Introduction to

Pharmacology
 Brief history of Pharmacology
Ø Medicaments have, since time immemorial,
been used for treating disease in humans and
animals.

Ø Belief in the curative powers of plants and

certain substances rested exclusively upon
traditional knowledge, that is, empirical
information not subjected to critical
examination.
 ORIGINS AND ANTECEDENTS
• As a science, it was born in mid- 19th century
• Boundaries of pharmacology are not sharply defined
nor are they constant
A synthesis of several biomedical sciences….

Ph
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Pharmacology
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…but unique in its own right

Ø Pharmacology came from the Greek words “Pharmacon”
meaning drug or medicine and “logos” meaning the truth
about or a rational discussion.

Ø Pharmacology is the science that deals with properties and

effects of drugs in relation to their interaction with living
systems.

Ø The objective of pharmacology is mainly to provide such

scientific data, using which one can choose a drug
treatment of proven efficacy and safety from the various
options available, to suit the individual patient.
Drug and Medicine
•Drug:- a chemical substance of known
structure, other than a nutrient or an
essential dietary ingredient, when
administered to living organism, produce
a biological effect.
•Medicine:- a chemical preparation which
usually but not necessarily contain one
or more drugs
• Substance that have medical importance or therapeutic
values
• Mostly, Drug + additives
 Drug information source

•Is an official code containing a selected list

of the established drugs & medical
preparations with descriptions of their
physical properties & tests for their identity,
purity & potency e.g. Indian Pharmacopoeia
(IP), British Pharmacopoia (BP).
Source of drugs

•Plant: digoxin, Morphine

•Animal: insulin
•Microorganism: penicillin
•Minerals: iron folate
•Genetic engineering e.g. Human insulin,
human growth hormone etc.
•Synthetic - Ciprofloxacin
Components of a Drug Profile
 Naming of drugs
 3 types of naming system

ØGeneric name:
o Non proprietary name
o Product must have this name
o Accepted internationally
o only one generic name for a drug
ØBrand name:
o Name by manufacturer
o several name for single drug may occur
o Expensive
The difference b/n generic product
and brand product is only the
additives but not active ingredient
ØC h e m i c a l n a m e : i n t e r e s t o f
chemists indicate the chemical
entity present in the drug

Which name is better to recommend in

prescribing drugs?
Cont’ed

Type of drug name Examples

Chemical name N-acetyl-para-aminophenol
Generic name Paracetamol
Trade name Panado, Tylenol, Dapa, Valadol,
Valorin, Helenol, etc

13
 Subdivisions of Pharmacology

v Neuropharmacology : study of the effect of drugs on

components of the nervous system (brain, spinal cord,
nerves)
Example: treatment of Alzheimer's

v Cardiovascular Pharmacology: study of the

effects of drugs on heart, vasculature, and kidney
that participate in cardiovascular function.

Example: treatment of high blood pressure (hypertension)

vBehavioral Pharmacology: study of the effects of drugs
on behavior

Example: treatment of Attention Deficit Disorders

v Endocrine Pharmacology: study of drugs that are

hormones or hormone derivatives

Example: creation of The Pill

v Molecular Pharmacology : study of the biochemical
and biophysical characteristics of interactions between
drug molecules and those of the cell

E.g..: Drug-Receptor Interaction

v Biochemical Pharmacology: study of how drugs act with

and influence the chemical ‘machinery’ of the organism

E.g..: signal transduction through G proteins

v Pharmacotherapeutics: is the study of the
use of drugs in the prevention, treatment
and diagnosis of disease.

v Toxicology: deals with the adverse effects

of drugs. It also deals with other chemicals
which are responsible for household,
environmental and industrial intoxications.
vC l i n i c a l P h a r m a c o l o g y : a p p l i c a t i o n o f
Pharmacodynamics and pharmacokinetics to patients
with disease.
Example: use of pharmacogenomics to tailor individual
medical treatment
v Chemotherapy: study of drugs used for treatment of
microbial/viral infection and malignancies

