Pharmacology I

B. Pharma
4 Semester
th

Unit I
GENERAL
PHARMACOLOGY - I
Prepared by – Nikita Gupta
(Assistant Professor)
 CHAPTER-1
INTRODUCTION
TO
PHARMACOLOGY
Pharmacology : The science of drugs (Greek: Pharmakon-drug; logos-
study)
• Pharmacology is the study of the therapeutic value and/or potential toxicity of
chemical agents on biological systems. In simple terms, it is study of all the
aspects of drug.
• It targets every aspect of the mechanisms for the chemical actions of both
traditional and novel therapeutic agents.
• Two important and interrelated areas are: pharmacodynamic and
pharmacokinetics.
• Pharmacodynamic (Greek: dynamic-power) (what drug does with
the body) are the study of the molecular, biochemical, and physiological
effects of drugs on cellular systems and their mechanisms of action.

• Pharmacokinetics (Greek: Kinesis-movement) (what body does

with the drug) deals with the absorption, distribution, and excretion of
drugs.
• Pharmacotherapeutics It is the application of pharmacological
information 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 stage of disease and the specific
features of a patient are a part of pharmacotherapeutics.
• Toxicology It is the 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.
• Clinical pharmacology It is the scientific study of drugs (both old and
new) in man . It includes pharmacodynamic and pharmacokinetic investigation
in healthy volunteers as well as in patients. Evaluation of efficacy and safety o
f drugs and comparative trials with other forms of treatment; surveillance of
patterns of drug use, adverse effects, etc. are also part of clinical
pharmacology. 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 parasites/malignant cell, but
have no/minimal pharmacodynamic effects in the recipient.
 HISTORY OF PHARMACOLOGY

• Knowledge of drugs and their uses in diseases are as old as history of

mankind.
• Primitive men gather the knowledge of healing and medicines by observing
the nature, noticing the animals while ill & personal experience after
consuming plants & herbs as remedies.
• Ancient civilizations discovered that extracts from plants, animals, &
minerals had medicinal effects on body tissue. These discoveries became the
foundation of Pharmacology.
• It is of intellectual interest to know how drugs are discovered and
developed. Often in the past, this was based on folklore or intelligent
observation (e.g. digitalis leaf, penicillin).
• Nowadays, new drugs are mostly developed by the organic chemist working
with a Pharmacologist, increasingly from basic knowledge about key
molecular targets.
• Usually some sort of biological screen is used to select among organic
molecules for optimum pharmacological activity.
 Historical developments in Pharmacology

• PEN PSAO (2700 BC) It was the great herbal Materia Medica written in China.
• Kahun Papyrus (2000 BC) is an oldest Egyptian document containing information
about veterinary medicines & uterine diseases of women.
• Ebers papyrus (1550 BC) also an Egyptian document containing information about
number of diseases & 829 prescription where castor oil, opium like drug are being
used.
• Hippocrates (460-375 BC) A Greek Physician “Father of Medicine”. First person
who recognized disease as abnormal reaction of body. He introduced use of
metallic salts for the treatment of disease.
• Theophrastus (380-287 BC) a great philosopher called father of Pharmacognosy.
He classified medicinal plants on the base of medicinal characteristicsfor the
preparation of drugs.
• Dioscorides (AD 57) a Greek, produced one of the first Materia medica of
approximately 500 plants & remedies.
• Claudius Galen (AD 129–200) first attempted to consider the theoretical
background of pharmacology.
• Paracelsus (1493–1541) a Swiss scholar and alchemist, often considered
Grandfather of Pharmacology. He introduces the use of chemicals for treatment of
disease.
• Valerius Cordus (1514-1544) He compiled the first Pharmacopeia where he
described techniques
• Francois Magendie (1783-1855) a French Physiologist laid down the dictum "Facts
and facts alone are the basis of science." Experimental procedures with animals are
the testing grounds for determination of drug action. He developed experiment to
elucidate the physiological processes and action of drugs on the body.
• (Frederich Sertürner) German Pharmacist’s assistant, isolated morphine—the first
pure drug—in 1805.
• Claude Bernard (1813-1878) investigated the plant extract curare & proposed a
site of action for this agent. Considered Father of Experimental Medicine.
• Rudolph Buchheim (1820-1879) A German pharmacologist in 1847 established
the first laboratory devoted to Experimental Pharmacology in the basement of
his home in Dorpat which is known as the Cradle of Experimental
Pharmacology.
• Oswald Schmiedeberg (1838-1921) Father of Pharmacology in 1872 set up an
Institute of Pharmacology in Strasbourg, France (Germany at that time).
• J.N. Langley (1852-1925 & Sir Henry Dale (1875-1968) pioneered
Pharmacology in England, taking a physiological approach.
• John J. Abel (1857-1938) established the first chair of Pharmacology in the
U.S.A. (U. Michigan, 1891) after training in Germany. Able went to Johns
Hopkins in 1893, and trained many U.S. pharmacologists. He is known as "The
Father of American Pharmacology". Co-founded the Journal of Pharmacology &
Experimental Therapeutics in 1909.
• L. Mayer Jones (1912-2002) regarded as father of modern veterinary
pharmacology. He authored first book of veterinary pharmacology therapeutics
in 1954.
 SCOPE OF PHARMACOLOGY

