Book Basic Concept in Pharmacology

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Basic Concepts in Pharmacology
Book · August 2019

DOI: 10.9734/bpi/mono/978-93-89246-87-2
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Author(s)
Subhash Chandra Kothiyal1*, Sarla Saklani1, Shrivatsa Kothiyal2

and Sarvesh Kumar3
1
Department of Pharmaceutical Chemistry, School of Sciences, H. N. B. Garhwal (Central) University,
Srinagar (Garhwal), Uttarakhand, India.
2
D. B. S. Public School, Muni Ki Reti, Lal Tappar, Rishikesh, Dehradun, Uttarakhand, India.
3
Government Polytechnic, Srinagar Garhwal, Uttarakhand, India.
*Corresponding author: E-mail: subhashkothiyal@gmail.com;
FIRST EDITION 2019
ISBN 978-93-89246-86-5 (Print)

ISBN 978-93-89246-87-2 (eBook)
DOI: 10.9734/bpi/mono/978-93-89246-87-2
_________________________________________________________________________________
© Copyright 2019 The Author(s), Licensee Book Publisher International, This is an Open Access article distributed under the
terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted
use, distribution, and reproduction in any medium, provided the original work is properly cited.
Contents
Preface i
Abbreviations 1
CHAPTER 1
History & Development of Pharmacology
1.1 Drug History & Development 4
1.2 The Nature and Sources of Drugs 5
1.3 Drug Nomenclature 6
1.4 Pharmacological Introduction 6
1.5 Types of Pharmacology 6
1.6 Branches of Pharmacology 7
CHAPTER 2
Routes of Drug Administration
2.1 Introduction of Routes of Drug Administration 8
2.2 Factor Affecting Routes of Drug Administration 8
2.2.1 Local routes 8
2.2.2 Systemic routes 9
2.3 Bioavailability 12
CHAPTER 3
Pharmacokinetics
(Pharmacon- Drug, Kinesis- Movement/motion)
3.1 Introduction 13
3.2 Biological Membrane 13
3.3 Specialized Transport 15
3.4 Absorption 15
3.5 Factor Affecting Absorption 16
3.6 Distribution 17
3.7 Redistribution 19
3.8 Biotransformation (Metabolism) 20
3.9 Factor Affecting Metabolism 23
3.10 Excretion 24
3.11 Nephron 24
3.12 Kinetics of Elimination 26
3.13 Factor Affecting Excretion 27
CHAPTER 4
Pharmacodynamics
(Pharmacon- Drug, Dynamic- Power)
4.1 Introduction 28
4.2 Principles of Drug Action 28
4.2.1 Stimulation/Excitement 28
4.2.2 Depression/ Dejection 28
4.2.3 Irritation/ Induced or Excitement 28
4.2.4 Replacement/ Substitution 29
4.2.5 Cytotoxic/ Neoplastic/Anticancer action 29
4.3 Mechanism of Drug Action 29
CHAPTER 5
Elementary Adverse Drug Reactions
5.1 Introduction 33
5.2 Types of ADR 33
5.3 Drug Allergy 35
5.4 Types of Allergy 36
CHAPTER 6
Concept of Toxicology
6.1 Introduction 37
6.2 Poison and Antidotes 37
6.3 Classification of Toxicity 37
6.4 Modern Classification of Toxicity 38
6.5 Teratogenicity 38
6.6 Carcinogenicity (Carcino means, which cause Cancer) 38
6.7 Iatrogenic/drug Induced Diseases (Iatros Means, Physician) 39
6.8 Toxicity Test 39
6.9 Lethal dose50 (Which cause to death on 50%) 39
6.10 Effective dose50 (Which effect to the drug in 50%) 39
CHAPTER 7
Drug Dependence
7.1 Introduction 40
7.2 Types of Drug Dependence 40
7.2.1 Psychological dependence 40
7.2.2 Physical dependence 40
7.2.3 Drug abuse 40
7.2.4 Drug addiction 40
7.4.5 Drug habituation 41
CHAPTER 8
Drug Tolerance
8.1 Introduction 42
8.2 Types of Drug Tolerance 42
8.3 Drug Resistance 43
CHAPTER 9
Bioassay (Biological Assay)
9.1 Introduction 44
9.2 Types of Assay 44
9.3 Principle of Bioassay 44
9.4 Bioassay of Insulin 46
9.5 Bioassay of Digitalis 48
9.6 Bioassay of Adrenaline 49
9.7 Bioassay of d-Tubocurarine 50
9.8 Bioassay of Acetylcholine 51
CHAPTER 10
Principle of Animal Study
10.1 Introduction 53
10.2 Animal Ethics 53
10.3 Animal Ethics Committee 53
10.4 Types of Variation 53
CONCLUSION 54
ACKNOWLEDGEMENTS 54
COMPETING INTERESTS 55
REFERENCES 55
Index 57
Preface
Pharmacology is a fascinating and multifaceted discipline that impacts both our professional careers
and personal lives. The study of pharmacology covers a broad spectrum of diverse yet interrelated
topics, such as botany, molecular chemistry, research, clinical observation, toxicology and patient
education. Medical pharmacology is a unique synthesis of basic pharmacology with clinical
pharmacology and pharmacotherapeutics. It is both a basic and an applied science. It forms the
backbone of rational therapeutics. Whereas the medical student and the prescribing physician are
primarily concerned with the applied aspects, correct and skilful application of drugs is impossible
without a proper understanding of their basic pharmacology.
The purpose of this book is not merely to be a source of information in basic pharmacology, but also
to present the background and context in which different classes of drugs have been developed and
are used. This book deals with drug interaction with living organism, drug dosage forms and biological
effects of drugs. Along with the development of new drug delivery systems. The present book first
edition is maintained, revisited and extensively updated. Latest therapeutic guidelines from
authoritative sources like WHO, British National Formulary, National Formulary of India, as well as
from eminent professional bodies have been incorporated.
As such this book should be useful to practitioners in the hospital doctors (MBBS & MD),
pharmaceutical and allied health sciences, hospital pharmacists, drug patent attorneys, government
scientists and regulatory personnel, and other seeking information concerning the design,
manufacture, and control of pharmaceutical dosage forms. In fact all those persons involved in new
drug discovery, dug mechanism of action and its effect. It can form the basis for the modern revision
of syllabi of courses of B. Pharm, M. Pharm and M. Sc. Pharmaceutical chemistry with specialization
in pharmaceuticals.
i
ii
Abbreviations
AA : Amino acid
AB : Antibody
Aq :Aqueous
AC : Adenylyl cyclase
ACE : Angiotensin II converting enzyme
Ach : Acetylcholine
AChE : Acetylcholinesterase
ACS : Acute coronary syndromes
ACT : Artemisinin-based combination therapy
ACTH : Adrenocorticotropic hormone
AD : Alzheimer’s disease
ADCC : Antibody-dependent cellular cytotoxicity
ADE : Adverse drug event
ADH : Antidiuretic hormone
ADHD : Attention deficit hyperactivity disorder
ADP : Adenosine diphosphate
Adr : Adrenaline
ADR : Adverse drug reaction
ADS : Anti diphtheritic serum
AES : Atrial extrasystole
AF : Atrial fibrillation
AFl : Atrial flutter
AG : Antigen
AGS : Antigasgangrene serum
AHG : Antihaemophilic globulin
AI : Aromatase inhibitor
AIDS : Acquired immunodeficiency syndrome
AIP : Aldosterone induced protein
ALA : Alanine
ALS : Amyotrophic lateral sclerosis
Am : Amikacin
AMA : Antimicrobial agent
AMB : Amphotericin B amp Ampoule
AMP : Adenosine mono phosphate
AMPA :Aminohydroxy methylisoxazole propionic acid
ANC : Acid neutralizing capacity
ANP : Atrial natriuretic peptide
ANS : Autonomic nervous system
ANUG : Acute necrotizing ulcerative gingivitis
AP : Action potential
AP-1 : Activator protein-1
APC : Antigen presenting cell
APD : Action potential duration
Aptt : Activated partial thromboplastin time
AQ : Amodiaquine
AR : Androgen receptor
ARB : Angiotensin receptor blocker
ARC : AIDS related complex
Abbreviations
ARS : Anti rabies serum

ARV : Antiretrovirus
AS : Artesunate
5-ASA : 5-Amino salicyclic acid
Asc LH : Ascending limb of Loop of Henle
AT-III : Antithrombin III
ATG : Antithymocyte globulin
ATP : Adenosine triphosphate
ATPase : Adenosine triphosphatase
ATPIII : Adult treatment panel III
ATS : Antitetanic serum
AUC : Area under the plasma concentration-time curve
A-V : Atrioventricular
AVP : Arginine vasopressin
AZT : Zidovudine
BAL : British anti lewisite
BAN : British approved name
BB : Borderline leprosy
BBB : Blood-brain barrier
BCG : Bacillus Calmette Guérin
BCNU : Bischloroethyl nitrosourea (Carmustine)
BCRP : Breast cancer resistance protein
BHC : Benzene hexachloride
BHP : Benign hypertrophy of prostate
BI : Bacillary index
BL : Borderline lepromatous leprosy
BMD : Bone mineral density
BMR : Basal metabolic rate
BNP : Brain nartriuretic peptide
BOL : 2-Bromolysergic acid diethylamide
BP : Blood pressure
BPN : Bisphosphonate
BSA : Body surface area
BT : Borderline tuberculoid leprosy
BuChE : Butyryl cholinesterase
BW : Body weight
BP :Boiling point
BZD : Benzodiazepine
C-10 : Decamethonium
CA : Catecholamine
CI : Chemical ionization
D : Doublet
ED50 : Effective dose
Et2O : Diethyl ether
LD50 : Lethal dose
Mg : Milligram
MHZ : Megahertz
2
Abbreviations
MP : Melting point
Ml : Milliliter
MF : Molecular Formula
µ(Mu) : Micro
MIC : Minimum inhibitory concentration
µm : Micrometer
nm : Nanometer
Ppm : Parts per million
RP : Reverse phase
Rel. Int. : Relative intensity
Syn : Synonym
s : Singlet
t : Triplet
Vern : Vernicular name
3
Chapter 1
Print ISBN: 978-93-89246-86-5, eBook ISBN: 978-93-89246-87-2

and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
1.1 Drug History & Development

The world’s oldest known pharmacological or therapeutic writings come from India and China. The
earliest Indian records are the Vedas. Although there are medical descriptions in Rigveda (3000 B.C).
It was Charaka, a renowned ancient Indian physician, and later Sushruta and Vagbhata, who
described various medicinal preparations included in Ayurveda, Charaka described about 300 herbal
drugs and classified them according to their effects,
The Chinese material medica ‘Pan Tsao’ was probably written in (2735 B.C) and contained many
plant and metallic preparations and a few animal products. Modern medicine is considered to date
from Hippocrates, a Greek physician (450 B.C), who for the first time introduced the concept of
disease as a pathologic process and tried to organize the science of medicine on the basis of
observation, analysis and deduction.
Herbs:-
(The word herb comes from the Latin word ‘herba’ meaning grass, green stalks or blades).
In general use, herbs are plants with savory or aromatic properties that are used for in medicine,
flavoring food or as fragrances. Herbs have a variety of uses including medicinal and in some cases,
spiritual. The term "herb" differs between culinary herbs and medicinal herbs; in medicinal or spiritual
use, any parts of the plant might be considered as "herbs", including leaves, roots, flowers, seeds,
root bark, inner bark (and cambium), resin and pericarp. Herbs have long been used as the basis of
traditional Chinese herbal medicine, with usage dating as far back as the first century CE and far
before. In India, the Ayurveda medicinal system is based on herbs. Which plant parts (flower, fruit,
root, leaves stem, bark and seed) contain medicinal properties that are called herbs.
Medicine:-
(Medicine is the science and practice of the diagnosis, treatment, and prevention of disease or a drug
or other preparation for the treatment or prevention of disease). Medicine encompasses a variety of
health care practices evolved to maintain and restore health by the prevention and treatment of
illness. Contemporary medicine applies biomedical sciences, biomedical research, genetics and
medical technology to diagnose, treat and prevent injury and disease.
Ayurvedic medicine:-
The word "ayurveda" is Sanskrit, Ayurveda, meaning knowledge of life and longevity. Ayurvedic
medicine is one of the world's oldest holistic healing systems. It was developed more than 3,000
years ago in India. It's based on the belief that health and wellness depend on a delicate balance
between the mind, body, and spirit. Ayurveda names seven basic tissues, which are plasma, blood,
_____________________________________________________________________________________________________
1
Department of Pharmaceutical Chemistry, School of Sciences, H. N. B. Garhwal (Central) University, Srinagar (Garhwal),
Uttarakhand, India.
2
3
muscles, fat, bone, marrow and semen. Ayurveda has historically divided bodily substances into
five classical elements (Sanskrit panchabhuta, viz. earth, water, fire, air and ether. Ayurveda also
names three elemental substances (called Vata, Pitta and Kapha). Ayurveda has eight ways to
diagnose illness, called pulse, urine, stool, tongue, speech, touch, vision and appearance. After all it is
a type of traditional Hindu medicine system that treats illness/disease using a combination of food,
herbs and breathing exercise.
Homeopathy:-
The term "homeopathy" was coined by Hahnemann (respected doctor in Germany) and derived from
two Greek words that mean “like disease”. Homeopathy is a system of alternative medicine created in
1796 by Samuel Hahnemann, based on his doctrine of like cures like. Homeopathy is an alternative
medical practice in which extremely dilute amounts of certain natural substances are used to treat
various ailments. It is a medical system based on the belief that the body can cure itself. Those who
practice it use tiny amounts of natural substances, like plants and minerals. It is a system of treating
disease or disease like condition, where we have using a very small amount of the drug/ chemical
substance/compound in high amount, which cause the disease or disease like condition.
Allopathy:-
(A western system of medicine, Western-American culture).
The term "allopathy" was coined in 1842 by C.F. Samuel Hahnemann. The system of medical practice
which treats disease by the use of remedies which produce effects different from those produced by
the disease under treatment. Allopathic medicine refers to the practice of traditional or conventional
Western medicine.The term allopathic medicine is most often used to contrast conventional medicine
with alternative medicine or homeopathy.
Drugs:-
(French term –Drogue, which means –A dry herb).
It is the single active chemical entity/compound/substance in a medicine that is used for

diagnosis/treatment/cure/prevention of a disease (allergy, cancer, tuberculosis, analgesic & AIDS etc).
This disease oriented definition of drug does not including contraceptives or improvement of health.
The WHO (1966) has given a more comprehensive definition-“Drug is any substance or product that
is used or is intended/consumption/intake to be used to modify/change or explore physiological
system or pathological states for the benefit of the recipients.”
1.2 The Nature and Sources of Drugs
The various sources of drugs are:
I. Natural source
II. Synthetic source
III. Other sources
I. Natural source:-
a) Plant (Morphine, digoxin, quinine, atropine, nicotine, reserpine and caffeine etc)
b) Animal (Insulin, thyroid extract, heparin, antivenom, gonadotropins and antitoxic etc)
c) Mineral (Liquid paraffin, magnesium sulfate, magnesium trisilicate, kaolin, Ca, I and Cl etc)
d) Microorganism (Bacteria and fungi, isolated from soil are important sources of antibacterial
substances, e.g., penicillin)
II. Synthetic source:-
a) Laboratory sources (e. g Analgesics, hypnotics, anticancer drugs, e.g. Paracetamol, Aspirin etc).
5
III. Other sources:-
a) Genetic engineering (DNA recombinant technology) e.g insulin and growth hormones, genes.
b) Hybridoma technique (e. g monoclonal antibodies).
1.3 Drug Nomenclature

A drug generally has three categories of names.
1) Chemical name (IUPAC Name).

