Understanding

Concepts of Pharmacology
Pharmacology

Prof Dr. Maryam Rashid

MBBS, MPhil, PhD
CMT, CME
(Certificate in Medical Teaching &
Editing)
HOD Pharmacology
Dental college AMDC
 Pharmacology
is the branch of science which deals with
Pharmacokinetic
(absorption, distribution, metabolism & excretion),
Pharmacodynamic aspects of a drug
(their effects, uses and mechanism of action) of a drug.
 Drug is
a substance that acts on biologic systems
at the chemical (molecular) level and alters their functions
and used for Diagnosis / Treatment / Prevention of a Disease
 Inactive form

of a drug which usually becomes active

after getting metabolized in the body

e.g., Levodopa which is metabolized into its active form ‘dopamine’

• Levodopa Dopamine
• α -Methyldopa α-methyl norepinephrine
• Prednisone Prednisolone
• Bacampicillin Ampicillin
 It is an

inactive, dummy preparation

which is deliberately used for its

nonspecific, psychological effect on a patient with symptoms or an

illness.
 These are the drugs or biological products

used for

Diagnosis / Treatment / Prevention of Rare Disease or condition.

• Source • Mechanism of Action
• Chemical Structure • Indications / Uses, with doses /
• Names forms

• Classification (with prototype) • Contraindications

• Routes of Administration • Side Effects

• Pharmacokinetics • Drug Interactions

 Every drug due to its

peculiar molecular structure

has

Specific Pharmacology

(specific Pharmacokinetics & Pharmacodynamics)

Beta Lactam Ring
Catechol Ring

Catecholamines
 Inhaled
Parenteral (IV)
Oral

Transdermal

Parenteral (SC, IM)

Topical
Rectal
 Absorption:
After permeating the membranes, it is the
Drug passage of drug molecules into the blood
Absorption stream from its site of application.

Regional
D or
Systemic Circulation

Other Sites of
Administration
For Systemic Uses:
•Enteral related to GIT – Oral, Sublingual, Rectal

•Parenteral other than GIT – Subcutaneous (SC), Intramuscular (IM),

Intravenously (IV), etc.
•Inhalational through lungs – Gen. Anaesthetics

•Transdermal through skin – Nitrates, Insecticides.

Insecticides
For Topical (Non-systemic) Uses:
•Local – Eye, Skin, Lungs (Aerosol), Anal, Vaginal, etc.
Sublingual / Buccal…
directly going into
Systemic Circulation
Systemic
Circulation
Orally
Absorbed into
portal circulation &
then into
Systemic Circulation
in varying amounts
Rectal
Almost 50%
Going directly into
Systemic Circulation;
Remaining 50%
Going into
Portal Circulation
Transdermal
Patch
Drug diffuses from transdermal reservoir
into subcutaneous tissue
Systemic
Heart
Circulation

Drug Distribution
Transdermal Patch
Going
constantly
( but may be
variably )
into
Systemic
Circulation

Subcutaneous
 Intravenous
100% going into
Systemic Circulation

Intravenous
 Intramuscular
Going almost 100%
into Systemic Circulation

Intramuscular
 Or
Inhalational Inhalational –
Through
ThroughInhalational
aerosol - like in
Bronchial
Devices - likeAsthma
in
drugs may remain
General Anesthesia
locally in lung tissue &
Drug
very molecules
little goes may go
into
Systemic
Almost 100%Circulation
into blood
 Absorption
Through Alveoli

Drug
Absorbed
 Epithelial
layer
Mucus
layer
Water Basement
Intestinal layer membrane
lumen
Capillary

Drug
molecules
Permeation is the movement of drug molecules across the body
membranes depending upon its lipid solubility
Transport / Permeation Processes:
•Passive Transport,
•Active Transport, Facilitated Diffusion,
•Endocytosis,

•Exocytosis and
•Pinocytosis.
 Epithelial
Mucus layer
layer
Water Basement
Intestinal
layer membrane
lumen
Capillary

Higher Lower
conc.
conc.