• It provides the rational basis for the therapeutic use of the drug.
• Before the establishment of this discipline, even though many remedies were
used, but doctors were reluctant to apply scientific principles to therapeutics.
• In 1920s, many synthetic chemicals were first introduced & the modern
Pharmaceutical companies began to develop.
• The Second World War was the impetus for accelerated research in
Pharmacology (the war time antimalarial program) in the U.S., & introduced
strong analytical & synthetic chemical approaches.
• Scientific understanding of drugs enables us to predict the pharmacological
effect of a new chemical that will produce a specified therapeutic effect.
• The scope of Pharmacology has expanded greatly over the last decade to
incorporate many new approaches such as Computer-assisted Drug Design,
Genetic screens, Protein engineering & Use of Novel Drug Delivery Vehicles
including Viruses & Artificial cells.
 Drug (French : Drogue- a dry herb) It is the single active
chemical entity present in a medicine that is used for diagnosis,
prevention, treatment/cure of a disease.
 WHO : “Any substance or product that is used or intended to be
used to modify or explore the physiological system or pathological
state for the benefit of the recipient”
 NATURE OF DRUGS
 All drugs are chemical entities with simple or complex molecules.
 Majority: organic compounds
 Weakly acidic (aspirin, penicillin)/weakly basic (morphine, chloroquine
/nonelectrolytes (alcohol, diethyl-ether).
 Most are solids: e.g. paracetamol, propranolol, furosemide, ampicillin, etc.,
 Some liquids: ethanol, glyceryl trinitrate, propofol, castor oil
 Few Gaseous: nitrous oxide
 Some purely inorganic: lithium carbonate, ferrous sulfate, magnesium hydroxide,
etc.
 Molecular weight
 Majority of drugs: range of 100- 1000 D
 Molecules<100D: No sufficiently specific features - shape, size,
configuration, chirality, distribution of charges, etc. to selectively bind
to only one/ few closely related target biomolecules, to the exclusion of
others.
 Larger molecules than 1000 D: do not readily pass through
membranes/barriers in the body to reach the target sites in various
tissues/cells.
  Few drugs are as small as lithium ion (7D), and some like heparin
( 10-20 KD), gonadotropins (>30 KD), enzymes, proteins, antibodies
(>50 KD) are much bigger.
 Bulky molecule drugs have to be administered parenterally. 
 Drugs : Xenobiotics.
 Many endogenous chemicals: hormones, autacoids, metabolites and
nutrients are also used as drugs.
A) Plant Sources-
 Alkaloids – Atropine (Atropa belladonna)
Morphine (Papaver somniferum)
 Glycosides- Digoxin (Digitalis purpura)
 Oils-
 Essential oil (Volatile oil)-leaves & Flower : eg. clove oil, peppermint,
eucalyptus
 Fixed oil- seeds : eg. ground nut, coconut, castor, olive oil
  Mineral oil : eg. liquid paraffin, hard & soft paraffin
 Gum- excretory products (gum acacia)
 Resins - Tolu balsam (cough mix)
 Tannins - catechu
B) Animal Sources
1) Hormones : Insulin (Pork-Porcine), (Beef-Bovine )
2) Vaccines: Polio, Anti-rabies
3) Sera: ATS (Anti-tetanus Serum)
4) Vitamins: Vit B12 from Liver extract
C) Microorganism: Antibiotics

D) Minerals: iron salts, calcium salts, lithium carbonate,

magnesium/ aluminium hydroxide, iodine.
E) Synthetic Chemicals: Synthetic glucocorticoids,
benzodiazepines, thiazides.

