Impaired judgment

Symptoms of alcohol withdrawal

• Anxiety
• Tremors
• Seizures
• Increase in blood pressure, pulse, and temperature
• Delirium

Hallucinogens

Symptoms of LSD use

 • Anxiety
• Frightening hallucinations
• Paranoid delusions
• Blurred vision
• Dilated pupils
• Tremors

Drugs are categorized into A, B&C with class A being subject to stiffer control

Class A Drugs (highly addictive) Class B Drugs

Alfentanil Oral Preparations of

Amphetamines

Cocaine Barbiturates

Heroin Codeine

Lofentamil Gluthethamide

LSD Pentazocine

Methadone Phenmetrazine

Morphine Pholcodine (cough syrup)

Pethidine

Opium

Phencyclidine

Ingectables of Class B

Class- C Drugs

Phentamine

Meprobamate (muscle relaxant)

Most benzodiazepines

Cannabis – became classified as a class C drug

Mazindol (used in anesthesia, added in January 2004

Diethylpropion

(Misuse of drug Act 1971)

Drug intoxication and drug overdose may be accidental or intentional. Drug withdrawal symptoms can
occur when use of substance is stopped or reduced. Withdrawal symptoms vary, depending on the abused
substance. The onset of withdrawal symptoms depends on the length of time the drug normally stays
within the body. Withdrawal can be life – threatening in some situations.

Treatment of drug dependency

• Detoxification
• Support
• Abstinence

Detoxification is the gradual withdrawal of an abused substance in a controlled environment. Sometimes

a drug with a similar action is substituted during the withdrawal process to reduce the unpleasant
symptoms and risks associated with withdrawals.

Drug abuse and dependence may lead to a fatal drug overdose. Relapse from drug abstinence may occur
and lead to recurrent dependence.

Complications of drug abuse

• Bacterial endocarditis
• Hepatitis
• Thrombophlebitis
• Pulmonary emboli
• Malnutrition
• Respiratory infections.
• Intravenous drug abuse
• Infection with HIV through shared needles.
• Drug induced loss of inhibitions may lead to unsafe
sexual practices

Increase in various cancer rates e.g. lung and pharynx cancer, are associated with nicotine use, mouth and
stomach cancer are associated with alcohol abuse and dependence