Crossing Cell Membrane – Concentration Gradient

 Epithelial
layer
Mucus
layer
Water Basement
Intestinal layer membrane
lumen
Capillary

Drug
molecules
Solubility is the ability of a drug molecule to diffuse through / cross /
permeate the lipid bilayers membrane.
i.e.,

Lipid solubility (bi-lipid membrane)

Un-ionization & pKa (ionized can’t cross)

Smaller size molecule (easily cross)

Proper blood flow (to maintain conc. gradient)

Surface area available, etc.

pKa of drugs: e.g.,
• Aspirin 3.5 ( more absorbed at stomach)
• Acetaminophen with pKa > 9
(will also be absorbed from intestines)
 Different
Systemic Body
Parts
Circulation
Metabolized or
un-metabolized
Liver
also

First Time
Entry
 Sites of
Drugs are Required Action
distributed in .. 2

4
Metabolic Sites
Drug 5
Vascular 1 Excretory Sites
compartment
Plasma Sites of
Proteins Unrequired
3
Actions
&
Storage
Distribution, after absorption, it is the reversible movement of drug
molecules to various body compartments, by permeating various
body membranes.
 Redistribution
(e.g., with Thiopental, General Anesthetics, etc)

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 1

BLOOD

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• The approximate or apparent Volume of the body compartments
that is required to accommodate the drug, in the same
concentration as it is in the plasma Or
• The ratio between the drug administered in the body and the drug
concentration in the plasma
For 70 kg patient:
• Plasma Volume (3 L),
• Blood Volume (5 L),
• Extracellular Fluid (12 -14 L),
• Total Body Water (40 - 42 L)
 Amount of drug in the body
Vd = ------------------------------------------------
Concentration in the blood
Given=20
Given=20units
units
22units
units 18 units
18 units

20
Vd = ---- = 10
2

Vascular Extra-vascular
compartment compartment

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 Amount of drug in the body
Vd= -----------------------------------------
Concentration in the blood
Given=20
Given=20 units
units
1818 units
units 2 units2 units

20
Vd = ---- = 1.1
18

Vascular Extra-vascular
compartment compartment

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 Amount of drug in the body
Vd= -----------------------------------------

Given=200
Given=20units
units
22units
units 198 units
198 units

20o
Vd = --- =10o
2

If drug-concentrations
in the vascular compartment is less,
Vd will be more
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A. Properties of Drugs

i. Affinity to bind Plasma Proteins & for Different Tissues.

ii. Lipid solubility / Lipid: Water Partition Coefficient

iii. Concentration Gradient

iv. Molecular Size & Weight

v. pKa of the drug

B. Patients Factors

i. Fat: lean body mass ratio, which can vary with Age, Sex, Obesity,
etc.

ii. Extent of Tissue Perfusion

iii. Presence of Effusion ( Fluid ) in Plasma & Peritoneal Spaces:

Diseases like CHF, Uremia, Cirrhosis.
• When drug has a High Plasma Proteins Binding,

Vd will low

so, the when the Vd is high, the plasma concentration will be low
and vice versa.
Drug Metabolism
•It is the chemical & enzymatic reactions in the drug molecules to
change its molecular structure.

a. Catabolic Reactions: break down them into their pieces

(metabolites) by Oxidation, Reduction, or Hydrolysis.

b. Anabolic Reactions: synthetic reactions, through conjugation.

a. Changes In Activity: majority metabolites after Oxidation, Reduction,
or Hydrolysis become inactive (eliminated) while other metabolites
retain activity (same or different).
• Elimination is the chemical change in the drug molecule to make it
inactive for the body; it can be achieved either by metabolism – (as in
majority of cases) or through excretion from the body.
i. Zero-Order Elimination Rate:
• Rate of elimination of a drug is independent of its plasma
concentration (or amount in the body); in this a constant amount of
drug is eliminated per unit time.
ii. First-Order Elimination Rate:
• Rate of elimination of a drug is directly proportional to its plasma
level (or the amount present); in this a constant fraction of the drug
is eliminated per unit time.
• Codeine Morphine
• Morphine Morphine-6-glucuronide
• Allopurinol Alloxanthin
• Primidone Phenobarbitone, PhenylEthylMalonAmide
• Digitoxin Digoxin
• Morphine Morphine – 3 – Glucornide (Neurotoxic)
• Isoniazid Monoacetyl – hydrazine (Hepatotoxic)
• Cyclophosphamide Acrolein (Hemorrhagic cystitis)
b. Changes in solubility: majority metabolites by Oxidation, Reduction, or
Hydrolysis become ionized / water soluble i.e., excretable (bio-
transformed) while other unionized will be conjugated to become
ionized / water soluble.
Biotransformation.
•It is the enzymatic or conjugated changes in the drug molecules to make
them ionized / water soluble, and thus excretable
Enzyme Induction (acceleration of metabolism):
• Increased / rapid metabolic activity of an enzyme (CYP 450)
resulting from its increased synthesis or decreased degradation, due
to the effect of an exogenous or endogenous substance. 
Enzyme Inhibition (depression of metabolism):
• Decreased / slow metabolic activity of an enzyme (CYP 450)
resulting from its decreased synthesis or increased degradation, due
to the effect of an exogenous or endogenous substance.
ORAL DOSE