F) Recombinant DNA Tech: Human Insulin, hGH,

interferons, erythropoietin etc.
 CLASSIFICATION OF DRUGS

 Site of action
 Chemical Structure
 Mechanism of Action
 Ionization of Drugs
 Therapeutic Uses
 Anatomical Therapeutics Classification (ATC)
Essential medicines (drugs )

 WHOs Definition: Medicines that satisfy the priority healthcare needs of the
population. They are selected with due regard to public health relevance,
evidence on efficacy and safety, & comparative cost effectiveness.
 Intended to be available within the context of functioning health systems at
all times and in adequate amounts, in appropriate dosage forms, with assured
quality & adequate information, & at a price the individual & the community
can afford.
 1977: 1st Model List of Essential Drugs along with their dosage forms and
strengths by WHO
 2017: 20th list with 433 medicines, including 25 FDCs.
 1996: National Essential Drugs List in India
 Revised in 2011
 2015: National List of Essential Medicines with 376 medicines, including 20
FDCs
 At Primary, Secondary & Tertiary levels
Essential drugs/medicines WHOs Criterias…….
 Adequate data on its efficacy & safety should be available from clinical studies.
 It should be available in a form in which quality, including bioavailability, & stability on
storage can be assured.
 Choice should depend upon pattern of prevalent diseases; availability of facilities &
trained personnel; financial resources; genetic, demographic & environmental factors.
 If 2/ more similar medicines: choice should be made on the basis of their relative
efficacy, safety, quality, price & availability. Cost-benefit ratio should be a major
consideration..
Some examples of Chemical, Generic, Brand Names
• Enteral
It means through gastro-intestinal tract. It includes oral,
sublingual and rectal routes.

• Parenteral
It means through routes other than enteral. It includes all
types of injections, inhalations.
• Local
It includes administration of a drug at the site where the desired action is
intended. It includes topical administration in oral cavity, gastro-intestinal tract,
rectum/anal canal, eye, ear, nose, bronchi, skin, intra-arterial, injection in deep
tissues e.g. joints.

• Systemic
It includes drugs administered to enter the blood to produce systemic effects.
• Oral
It means drugs taken by mouth e.g. tablets, capsules,
syrups, mixtures etc.

• Intravenous
It includes drugs injected directly in to blood stream
through a vein. It may be administered as: bolus,
slow intravenous injection or an intravenous infusion.
• Intrathecal
It includes drugs injected in to the sun-arachnoid space
e.g. spinal anaesthetics like lignocaine.

• Intra-articular
It includes drugs injected directly in to the joint space
e.g. hydrocortisone injection for rheumatoid arthritis.
• Subcutaneous
It includes drugs injected in to the sub-cutaneous tissues of the
thigh, abdomen and arm e.g. adrenalin, insulin etc.

• Intradermal
It includes drugs injected in to the dermis layer of the skin
e.g. tuberculin and allergy tests.
• Intramuscular
It includes drugs injected in to large muscles such as deltoid,
gluteus maximus and vastus lateralis. A volume of 5-10 ml
can be given at a time e.g. paracetamol, diclofenac.

• Intraosseous
It includes injecting a drug directly in to the marrow of a bone.
• Transdermal (patch)
It includes administration of a drug in the form of a patch
or ointment that delivers the drug into the circulation for
systemic effect.

• Rectal
It includes administration of drugs in the form of
suppository or enema in to the rectum.
• Sublingual
In this case, the preparation is kept under the tongue. The drug is absorbed
through the buccal membrane and enters the systemic circulation
bypassing the liver e.g. nitroglycerine for acute angina attack.
• Inhalation
It includes volatile gases and liquids which are given by
inhalation for systemic effects e.g. general anaesthetics.