2) Non-proprietary name (Govt. authority name e.g IP, BP & USP).
3) Proprietary/Brand name (Owner or manufacturer name).
1) Chemical name:- It describes the substance chemically through International union of pure and
applied chemistry (IUPAC) e. g. butenol-1, isopropyl amino and propan-2-ol etc.
2) Non-proprietary name:- It is the name accepted by a competent/Government scientific

body/authority/committee e.g the United States Adopted Name (USAN) by the USAN council.
Similarly there is the British Approved name (BAN) of a drug. The non-proprietary names of
newer drugs are kept uniform by an agreement to use the recommended International
Nonproprietary Name (rINN) in all member countries of the WHO.
3) Proprietary/Owner (Brand) name:- It is the name assigned/designed by the manufacturer/owner

and is his/her property or trade mark. One drug may have multiple/different proprietary names,
e.g ALTOL, ATCARDIL, ATECOR, ATEN, BETACARD, LONOL, TENOLOL, TENORMIN for
atenolo from different manufacturers. Brand names are deigned to be catchy/short/easy to
remember and often suggestive e.g LOPRESOR suggesting drug for lowering blood pressure.
Brand names generally differ in different countries, e.g timolol maleate eye drops are marketed as
TIMOPTIC in USA but as GLUCOMOL in India.
Composition of Drugs:- Inorganic drugs have simple formula, whereas organic drugs have a
complex one. The most active amongst drugs are those containing alkaloids and glycosides.
1) Inorganic drugs (Acids, Bases and Salts).

2) Organic drugs (Alkaloids, glycosides, tannins, saponins etc).
1.4 Pharmacological Introduction

The ‘father of pharmacology’- Oswald Schmiedeberg.
Pharmacology is the science of drugs (Greek: Pharmacon—drug; logos—discourse in). In a broad

sense, it deals with interaction of exogenously (outer side of body) administered chemical molecules
with living systems, or any single chemical substance which can produce a biological response is a
‘drug’. It encompasses all aspects of knowledge about drugs, but most importantly those that are
relevant to effective and safe use for medicinal purposes. For thousands of years most drugs were
crude natural products of unknown composition and limited efficacy. Rudolf Buchheim, who founded
the first institute of pharmacology in 1847 in Germany.
1.5 Types of Pharmacology

The two main divisions of pharmacology are pharmacodynamics and pharmacokinetics.
1) Pharmacodynamics
2) Pharmacokinetic
Pharmacodynamics:-
(Greek: Dynamis—power) What the drug does to the body.

This includes physiological and biochemical effects of drugs and their mechanism of action at organ
system/subcellular/macromolecular levels, e.g.—Adrenaline → interaction with adrenoceptors → G-
6
protein mediated stimulation of cell membrane bound adenylyl cyclase → increased intracellular cyclic
3´,5´AMP → cardiac stimulation, hepatic glycogenolysis and hyperglycaemia, etc.
Pharmacokinetics:-
(Greek: Kinesis—movement) What the body does to the drug.
This refers to movement of the drug in and alteration of the drug by the body; includes absorption,
distribution, binding/localization/storage, biotransformation and excretion of the drug, e.g. paracetamol
is rapidly and almost completely absorbed orally attaining peak blood levels at 30–60 min; 25% bound
to plasma proteins, widely and almost uniformly distributed in the body (volume of distribution ~
1L/kg); extensively metabolized in the liver, primarily by Glucuronide and sulfate conjugation into
inactive metabolites which are excreted in urine; has a plasma half life (t½) of 2–3 hours and a
clearance value of 5 ml/kg/min.
1.6 Branches of Pharmacology

Some other important aspects of pharmacology are:
Pharmacotherapeutics:-
It is the scientific study of drugs together with knowledge of the disease for its prevention, mitigation or
cure. Selection of the most appropriate drug, dosage and duration of treatment taking into account the
specific features of a patient are a part of pharmacotherapeutics.
Clinical pharmacology:-
It is the scientific study of drugs (both old and new) in man. It includes pharmacodynamic and
pharmacokinetic investigation in healthy volunteers and in patients. The aim of clinical pharmacology
is to generate data for optimum use of drugs and the practice of ‘evidence based medicine’.
Chemotherapy:-
It is the treatment of systemic infection/malignancy with specific drugs that have selective toxicity for
the infecting organism/malignant cell with no/minimal effects on the host cells. Drugs in general, can
thus be divided into:
Pharmacodynamic agents:- These are designed to have pharmacodynamic effects in the recipient.
Chemotherapeutic agents:- These are designed to inhibit/kill invading parasite/malignant cell and
have no/minimal pharmacodynamic effects in the recipient.
Pharmacy:-
It is the art and science of compounding and dispensing drugs or preparing suitable dosage forms for
administration of drugs to man or animals. It includes collection, identification, purification, isolation,
synthesis, standardization and quality control of medicinal substances. The large scale manufacture
of drugs is called Pharmaceutics. It is primarily a technological science.
Toxicology:-
It is the scientific study of drugs poisonous effect and other chemicals (household, environmental
pollutant, industrial, agricultural, homicidal) with emphasis on detection, prevention and treatment of
poisonings. It also includes the study of adverse effects of drugs, since the same substance can be a
drug or a poison, depending on the dose.
________________________________________________________________________________
7
Chapter 2

and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
2.1 Introduction of Routes of Drug Administration

(Routes or Way/Passes and administration or management).
The routes of administration are depends on drug and as well as patients related factors. The routes
can be divided into two classes.
2.2 Factor Affecting Routes of Drug Administration
Note- Factor affecting choice of route:-
 Physical and chemical properties of the drug (solid/liquid/gas, solubility, stability, pH,
irritancy).
 Site of desired action-localized and approachable generalized and not approachable.
 Rate and extent of absorption of the drug from different routes.
 Effect of digestive juices and first pass metabolism on the drug.
 Rapidity with which the response is desired (routine treatment or emergency).
Routes are basically two types.
I. Local routes
II. Systemic routes
2.2.1 Local routes
A) Topical route
B) Deeper tissues
C) Arterial supply
A) Topical route:-
This refers to external/(outer surface of body) application of the drug to the surface for localized
action. It is often more convenient or suitable as well as encouraging to the patient. These are another
two types.
a) Skin
b) Mucus membrane
a) Skin:-
Drug is applied as cream, lotion, ointment, jelly, paste, powder, dressing and spray etc.
_____________________________________________________________________________________________________
1
Uttarakhand, India.
2
3
b) Mucus membrane:-
The dosage form depends on the site.
Mouth and pharynx- Paints, lozenges, mouth washes, gargles.

Eyes, ear and nose- Drops, ointment, irrigation, nasal spray.
Gastrointestinal tract GIT)- Non-absorbable drugs given orally e.g. magnesium
Hydroxide, sucralfate, neomycin.
Bronchi and lungs- Volatile liquid, gases and fine powder (Aerosols and
salbutamol etc).
Urethra- Jelly (lidocaine), ointment and irrigating solutions.
Vaginal- Tablet, inserts, cream, powder, douches.
Anal canal- Ointment, suppositories.
B) Deeper tissues:-
In this routes, drug is apply for certain deep areas can be approached by using a syringe and needle,
but the drug systemic absorption is very slow/minimum or absent, e.g. Intraarticular injection
(hydrocortisone acetate), Intrathecal injection (lignocaine, amphotericin B)
C) Arterial supply:-
It is used for close intra-arterial injection, where the drug injected for contrast media in angiography. In
this route anticancer drugs can be infused in femoral or brachial artery to localize the effect for limb
malignancies.
2.2.2 Systemic routes
The drug administered through systemic routes is intended/reaches to be absorbed into blood and
distributed all over the body, including the site of action, through circulation, these are various types.
A) Oral
B) Sublingual (SI) Buccal
C) Nasal
D) Inhalation
E) Rectal
F) Cutaneous
G) Parenteral
A) Oral:-
Oral route is the oldest and commonest mode of drug administration. It is safer more convenient or
suitable, does not need assistance, non-invasive, often painless, the medicament need not be sterile
and so is cheaper. Both solid (tablet, capsule, powder etc) and liquid (syrups, emulsion, suspension,
elixirs, solution etc) dosage forms can be given orally.
Note- Limitation of oral route of Administration:-
 Action is slower and thus not suitable for emergencies.

 Unpalatable drugs (paraldehyde) are difficult to administer, drug may be filled in capsules to
circumvent this.
 May cause nausea and vomiting (emetine).
 Cannot be used for uncooperative/unconscious/vomiting patient.
 Certain drugs are not absorbed (streptomycin).
 Other are destroyed by digestive juices (penicillin, Insulin) or in liver (nitroglycerin,
testosterone, lignocaine).
 Easy to intake for administration and no need of any maintenance.
9
B) Sublingual (SI) Buccal:-
The tablet or pellet containing the drug is placed under the tongue or crushed in the mouth and
spread over the buccal mucosa. Only lipid soluble and non-irritating drugs can be administered in this
route. Absorption is relatively rapid and action can be produced in minutes. The chief advantage is
that liver is bypassed and drugs with high first pass metabolism with absorbed directly into systemic
circulation e.g. nitroglycerine, isoprenaline, clonidine.
C) Nasal:-
The mucus membrane of the nose can readily absorb many drugs, digestive juices and liver are
bypassed. However only certain drugs like posterior pituitary powder and desmopressin applied as a
snuff or spray or nebulized solution have been used by this route.
D) Inhalation:-
Volatile liquids and gases are given by in this route for systemic action, e. g. general anesthetics, amyl
nitrite. Absorption takes place from the vast surface of alveoli and action is very rapid or fast. Thus in
this route controlled administration is possible with moment to moment adjustment.
E) Rectal:-
Certain irritant and unpleasant drugs can be put into rectum as suppositories or retention enema for
systemic effect. This route can also be used, when the patient is having recurrent vomiting. In this
route absorption is slower, irregular and often unpredictable. Rectal inflammation can be cure by best
result from irritant drugs in this route, e. g. Indomethacin, paraldehyde, diazepam, aminophylline etc.
F) Cutaneous:-
Highly lipid soluble drugs can be applied over the skin for slow and prolonged absorption and the liver
is also bypassed. The drug can be applied over specified area of skin.
Transdermal therapeutic system- these are recently developed devices in the form of adhesive
2
patches of various shapes and sizes (5-20 cm ). Which deliver the contained drug at a constant rate
into systemic circulation via the stratum corneum. The drug is delivered at the skin surface by
diffusion for percutaneous absorption into circulation. Transdermal patches of nitroglycerine, nicotine
and estradiol are available in India, while those of isosorbide dinitrate, hyoscine and clonidine are
available in other countries.
G) Parenteral:- (Par-beyond, Enteral-intestinal)
This doses form refers to administration by injection directly into the tissue, fluid or blood without
having to cross the intestinal mucosa. In this route action is faster and surer (valuable in
emergencies). Gastric irritation and vomiting are not provoked.
a) Intradermal
b) Subcutaneous (S.C)
c) Intramuscular
d) Intravenous
e) Intraarticular
f) Intra-arterial
g) Intrathecal
h) Intracisternal
i) Intracardiac
j) Intracameral
k) Intrasynovial
10
a) Intradermal:-
The drug is injected/projected into the skin dermis and epidermis layer. The volume of injection
usually between 0.1-0.2 ml. this route used for skin raising a bleb (e. g BCG vaccine, sensitivity tests)
or scarring/multiple puncture of the epidermis through a drop of the drug is done. This route is
employed for specific purposes only.
b) Hypodermic/Subcutaneous:-
The drugs is deposited in the loose subcutaneous tissue, which is richly supplied by nerves (irritant
drugs can’t be injected this route) but is less vascular (absorption is slower than intramuscular). Only
small volumes can be injected s.c. Self injection is possible in this route because deep penetration is
not needed. The route should be avoided in shock patients who are vasoconstricted absorption will be
delayed. The volume of injected drugs usually between 0.5-1.0 ml. some special forms of this route
are:
1) Dermojet
In this method needle is not used and a high velocity jet of drug solution is projected/injected from a
microfine orifice using a gun like implement. It is essentially painless and suited for high amount of
mass inoculation.
2) Pellet implantation
The drug in the form of a solid pellet is introduced with a trochar and cannula. This drug provides
sustained release of the drug over weeks and month’s e.g DOCA, testosterone.
3) Sialistic/Non-degradable/Biodegradable
In this route crystalline drug is packed in tubes or capsules made of suitable materials and implanted
under the skin. This drug provides sustained release of the drug over one year to three years. This
has been tried for contraceptives, hormones and microbial infection.
c) Intramuscular:-
The drug is injected in one of the large skeletal muscles deltoid, triceps, gluteus maximus, rectus
femoris etc. It is less painful, but self injection is often impracticable because deep penetration is
needed. Intramuscular injections should be avoided in anticoagulant treated patients, because it can
produce local haematoma. The volume rarely exceeds 2.0 ml.
d) Intravenous:-
The drug is injected as a bolus (Greek: - bolos-lump) or infused slowly over hours in one of the
superficial veins. The drug reaches directly into the blood stream and effects are produced
immediately (suitable for emergency). Only aqueous solutions are to be injected i. v and there are no
depot preparations for this route. The dose of the drug required is smallest (bioavailability is 100%)
and even large volumes can be infused. The volumes of such injection can vary from 1.0 -500ml.
some time it is more than 500ml also.
e) Intraarticular:-
The drug is injected in certain deep areas, where the systemic absorption is slow. The drug is used in
this route into knee, elbow and solder joint.
f) Intra-arterial:-
The close intra-arterial injection is used for contrast media in angiography, anticancer drugs can be
infused/used in femoral or brachial artery to localize the effect for limb malignancies. The drug is
injected into artery terminating in target area.
11
g) Intrathecal:-
Into the subarachnoid space surrounding spinal cord which contains cerebro-spinal cord, which
contains cerebro-spinal fluid. Injection are generally made in the filum terminale area. Volumes up to
10 ml can be injected.
h) Intracisternal:-
Into the cistern containing cerebro-spinal fluid.
i) Intracardiac:-
Into the heart chamber.
j) Intracameral:-
Into the eye ball.
k) Intrasynovial:-
Into a joint fluid area.
2.3 Bioavailability
(Biological- all living organism, Availability-available/Present).
The rate and amount of unchanged drug absorption into body, through different site of administration
(oral, IV, IM & subcutaneous) into systemic circulation/target organ (blood, tissue, fluid & organ) is
called bioavailability.
Measurement of bioavailability:-
A) Pharmacokinetics
B) Pharmacodynamics
A) Pharmacokinetics:-
This refers to movement of the drug in and alteration of the drug by the body; includes absorption,
distribution, binding/localization/storage, biotransformation and excretion of the drug.
B) Pharmacodynamics:-
This includes physiological and biochemical effects of drugs and their mechanism of action at organ
system/sub cellular/macromolecular levels,
_________________________________________________________________________________
12
Chapter 3
Pharmacokinetics
and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
3.1 Introduction
Pharmacokinetics is the quantitative study of drug movement in through and out of the body. Intensity
of response is related to concentration of drug at the site of action, which in turn is dependent on its
pharmacokinetic properties. All pharmacokinetic process involves transport of drug across biological
membranes.
Drugs are transport across the biological membranes by two ways:-
1. Passive diffusion and filtration