Example: treatment of cancer (anti-angiogenic agents)

v Veterinary Pharmacology: study of the use of drugs

for disease and health problems unique to animals.
 Aspects of Pharmacology
1. Pharmacokinetics: is the study of the absorption,
distribution, metabolism and excretion of drugs.
‘what the body does to the drug’
2. Pharmacodynamics: is the study of the molecular,
biochemical, and physiology effects of drugs on
cellular systems and their mechanisms of action.
‘what the drug does on the body’
Pharmacokinetics
ØPharmacokinetics deals with Absorption,
Distribution, Metabolism and Excretion of
drugs.
ØTo produce its characteristic effects, a drug
must be present in appropriate concentration
at its site of action.
ØConcentration at the site of action depends on
absorption, distribution, binding or localization
in tissues, biotransformation, and excretion.
ØAll phases of pharmacokinetics involve drug
movement
 Drug Absorption
ØAbsorption is the movement of a drug from
its site of administration into the central
compartment (blood) and the extent to which
this occurs.
• In order for a drug to be absorbed, it must be
able to pass through cell membranes
• Translocation of a drug from one side of the
biological barrier (cell membrane) to the other
is called biotransport of drug.
Cell membranes

ØC e l l m e m b r a n e s a r e b i l a y e r o f
amphipathic lipids, with their
hydrocarbon chains oriented inward to
form a continuous hydrophobic phase
and their hydrophilic heads oriented
outwards.
ØIntrinsic and extrinsic membrane proteins
embedded in the bilayer serve as receptors to
elicit electrical/chemical signaling pathways
and provide selective targets for drug actions.
ØIntrinsic proteins, which extend through the
full thickness of the membranes, surround fine
aqueous pores.
ØPassage of drugs through cell membranes
fo l l o w s o n e o r a c o m b i n a t i o n o f t h e
following major mechanisms.
v Passive diffusion
v Carrier mediated transport
ü Facilitated diffusion
ü Active transport
v Endocytosis
v Ion pair transport
Passive diffusion
ØAlso called non-ionic diffusion, is the major
(more than 90%) mechanism for absorption of
drugs.

ØThe driving force for this process is the

concentration gradient or electrochemical
gradient (defined as the difference in the drug
concentration on either side of the membrane).
Fick’s first law of diffusion

•Passive diffusion is best expressed by this

law, which states that drug molecules
diffuse from a region of higher
concentration to one of lower concentration
until equilibrium is attained and that the
rate of diffusion is directly proportional to
the concentration gradient across the
membranes.
Where

Ø = rate of drug diffusion.

Ø D = diffusion coefficient of the drug through the
membrane.
Ø A = surface area of the absorbing membrane for drug
diffusion
Ø Km/w= Partition coefficient of the drug between the
lipoidal membrane and the aqueous GI fluids.
Ø CGIT – C = Difference in the concentration of drug in the GI
fluids and the plasma, called as the concentration gradient.
Ø h = thickness of the membrane.
Some generalizations concerning passive
diffusion
ØIt is energy independent and non-saturable
process
ØDrugs move down a concentration gradient
ØThe rate of drug transfer is directly proportional
to the concentration gradient between GI fluids
and the blood compartment
ØGreater the area and lesser the thickness of
the membrane, faster the diffusion

ØGreater the Km/w partition coefficient of

drug, faster the absorption
Øwater soluble drug (ionized or polar) is readily
absorbed via aqueous channels or pores in cell
membrane.
ØLipid soluble drug (nonionized or non polar) is
readily absorbed via cell membrane itself.
Carrier mediated transport