• Endotracheal
It includes a catheter inserted in to the trachea for primary
purpose of establishing and maintaining an airway to ensure
adequate exchange of oxygen and carbon dioxide.
The broad classification is presented in Fig. 1.1.
Fig. 1.2 indicates pictorial
presentation of various injectable
routes.
 AGONISTS

• An agonist is a chemical which binds to a receptor and activates the

receptor to produce a biological response. Receptors can be activated
by either endogenous agonists (like hormones or neurotransmitters)
or exogenous agonists (like drugs).
• Agonists can be divided into following sub-categories:
Full agonists
They bind to and activate a receptor with the maximum
response that an agonist can elicit at the receptor e.g.
isoproterenol mimics the action of adrenaline at β-
adrenoceptors.
 Co-agonists
A co-agonist works with other co-agonists to produce the desired effect
together; e.g. NMDA receptor activation requires binding of glutamate,
glycine and D-serine co-agonists.
 Partial agonists
Partial agonists like buprenorphine also bind and activate a given receptor but
have only partial efficacy at the receptor relative to a full agonist, even at
maximal receptor occupancy.
 Selective agonists
A selective agonist is selective for a specific type of receptor only; e.g. buspirone is a
selective agonist for serotonin 5-HT1A.
 Inverse agonists

An inverse agonist is an agent which binds

to the same receptor binding-site as an
agonist and inhibits the constitutive activity
of the receptor. Inverse agonists exert the
opposite pharmacological effect to that of
an agonist. This is unlike an antagonist; e.g.
Cannabinoid inverse agonists rimonabant.
 Irreversible agonists
An irreversible agonist is a type of agonist which binds permanently to a
receptor through formation of covalent bonds.
 Antagonists (Competitive and Non-
competitive)
• An antagonist is a type of receptor ligand or drug which blocks
or dampens a biological response by binding to and blocking a
receptor rather than activating it like an agonist. They are
sometimes called as blockers e.g. α-blockers, β-blockers,
calcium channel blockers etc.
• Antagonists have affinity but no efficacy for their cognate
receptors. The concept of affinity and efficacy is presented
below.
 Affinity
The affinity of an antagonist for its binding site is its ability to bind to a
receptor. It determines the duration of inhibition of agonist activity. It can be
measured experimentally.