2. Specialized transport
Fig. 1. Schematic depiction of pharmacokinetic processes
3.2 Biological Membrane
This is a bilayer (about 100 A° thick) of phospholipid and cholesterol molecules, the polar groups
(glyceryl phosphate attached to ethanolamine/choline or hydroxyl group of cholesterol).
_____________________________________________________________________________________________________
1
Uttarakhand, India.
2
3
Pharmacokinetics
Fig. 2. Structure of the organisation of biological membrane
1) Carrier Transport
a) Active carrier transport

b) Facilitated diffusion/transport
2) Pinocytosis
Simple passive/lipid diffusion:-
The drug diffuses across the membrane in the direction of its higher concentration to lower
concentration gradient. Lipid soluble (water insoluble) drugs diffuse by dissolving in the lipoidal matrix
of the membrane on this way.
Filtration/aqueous diffusion:-
Filtration is passage of drugs through aqueous pores in the membrane or through paracellular spaces.
Water soluble (lipid insoluble) drug across biological membrane by filtration (lower concentration to
higher concentration gradient) if their molecular size is smaller than the diameter of the pores.
Fig. 3. Illustration of passive diffusion and filtration across the lipoidal biological membrane
with aqueous pores
14
Pharmacokinetics
3.3 Specialized Transport
This can be carrier mediated or by pinocytosis.
a) Carrier transport
i) Active carrier transport

ii) Facilitated diffusion/transport
b) Pinocytosis
a) Carrier transport:-
The drug combines with a carrier present in the membrane and the complex then translocates from
one face of the membrane to the other. The host membranes/protein serves as carrier or transporters
for ions, nutrients, metabolites, transmitters etc across the membrane. Carrier transport is specific,
saturable and competitively inhibited by analogues which utilize the same carrier. This is of two types.
i) Active transport:-
This movement process occurs against the concentration gradient and is inhibited by metabolic
poisons. Where energy is requires for electrochemical gradient from lower to higher concentration e.
g. levodopa and methyldopa.
ii) Facilitated diffusion:-
This proceeds more rapidly than simple diffusion and translocates even nondiffusible substrates, there
is no need of energy for the transports of drugs and the transports also goes to direction of
electrochemical gradient from higher to lower concentration.
b) Pinocytosis:-
It is the process of transport across the cell in a particulate form by formation of vesicles (small &
hollow bag like structure in body). This is applicable to proteins and other big molecules, and
contributes little to transport of most drugs.
3.4 Absorption
Absorption derived from (Absorb means, intake or accept & formation means process).
Generally, absorption, the process of solid, liquid, gas or other substance being taken in any route
that is called absorption e. g. plant absorb oxygen. In pharmacological definition absorption is
movement of the unchanged drug from its site of administration (oral, IV, IM, topical and skin etc) into
the systemic circulation (blood, fluid and tissue, etc).
Classification:-
i. Enternal route
ii. Parenteral route
iii. Topical route
i. Enternal route: -
By these routes the drug is the epithelial lining of the gastrointestinal tract, sublingual or buccal and
also rectal. No ionized lipid soluble drugs are readily absorbed from stomach as well as intestine at
rates proportional to their lipid: water partition coefficient.
15
Pharmacokinetics
ii. Parenteral route: -
Par-beyond, Enternal-Intestinal,
By these routes the drug is deposited directly in the vein, blood, fluid and tissue, in the vicinity of the
capillaries (e. g. Intravenous, Intramuscular, Intradermal, Intraspinal and Intraarticular etc) lipid soluble
drugs pass readily across the whole surface of the capillary endothelium.
iii. Topical route:-
In these routes (skin, eye, ear, nose, inhalation, cornea, mucus membrane and intravaginal) the
systemic absorption after topical application depends primarily on lipid solubility of drugs.
The factors affecting GI absorption of a drug are:-
A) Physicochemical factors: - Including factors relating to the physical and chemical properties
of the drug and dosage form characteristics and pharmaceutical ingredients.
1) Drug solubility and dissolution rate
2) Particle size and effective surface area
3) Polymorphism and amorphism
4) Salt form of the drug
5) Pseudo polymorphism (hydrate/solvates)
6) Lipophilicity of the drug
7) pKa of the drug and gastrointestinal pH
8) drug stability
9) Stereochemical nature of the drug
B) Pharmaceutical (Manufacturing) factors:-

1) Buffer
2) Pharmaceutical ingredients (excipients/adjuvant)
3) Nature and type of dosage form
4) Product age and storage condition
C) Biological (Patient related) factors:-

1) Age
2) Sex (male/female)
3) Species (man/animal/insect)
4) Disease state
5) Route of drug administration
6) Gastrointestinal pH
3.5 Factor Affecting Absorption

These are some another factor, which is played a major role in absorption.
i. Aqueous solubility
ii. Concentration
iii. Area of absorbing surface
iv. Vascularity of the absorbing surface
v. Route of administration
i) Aqueous solubility:-
Solid dosage form drugs given as watery solution is absorbed faster than when the same is given in
solid form or as oily solution.
ii) Concentration:-
Drug given as concentrated solution is absorbed faster than from dilute solution.
16
Pharmacokinetics
iii) Area of absorbing surface:-
Larger is the surface area, faster is the absorption.
iv) Vascularity of the absorbing surface:-
Blood circulation removes the drug from the site of absorption and maintains the concentration
gradient across the absorbing surface.
v) Route of administration:-
This affects drug absorption, because each route has its own peculiarities e. g. oral, topical and
subcutaneous.
3.6 Distribution
Distribute- to share, separate and divided any things,
Distribution provides information on the extent/amount and time course of tissue accumulation and the
elimination of drug and/or its metabolites. The disposition of drug into the organs and tissues via
circulation depends upon the nature of the drug. The more lipophilic the drug is, the better will be the
distribution into the organs and tissues.
After absorption of drugs enters or passes through the various body fluid compartments such as
blood, plasma, tissue and fluid, which is called distribution. On the other way it is a reversible transfer
of drugs between one compartment to anther compartment. Distribution carried out by the one
compartment is blood or plasma and another compartment is extra vascular fluids and other body
tissues.
Fig. 4. Illustration of the concept of apparent volume of distribution (V). In this example, 1000
mg of drug injected i.v. produces steady-state plasma concentration of 50 mg/L, apparent
volume of distribution is 20 L
Volume of distribution:-
The volume of distribution (Vd), also known as apparent volume of distribution, is a pharmacological,
theoretical volume that the total amount of administered drug would have to provide the same
concentration as it is in blood plasma. If the amount of drug (X) and the resulting concentration (C) are
known, then the volume of distribution (Vd) can be calculated using the simplified equations.
17
Pharmacokinetics
X =Vd/C,
Where X = amount of drug in body,

Vd = volume of distribution
C = plasma concentration
Volume of distribution = Total amount of drug administered

Drug present in plasma concentration
The interaction of drugs and protein complex formation is called protein binding of drug, it is two
types.
a) Intracellular/Primary receptor
b) Extracellular/Secondary/Silent receptor
a) Intracellular/Primary receptor: - The drugs bound with cell protein, which may be drug receptor
and such binding show a pharmacological response and such receptor, which bind/interact with drug
called primary receptor.
b) Extracellular/Secondary/Silent receptor: - The drugs bind to extracellular protein, which is not

show a pharmacological response that is called secondary or silent receptor. The most silent or
secondary receptor of extracellular protein is plasma protein (particularly albumin).
A drug in the body can interact with several tissue components of which are generally the
macromolecules, proteins, DNA and adipose.
Binding of drug are two types:-
A. Binding of drug to blood components

a) Plasma protein
b) Blood cells
B. Binding of drug to extra vascular tissues
A. Binding of drug to blood components:- The plasma protein and blood cells are a complex form
of blood but these are separately bind with drugs and produces different pharmacological effects on
these components.
a) Plasma protein drug binding:- It is a reversible process of drug interaction, where the interaction
of drugs and plasma proteins (human albumin serum, α acid glycoprotein, lipoprotein and α1-α2
globulin) complex formation is called plasma protein drug binding. The plasma proteins bound drug
nor metabolized nor excreted or nor pharmacologically active and these are not show a
pharmacological response.
A) Human albumin serum

B) α acid glycoprotein
C) Lipoprotein
D) α1-α2 globulin
E) β1 - β2 & γ globulin
b) Blood cells binding:- The RBC is a major cell component of drug binding it is bind with drugs and
shows a pharmacological response. It has been shown that the rate and extent/amount of entry into
RBC is more for lipophilic/lipid soluble drugs, e.g. phenytoin. Hydrophilic/water soluble drugs like
ampicillin do not enter RBC.
A) Hemoglobin
B) Carbonic anhydrase
C) Cell membrane
18
Pharmacokinetics
A) Hemoglobin:-
It has a molecular weight of 64,500 (almost equal to that of HSA) but is 7 to 8 times the concentration
of albumin in blood. Drugs like phenytoin, pentobarbital and phenothiazines bind to haemoglobin.
B) Carbonic anhydrase:-
Drugs known to bind to it are acetazolamide and chlorthalodone (i.e cabonic anhydrase inhibitors).
C) Cell membrane:-
Imipramine and chlorpromazine are reported to bind with the RBC membrane.
B. Binding of drug to extra vascular tissues:-
A drug can bind to one or more of the several tissue components. The drugs bind to extra vascular
tissue are Liver>kidney>lungs>muscle>intestine other are skin, eye, hair, bone, fat. Several example
of extravascular tissue drug binding are:
Liver:- As stated earlier, epoxides of a number of halogenated hydrocarbons and paracetamol bind
irreversibly to liver tissues resulting in hepatotoxicity.
Lungs:- Basic drugs like Imipramine, chlorpromazine and antihistamines accumulate in lungs.
Kidney:- Metallothionin, a protein present in kidney, binds to heavy metals such as lead, mercury and
cadmium and results in their renal accumulation and toxicity.
Skin:- Chloroquine and phenothiazines accumulate in skin by interacting with melanin.
Eyes:- The retinal pigments of the eye also contain melanin. Binding of chloroquine and
phenothiazines to it is responsible for retinopathy.
Hairs:- Arsenicals, chloroquine and phenothiazines are reported to deposit in hair shafts.
Bones:- Tetracycline is a well known example of a drug that binds to bones and teeth. Administration
of this antibiotic to infants or children during odontogenesis results in permanent brown yellow
discoloration of teeth. Lead is known to replace calcium from bones and cause their brittleness.
Fats:- Lipophilic drugs such as thiopental and the pesticide DDT accumulate in adipose tissue by
partitioning into it. Receptors have stated that adipose localization of drugs is a result of binding
competition between adipose and non adipose tissue (lean tissues like muscles, skin and viscera) and
not partitioning.
Nucleic acids:- Molecular components of cells such as DNA interact strongly with drugs like
chloroquine and quinacrine resulting in distortion of its double helical structure.
3.7 Redistribution
When highly lipid soluble drugs given in intravenous and inhalational, its distributed to organs with
high blood flow ( i. e. brain, heart, kidney etc) later less vascular but more bulky tissues (muscle, fat)
take up the drug plasma concentration falls and the drug is not involve these site. Greater the lipid
solubility of the drug, faster is its redistribution.
Kinetics of protein drug binding:- If P represents proteins and D the drug, then applying low of
mass action to reversible protein drug binding: we can write;
19
Pharmacokinetics
P + D ↔ PD
At equilibrium
Ka = [PD]
[P][D]
[PD] = Ka [P][D]
Where, [P] = concentration of free protein

[D] = concentration of free drug
[PD] = concentration of protein drug complex
Ka = association rate constant
Factor affecting drugs distribution are:-
1. Physiochemical properties of drug
a) Particle size
b) Aqueous/lipid solubility
c) pKa value of drug
d) Diffusion of drug
e) Ph
f) Mass
2. Pharmaceutical factor
a) Lipid : water partition

b) Drug interaction
c) Coefficient of the drug
d) Binding of drug to blood components
3. Biological factors
a) Organ/tissue size
b) Age
c) Diet
d) Obesity
e) Pregnancy
f) Degree of plasma protein binding
g) Fat lean body mass ratio
h) Disease state
3.8 Biotransformation (Metabolism)
(Biological - All living organism, Transfer- shifting, Formation- process).
Biotransformation means the chemical processes in living things that change food or other
substances into energy and materials for growth and other effect. It is a chemical alteration or change
of the drug in the body from one phase to another phase. It is needed to render nonpolar (lipid
soluble) compounds polar (lipid insoluble) so that they are not reabsorbed in the renal tubules and are
excreted. The primary site for drug metabolism is liver, other are- lungs, kidney, intestine, skin and
plasma.
Biotransformation of drugs may lead to the following.
Inactivation:-
Most drugs and their active metabolites are rendered inactive or less active, e. g. ibuprofen,
paracetamol, lidocaine, chloramphenicol, propranolol and its active metabolite 4-hydroxypropranolol.
20
Pharmacokinetics
Active metabolite from an active drug:-
Many drugs have been found to be partially converted to one or more active metabolite; the effects
observed are the sum total of that due to the parent drug and its active metabolite.
Activation of inactive drug:-
Few drugs are inactive as such and required conversion in the body to one or more active
metabolites. Such a drug is called a prodrug. The prodrug may offer advantages over the active form
in being more stable, having better bioavailability or other desirable pharmacokinetic properties or less
side effects and toxicity. Some prodrugs are activated selectively at the site of action.
The biotransformation of drugs depends on the two enzymes:-
1. Microsomal
2. Non-microsomal
1. Microsomal enzymes:- These are located on smooth endoplasmic reticulum, attached with inside
the cell and present in liver, kidney, intestine, mucosa and lungs. They catalyse most of the oxidation,
reduction, hydrolysis and Glucuronide conjugation.
2. Non-microsomal enzymes:- These are present in the cytoplasm and mitochondria of hepatic
(liver) cell as well as in other tissues including plasma. The flavor-protein oxidases, esterases,
amidases and conjugases are non-microsomal.
Biotransformation reactions can be classified or categorized into:

According to R. T. Williams:-
1. Phase I/Non-synthetic/Functionalization reaction