ØInvolves binding of the drug to specific receptors

on the membrane for translocation into the
cytoplasm
ØCharacteristics of carrier mediated transport
vSelectivity (structure specific)
vCompetitive inhibition by chemical congeners
vSaturability
vMovement against electrochemical gradient (active
transport)
vAlong concentration gradient (Facilitated diffusion)
Endocytosis
• The process by which the substance is engulfed
by the cell membrane and carried into the cell by
pinching off of the newly formed vesicle inside
the membrane
• Phagocytosis (large molecule), pinocytosis( small
molecule)
 Ion pair transport
•Strong electrolyte drugs highly
ionized at all physiologic pH &
penetrate poorly
• when the ionized drug is
linked with an oppositely
charged ion, an ion pair is
formed with neutral charge-
diffuse more easily.
• Eg propranolol paired with oleic
acid
Factors that modify absorption
q Absorption is governed by:-
Ø The route of administration
Ø Physico-chemical properties of drug
Ø Nature of the dosage form
Ø Physiological factors
Ø Pharmacogenetic factors
Ø Disease states
Routes of drug administration
FDrugs are administered for either their action in the
locality of their administration or for general systemic
purpose.
FMany factors such as the nature of the target tissue,
Physico-chemical properties of the drug, the disease
state etc… dictate the route the drug should be
administered
FRoute of drug administration affect the extent of
absorption and hence affect bioavailability
vEnteral: drug placed directly in the GI
tract
• Sublingual, Oral & Rectal
vParentral: Drug delivered in the
systematic circulation without crossing
intestinal mucosa
• Intravascular, Intramuscular &
Subcutaneous
 1. Systemic routes of administration

FRefers to the administration of drugs though

the mouth, mostly, for systemic effect.
FIt is the most common method of drug
administration
F Involve many steps before absorption (dissolution,
disintegration)
FAdvantages

ØMost convenient and economical, Safest

ØO f t e n p a i n l e s s , n e e d n o a s s i s t a n c e f o r
administration

ØBoth solid dosage forms and liquid dosage forms

can be administered

ØReverse of dose management is easily done (how?)

FDisadvantages

ØAction slower and thus not suitable for emergencies

(why?)
ØUnpalatable drugs difficult to administer
ØNot suitable for uncooperative /unconscious/ vomiting
patients
ØCertain drugs are not absorbed sufficiently and also
Irregular absorption (drug- food interaction)
ØIrritation to GI (N&V)
ØHigh first pass effect
• Some drugs are destroyed by digestive juice or liver
enzymes (first pass metabolism)
• S o m e d r u g d e st r u c te d by G I f l o ra ( d i gox i n ) ,
enzyme(insulin), pH (penicillin)
• Liver metabolism ( highly enzymatic)
üBA from PO < 1 --- b/c of FPE
1.2. Sublingual administration
FTablets are placed under the tongue or crushed in
the mouth and spread over the buccal mucosa

FNon polar and hence lipid soluble drugs are rapidly

absorbed

FDrug is protected from first pass metabolism as

there is direct drainage into the superior vena cava.
 1.3. Rectal administration
FCertain irritant and unpleasant drugs can be put into the
rectum as suppositories or enema for systemic effect.

FThis is often useful when oral ingestion is precluded by

vom i t i n g o r w h e n t h e p at i e nt i s u n co n sc i o u s a n d
uncooperative.
FFPE is minimal by 50% from PO
FIt is rather inconvenient and embarrassing
FAbsorption is slower, irregular and often unpredictable
and unreliable
1.4. Parenteral route
FPar = beyond and enteral = intestine
FDrug directly introduced into tissue fluids or blood
without having to cross the intestinal mucosa.
FRoutes include
ØIntravenous
ØIntramuscular Major parenteral routes
ØSubcutaneous
FOther parenteral routes include
ØIntra-arterial
ØIntrathecal
ØIntraarticular
FAdvantages
ØAction faster (hence valuable in emergencies)

ØEmployed in unconscious/uncooperative/vomiting patients

ØNo interference of food or digestive juice and first pass

effect is bypassed to a certain extent.
FDisadvantages
ØPreparation is costlier
ØNeed of assistance by others during administration
a. Intravenous administration
FDrug injected as a bolus or infused slowly over
hours in one of the superficial veins, the drug directly
reaches into the blood stream and effects are
produced immediately
FDose required is smallest as bioavailability is 100%
FEven large volumes can be infused through this
route
FOnly sterilized aqueous solutions can be injected
FIt is the most risky route
b. Intramuscular administration

FDrug is injected in one of the large skeletal muscles:

deltoid, triceps, gluteus maximus, rectus femoris etc.