 Efficacy and Potency

By definition, antagonists display no efficacy to activate the receptors to
which they bind. Antagonists do not maintain the ability to activate a receptor.
However, once bound they will inhibit the function of agonists, inverse
agonists and partial agonists.
 Competitive Antagonists
• Competitive antagonists bind to receptors at the same binding site (active site) as
the endogenous ligand or agonist, but without activating the receptor.
• Agonists and antagonists compete for the same binding site on the receptor.
Once bound, an antagonist will block binding of agonist.
• Sufficient concentration of an antagonist will displace the agonist from the
binding sites, resulting in a lower frequency of receptor activation.
• The level of activity of the receptor will depend on relative affinity of each
molecule for the site and their relative concentrations.
 Non-competitive Antagonists
• A non-competitive antagonist is a type of unsurmountable antagonist that
may act in one of two ways: by binding to the active site of receptor or by
binding to an allosteric site of the receptor. If it binds to the allosteric site, it
is called as allosteric antagonist.
• In both the cases, end-results are functionally similar. Unlike competitive
antagonists, which affect the amount of agonists necessary to achieve a
maximal response but do not affect the magnitude of that maximal response,
non-competitive antagonists reduce the magnitude of the maximum
response that can be attained by any amount of agonists.
 Dose-response Curve
• Dose-response relationships, or exposure-response relationship can be
conveniently used to know the type of antagonism.
• Dose-response relationship describes the change in effect of an organism
caused by differing levels of exposure (or doses) to a stress or (usually a drug)
after a certain exposure time.
• Biologic effect is usually placed on Y-axis in terms of percentage. Drug
concentration is depicted on X-axis in terms of units of dose. Dose-response
curve is usually S-shaped as depicted in Fig. 1.3.
EC50 = Drug dose that shows 50% of maximal response.
Fig. 1.3: Effect of drug antagonists
 Spare Receptors
• Spare receptors are defined as those receptors without combining
with which maximal response can be obtained. In order to
understand this concept, understanding of receptor occupancy
theory is essential.
 Receptor Occupancy Theory
• Consider dose response curves A, B and C for an agonist along with various
antagonists. (Fig. 1.4) In this graph, X-axis indicates log agonist (M)
indicating that log molar concentration of agonist is plotted.
• Y-axis indicates percentage of maximal effect. In Fig. 1.4, maximal responses,
as shown in dose-response curves B and C have been obtained with
incremental change in concentrations of agonists in presence of antagonists, as
needed for 50% of effects.
• Further, the maximal response (100%) has not changed as indicated in
dose response curve B and C, even in presence of antagonist which has
occupied certain fraction of receptors.
• In other words, maximal response in case of dose-response curve A was
obtained without binding to all receptors.
• These receptors, without binding with which maximal response was
obtained, are termed as spare receptors.
Fig. 1.4: Pharmacodynamics
• The presence of spare receptors increases sensitivity to the agonist
• The likelihood of a D-R interaction increases in proportion to the number of
receptors available;
 The sensitivity (EC50) of a cell or tissue to a particular conc. of agonist
depend on:
• the affinity of the receptor for binding agonist (Kd)
• but also on the total no. of receptors present compared with the number
actually needed to elicit a maximal (degree of spareness)
 Addiction
• Addiction is a brain disorder characterized by compulsive engagement in
rewarding stimuli despite adverse consequences.
• It is related to addictive behaviour which is both rewarding and reinforcing.
• Rewarding stimuli are interpreted by brain as intrinsically positive and
desirable or as something to be approached.
• Reinforcing stimuli increase the probability of repeating behaviour paired with
them. Addiction is caused by addictive drug, consumption of which compels
addictive behaviour.
 Tolerance
• Drug tolerance is defined as, "the diminishing effect of drug resulting from
repeated administration at a given dose".
• Drug tolerance is a pharmacological concept describing subjects’ reduced
reaction to a drug following its repeated use.
• Increasing its dosage may re-amplify the drug’s effects, however this may
accelerate tolerance, further reducing the drug’s effects.
 Dependence
• It is defined as, "an adaptive state associated with a withdrawal syndrome
upon cessation of repeated exposure to a stimulus (e.g. drug intake)".
• Withdrawal syndrome is identified as a set of symptoms that occur upon
cessation of repeated drug use.
• Dependence is of two types: physical and psychological.
 Tachyphylaxis
• Tachyphylaxis is a sub-category of drug tolerance referring to cases of sudden,
short term onset of tolerance following the administration of drug. It is a rapid and
short term onset of drug tolerance.
• It can occur after an initial dose or after a series of small doses.
• Increasing the dose of the drug may be able to restore the original response.
 Idiosyncrasy
• Idiosyncratic drug reactions occur rarely and unpredictably amongst the
population.
• They frequently occur with exposure to new drugs. They are listed as rare
adverse drug reactions.
• They do not appear to be concentration dependent. A minimal amount of drug
will cause an immune response but only after second administration; since
development of antibodies need time and first dose is mandatory.
• The proposed mechanism of most idiosyncratic drug reactions is immune-
mediated toxicity.
 Allergy
• Allergic reaction to a drug will not occur on the first exposure to a
substance. The first exposure allows the body to create antibodies and
memory lymphocyte cells for the antigen.
• Subsequently antibodies or lymphocytes interact with the antigen causing
what we understand as allergic reactions.
Following signs and symptoms are observed with allergy:
 Hives
 Itching
 Rash
 Fever
 Facial swelling
 Risk Factors
• Risk factors for drug allergies can be attributed to the drug itself or the
characteristics of the patient.
• Drug-specific risk factors include dose, route of administration, duration of
treatment, repetitive exposure to the drug.
• The patient related factors include concurrent illness, age, sex, specific genetic
polymorphism and inherent predisposition to react to multiple unrelated drugs.
• A drug allergy is more likely with large doses and extended exposure.
 Mechanisms
• Drug allergies are related to drug hypersensitivity. Drug hypersensitivity reactions
are the mediators of a drug allergy.
• There are two mechanisms for drug allergy: IgE mediated or non-IgE mediated.
• In IgE-mediated reactions drug allergens bind to IgE antibodies, which are
attached to mast cells and basophils, resulting in IgE cross-linking, cell activation
and release of performed and newly formed mediators.
• In case of non- IgE mediated reactions, probably other immunoglobulins are
involved.
 CHAPTER -2
PHARMACOKINETICS
 PHARMCOLOGY TERMS