2. Phase II/ Synthetic/Conjugation reaction
Based on latest researcher:-
3. Phase III/Specially for Glutathione conjugation, excreted via Bile in the Gut
1. Phase I /Non-synthetic/ Functionalization reaction:-
A functional group is generated or exposed; metabolite may be active or inactive.
Oxidation:-
This reaction involves addition of oxygen (negatively charged radical) or removal of hydrogen
(positively charged radical). Oxidations are the most important drug metabolizing reactions. Oxidative
reactions are mostly carried out by a group of aromatic, olefins, allylic, aliphatic and alicylic
compounds.
Reduction:-
This reaction is the converse of oxidation and involves cytochrome P-450 enzymes working in the
opposite direction. Alcohols, carbonyl, aldehydes, quinones are reduced drugs
Hydrolysis:-
This is cleavage of drug molecule by taking up a molecule of water. Hydrolysis occurs in liver,
intestines, plasma and other tissues. Examples of hydrolysed drugs are choline esters, amides,
procaine, lidocaine, procainamide, aspirin, carbamazepine-epoxide, pethidine, oxytocin.
Ester + H2O →Acid + Alcohol
21
Pharmacokinetics
Cyclization:-
This is formation of ring structure from a straight chain compound, e.g. proguanil.
Decyclization:-
This is opening up of ring structure of the cyclic drug molecule, e.g. barbiturates, phenytoin.
2. Phase II/ Synthetic/Conjugation reaction:-
An endogenous radical is conjugated to the drug, metabolite is mostly inactive; except few drugs, e. g.
glucuronide conjugate of morphine and sulfate conjugate of minoxidil are active.
These involve conjugation of the drug or its phase-I metabolite with an endogenous substrate, usually
derived from carbohydrate or amino acid, to form a polar highly ionized organic acid, which is easily
excreted in urine or bile. Conjugation reactions have high energy requirement.
Glucuronide acid conjugation:-
This is the most important synthetic reaction carried out by a group of UDP-glucuronosyl transferases
(UGTs). Compounds with a hydroxyl or carboxylic acid group are easily conjugated with glucuronic
acid which is derived from glucose. Examples are- chloramphenicol, aspirin, paracetamol, diazepam,
lorazepam, morphine and metronidazole.
Acetylation:-
Compounds having amino or hydrazine residues are conjugated with the help of acetyl coenzyme-A,
e.g. sulfonamides, isoniazid, PAS, dapsone, hydralazine, clonazepam, procainamide. Multiple genes
control the N-acetyl transferases (NATs), and rate of acetylation shows genetic polymorphism (slow
and fast acetylators).
Methylation:-
The amines and phenols can be methylated by methyl transferases (MT); methionine and cysteine
acting as methyl donors, e.g. adrenaline, histamine, nicotinic acid, methyldopa, captopril,
mercaptopurine.
Sulfate conjugation:-
The phenolic compounds and steroids are sulfated by sulfotransferases (SULTs), e.g.
chloramphenicol, methyldopa, adrenal and sex steroids.
Glycine conjugation:-
Salicylates, nicotinic acid and other drugs having carboxylic acid group are conjugated with glycine,
but this is not a major pathway of metabolism.
α- Amino acid conjugation:-
Compounds having organic and inorganic residues are conjugated with the help of α- Amino acid;
these are not a major pathway of metabolism.
Ribonucleoside/nucleotide:-
This pathway is important for the activation of many purine and pyrimidine antimetabolites used in
cancer chemotherapy. A variety of metabolites (some more, some less) of a drug may be produced.
22
Pharmacokinetics
Stereoisomers of a drug may be metabolized differently and at different rates, e.g. S-warfarin rapidly
undergoes ring oxidation, while R-warfarin is slowly degraded by side chain reduction.
Fig. 5. Simultaneous and/or sequential metabolism of a drug by phase I and phase II reactions
On the basis of latest research:-
3. Phase III/Glutathione conjugation:-
This is carried out by glutathione-S-transferase (GST) forming a mercapturate. It is normally a minor

pathway. However, it serves to inactivate highly reactive quinone or epoxide intermediates formed
during metabolism of certain drugs, e.g. paracetamol. When large amount of such intermediates are
formed (in poisoning or after enzyme induction), glutathione supply falls short—toxic adducts are
formed with tissue constituents → tissue damage.
3.9 Factor Affecting Metabolism
Factor affecting drugs metabolism are:-
1. Physiochemical properties of drugs
a) Induction & inhibition of drug metabolizing enzymes

b) Environmental chemicals
a) Species differences
b) Strain differences
c) Sex differences
d) Age
e) Diet
f) Pregnancy
g) Hormonal imbalance
h) Disease states
23
Pharmacokinetics
3.10 Excretion
Excretion derived from ‘Excrete’, which means to pass out solid or liquid waste material from the body
or pass out the waste material internal phase to external environmental condition.).
3.11 Nephron
(A basic functional unit of kidney, each kidney contains 1 million nephron). Nephron is a coil like cell
present in kidney, which are filtered the blood and separate the water and blood through tubular cell.
Drugs and their metabolites are removed from the body is called excretion or it is an irreversible loss
of drug from body, where the drug metabolites transfer from internal to external environment.
These are categorized in two types.
1. Renal
2. Non-renal
1. Renal
All most all drugs and their metabolites are excreted by kidney. The kidney is responsible for excreting
all water soluble, non-volatile, small size and metabolized slowly substances/drugs. The amount of
drug or its metabolites ultimately present in urine is the sum total of glomerular filtration, tubular
reabsorption and tubular secretion.
Net renal excretion = (Glomerular filtration + Tubular secretion) – tubular reabsorption
Fig. 6. Schematic depiction of glomerular filtration, tubular reabsorption and tubular secretion
of drugs FD—free drug; BD—bound drug; UD—unionized drug; ID—ionized drug; Dx—actively
secreted organic acid (or base) drug
Urine: -
Urine excreted by through the kidney. It is the most important channel of excretion for majority of
drugs. All most all drugs and their metabolites are excreted by the kidney to some extent or the other.
24
Pharmacokinetics
Agents that are excreted in urine are, water soluble, non-volatile and small in molecular size (less
than 500 Daltons).
Kidney:-
The processes which determine the elimination/excretion of a drug in the urine are:
Glomerular filtration/Passive glomerular filtration:-
Only the unbound fraction of unionized drugs is filtered at the glomerulus, but they are reabsorbed by
diffusion back from tubular lumen into the cells lining the tubules. Glomerular capillaries have pores
larger than usual; all nonprotein bound drug (whether lipid-soluble or insoluble) presented to the
glomerulus is filtered. Thus, glomerular filtration of a drug depends on its plasma protein binding and
renal blood flow. Glomerular filtration rate (g.f.r.), normally ~ 120 ml/min, declines progressively after
the age of 50, and is low in renal failure.
Active tubular secretion:-
Many weak acids (anionic substances) and weak bases (cationic substances) are actively secreted by
proximal tubules by carrier mediated systems involving transporters such as p-glycoprotein and the
multidrug resistance associated protein type 2 (MRP2). This is the active transfer of organic acids and
bases by two separate classes of relatively nonspecific transporters (OAT and OCT) which operate in
the proximal tubules.
(a) Organic acid transport: - (through OATP) operates for penicillin, probenecid, uric acid,
salicylates, indomethacin, sulfinpyrazone, nitrofurantoin, methotrexate, drug glucuronides and
sulfates, etc.
(b) Organic base transport:- (through OCT) operates for thiazides, amiloride, triamterene,
furosemide, quinine, procainamide, choline, cimetidine, etc.
Passive tubular reabsorption:-
This occurs by passive diffusion and depends on lipid solubility and ionization of the drug at the
existing urinary pH. Lipid-soluble drugs filtered at the glomerulus back diffuse in the tubules because
99% of glomerular filtrate is reabsorbed, but nonlipid-soluble and highly ionized drugs are unable to
do so. Changes in urinary pH affect tubular reabsorption of drugs that are partially ionized—
• Weak bases ionize more and are less reabsorbed in acidic urine.
• Weak acids ionize more and are less reabsorbed in alkaline urine.
2. Non-renal:-
These routes are not depends upon the kidney and their metabolites are excreted by different another
organ e. g. skin, intestine, lungs, milk etc.
Skin:-
Arsenic and heavy metals like mercury and excreted in small quantities through the skin. Arsenic gets
incorporated in the hair follicle on prolonged administration. This phenomenon is used for detection of
arsenic poisoning.
Intestine:-
Heavy metals are excreted through the intestine and can produce intestinal ulceration. Laxatives like
cascara and senna, which act mainly on the large bowel are partly excreted into that area from the
blood stream, after their absorption from the small intestine.
25
Pharmacokinetics
Lungs:-
Volatile general anesthetics and certain other drugs like paraldehyde and alcohol are partially
excreted by the lungs.
Milk:-
The excretion of drug in milk is not important for the mother, but the suckling (who intake the milk)
infant inadvertently receives the drug. Most drugs enter breast milk by passive diffusion. As such
more lipid soluble and less protein bound drugs cross better. However the total amount of drug
reaching the infant through breast feeding is generally small and majority of the drugs can be given to
lactating mothers without ill effects on the infant.
Faeces:-
Apart from the unabsorbed fraction, most of the drug present in faeces is derived from bile. Liver
actively transports into bile organic acids (especially drug glucuronides by OATP and MRP2).
Exhaled air:-
Gases and volatile liquids (general anaesthetics, alcohol) are eliminated by lungs, irrespective of their
lipid solubility.
Saliva and sweat:-
Certain drugs like iodides and metallic salts are excreted in the saliva. These are of minor importance
for drug excretion.
Bile:-
Drugs such as phenolphthalein deoxycycline and cefoperazone appear in high concentration in the
bile. Such drugs may get repeatedly reabsorbed from the intestine and reexcreted in bile, for excreting
a prolonged action.
3.12 Kinetics of Elimination
The knowledge of kinetics of elimination of a drug provides the basis for, as well as serves to devise
rational dosage regimens and to modify them according to individual needs. There are three
fundamental pharmacokinetic parameters.
1. Bioavailability (F)
2. Volume of distribution (V)
3. Clearance (CL)
Clearance (CL):-
The clearance of a drug is the theoretical volume of plasma from which the drug is completely
removed in unit time (analogy creatinine clearance. It can be calculated as
CL = Rate of elimination/C, Where C is the plasma concentration.
Drugs are eliminated from the body by:
1. First order kinetics

2. Zero order kinetics
26
Pharmacokinetics
3.13 Factor Affecting Excretion
Factor affecting drugs excretion are:-
1. Physiochemical properties of drugs

2. Plasma concentration of the drug
3. Distribution & binding characteristics of the drug
4. Urine Ph
5. Blood flow to the kidney
6. Drug interaction
i) Age
j) Diet
k) Pregnancy
l) Hormonal imbalance
m) Disease states
_________________________________________________________________________________
27
Chapter 4
Pharmacodynamics
and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
4.1 Introduction
How to drug interact into the body.

Pharmacodynamics refers to the relationship between drug concentrations at the site of action and
the resulting effect, including the time course and intensity of therapeutic and its adverse effects.
Pharmacodynamics is the study of drug effects. It starts with describing what the drugs
pharmacological and biochemical effect; when it reaches the site of action in body and goes on to
explain how they do it. The site of drug action or where a drug acts, and the mechanism of drug action
or how a drug acts, are the two fundamental and complex problems in pharmacodynamics.
Modification of the action of one drug by another drug is also an aspect of pharmacodynamics.
4.2 Principles of Drug Action
Drugs do not impart new functions to any system, organ or cell; they only alter the pace of ongoing
activity. However, this alone can have profound medicinal as well as toxicological impact. The basic
types of drug action can be broadly classed as:
1. Stimulation/Excitement
2. Depression/Dejection
3. Irritation/Induced or Excite
4. Replacement/Substitution
5. Cytotoxic/Neoplastic/Anticancer action
4.2.1 Stimulation/Excitement
Increase in the activity of specialized cells is called stimulation e.g. adrenaline stimulates heart,
pilocarpine stimulates salivary glands. However, excessive stimulation may ultimately lead to
depression.
4.2.2 Depression/ Dejection
Decrease in the activity of specialized cells is called depression e. g. quinidine depresses the
myocardium (Heart chamber cell) while barbiturates depress the central nervous system, omeprazole
depresses gastric acid secretion.
4.2.3 Irritation/ Induced or Excitement
The term irritation indicates that a drug produces adverse effects on the growth, nutrition and
morphology of living tissues. It produces changes in the cellular structure and can produce
_____________________________________________________________________________________________________
1
Uttarakhand, India.
2
3
Pharmacodynamics
inflammation, corrosion and necrosis of cells. This may result in diminution or loss of function. The
cellular changes produced are:
a) Astringent effect
b) dehydration
4.2.4 Replacement/ Substitution
Drugs may be used as replacement when the production of endogenous substances is reduced. This
replacement finds an important application in the treatment of hormonal deficiencies, e.g. levodopa in
parkinsonism, insulin in diabetes mellitus, iron in anemia.
4.2.5 Cytotoxic/ Neoplastic/Anticancer action
(Damage to the cell wall or the nucleus e. g. anticancer drugs).

Selective cytotoxic action on invading parasites or cancer cells, attenuating them without significantly
affecting the host cells is utilized for cure/palliation of infections and neoplasms, e.g. penicillin,
chloroquine, zidovudine, cyclophosphamide, etc.
4.3 Mechanism of Drug Action
Drug or its effects are being used as synonyms. It is useful to term the initial consequences of drug
cell interaction as action of the drug; the events that follow are called drug effects. A drug may act by
virtue of its.
1. Physical action
2. Chemical action
3. Through enzymes
a) Stimulation
b) Inhibition
1) Specific
a) Competitive
b) Non-competitive
2) Non-specific
4. Through receptor
Physical action:-
 Colour: - A pleasant colour may exert a psychological effect e. g. tincture of cardamom.

 Physical mass: - Compounds like agar and psyllium seeds absorb water when administered orally
and swell in size.
 Smell: - Volatile oils like peppermint oil are used to mask the unpleasant smell of mixtures.
 Taste: - Compounds with a bitter taste reflexly increase the flow of hydrochloric acid in the
stomach and improve the appetite.
 Osmolality: - Osmotic diuretics like mannitol, osmotic purgatives like magnesium sulfate.
 Adsorption: - Kaolin and activated charcoal in the treatment of diarrhea.
 Soothing-demulcent:- Syrups as pharyngeal demulcents in the treatment of cough, calamine
lotion in eczema.
 Reduction in surface tension:- Cationic surfactants like certrimide for cleaning the skin.
 Electric charge:- Heparin a strongly acidic compound exerts its anticoagulant effect by virtue of its
negative charge.
131
 Radioactivity: - I in the treatment of hyperthyroidism.
29
Pharmacodynamics
 Radio-opacity:- Barium sulphate as barium meal organic iodine compounds for the visualization
of the urinary and biliary tracts.
Chemical action:-
 Acidity or alkalinity:- Antacids in the treatment of peptic ulcer.