Absorption Passes un-metabolized Bioavailability

Bioavailability:

The fraction or percentage of the administered dose of drug that

reaches into systemic circulation in unchanged / un-metabolized form,
when given through any route.

Why not amount of a drug ? Why “a fraction” ?

Why not amount of a drug ? Why “a fraction” ?

Drug A, 1 mg is given, only 0.5 mg (50%) reached un-metabolized

If, Drug A, 10 mg is given, now 5 mg (50%) reached un-metabolized.

Here, amount changed but percentage remains the seme.

First-Pass Effect:
• After oral / partly rectal absorption it is the pre-systemic (extensive
and rapid) metabolism of drug molecules which may occur while
passing for the first time through metabolic sites of GIT / Liver
leading to decreased (sub-therapeutic) bioavailability
Excretion is the removal of drug from the body through
excretory organs, in active or inactive form present
systemically.
Half–Life (t ½):
• Time required by a drug to reduce its amount by 50% as compare to
its previous levels during elimination (or sometimes during a
constant infusion).
Half-life mainly depends on Vd & the CL.

0.693 x Vd

t1/2 =

CL

0.693 = approx. 0.7 which is log of 2

i.e., twofold (50%) decrease in drug concentrations

 Dose

Distribution
Distribution
Blood Tissue
α - Phase t½α
Elimination t½β

Elimination β – Phase
(Metabolism & Excretion)

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1. t½ - 50 % drug is eliminated.

2. t½ - 75% (50 + 25) drug is eliminated.

3. t½ - 87 .5 % (50 + 25 + 12.5) is eliminated

4. t½ - 93.75 % (50 + 25 + 12.5 + 6.25)

5. t½ - 96. 875% (50+25+12.5+6.25+3.125)

which is taken as almost 100 %, otherwise ……

6. t½ - 96. 875% (50+25+12.5+6.25+3.125+1.56)

7. t½ - 98.435 (50+25+12.5+6.25+3.125+1.56+0.78)

8. t½ - 99.215
(50+25+12.5+6.25+3.125+1.56+0.78+0.39)

9. t½ - 99.605
(50+25+12.5+6.25+3.125+1.56+0.78+0.39)
 Short Half-lives

Drug Half-Life (h)

Adenosine < 10 sec

Aspirin 0.25
Cephalexin 0.90
Hydralazine 1.0

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 Long Half-lives

Drug Half-Life

Amiodarone 80 – 120 days

Chloroquine 214 h

Digoxin 50 h
Fluoxetine 53 h
Imipramine 18 h

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• It is defined as the volume of blood or body fluids cleared
off the drug per unit time, Or
• it is that volume of plasma / body fluids from which the
active drug is completely removed / eliminated in per unit
time (as clearance of creatinine)

CL = Rate of elimination/C, where C is the plasma conc.