‘Pharmaco’
Drug/ Medicine

‘Pharmacotherapeutics’ ‘Pharmacokinetics’ ‘Pharmacodynamics’

Tx of disease with Study of adsorption, Blood MOA of drug
Medicine levels,distribution,Biotrans Effects: Biological
formation,excretion and physiological
 PHARMACOKINETICS

• Pharmacokinetics is the quantitative study of drug movement in, through & out
of the body.
• It is the study of process by which a drug is absorbed, distributed, metabolized
& eliminated by the body.
• The absorption, distribution, metabolism, and excretion of a drug all involve its
passage across cell membranes.
• Pharmacokinetic properties are affected by the route of administration and the
dose of administered drug.
Biological membrane are the outermost layer of the cell consisting of
phospholipid bilayer along with membrane proteins & sugar molecules
embedded within it. It maintains the integrity of the cell and allows transport of
ions & molecules across it.
Transport across the cell membrane/biological membrane

 Passive Transport
• It does not require energy
 Passive Diffusion
• The process in which drug molecules are transported by
diffusion process along a concentration gradient across
the lipid bilayer is known as passive diffusion. This type
of transport does not require energy.

• It is directly proportional to the concentration gradient

across the membrane, the lipid-water partition
coefficient of the drug and the membrane surface area
exposed to the drug. The greater the partition
coefficient, the higher is the concentration of drug in the
membrane, and the faster is its diffusion.
 Facilitated Diffusion
• The process in which drug molecules are transported across the biological
membrane through concentration gradient with the help of carrier protein is
known as Facilitated Diffusion.
 Active transport
• The transport of molecules across a membrane against a concentration gradient
that requires energy is known as active transport.
• This energy can be obtained from ATP hydrolysis (primary active transport) or
from an electrochemical gradient of an ion such as Na+ or H+ (secondary active
transport).
 Primary active transport
• The membrane transport that directly couples with ATP hydrolysis is called
primary active transport. ABC transporters are examples of primary active
transporters.
 Secondary active transport:
• It requires an ion electrochemical gradient to drive the uphill transport of another
solute. The downhill movement of one species drives the uphill movement of the
other.
• This can be symport (in which both types of molecule or ion travel across the
membrane in the same direction) or antiport (in which the two species travel in
opposite directions)
 Endocytosis
• It is a form of active transport in which a cell transports molecules into
the cell by engulfing them using energy.
• Endocytosis includes pinocytosis(cell drinking) and phagocytosis (cell
eating).
 Receptor mediated endocytosis is a highly selective type of endocytosis in
which cell takes up specific ligand. A vesicle is formed when a specific ligand
binds to receptors on plasma membrane
• Phagocytosis (Phago = eat) is a form of endocytosis in which cell engulfs a
large solid particles such as worn out cell, whole bacteria or virus.
• Pinocytosis (Pino = drink) is a type of endocytosis in which a tiny droplet of
extracellular fluid is taken to form vesicles and all solutes dissolved in
extracellular fluid are brought into the cell.
 DISTRIBUTION

 Distribution is followed by absorption. The drug passes through several

body fluid compartments depending upon its physicochemical properties.
Different fluid compartments are:
 Plasma
 Interstitial fluid
 Transcellular Fluid
 Intercellular fluid
 Vd = total amount of drug absorbed
plasma concentration
 Factors affecting volume of distribution
1. Lipid-water partition coefficient of drug
2. Pka value of the drug
3. Degree of plasma protein binding
4. Affinity to different tissues
5. Fat lean body mass ratio
6. Diseases
 Blood Brain Barrier
• Penetration of drug into brain & CSF require crossing of blood brain barrier and
blood CSF barrier. The blood brain barrier is made up of capillary endothelial cells
tightly joined together lacking paracellular spaces. BBB are lipophilic so they do not
allow the movement of non-lipid drugs. They also contain enzymes that prevent
entry of catecholamines in active forms. They are very selective to the entry of
drugs.