 Chelation:- The chelating agent forms a ring structure with the molecules of lead, copper and
other metals. This ring structure is non toxic and water soluble and is excreted in the urine.
Through enzymes:-
Almost all biological reactions are carried out under catalytic influence of enzymes. Drugs can either
increase or decrease the rate of enzymatically mediated reactions.
Enzyme stimulation:-
Drugs may act by either increasing the rate of enzymatically mediated chemical reactions in the body
is called enzyme stimulation. Thus, stimulation of enzymes by drugs, that are truly foreign substances,
is unusual. Enzyme stimulation is relevant to some natural metabolites only, e.g. adrenaline
stimulates adenylyl cyclase, pyridoxine acts as a cofactor and increases decarboxylase activity.
Enzyme inhibition:-
Some chemicals (heavy metal salts, strong acids and alkalies, formaldehyde, phenol, etc.) denature
proteins and inhibit all enzymes non-selectively. However, selective inhibition of a particular enzyme is
a common mode of drug action. Such inhibition is either competitive or noncompetitive e.g. denaturing
by alcohol or heavy metals or specific, inhibition of carbonic anhydase by acetazolamide and that of
angiotensin converting enzyme (ACE) by captopril. It is occurs and commonly two types specific and
non-specific.
Specific:-
Where drug inhibition process carried out by a specific (selectively only one enzyme) enzyme without
affecting anther enzymes, that is called specific inhibition, these are another two types.
Competitive (equilibrium type):-
When drug competes with normal substrate or coenzyme for the catalytic binding site of the enzyme
so that the product is not formed or a nonfunctional product is formed and a new equilibrium is
achieved in the presence of the drug.
Non-competitive (non-equilibrium type):-
A non-equilibrium type of enzyme inhibitor reacts with adjacent site and not with the catalytic site or
enzyme site and enzymes loses his catalytic enzymatic properties.
Non-specific:-
When tertiary structure nature enzymes are comes in the contact of drugs and their chemical
compounds, they inhibit the enzymatical process that is called non-specific inhibition.
Through receptor:-
Many drugs act by binding to specific protein macromolecules in the cell membrane or in the cytosol
and regulate the cell function by altering enzyme activity, permeability to ions, conformational features
or genetic material in the nucleus.
30
Pharmacodynamics
Receptor:-
It is defined as a macromolecule or protein interact/attached/binding with drugs that is called

receptors. Though, in a broad sense all types of target biomolecules, including the effectors
(enzymes, channels, transporters, etc.) with which a drug can bind to produce its action have been
denoted as ‘receptors’. It is therefore better to reserve the term ‘receptor’ for purely regulatory
macromolecules, which combine with and mediate the action of signal molecules including drugs.
Nature of receptor:-
Receptors are regulatory macromolecules and mostly protein through nucleic acid may also serve as
receptor.
Receptor theory:-
After studying quantitative aspects of drug action, Clark (1937), propounded a theory of drug action
based on occupation of receptors by specific drugs and that the pace of a cellular function can be
altered by interaction of these receptors with drugs which, in fact, are small molecular ligands. He
perceived the interaction between the two molecular species, viz. drug (D) and receptor (R) to be
governed by the law of mass action, and the effect (E) to be a direct function of the drug receptor
complex (DR) formed:
D + R → DR → E (Effect)
Drug Receptor Drug receptor complex
Also drug and receptor have stand or bind in lock and key relationship.
Types of receptor:-
1. Type 1 (Channel linked, Ionotropic)

2. Type 2 (G-protein coupled, GPCR) Metabotropic
3. Type 3 (Kinase linked)
4. Type 4 (Receptor that regulate gene transcription)
Type 1 (Channel linked, Ionotropic):-
Ion channels are cell membrane, which binding with drugs and cross the ions in membranes e. g Na,
Cl, K etc.
Type 2 (G-protein coupled, GPCR) Metabotropic:-
Guanosine nucleotide binding proteins involved with receptor and regulate (GPCR) in brains and gut,
which either stimulate or inhibit in action (Gi) or (Gs), where G is Guanosine diphosphate or
triphosphate.
a) Adenylylcyclase, CAMP Pathway

b) Phospholipase, IP3, DAG Pathway
c) Channel regulation
Type 3 (Kinase linked):-
The third family of cell surface receptors are tyrosine kinase e.g. insulin and atrial natriuretic peptide
receptors. Tyrosine kinase activates themselves by autophosphorylation after the hormone binds to
them. The autophosphorylated tyrosine kinase then phosphorylates intracellular proteins on the
tyrosine residues.
31
Pharmacodynamics
Fig. 7. Diagrammatic representation of G-protein coupled receptor molecule
Type 4 (Receptor that regulates gene transcription):-
These kinds of receptor present in the cytoplasm, those for thyroid hormones are present in the
nuclear chromatin. These receptors, after activation by hormone binding, act on the genetic material
in the nucleus to initiate or inhibit the process of transcription.
The following terms are used in describing drug-receptor interaction:
 Affinity: - It is the ability of drugs to combine with receptor, which is called affinity.
 Intrinsic activity (Efficacy):- It is the ability of drugs to activate the receptor, which is called
efficacy.
 Agonist: - An agents or drugs, which activate a receptor to produce an effect similar to that of the
physiological signal molecule.
 Competitive antagonists: - Competitive antagonists have affinity but no intrinsic activity (IA = 0),
e.g. propranolol, atropine, chlorpheniramine, naloxone.
 Inverse agonist: - An agents or drugs, which activates a receptor to produce an effect in the
opposite direction to that of the agonist.
 Antagonist: - An agents or drugs, which prevents the action of an agonist on a receptor or the
subsequent response, but does not have any effect of its own.
 Partial agonist: - An agents or drugs, which activates a receptor to produce sub maximal effect
but antagonizes the action of a full agonist.
 Ligand (Latin: ligare—to bind) Any molecule or drugs, which attaches selectively to particular
receptors or sites. The term only indicates affinity or ability to bind without regard to functional
change: agonists and competitive antagonists are both ligands of the same receptor.
_________________________________________________________________________________
32
Chapter 5

and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
5.1 Introduction
Elementary (Which is connected with first stage or basic stage of a course study).
Adverse (Negative or undesirable or unwanted or unpleasant (not likely to produce a good result).
It is undesirable or unpurpose or unplan consequence of drug administration. Any response which is

undesirable or unintended and occurs in doses ordinarily employed for therapy or diagnosis. It may
develop prompty or only after prolonged medication or even after stoppage of drug. It is a broad term,
includes all kinds of noxious effect-trivial, serious or even fatal.
5.2 Types of ADR

Classification/Types:-
1. Type A (Predictable/Known reaction).

2. Type B (Unpredictable/Unknown reaction).
Predictable:- These are based on pharmacological properties or effects of drug including their low
and high dose concentrations. Which means that they are augmented, but qualitatively normal
response to the drug; include side effects, toxic effects and consequences of drug withdrawal. They
are more common, dose related and mostly preventable and reversible.
1) Side effect
a) Primary side effect

b) Secondary side effect
2) Toxic effect
Unpredictable:- These are based on peculiarities (strange or unusual feature or habit) of patient, not
for drug action include different drugs for different actions. They are less common, often non-dose
related, generally more serious and require withdrawal of the drug. Some of these reactions can be
predicted and prevented if their genetic basis is known and suitable test to characterize the
individual’s phenotype is performed.
1) Drug allergy (Immunological or immune system bind with chemical substance).
2) Idiosyncrasy (Genetically abnormal reaction with a chemical substance).
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1
Uttarakhand, India.
2
3
Side effect:-
It is unwanted but often unavoidable pharmacodynamic effects which are occur at therapeutic doses.
Generally it is not serious and easily predicted from the pharmacological profile of a drug and is
known to occur in a given percentage of drug recipients. A side effect may be based on the same
action as the therapeutic effect.
Primary side effect example:-
1. Atropine is used in preanaesthetic medication for its antisecretory action and produces dryness of
mouth as a side effect.
2. Codeine used for cough produces constipation as a side effect.
3. Estrogen is used for hormonal deficiency and produces nausea as a side effect.
4. Glyceryl trinitrate relieves angina pectoris and produces or responsible for postural hypotension
and throbbing headache.
5. Promethazine produces sedation which is unrelated to its antiallergic action.
6. Sulfonamide used for antibacterial and produces hypoglycemia as a side effect.
Secondary side effect example:-
These are indirect consequences of a primary action of the drug e. g.

Tetracycline’s (corticosteroids drug), which is used for bacterial suppression or inhibition and produce
or activate to weak host or defence cell after the host or defence cell are weak than further
tuberculosis gets activated.
Toxic effect:-
It is predictable and dose related. These are the result of excessive or hyper (high) pharmacological
action of the drug due to over dosage or prolonged use. Over dosages are basically three types
(accidental, homicidal, suicidal). The CNS, CVS, kidney, liver, lung, skin and blood forming organs are
most commonly involved in drug toxicity. Toxicity may result from extension of the therapeutic effect
itself, e.g. coma by barbiturates, complete A-V block by digoxin, bleeding due to heparin.
Another action of the drug can also be responsible for toxicity, e.g.—
1. Morphine (analgesic) causes respiratory failure in over dosage.

2. Imipramine (antidepressant) overdose causes cardiac arrhythmia.
3. Streptomycin (antitubercular) causes vestibular damage on prolonged use.
4. Regular or usual dose of gentamicin produce of renal failure.
5. High dose of atropine causing delirium or drug induced tissue damage.
6. Hepatic necrosis from paracetamol over dosage.
Drug Allergy:-
It is an immunologically mediated reaction producing stereotype symptoms, which are unrelated to

pharmacodynamics profile of drug. It is largely independent of dosage. It is also called
hypersensitivity.
Idiosyncrasy:-
It is genetically abnormal reactivity to a chemical substance or drug. That is depending on genotype or
chromosome. The drug or chemical substance interacts with some unique feature of the individual
and produces the uncharacteristic reaction. Certain drug effects due to peculiarities of an individual
(for which no definite genotype has been described) are included among idiosyncratic reactions, e.g.:-
1. Barbiturates cause excitement and mental confusion in some individuals.

2. Quinine/quinidine cause cramps, diarrhoea, purpura, asthma and vascular collapse in some
patients.
34
3. Chloramphenicol produces nondose-related serious aplastic anaemia in rare individuals.
Severity of Adverse drug reactions:-
Minor- No therapy, antidote or prolongation of hospitization is required.
Moderate- Require change in drug therapy, specific treatment or prolongs hospital stay by at least
one day.
Severe- Potentially life threatening, cause permanent damage or require intensive treatment.
Lethal- Directly or indirectly contributed to death of the patients.
Prevention of adverse effects to drugs:-
Adverse drug effects can be minimized but not altogether eliminated by observing the following
practices:
1. Avoid all inappropriate use of drugs in the context of patient’s clinical condition.
2. Use appropriate dose, route and frequency of drug administration based on patient’s specific
variables.
3. Elicit and take into consideration previous history of drug reactions.
4. Elicit history of allergic diseases and exercise caution (drug allergy is more common in patients
with allergic diseases).
5. Rule out possibility of drug interactions when more than one drug is prescribed.
6. Adopt correct drug administration technique (e.g. intravenous injection of vancomycin must be
slow).
7. Carry out appropriate laboratory monitoring (e.g. prothrombin time with warfarin, serum drug
levels with lithium).
5.3 Drug Allergy
Allergy, Greek word “allos” means ergos or energy.
1906 Viennese pediatrician Clemens Van Pirquet after noted hypersensitivity to normal innocuous by
dust, pollen and other substances. Some people serve allergies to environmental or dietary allergen
and medication in these results called anaphylaxis. It occurs when a person’s immune system reacts
to normally harmless (harmful) chemical substance in the environment. A chemical substance that
causes a reaction of allergy is called an allergen. These reactions are acquired (normal) predictable
and rapid.
An allergy is a hypersensitivity disorder of the immune system. It is an immunologically mediated

reaction producing stereotype symptoms, which are unrelated to pharmacodynamics profile of drug. It
is largely independent of dosage. It is also called hypersensitivity, but does not refer to increased
response, which is called super sensitivity. Drug antigens (AG) bind with endogenous protein and
induce production of antibody (AB) or sensitized lymphocytes.
Symptoms:-
A) Red eyes
B) Itching
C) Runny nose
D) Eczema
E) Hives
F) Asthma attack
G) Inflammation
35
5.4 Types of Allergy
1. Humoral
a) Type I (Immediate hypersensitivity reactions)

b) Type II (Cytotoxic type reaction)
c) Type III (Immune complex mediated reaction)
2. Cell-mediated
a) Type IV (Cell mediated reaction/Delayed hypersensivity)

b) Type V (Antireceptor type)
Type I (Immediate hypersensitivity reactions):-
Antigens (drugs) reacts with antibodies (IgE), which get fixed to the mast cells and releasing
mediators like histamine and caused allergies, resulting in urticaria, itching, angioedema,
bronchospasm, rhinitis or anaphylactic shock. Anaphylaxis is usually heralded by paresthesia,
flushing, swelling of lips, generalized itching, wheezing, palpitation followed by syncope. The
manifestations occur quickly after challenge and are called immediate hypersensitivity. Antihistaminic
drugs are beneficial in some of these reactions.
Type II (Cytolytic type reaction):-
In this case IgG and IgM antibodies bind with antigens (drugs) and present in surface of the cell and
activated in Cytolytic cells and causes to allergies e.g. thrombocytopenia, agranulocytosis, aplastic
anaemia, haemolysis, organ damage (liver, kidney, muscle), systemic lupus erythematosus.
Type III (Immune complex mediated reaction):-
Soluble antigens (chemical substance/drugs) bind with IgG antibody on vascular endothelium in vivo
form and release histamine where giving rise to a destructive inflammatory response. Manifestations
are rashes, serum sickness (fever, arthralgia, lymphadenopathy), polyarteritis nodosa, Stevens-
Johnson syndrome (erythema multiforme, arthritis, nephritis, myocarditis, mental symptoms). The
reaction usually subsides in 1–2 weeks.
Type IV (Cell mediated reaction/Delayed hypersensivity):-
These are activation of T-lymphocytes receptors by drug or antigen (AG). On contact with the AG
these T cells produce lymphokines which attract granulocytes and generate an inflammatory
response, e.g. contact dermatitis, some rashes, fever, photosensitization. The reaction generally
takes > 12 hours to develop.
Type V (Antireceptor type):-
In this case antigen (AG) or drugs are directly against the antibody and either activated or either
inhibited the receptor and then produces to allergies.
_________________________________________________________________________________
36
Chapter 6
and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
6.1 Introduction
History and development of toxicology:-
Adverse Drug Reaction/effect:-
1) Predictable/Known (Side effect and Toxic effect).