 CLEARANCE
Q Liver Q

Portal Ci Co Systemic
Circulation Circulation

CLLiver
Oral Intravenous
Dose Dose

Gut

CLother CLrenal
Systemic Clearance is the sum of:

Hepatic Clearance,

Renal Clearance,

Plasma / Blood Clearance,

Other tissue Clearance

 Drug Conc.
Drug Conc. in the Plasma Drug Conc.
Entering at Leaving

Steady State
Where it acts ? ….. Site of Action
•may be receptor like Cholinergic, Adrenergic, Histaminergic
Receptors, etc
•Enzyme like Cholinesterase, Xanthine Oxidase, Cyclooxygenase
Enzymes, etc)
•Ionic Fluxes like Na+ /Ca+ Channels) etc.
How it acts ? ….. Mechanism of Action
•Modify the Biochemical /Physiological Cellular Functions like
increases cAMP or cGMP; inhibition of Cyclooxygenase, Na +/K+
ATPase, Enzymes, etc.
What are the Effects ?...
•Pharmacological Effects
•Usable or Adverse Effects like Increase in Force of Contraction
of Heart, Stimulation of Vomiting Center, Bone Marrow
Depression, etc
Desirable & Un-Desirable
& / or
Useable & Non-useable

Uses & Side effects / Toxic

• Side Effects • Genotoxic
• Adverse Effects • Intolerance / Tolerance
• Toxic Effects: • Tachyphylaxis

Pharmacological • Idiosyncrasy

Pathological • Hypersensitivity Reactions

Transmembrane signalling

It is the modification of intracellular receptor activity

when a ligand binds to the extracellular domain of the
receptor to activate it.
 Basic Signaling Mechanisms are

Five

each uses a different strategy

to overcome the barrier posed by the lipid bi-layer

of the plasma membrane

Intracellular Transmembrane Receptors
1. receptors 2. Tyrosine 3. Cytokine 4. Ligand-Gated 5. G-Proteins
Kinase Receptors Channels linked
Ligand binding and channel opening

occur on a millisecond timescale.

Receptors include:

nACh, GABAA, Glutamate, 5-HT3

To control different aspects of Cell Function

1. Adenylyl Cyclase, for cAMP formation

2. Phospholipase C, for Inositol Phosphate and Diacylglycerol

(DAG) formation

3. Ion Channels, esp. for Ca+2 & K+ Channels

5. Protein kinases system controls the activity of many
signaling pathways controlling cell growth and
proliferation, smooth muscle contraction, etc.
Spare Receptor
• These are the receptors present in a particular tissue in excess of the
receptors actually needed to elicit the maximal biologic response;  
• In other words, spare receptors are said to exist if the maximal drug
response is obtained at less than maximal occupation of the
receptors.
• Affinity is the chemical property of a drug (due to its
specific molecular structure) to show specific attraction for
binding to particular tissue receptors.
• Efficacy is the capability of a drug molecule (due to its
specific structure) to produce its maximum possible effect
through receptor activation.
Agonist (or Full Agonist).
•A chemical substance which binds to the receptor (present for
physiological endogenous substance) and activates it to produce
the response resembling the receptor’s physiological activity;
•They have full affinity & maximal efficacy to produce maximum
possible response.
Agonist/receptor Agonist/receptor/
Complex Transducer transducer Complex

A R + T A R T

Affinity of Agonist-receptors complex

for
Transducer
 Agonist / receptor /
transducer Complex

A R T Response

So
Like
Few
they drugs
So may
they bindbind
may
cause to their receptors
with the
persistent with
receptors
depolarization
Succinylcholine
covalent bonds
irreversibly, Phenoxybenzamines
which are very
/ persistently
which is usually ultimately strong
inhibition
Partial Agonist
•It is the chemical substance which binds to the receptor with
full affinity but has lesser / sub-maximal efficacy so it usually
produces sub-maximal / partial response;
•It acts as an antagonist for the full agonist or endogenous
physiological substance.
Biased Agonist.
•Biased Agonist activates the non-conventional signaling pathway like β-
arrestin–mediated signaling (and not the conventional G protein-
coupled–mediated signals).
•Example: β1 receptors are coupled through β-arrestin, which are thought
to be cardioprotective, while conventional GPC Signaling produces
cardiac stimulation which may be deleterious esp. in MI.
Inverse Agonist
•It is an agonist which has affinity only for the inactive form
(Ri) of the receptor with intrinsic activity opposite to
endogenous substances / agonists and thus produces
opposite effect.
Antagonist:
•An agent which prevents / blocks the effects of a natural
ligand or a drug;
•Usually it binds to the same receptor for the natural ligand or
drug; it has only affinity but no intrinsic activity = 0
Potency
•It is the ability of a drug to produce the required effect with
minimum possible dose.
•Drugs of high potency generally have high affinity for the
receptors; such drugs occupy a significant proportion of the
receptors even at low concentrations.
 Maximal Effect