 Placental Barrier
• Placental membranes are lipoidal so they allow the entry of lipophilic drugs &
restrict the entry of hydrophilic drugs. Placental barrier limits foetal exposure of
maternally administered drugs. Placenta is also a site for metabolism of drugs.
However high concentration drugs taken for long periods may gain access to
placenta.
 Plasma Protein Binding
• Most of the drugs have physicochemical affinity for the plasma proteins and get
reversibly bound to it. Acidic drugs bind to plasma albumin & basic drugs bind to
α1 acid glycoprotein. Protein bound drugs generally have longer duration of action
as they remain in body for long time. 
• Binding of some benzodiazepines: Flurazepam 10% Alprazolam 70 % Diazepam
99%

 Tissue Storage
• Drug may accumulate in specific organs by active transport or get bound to
specific tissue components. Drugs stored in tissues are unequally distributed &
have large volume of distribution & longer duration of action. Some may also
cause local toxicity. e.g: sequestration of tetracycline in bone & teeth causes
discoloration of teeth
 METABOLISM
• Metabolism(Biotransformation) means chemical alteration of a drug into
body to less toxic form. The elimination of xenobiotics depends upon its
conversion into water soluble compounds catalyzed by enzymes. The
primary site of drug metabolism is liver. Metabolism also occurs in
lungs, kidney, plasma & blood.
 ABSORPTION

• Absorption is movement of the drug from its site of administration into the
circulation.
• Not only the fraction of the administered dose that gets absorbed, but also
the rate of absorption is important.
 factors affecting absorption are:

 Aqueous solubility - Drugs given in solid form must dissolve in the

aqueous bio phase before they are absorbed.
 Concentration- Passive diffusion depends on concentration gradient; drug
given as concentrated solution is absorbed faster than from dilute solution.
 Area of absorbing surface - Larger is the surface area, faster is the
absorption.
 Vascularity of the absorbing surface - Blood circulation removes
the drug from the site of absorption and maintains the
concentration gradient across the absorbing surface
 Route of administration - This affects drug absorption, because
each route has its own peculiarities.
 BIOAVAILABILITY

• Bioavailability refers to the rate and extent of absorption of a drug from a

dosage form as determined by its concentration-time curve in blood or by its
excretion in urine .
• It is a measure of the fraction (F ) of administered dose of a drug that
reaches the systemic circulation in the unchanged form.
• Plasma concentration-time curves depicting bioavailability differences
between three preparations of a drug containing the same amount.
 BIOEQUIVALENCE

• Oral formulations of a drug from different manufacturers or different

batches from the same manufacturer may have the same amount of the
drug (chemically equivalent) but may not yield the same blood levels—
biologically inequivalent.
• Two preparations of a drug are considered bioequivalent when the rate and
extent of bioavailability of the active drug from them is not significantly
different under suitable test conditions.
 EXCRETION

• Excretion is the passage out of systemically absorbed drug. Drugs and their
metabolites are excreted in:

1. Urine The kidney is responsible for excreting all water soluble substances. The
amount of drug or its metabolites ultimately present in urine is the sum total of
glomerular filtration, tubular reabsorption and tubular secretion.

2. Faeces Apart from the unabsorbed fraction, most of the drug present in faeces is
derived from bile. Liver actively transports into bile organic acids, organic bases,
other lipophilic drugs and steroids by distinct nonspecific active transport
mechanisms. Relatively larger molecules are preferentially eliminated in the bile.
3. Exhaled air Gases and volatile liquids (general anaesthetics, alcohol) are
eliminated by lungs, irrespective of their lipid solubility. Alveolar transfer
of the gas / vapour depends on its partial pressure in the blood. Lungs also
serve to trap and extrude any particulate matter that enters circulation.
4. Saliva and sweat These are of minor importance for drug excretion. Lithium,
pot. iodide, rifampicin and heavy metals are present in these secretions in
significant amounts. Most of the saliva along with the drug in it, is swallowed
and meets the same fate as orally taken drug.
5. Milk The excretion of drug in milk is not important for the mother,
but the suckling infant inadvertently receives the drug. Most drugs
enter breast milk by passive diffusion. However, the total amount of
drug reaching the infant through breast feeding is generally small and
majority of drugs can be given to lactating mothers without ill effects
on the infant.
 BIOTRANSFORMATION

Classification (two) Phases of Biotransformation

• Phase I or Non-synthetic – metabolite may be
active or inactive
• Phase II or Synthetic – metabolites are inactive
(Morphine – M-6 glucuronide is exception)
 PHASE I METABOLISM

• Phase I reaction introduces a functional group(-OH,-NH2,-SH) and usually

result in increase of hydrophilicity of drug molecules.