2) Unpredictable/Unknown (Drug allergy and Idiosyncrasy).
When a drug is used in therapeutic dose it may manifest some unwanted action simultaneously, these
are called side effects. The unwanted or adverse effects produced at higher doses are called toxic
effects.
Toxicology (means toxic-poison and logos-discourse in or detail study).
It is the scientific study of poisonous effect of drugs and other chemicals (household, environmental
pollutant, industrial, agricultural, homicidal) with emphasis on detection, prevention and treatment of
poisonings. It also includes the study of adverse effects of drugs, since the same substance can be a
drug or a poison, depending on the dose.
The father of toxicology was Paracelsus Greek physician and scientist, which was describe in 16
century for all substance are poison, and if there is nothing, that is not poison. After that toxicology
was described by modern father of toxicology (Mathieu orfilla). Other common agent having toxic or
fatal effects includes insecticides (killing insect) and pesticides (especially insect and animals, which
destroy plant food).
6.2 Poison and Antidotes

Poison:- Which chemical substances or drugs that cause or produce harmful/dangerous/fatal
effects/symptoms on living organism (human and animal) that is called poison. These are basically
household, environmental, pollutant and industrial etc.
Antidotes:- Which chemical substances or drugs, those prevent or inhibit poison or disease from
having an effect, which is called antidotes
6.3 Classification of Toxicity
Classification based on drug toxicity:-
1) Acute toxicity
2) Sub acute toxicity
3) Chronic toxicity
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Uttarakhand, India.
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3
Acute toxicity:- When any drug or chemical substance produce or occurs toxicity effects within 24
hours, this one called is acute toxicity.
Sub acute toxicity:- When it takes within days to week for produces or occurrence for toxicity effects,
which is called sub-acute toxicity.
Chronic toxicity:- When it takes within months to years for produces or occurrence for toxicity effects
that is called chronic toxicity e. g cancer.
6.4 Modern Classification of Toxicity
Modern classification of toxicity:- These are based on their different sources.
1) Target organ toxicity

2) Based on their intended/use
3) Based on their source
4) Based on their state
5) Based on their nature
6) Based on their biochemical mechanism
Target organ toxicity:- These types of drug are basically target on a particular organ e. g
paracetamol for liver, morphine & adrenaline for heart etc.
Based on their intended/use:- Those drugs are basically depends upon intended or use of our daily
life as well as occasionally life e. g DDT, urea, alcohol, methanol etc.
Based on their source:- These types of drug are found in natural form in the universe which is two
types’ plant and animal toxin e. g snake venom, scorpion venom, morphine, quinine etc.
Based on their state: - Gases, metals and dusts etc.
Based on their nature:- Halogenated (These are a set of five chemicals or elements Cl, F, Br and I
react with hydrogen and produce acid or salts) and hydrocarbon (These chemicals are made up of
hydrogen and carbon only e. g petrol, gases, coal, diesel and natural gases.
Based on their biochemical mechanism:- Those chemical substances or drug are basically
affected on our nervous system and worse or low quality products.
6.5 Teratogenicity
It refers to capabilities or ability of drug to cause or change foetal (fully developed embryo in womb)
abnormalities, when administrated to the pregnant women. The importance of teratogenicity was
realized after thalidomide tragedy in Europe in 1961. The drug thalidomide was introduced as a
sedative and become popular especially in pregnant women. They however gave birth to babies who
had sealed limbs (phocomelia). Drug can effect foetal at 3 stages.
1. Fertilization and implantation (conception to 17 day’s failure to pregnancy, which often goes
unnoticed).
2. Organogenesis (18 to 55 days of gestation) most vulnerable period, deformities are produced.
3. Growth and development (56 days to onwards) development and functional abnormalities can
occur.
6.6 Carcinogenicity (Carcino means, which cause Cancer)
It refers to the ability of a drug to induce or cause neoplasia or cancer or development of cancer. For
example prolonged use of estrogen may cause endometrial cancer. It refers oxidation of drug and
38
production of reactive intermediate which affect gene and cause structural changes in the
chromosomes.
6.7 Iatrogenic/drug Induced Diseases (Iatros Means, Physician)
The word “Iatros” means physician and “Induce” means excite thus diseases produced as a result of
drug therapy by physician are termed as iatrogenic diseases or physician induced diseases.
Sometimes drug themselves may produce certain pathological syndromes, these are called physician
induced diseases and functional disturbances diseases caused by drugs. Iatrogenic disease indicates
a pathological syndrome, e. g Parkinsonism produced by reserpine or chlorpromazine or
phenothiazine, peptic ulcer produced by aspirin and Indomethacin etc.
6.8 Toxicity Test
Acute toxicity test:- In this study a drug is tested to determine LD50 i. e lethal dose for 50% of
mortality (death) in a group of animals. Various doses range from 0 to 100 percent mortality are
administered to a group of 10 animals. The mortality in each group within a fixed period of time (e. g
one day to two days) is determined. Acute toxicity is carried out in two species preferably one rodent
and another non-rodent.
Sub acute toxicity test:- In this test, three doses of drug are administered for a period of one month
to six (6) months in two species of animals and the effect on various organs are studied. One should
carry out clinical chemistry, physiological signs, hematology, autopsy studies, histology (where tested
urine, blood, immune system etc) and electron microscopy studies particularly of the target organs of
drug producing toxicity. It is now a pre requisite for advancing a drug for clinical trial.
Chronic toxicity test:- These studies are required when the drug is intended to be used in humans
for prolonged periods. It is usually carried out concurrently with clinical trials. The study is carried out
in different animal species and the drug is administered for period of one year to 2 years. In this study
clinical chemistry, physiological signs, hematology, autopsy studies, histology etc are also carried out
in animals.
Teratogenicity test:- In this test effect of drug on mating behavior, reproduction, parturition, progeny
and birth defects are studied in animals.
Carcinogenicity test:- This test is required when a drug is intended to be used in human for
prolonged period. This is carried out in two species and drug is administered for a period of at least
two years. Hematology, autopsy studies and histology studies are carried out in animals.
6.9 Lethal dose50 (Which cause to death on 50%)
It is dose (mg/kg), which would be expected to kill one half (50%) of an unlimited population of the
same species and strain.
6.10 Effective dose50 (Which effect to the drug in 50%)
It is dose (mg/kg), which produce a desired response in one half (50%) of the test population in
different or same species.
_________________________________________________________________________________
39
Chapter 7
Drug Dependence
and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
7.1 Introduction
Drug dependence is a state in which use of drugs for personal satisfaction is accorded a higher
priority than other basic needs, often the face of known risk of health that is called drug dependence.
These are various problems.
7.2 Types of Drug Dependence
1) Psychological dependence
2) Physical dependence
3) Drug abuse
4) Drug addiction
5) Drug habituation
7.2.1 Psychological dependence
When the individual person believes that he/she is well cure or satisfaction only through drug or the
mental level is already set for achieved by only through drug action or uses and if the drug is not
taken then other liking effects is optimize (produce) to negative effect e. g. Benzodiazepines.
7.2.2 Physical dependence
It is found on repeated action or administration of drug, which is continue presence in body and
maintain physiological similarity or equilibrium. Discontinue of drug result in same characteristic
syndrome e. g Barbiturates, alcohol, opioids etc.
7.2.3 Drug abuse
It is refer to use of drug by self medication or treatment in a manner and amount for an approved
medical and social culture. It is use of illicit drug.
Continuous use- Alcohol, opioids, sedatives etc.

Occasional use- Cocaine, sexual drug, alcohol etc.
7.2.4 Drug addiction
It is a condition, where the use of drug involvement with a high level or over dose use of drug or
physical dependency of such drug is continued and high e. g. Morphine, regular use of alcohol,
cocaine etc.
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Uttarakhand, India.
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Drug Dependence
7.4.5 Drug habituation
It denotes that less intensive involvement with drugs and it withdrawal (quite) produce only mild
(lightly) discomfartable e. g. Tea, coffee, tobacco, social drinking etc.
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41
Chapter 8
Drug Tolerance
and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
8.1 Introduction
Tolerance, which means tolerate or bear, when an unusually large dose of drug is required to its
optimum or maximum effect or response ordinarily produced by the normal therapeutic dose of the
drug, that is called drug tolerance. It means requirement of higher dose of a drug to produce a given
response.
8.2 Types of Drug Tolerance
These are basically two types.
1) True tolerance
a) Natural tolerance
i) Species tolerance
ii) Racial tolerance
b) Acquired/Attain tolerance
i) Tissue tolerance
ii) Cross tolerance
2) Apparent/direct or pseudo/clear tolerance
Natural tolerance:-
The species/individual is inherently less sensitive to the drug, e.g. rabbits are tolerant to atropine,
black races are tolerant to mydriatics. Certain individuals in any population are hyporesponders to
certain drugs, e.g. to β adrenergic blockers or to alcohol.
Species tolerance:-
Certain animal species can tolerate certain drugs in different quantities or e. g human tolerate family,
rabbit tolerate belladonna etc.
Racial tolerance:-
Some drugs or substances tolerate by a particular breed that is called racial tolerance e. g. caste or
community tolerance in India etc.
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Uttarakhand, India.
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3
Drug Tolerance
Acquired tolerance:-
It is depend on drug repeated administration and development in weeks or months. e. g alcohol,

barbiturates, nitrites, xanthenes etc.
Tissue tolerance:-
These are basically depends upon the tissue or organ of the system, where drug react.
Cross tolerance:-
When the same group shows two different drug tolerances that is called cross tolerance. It refers
pharmacologically related effect e. g pharmacodynamics and pharmacokinetics e. g. alcohol for
barbiturates and general anesthetic and morphine and pethidine tolerance.
Apparent/direct or pseudo/clear tolerance:-
It is acute type of tolerance and which is depend on doses of a drug repeated or continued usage in
quick succession result in marked reduction in response e. g. cocaine, arsenic, ephedrine, tyramine
and nicotinic.
8.3 Drug Resistance
It refers to tolerance of microorganisms to inhibitory action of antimicrobials e.g. Staphylococci to

penicillin. It means these are refers decreased responses of drug through prolonged usage of drug,
where increased doses will not produce same therapeutic effect as compared to ordinary or usual
drug that is called drug resistance. It is go to generation to generation through of microbes as like
sulphas and streptomycin.
_________________________________________________________________________________
43
Chapter 9

and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
9.1 Introduction
Assay/Standardization:-
The experimental study of drugs or chemical substances for quality and purity, which is called assay.
Assay is the estimation of the amount or the activity of an active principle in a unit quantity of the
preparation. It can be divided into three types.
9.2 Types of Assay
1) Physical assay
2) Chemical assay
3) Biological assay
Physical assay:-
Where carried out of any drugs or chemical substance physical quality and purity test e. g. colour,
taste, smell, pH, M. P, B. P etc.
Chemical assay:-
There is used of drugs or chemical substance chemical quality and purity e. g. acidic, basic, chelating
form etc.
Biological assay:-
Biological, means the scientific study of drugs in living organisms (plant, animal and man) and
observation of pharmacological effect of living tissue, micro/macro or immune cells or animal is known
as biological assay or bioassay. Other synonyms are biometrics or biological standardization. It is less
accurate, less elaborate, more laborious, more troublesome and more expensive.
The purpose of bioassay is to ascertain the potency of a drug and hence it serves as the research.
Other purpose of bioassay is to standardize the preparation so that each contains the uniform
specified pharmacological activity. It is also help in diagnosis of various conditions e. g
gonadotrophins for pregnancy.
9.3 Principle of Bioassay
The basic principle of bioassay is to compare the test substance with the International standard
preparation (Standard substance) of the same drug and calculate or find out how much test substance
is produce same biological effects as produced by standard. The standard drug produced same effect
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Uttarakhand, India.
2
3
in all animal species and same dose given same degree of pharmacological response in same animal
or animal species under standard condition e. g adrenaline will always show/elicit same effect or
same degree of rise blood pressure when given in the same dose in the same animal and animal
species. In India, standard drugs are maintained in Central Drug Research Institute (CDRI) Lucknow
and Central Drug Laboratory, Kolkata.
Agonist:-
It activates a receptor to produce an effect similar to that of the physiological signal molecule.
Types/Methods:-
An agonist may produce graded response or quantal response. Graded response means that the
response is proportional to the dose and response may lie between no response and the maximum
response. Quantal response means, that the response is in the form of “all or none” i. e either no
response or maximum response.
1) Quantal (Quantity or amount)
a) End point method
2) Graded (Management order)
a) Matching or bracketing method

b) Graphical method
End point method:-
In this method the experimental based on test and standard series and their potency and average
results calculate of two groups of animals (one receiving standard and other the test) are done. Two
series of such experiments –one using standard digitalis and other using test preparation of digitalis is
done and then potency is calculated as follows.
Conc. of Unknown = Dose of Std. X Conc. of Std.

Dose of test
Matching or bracketing method:-
In this method a constant dose of test is compared with different dose of standard till the exact match
is obtained between test dose and standard dose. Initially two responses of the standard are taken. In
end take the response of the double dose of the standard and test, which matches. These should give
equal response. Concentration of the test sample can be determined as follows. However this method
is particularly useful if the sensitivity of the preparation is not stable. Bioassay of histamine on guinea
pig ileum is preferably carried out by this method.

Dose of test
Fig. 8. Structure of the matching or bracketing method
45
Graphical method:-
This method is based on the assumption or intake of dose and its response relationship. The log dose
response curve is plotted and the dose of std. producing the same response as produced by the test
sample is directly read from the graph. Advantage of this method is that, it is a simple method and
chances of errors are less if the sensitivity of the preparation is not changed. The mean responses are
calculated and plotted against log dose and amount of standard producing the same response as
produced by the test is determined mathematically.