EFFECT

EFFICACY
POTENCY

ED5
0

Log [Dose]
 A B C D

EFFECT

Log [Dose]

Order of Potency of Drugs A>B>C>D

 A C

B
D
RESPONSE

ED50

Rank Order of Potency: A>B>C>D

Rank Order of Efficacy: A=C>B>D
 % population responding to a drug
e.g., lowering Systolic BP by 10 mmHg

% Population
Responding
17
13 14
11 11
8 9
7
5 4
1 100 %
1 10 20 30 40 50 60 70 80 90 100
Dose (mg/kg)
 TxD1 – 1 X 100
Standard Margin of Safety = ------------------------
ED99
Tolerance
•After attaining the full, therapeutic response, it is a gradual decreased
response of a drug when used in a therapeutic schedule;
•if the same pharmacological response is required, the dose of the drug
may be increased, e.g., Opioids, etc.
• While Resistance is usually loss of response and is seen with
chemotherapeutic drugs, like Antimicrobials, Antituberculars,
Antivirals, Anti-cancers, etc.

100
Tachyphylaxis
•A rapid decrease in the response to a drug after repeated doses over a
short period of time e.g., Indirectly acting Sympathomimetics,
Hydralazine, etc.
•Increasing the dose of the drug WILL NOT increase the response
• Due to rapid exposure of the drug to the tissue, it becomes
desensitized / insensitive.
• But by giving time to the tissue it regain its sensitivity, e.g.,
Nitroglycerine, Hydralazine, etc.
Iatrogenic Diseases
• ‘Iatrogenic’ means ‘caused by physician’;

the harmful effects of a drug are produced when it is used for the
treatment of some disease,

e.g.,

adrenocorticosteroids, while being used for longer time due to its anti-
inflammatory use, may cause Cushing’s Syndrome.
103
Idiosyncrasy
An abnormal, unexpected responses of a drug usually due to some
genetic differences in drug metabolism or responsiveness or
hypersensitivity,
e.g.,
G6PD deficiency hemolytic anemia with Primaquine / sulfonamide;
Aplsatic Anemia due to Chloramphenicol
104
Supersensitivity
•Increased responsiveness of the tissue-receptors to the usual doses or
endogenous substances, usually due to up-regulation of the receptors
like of β1-receptors when blocked for longer time, cholinergic receptors
blocked by Thiothixene

105
Hypersensitivity
•Immunological Problems:

Four Types:

from skin rash to acute anaphylaxis

106
Superinfection
•Infection of some opportunistic micro-organisms like , resistant strain of
C. difficile, Candida albicans, due to alteration in the normal bacterial
flora of GIT / respiratory tract / genitourinary tract, usually by broad
spectrum antibiotics,

e.g., Tetracyclines, Chloramphenicol, etc.

1. Additive, e.g., more sedation with addition of CNS depressants

2. Synergistic (Greek: Syn-together; ergon-work) acting in the same

direction, e.g., combination of penicillins & aminoglycosides increase
the antimicrobial spectrum
 Drug Combinations Basis of Potentiation

1. Levodopa + carbidopa 1. Inhibition of peripheral

metabolism

2. Noradrenaline + cocaine 2. Inhibition of neuronal uptake

3. Sulfamethoxazole + 3. Sequential blockade

trimethoprim
4. Antagonistic
• Chemical: at molecular level
• Physiological: at functional level
• Pharmacological: at receptors, etc.
• Dispositional: at PPB
Fetal development
Damages to the fetus during pregnancy
Damages to the fetus during lactation
 A branch of Pharmacology

which deals with doses of drugs

Estimated Dose
Depending upon
Therapeutic Range

Maximum
Therap. Conc.

Minimum
Therap. Conc.

2
3
1

Different Doses
Branch of Pharmacology which deals with the study of Genetic Factors
which can affect the response of a drug