1. OXIDATION It is the most important drug metabolizing reaction.

Oxidation involves addition of oxygen or negatively charged radicals. It is
mostly carried out by monooxygenases enzymes in liver.eg: cytochrome
P450, NADPH, etc.

2. REDUCTION It is the reverse of oxidation. Reduction is the removal of

oxygen or addition of hydrogen. Drugs like alcohol, aldehydes & quinines
are reduced. Cytochrome P450 enzymes act on opposite direction in
reduction process.
3. HYDROLYSIS : it is the cleavage of drug molecules by addition of water.
Different enzymes catalyze hydrolytic reactions are carboxylesterases,
peptidases, epoxide hydrolases, etc. It occurs in liver, intestines, plasma & other
tissues.
4. CYCLIZATION : It is the formation of ring structure from straight chain
compound. eg: Proguanil
5. DECYCLIZATION : it is the opening of ring structure from cyclic
compounds. eg: barbiturates
 PHASE II METABOLISM

1. GLUCURONIDE CONJUGATION: It is the conjugation reaction carried

out by Uridine Di-Phospho-Glucuronic Acid (UDP-GA). Drugs with
hydroxyl & carboxylic acid are easily conjugated by glucuronic acid. Eg:
chloramphenicol, aspirin, paracetamol, diazepam, morphine, metronidazole,
etc.
2. SULFATE CONJUGATION: It is the conjugation reaction carried out by
sulfotransferases (SULTs). e.g: methyldopa, steroids, etc.
3. GLUTATHIONE CONJUGATION : It is the conjugation reaction carried
out by Glutathione-S-Transferase (GST). It is responsible for inactivation of
highly reactive quinine or epoxide intermediates formed during metabolism.
e.g: paracetamol
4. AMINO ACID CONJUGATION : It is the conjugation reaction carried out
by glycine, taurine or glutamine. e.g: salicylates
5. ACETYLATION : it is carried out by Acetyl Coenzyme-A. Drugs
having amino or hydrazine residues are conjugated by acetylation.
Eg.: sulphonamides, isoniazid, dapsone, clonazepam, etc.

6. METHYLATION : It is carried out by methyltransferases. Drugs

having amine & phenols can be methylated by methyltransferases. e.g:
adrenaline, histamine, captopril, etc.
 Enzyme Inhibition

• One drug can inhibit metabolism of other – if utilizes same enzyme

• However not common because different drugs are substrate of different CYPs
• A drug may inhibit one isoenzyme while being substrate of other isoenzyme –
quinidine
• Some enzyme inhibitors – Omeprazole, metronidazole, isoniazide,
ciprofloxacin and sulfonamides
 Microsomal Enzyme Induction

• CYP3A – antiepileptic agents - Phenobarbitone, Rifampicin and glucocorticoide

• CYP2E1 - isoniazid, acetone, chronic use of alcohol
• Other inducers – cigarette smoking, charcoal broiled meat, industrial pollutants
– CYP1A
• Consequences of Induction:
• Decreased intensity – Failure of OCPs
 Increased intensity – Paracetamol poisoning (NABQI)
 Tolerance – Carbmazepine
 Some endogenous substrates are metabolized faster – steroids, bilirubin
 Kinetics of Elimination

• Pharmacokinetics - F, V and CL
• Clearance: The clearance (CL) of a drug is the theoretical volume of
plasma from which drug is completely removed in unit time
CL = Rate of elimination (RoE)/C
• Example = If a drug has 20 mcg/ml and RoE is 100 mcg/min
CL = 100/20 = 5 ml /min
• First Order Kinetics (exponential) : Rate of elimination is directly
proportional to drug concentration, CL remaining constant
• Constant fraction of drug is eliminated per unit time.

• Zero Order kinetics (linear) : The rate of elimination remains constant

irrespective of drug concentration
• CL decreases with increase in concentration
• Alcohol, theophylline, tolbutamide etc.
Thank You

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