Dose of test
Fig. 9. Structure of the graphical method
9.4 Bioassay of Insulin
Standard preparation and unit:- It is pure, dry and crystalline insulin. One unit contains 0.04082 mg.
this unit is specified by Ministry of Health, Government of India and is equivalent to international unit.
Preparation of standard solution:- Accurately weigh 20 units of insulin and dissolve it in NaCl
solution. Acidify it with HCl to Ph 2.5. Add 0.5% phenol as preservative. Add 1.4% to 1.8% glycerin.
Final volume should contain 20 units/ml. store the solution in a cool place and use it within six months.
Preparation of test sample solution:- The solution of the test sample is prepared in the same way
as the standard solution.
Method of bioassay:- There are two methods
1. Rabbit method
2. Mouse method
1) Rabbit method:-
Selection of rabbits:- They should be healthy, weighing about 1800-3000 gms. They should then be
maintained on uniform diet but are fasted for 18 hrs, before assay. Water is withdrawn during the
experiment.
Standard and Sample Dilution:- These are freshly prepared by diluting with normal NaCl solution so
as to contain. 1 units/ml and 2 units/ml.
46
Doses:- The dose which can produce suitable fall in blood sugar level is calculated for the standard.
Principle:- The potency of a test sample is estimated by comparing the hypoglycemic effect of the
sample with that of the standard preparation of insulin. Any other suitable method can also be used.
Experimental procedure:- Animals are divided into four groups of 3 rabbits each. The rabbits are
then put into an animal holder. They should be handled with care to avoid excitement.
First phase/part of the Test:- A sample of blood is taken from the marginal ear vein of each rabbit.
Presence of reducing sugar is estimated per 100 ml. of blood by a suitable chemical method. This
concentration is called ‘Initial Blood Sugar Level’. The four groups of rabbits are then given
subcutaneous injection of insulin as follows:
From each rabbit, a sample of blood is withdrawn upto 5 hrs. at the interval of 1 hr. each Blood sugar
is determined again. This is known as ‘Final Sugar Level’.
Second phase/part of the Test (Cross over test):- The same animals are used for the second part.
The experiment can be carried out after one week. Again they are fasted and initial blood sugar is
determined. The grouping is reversed, that is to say, those animals which received the standard are
given the test and those which received the test are now given the standard. Those animals which
received the less dose of the standard are given the higher dose of the test sample and vice versa.
This test is known as ‘Twin Cross Over Test’.
Mean percentage decrease in blood sugar of the first and second part is calculated.
2) Mouse method
Mice show characteristic convulsions after subcutaneous injection of insulin at elevated temperatures.
The percentage convulsions produced by the test and standard preparation are compared.
Selection of mice:- Minimum 100 mice weighing between 18-22 gms. of the same strain are used.
They should be maintained on constant diet. They should be fasted 18 hrs. prior to the experiment.
Standard and Sample Dilution:- Dilutions are prepared with sterile saline solution, so as to contain
0.064 units/ml (Standard dilution I) and 0.096 units/ml. (Standard dilution II). Similarly, test sample
solutions are also prepared.
Mice are divided into 4 groups each containing 25 and insulin is injected subcutaneous as follows.
47
Mice are put in an air incubator at 33°C and observed for one and half hr. an air incubator with a glass
front provided with six shelves is used. The temperature is thermostatically controlled. Two mice are
kept in each of the boxes made up of perforated sheets of metal. The mice which convulse or die are
taken out of the incubator and observed. Convulsive mice may be saved by an injection of 0.5 ml. of
5% dextrose solution. Percentage convulsions produced by the test sample are compared with those
of the standard sample.
Those animals which survive may be used again for another expt. After an interval of one week.
Dose S1 0.25 ml S2 0.25 ml T1 0.25 ml T2 0.25 ml

Convulsions
Percentage Convulsions
Calculations:-
Log ratio of doses (I) = ─

Variance of doses (E) = ( 2 − 1 + 2 − 1)
Slope = b= tan a = =
Variance of preparation (F) = ( 1 − 2 − 1 − 2)
Log potency ratio M =
3) Rat diaphragm method:-
In this method increase in glycogen content of the muscle or increase in glucose uptake by muscle in
response to insulin is taken as the index of potency of insulin.
4) Rat epididymal fat-pad method:-
The ability of insulin to increase CO2 production by the fat –pad is taken as the parameter for the
measurement of potency of the insulin preparation.
5) Radioimmunoassay:-
It is the estimation of the concentration of the substance in a unit quantity of preparation using
radiolabelled antigens. A number of drugs are estimated now a day by radioimmunoassay methods
because these methods are highly specific and highly sensitive.
The radioimmunoassay of insulin is based on the ability of human insulin (unlabelled) to displace
beef’s insulin (which may be labeled) from the binding sites (i. e. antibodies). The method involves the
following steps.
I) Bovine insulin is injected into the sheep. After a week the serum containing antibodies
produced against bovine insulin is collected from the blood of the sheep.
II) The serum containing antibodies is exposed to radiolabelled insulin and the bound vs free
ration is determined.
III) The mixture of antigen-antibodies (labeled) is then added in different test tubes labelled as
standard and test. About 6 concentrations of the standards are taken. They are then added to
different tubes and the bound vs free ratio is again determined using gamma counter
(Scientillation counter).
IV) Standard curve are determined and the concentration of test insulin is determined using this
standard curve.
9.5 Bioassay of Digitalis

Principle:- Potency of the test sample is compared with the standard preparation by determining the
action on the cardiac muscle. Any other equivalent method which gives results similar to those
obtained by this method, which is also valid.
48
Standard preparation and units:- The standard preparation is a mixture of dried and powder digitalis
leaves (1 unit = 76 mg).
Preparation of extracts:- The extraction process carried out by dehydrated alcohol in a continuous
extraction apparatus for six hours. The final extract should contain 10 ml. (5 ml. alcohol + 5 ml. water)
per 10 gm. of digitalis powder. It should be stored in between + 5°C.
Methods:-
1) Guinea pig method (End point method)

2) Pigeon method
Guinea pig method (End point method):-
Standard and test sample extracts are diluted with normal saline in such a way that 1 g. of digitalis
powder is diluted to 80 ml.
A guinea pig is anaesthetized with a suitable anesthetic. It is dissected on the operation table. A pin is
inserted in the heart such that it gets inserted in the apex of the heart. In this way we can observe the
heart beats by up and down movements of the pin. The injection is continued through venous cannula
until the heart is arrested in systole. The amount of extract required to produce this effect is taken as
the lethal dose of the extract. Another set of 19 animals of the same species are used for this
experiment and the average lethal dose is determined.
The potency of the test sample is calculated in relation to that of the standard preparation by dividing
the average lethal dose of the sample to the test and expressed as units per gram.
Pigeon method:- Minimum 6 pigeons are used for testing each sample. They should be free from
gross evidence of disease or emaciation. Food is withheld 16-28 hrs before the experiment. Pigeons
are divided on the basis of their sex, weight and breed into two groups. They are anaesthetized with
anesthetic ether.
One side is the wing is dissected and the alar vein is cannulated by means of a venous cannula.
Dilutions are made with normal saline. The potency of the test sample is determined by dividing the
mean lethal dose of standard by the mean lethal dose of the test sample.
In pigeons stoppage of heart is associated with a characteristic vomiting response called ‘emesis’.
The milk from the crop sac of pigeons is being ejected out. This may be taken as the end point
response of digitalis.
9.6 Bioassay of Adrenaline
Principle:- Potency of the test sample is estimated by comparing the rise in blood pressure of the test
sample with that produced by a standard preparation of adrenaline.
Standard preparation and units:- The standard preparation is based on Indian Pharmacopoeia.
Which represents the specific rotation of 4% w/v solution of the standard adrenaline in 0.1N HCl
should lie between -5°C to +5°C. dilution of adrenaline are prepared by diluting it with saline. A
suitable concentration is 1: 10,000.
Methods:-
1) Dog method
2) Cat method
3) Rabbit method
4) Rat method
5) Straub’s method
49
Anaesthetized Dog method:- A medium size dog (10-13 kg) is anaesthetized with pentobarbitone
sodium in a dose of 25mg/kg, intravenous. Artificial respiration is given through tracheal tube, if
necessary. BP is recorded on a kymograph after cannulating carotid artery with arterial cannula and
connecting the same with a mercury manometer.
The animal should be given 0.001-0.002 mg of atropine sulphate to paralyse the vagi. This paralysis
is confirmed by stimulating vagi by electrical stimulation.
Adrenaline is injected into the femoral vein through venous cannula. Two successive responses of the
same dose of adrenaline are noted. The similar responses after the same doses of adrenaline are an
indication that there is no variation in B.P. and use for animal in assay. Then the test and standard
samples are given in alternate till both produce similar rise in BP. Injections are given at intervals of 5
minutes. Potency of the test sample is compared with that of the standard sample.
Cat spinal method:- Refer pressor activity of posterior pituitary extract and apply the same method.
Rabbit Duodenum method:- A rabbit weighing 2-3kg and is killed by head blow method and bled to
death. The animal is dissected out, the abdominal organs are exposed to isolate the duodenum. The
duodenum is suspended in the inner bath of the mammalian organ bath.
Fig. 10. Structure of the rabbit duodenum method
Inner bath maintained at 37.5°C. The muscle is allowed to stabilize for 30 min. adrenaline is
bioassayed by graphical method.
De Jalon’s method on Rat’s Uterus: - This method was first demonstrated by Dejalon.
A virgin female rat, weighing about 100-150 gm is used for the experiment. NaCl 9.0 gm, CaCl2 0.06
gm and KCl 0.45 gm. Dextrose 0.5 gm NaHCO3 0.5 gm and distilled water 1000 ml. this solution
0
abolishes the rhythmic contraction of the uterus. It is maintained at 37 C and bubbled continuously
with air.
Two identical contractions for 30 sec. with carbachol are recorded (0.75 mg/ml). Then selecting three
different doses of standard adrenaline and one intermediate dose test adrenaline the percentage
reduction of carbachol induced concentration are recorded.
Straub’s method:- In this method a glass cannula is passed through the aorta and valves into the
ventricle of heart so that the solution is pumped up and down in the cannula with every beat. This
preparation has been widely used for the detection of small quantity of adrenaline. Adrenaline
increases the force of contraction of the ventricle. The increases force produced by the test sample is
compared with that of the standard preparation.
9.7 Bioassay of d-Tubocurarine
Principle:- d- Tubocurarine hydrochloride is injected into the marginal vein of a rabbit’s ear till the
rabbit’s neck muscles are relaxed such that the animal can’t hold its head up. The total amount of test
50
sample required to produce the end point is compared with the total amount of the standard sample
required to produce similar endpoint.
Selection of rabbits:- Rabbits weighing 2kg are used. Animals should be free from disease, obtained
from a healthy colony and should be accustomed with the experimental procedure.
Experimental procedure:- Minimum 8 rabbits are used. First group will receive standard sample and
the second group will receive the sample under test. D-Tubocurarine solution is injected at a constant
speed by infusion apparatus through the marginal vein.
Methods:-
1) Rabbit method.
2) Frog rectus abdominis muscle method.
Rabbit method:- Injection should be given at a rate of 0.4 ml/min and should take about 10 min.
infusion is continued till the rabbit will not be in a position to hold its head erect or there will be no
response by focusing light on the eyes and the neck gets elongated and toneless.
Suitable dose of d-tubocurarine is 0.012% w/v in saline. Rabbits recover immediately from the effect
of curarization. During the expt. there is a possibility of respiratory embarrassment which is treated by
injecting neostigmine methyl sulphate (0.05 mg) and atropine sulphate immediately through the
marginal ear vein.
Cross over test is carried out to minimise biological error due to animal variation. Those rabbits which
received the standard sample on the first day will be given test sample on the second day of expt. and
vice versa. Mean dose which produces head drop of the test sample is compared with the mean dose
of standard preparation.
Frog rectus abdominis muscle method:- A frog is pithed and laid on its back on a cork covered
board to which it is pained. The rectus abdominis muscle of one side is dissected from the pelvic
girdle to its insertion in the cartilage of the pectoral girdle. The muscle is then pinned to the cork by
four pins to keep its normal length while a thread is sewn through each end.
It is then mounted in the organ bath containing frog’s Ringer solution which contains NaCl, 6.5 gm,
KCl 0.29 gm, CaCl2 0.24 gm, NaHCO3 0.4 gm, glucose 1.5 gm and distilled water 2000 ml.
Oxygenation is carried out to keep the tissue alive. The muscle is stabilized for 30-45 min. in order to
get critical quantitative response. The responses are recorded using isotonic frontal writing lever with
1 G. tension. Three doses of the standard sample and one intermediate dose of the test sample are
selected and reduction in height of contraction induced by acetylcholine is noted down.
Acetylcholine contraction is recorded on slow moving drum for 90 sec. d-tubocurarine is allowed to act
for 30 sec. the percentage reduction at each dose level is calculated and logdose response curve of
the standard drug is plotted. A linear response will be obtained. The potency of test sample is
calculated from the standard curve.
9.8 Bioassay of Acetylcholine
Principle:- The potency of the test sample is compared with that of the standard preparation. There
are several biological methods for its assay.
Methods:-
1) Frog rectus abdominis muscle method

2) Cat’s blood pressure method
3) Guinea pig ileum method
51
4) Anaesthetized rats methods

5) Leech muscle method
6) Rabbit’s intestine & tracheal chain method
7) Isolated heart preparations
Frog rectus abdominis muscle method:- Dissect the rectus muscle and arrange the assembly as
per assay of d-tubocurarine. Plot log dose response curve and find out the potency of the sample of
acetylcholine.
Cat’s blood pressure method:- A cat is anaesthetized with suitable anaesthetic. The carotid artery is
cannulated for recording BP. Femoral vein is cannulated for injecting acetylcholine. Trachea is
cannulated for giving artificial respiration. Acetylcholine produces a fall in BP by dilating peripheral
blood vessels. This principle is utilized for its bioassay. The extent to which BP falls due to the test
sample is compared with the fall by the standard preparation.
Guinea pig ileum method:- Guinea pig is killed by a blow on the head and bled to death. The
abdominal wall is dissected out so as to isolate the ileum the faecal matter mesentery and blood
vessels are removed from the piece of ileum. It is ligated on both sides and suspended in mammalian
organ bath containing tyrode solution maintained at 37.0°C and oxygenated continuously.
Acetylcholine contracts the ileum. This principle is utilised for its bioassay. The extract of contraction
by the test sample is compared with the standard preparation of acetylcholine.
Anaesthetized rats methods:- Compare the extent of fall in BP of the test sample with that produced
by the standard preparation.
Leech muscle method:- Compare the contractions produced by the standard and test samples on
eserinised dorsal muscle of the leech. This muscle is highly sensitive (pictograms) to acetylcholine.
Rabbit’s intestine & tracheal chain method:- Ach contracts these tissues.
Isolated heart preparations:- Rabbits auricle, frog’s heart, rabbit’s heart on venous merceneria’s
heart is used. Ach decreases the force and rate of the heart.
_________________________________________________________________________________
52
Chapter 10

and Sarvesh Kumar3
DOI: 10.9734/bpi/mono/978-93-89246-87-2
10.1 Introduction
Animal studies are a recently recognized field in which animals are studied in a variety of cross-
disciplinary ways. In essence, it seeks to understand how humans study and conceive of other-than-
human animals, and how these conceptions have changed over time, across cultures, and across
different ways of thinking. The growth of human-animal studies (HAS) over the past twenty years can
be seen in the explosion of new books, journals, conferences, organizations, college programs, list
serves, and courses, both in the United States and throughout India, Europe, Australia, New Zealand,
and Canada. Animals are widely used in different area of research to explore normal and abnormal
biological mechanisms or activity of nervous system and other function, to identify the genetic basis of
disease states, and to provide models of human disorders and diseases for the development of new
treatments. Numerous laws, policies, and regulations are in place governing the use of animals in
research.
10.2 Animal Ethics
It is a human animal relationship and how animal ought to treated. This includes animal right, animal
law, animal welfare, animal cognition, wild life sanctuaries & conservation and moral status of animal.
10.3 Animal Ethics Committee
The animal ethics committee is which committee where the use of animal in research and teaching
and also their role including use of drugs and supply of animals for study purpose. No any research
will be carried out without approval of animal ethical committee, which is a show various terms.
a) A Veterinarian
b) Animal researcher
c) Animal house
d) Animal food
e) Animal lover peoples
10.4 Types of Variation

The variations in any substance/things are basically three types.
1. Physical variation
2. Chemical variation
3. Biological variation
Physical variation:-
This includes colour, shape, size, stability and molecular weight etc.
_____________________________________________________________________________________________________
1
Uttarakhand, India.
2
3
Chemical variation:-
In this includes acidic, basic, salt, complex/chelating nature, pH and solubility etc.
Biological variation:-
The natural variability in a species/living organism/biological compound which is due to physiological

difference in a particular species that is called biological variation and also biological variations are
any difference between two same species in their cells, organ, tissue or group of organism either
caused either by genetic differences (genotypic variation) is called biological variation.
Genotypic variation are caused by different number or structure of chromosomes or difference in

genes carried out by chromosomes e. g eye colour, body form and size and disease resistance etc
are genotypic variation.
CONCLUSION
The book develops new perspectives in basic and conceptual knowledge in pharmacology. The
world’s oldest known pharmacological or therapeutic writings come from India and China. Herbs have
a variety of uses including medicinal and in some cases, spiritual. Several factors such as Physical
and chemical properties of the drug (solid/liquid/gas, solubility, stability, pH, irritancy) has been
involved. The study refers to movement of the drug in and alteration of the drug by the body; includes
absorption, distribution, binding/localization/storage, biotransformation and excretion of the drug. All
pharmacokinetic process involves transport of drug across biological membranes. Distribution carried
out by the one compartment is blood or plasma and another compartment is extra vascular fluids and
other body tissues. Pharmacodynamics describing what the drugs pharmacological and biochemical
effect; when it reaches the site of action in body and goes on to explain how they do it. Antigens
(drugs) reacts with antibodies (IgE), which get fixed to the mast cells and releasing mediators like
histamine and caused allergies, resulting in urticaria, itching, angioedema, bronchospasm, rhinitis or
anaphylactic shock. Drug dependency determine the use of drugs for personal satisfaction is
accorded a higher priority than other basic needs, often the face of known risk of health that is called
drug dependence. Bioassay ascertains the potency of a drug and hence it serves as the research as
well as standardizes the preparation so that each contains the uniform specified pharmacological
activity. Animal studies recently recognized field in which animals are studied in a variety of cross-
disciplinary ways. In essence, it seeks to understand how humans study and conceive of other-than-
human animals, and how these conceptions have changed over time, across cultures, and across
different ways of thinking.
ACKNOWLEDGEMENTS
I am thankful to Dr. Sarla Saklani, Head, Department of Pharmaceutical Chemistry H. N. B. Garhwal

(Central) University Srinagar (Garhwal) Uttarakhand for her inspiration and blessings.
I thank Dr. Hemlata Bhatt and Mr. Arun Kumar Bishnoyi, Assistant Professor, Department of
Pharmaceutical Sciences H. N. B. Garhwal (Central) University Srinagar (Garhwal) Uttarakhand for
giving his valuable advice on the work.
I offer my profound regards to Dr. Faruk Abdul, Head, Department of Pharmaceutical Science and Dr.
Abhay P. Mishra for his inspiration and motivation.
I am thankfull to all researcher and staff members of Department of Pharmaceutical Chemistry and
Pharmaceutical Sciences, H. N. B. Garhwal (Central) University Srinagar (Garhwal) Uttarakhand for
their help and moral support.
I would like to express my gratitude to my parents, sisters and particularly to my elder brothers Mr.
Mukesh Chandra Kothiyal and my wife Shrivatsa Semwal Kothiyal, who have helped me enormously
and given me a lot of moral and mental support during designing the book.
54
Last but not the least, I would like to thank all the persons who helped in designing, planning and
finishing this book. Firstly we would like to thank our family members for their continued
encouragement, support and assistance. Without them, it would not have been possible to complete
the book.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
REFERENCES
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New Delhi, (7) Seventh Edition; 2013.
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Prakashan (p) Ltd, Mumbai, (20) Twentieth Edition; 2007.
3. Katzung BG, Basic and Clinical Pharmacology, Mc Graw-Hill New York, (9) Ninth Edition; 2004.
4. Rang HP, Dale MM, Ritter JM, Pharmacology, Churchill Livingstone Edinburgh, (5) Fifth Edition;
2003.
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Prakashan Ahmedabad, (8) Eighth Edition; 1997-98.
6. Brunton LL, Chabner BA, Knollman BC (Eds): Goodman and Gilman’s The Pharmacological
Basis of Therapeutics, McGraw-Hill, New York, (12) Twelve Edition; 2011.
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Lange Medical Books/McGraw-Hill, New York; 2012.
8. Sweetman SC, Martindale, The Complete Drug Reference, The Pharmaceutical Press, The
Royal Pharmaceutical Society of Great Britain, London, (37) Thirty seven Edition; 2011.
9. British National Formulary, BMJ Publishing Group and RPS Publishing, London, No 62; 2011.
10. Katzung BG, Masters SB, Trevor AJ, Basic and Clinical Pharmacology, Lange medical book,
Tata McGraw-Hill, New Delhi, (12) Twelve Edition; 2012.
11. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G, Pharmacology, Elsevier, Churchill
Livingstone, Edinburgh, (7) Seventh Edition; 2012.
12. Bennett PN, Brown MJ, Clinical Pharmacology, Churchill Livingstone, Edinburgh, (10) Tenth
Edition; 2008.
13. Essential Medicines, WHO Model List, WHO, Geneva; 2011.
14. National List of Essential Medicines, Govt. of India, Ministry of Health & Family Welfare,
Directorate General of Health Services, New Delhi, (17) Seventeenth Edition; 2011.
15. Agarwal AK, Singhal RK, Jain DG, Upadhyay R, Rewari BB, Emergency Medicine: Association
of Physicians of India, Delhi State Chapter, Jaypee Brothers, New Delhi; 2005.
16. Hadjipavlou G, Mok H, Yatham LN, Pharmacotherapy of bipolar II disorder: A critical review of
current evidence. Bipolar Disord. 2004;6:14-25.
17. List of drugs banned for marketing in India, Drugs Control Organisation, Govt of India,
Available: http//www.drugscontrol.org/ban_drugs.htm.
18. Sharma HL, Sharma KK, Principles of Pharmacology, Paras Medical Publisher, Hyderabad,
Edition (2); 2011.
19. National Formulary of India, Indian Pharmacopoeia Commission, Ministry of Health and Family
Welfare, Govt. of India, Edition (4); 2010.
55
Biography of author(s)
Dr. Subhash Chandra Kothiyal

Uttarakhand, India.
He is presently working as Assistant Professor (Pharmaceutical Chemistry), Department of Pharmaceutical Chemistry, H. N. B.

Garhwal (A Central University) Srinagar Garhwal, Uttarakhand. He was awarded “Young Scientist Award” of the year 2012,
2015 and 2016 by National level scientific congress/conferences and Uttarakhand Council of Sciences & Technology (UCOST)
Govt. of Uttarakhand. He has a total of 48 papers (38 International, 10 National) in various peer reviewed National and
International journals of high impact to his credit. He has participated in various International and National conferences,
seminar, workshop, presented research work and published 36 (8 International, 28 National) Scientific Abstracts. He is peer
reviewer for various pharmaceutical and plant science journals of Elsevier, Taylor & Francis, Bentham, Willy, Springer and
Informa. He has also published three books e. g entitled “Tool and Technique of Chromatography” published by Lambert
Academic Publishing, Germany.
Dr. Sarla Saklani

Uttarakhand, India.
She is presently Head of Department of Pharmaceutical Chemistry, H. N. B. Garhwal University Srinagar (Garhwal),
Uttarakhand. She has a very rich teaching and research experiences of more than 28 years. She has published more than 70
papers in various International and National journals of repute. She has also published 5 books.
Mrs. Shrivatsa Kothiyal

D. B. S. Public School Rishikesh Dehradun, Muni Ki Reti & Lal Tappar Rishikesh, Dehradun, Uttarakhand,India.
She is presently working as Principle, D. B. S. Public School Rishikesh Dehradun Uttarakhand. She has very rich teaching
experiences of more than 8 years.
Mr. Sarvesh Kumar

Govt. Polytechnic Srinagar Garhwal Uttarakhand, India.
He is presently working as Lecturer Govt. Polytechnic Srinagar Garhwal, Uttarakhand. He has a very rich teaching and
research experiences of more than 07 years.
_________________________________________________________________________________
56
Index
A
Absorption of drugs,17
Acetylation,22
Active tubular secretion,25
Active transport,15
Acute toxicity,37
Acetylcholine,51
Acquired,42
Adverse drug reactions,33
Adrenaline,6
Affinity,32
Agonist,32
α- Amino acid,22
Allopathy,5
Antireceptor,36
Antidotes,37
Animal study,53
Animal ethics,53
Apparent,42
Aqueous solubility,16
Arterial supply,8
Ayurvedic medicine,4
BAN (British approved name),6

Bile,26
Bioavailability,26
Biological membrane,13
Biological factor,20
Bioassay,44
Biotransformation,20
Biological variation,53
Blood cells,18
Bones,19
Buccal,9
Cat method,49
Carbonic anhydrase,18
Carrier transport,14
Carcinogenicity,38
Cell membrane,18
Cell mediated,36
Chemical name,6
Chemical action,29
Chemical assay,44
Chemotherapy,7
Chronic toxicity,37
Chemical variation,53
Clearance,26
Concentration,16
Conjugation reactions,22
Cross tolerance,42
Competitive,29
Cutaneous,9
Index
Cytotoxic,28
Depression,28
Deeper tissues,8
Dermojet,11
Decyclization,22
De Jalon’s method,50
Digitalis,48
Dog method,49
Drug definition,5
Absorption,15
Drug abuse,41
Drug addiction,40
Drug allergy,33
Definition,5
Dependence,40
Distribution,17
Excretion,24
Drug habituation,41
Drug Nomenclature,6
Drug Resistance,43
Sources,5
Drug Tolerance,42
d-tubocurarine,50
Effective,39
Elimination,26
End point,45
Enzyme inhibition,30
Stimulation,28
Extra vascular tissues,18
Extracellular receptor,18
Enternal route,15
Excretion,24
Exhaled air,26
Eyes,19
Faeces,26
Fats,19
Facilitated diffusion,14
First pass (presystemic) metabolism,8
Filtration: of drugs,14
Frog rectus method,51
Graded,45
Glucuronide,22
Glutathione,23
Glycine,22
Graphical,45
58
Index
Guinea pig method,49
Hairs,19
Herb,4
Hemoglobin,18
Humoral,36
Homeopathy,5
Hydrolysis,21
Hypodermic,11
Iatrogenic,39
Idiosyncrasy,33
Irritation,28
Inactivation,20
Immediate hypersensitivity,36
Inhalation of drugs,9
Intra-arterial injection,9
Intraarticular injection,9
Intracardiac,10
Intradermal (i.d.) injection,10
Intrathecal,10
Intramuscular injection (i.m.),11
Intravenous injection (i.v.),35
Intrinsic activity,32
Insulin,47
Intestine,25
Intracellular/Primary receptor,18
Isolated heart preparations,52
Kinase linked,31
Kinetics of drug elimination,26
Leech muscle method,52

Lethal,35
Ligand,32
Local routes,8
Lungs,19
Matching,45
Mechanism of drug action,29
Medicine,4
Methylation,22
Microsomal enzymes,21
Milk,26
Mouse method,46
Moderate,35
Mucus membrane,8
59
Index
Nasal route of administration,9

Natural tolerance,42
Nephron,24
Non-renal,24
Non-proprietary name,6
Non-competitive,29
Non-specific,30
Non-microsomal,21
Nucleic acids,19
Oral route of administration,9

Osmolality,29
Other sources,5
Oxidation,21
Parenteral,9
Passive tubular reabsorption,25
Passive diffusion,13
Pellet implantation,11
Pinocytosis,14
Pigeon method,49
Pharmacy: definition,7
Pharmacodynamics,12
Pharmaceutical factors,16
Pharmacogenetics,6
Pharmacokinetics,7
Pharmacology: definition,7
Pharmacotherapeutics,7
Physical dependence,40
Physical variation,53
Physicochemical factors,16
Physical Assay,44
Physical action,29
Plasma protein binding of drugs,20
Poison,37
Predictable,37
Psychological,40
Proprietary name,6
PKa,16
Quantal,45
Rabbit method,46
Racial tolerance,41
Radioimmunoassay,48
Rat method,49
Receptors,31
60
Index
Rectal administration,9
Reduction,21
Redistribution,19
Replacement,28
Ribonucleoside,22
Routes of administration,8
Saliva,26
Secondary side effects,33
Severe,35
Sialistic,11
Side effects,33
Skin,8
Sources of drugs,5
Species tolerance,42
Specialized transport,15
Specific,30
Straub’s method,49
Stimulation,28
Sub acute,38
Subcutaneous injection (s.c.),47
Sublingual administration,10
Super sensitivity,35
Sulfate moiety,5
Sweat,26
Synthetic,21
Synthetic source,5
Systemic routes,9
Teratogenicity,38
Tissue tolerance,42
Through enzymes,29
Topical application of drugs,16
Topical route,16
Toxic effects,33
Toxicology: definition,37
True tolerance,42
Tubular reabsorption of drugs,25
Unpredictable,33
Urinary excretion of drugs,25
USAN (United States adopted name),6
Variation,53
Vascularity of the absorbing surface,16
Volume of distribution (V),17
61
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Basic Concepts in Pharmacology

Book · August 2019

Subhash Chandra Kothiyal Sarla Saklani

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India . United Kingdom

Subhash Chandra Kothiyal1*, Sarla Saklani1, Shrivatsa Kothiyal2

FIRST EDITION 2019

ISBN 978-93-89246-86-5 (Print)

ARS : Anti rabies serum

History & Development of Pharmacology

1.1 Drug History & Development

(A western system of medicine, Western-American culture).

(French term –Drogue, which means –A dry herb).

It is the single active chemical entity/compound/substance in a medicine that is used for

1.2 The Nature and Sources of Drugs

The various sources of drugs are:

II. Synthetic source:-

III. Other sources:-

1.3 Drug Nomenclature

1) Chemical name (IUPAC Name).

2) Non-proprietary name:- It is the name accepted by a competent/Government scientific

3) Proprietary/Owner (Brand) name:- It is the name assigned/designed by the manufacturer/owner

1) Inorganic drugs (Acids, Bases and Salts).

1.4 Pharmacological Introduction

Pharmacology is the science of drugs (Greek: Pharmacon—drug; logos—discourse in). In a broad

1.5 Types of Pharmacology

(Greek: Dynamis—power) What the drug does to the body.

(Greek: Kinesis—movement) What the body does to the drug.

1.6 Branches of Pharmacology

Routes of Drug Administration

2.1 Introduction of Routes of Drug Administration

2.2 Factor Affecting Routes of Drug Administration

Note- Factor affecting choice of route:-

Routes are basically two types.

2.2.1 Local routes

The dosage form depends on the site.

Mouth and pharynx- Paints, lozenges, mouth washes, gargles.

2.2.2 Systemic routes

Note- Limitation of oral route of Administration:-

 Action is slower and thus not suitable for emergencies.

B) Sublingual (SI) Buccal:-

G) Parenteral:- (Par-beyond, Enteral-intestinal)

Into the cistern containing cerebro-spinal fluid.

Into the heart chamber.

Into the eye ball.

Into a joint fluid area.

(Biological- all living organism, Availability-available/Present).

Drugs are transport across the biological membranes by two ways:-

1. Passive diffusion and filtration

Fig. 1. Schematic depiction of pharmacokinetic processes

3.2 Biological Membrane

Fig. 2. Structure of the organisation of biological membrane

a) Active carrier transport

Simple passive/lipid diffusion:-

3.3 Specialized Transport

This can be carrier mediated or by pinocytosis.

i) Active carrier transport

ii) Facilitated diffusion:-

ii. Parenteral route: -

iii. Topical route:-