FMuscle is less richly supplied with sensory nerves

and (mild irritants can be applied) and is more
vascular (absorption is faster)
c. Subcutaneous administration

FThe drug is deposited in the loose subcutaneous tissue

FIs richly supplied by nerves (unsuitable for irritant drug

administration) but is less vascularized (slow absorption)

FSelf injection is simple

FOily solution or aqueous suspensions can be injected for

prolonged action
 Comparing oral administration with parenteral
administration
vOral route preferred to parenteral
except for certain situations (i.e.,
emergencies, drugs destroyed by gastric
acidity, when drug levels are to be
tightly controlled, when severe irritation
would occur, for depot preparations,
and when patients cannot take oral
drugs).
 1.5. Pulmonary administration
FSuitable for gaseous and volatile drugs
FAbsorption of inhalants mainly depend on particle size
FRapid absorption due to large surface area
FSolutions can be atomized and the fine droplets in air
(aerosol) inhaled
FAdvantage: Rapid absorption (onset of action), avoidance
(minimum) of hepatic first pass loss, local application to the
pulmonary system, used for both local action (asthma),and systemic
action (general anesthetic)
FDisadvantage: Poor ability to regulate the dose and irritation of
the pulmonary mucosa, difficult to put drug in aerosol, volatile or
gas state
2. Topical administration
FApplication could be on mucous membranes, skin
or the eye.

FMucous membranes
ØDrugs are applied on the mucous membranes of the
conjunctiva, nasopharynx, oropharynx, vagina and colon
usually for their local effects.

ØAbsorption through mucous membranes occur readily to

cause systemic effects
FSkin
ØAbsorption is proportional to the surface area and
lipid solubility of the drug.
ØConditions that increase cutaneous blood flow
enhance absorption.
ØSystemic absorption from skin is sometimes a reason
of toxicity.
FEye
ØOphthalmic preparations are meant for their local
action
ØSystemic absorption that results from drainage
thought the nasolacrimal canal is usually undesirable
ØVery little is lost through drainage; hence, systemic
side effects are minimized.
Physico-chemical properties of drug

•Molecular weight
•Chemical and enzymatic stability
• The drug should be stable in gastric acid and in gut
enzymes. e.g. Penicillin G is highly acid labile, or
unstable in acid.
•Aqueous and lipid solubility
• For better absorption a drug must have optimum
water and lipid solubility or a optimum partition
coefficient. If it is highly lipid soluble it would not
dissociate in the circulation i.e. Ion trapping. On the
other hand, if it is highly water soluble then it will
not cross the biological membrane.
• Drugs exist in two forms ionized (water
soluble & nonionized forms (lipid
soluble) in equilibrium.
Drug ionized + nonionized

• Nonionized form is absorbable.

• Nonionized / ionized fraction is determined
by pH and pKa according to Henderson-
Hasselbach
 •pH of media
•P Ka of the drug
ü HA H ++ A-
+
ü HB B +H+

ü HB +, A -& H + Usually unable to penetrate the lipid membrane

•A protonated form of a weak acid – is
neutral, more lipid soluble better
absorption via the lipid bilayer of the
cell membrane
•Unprotonated form of a weak base – is
neutral & more lipid soluble, thus
better absorbed via the cell membrane
 Drug dosage forms

• Different dosage forms have different rate and extent

of absorption.

• A syrup have fast rate of absorption as compare to tablet

• A capsule have fast rate of absorption than table
• Controlled-release dosage form have a uniform absorption and
less side effects
 Physiological factors

• Gastrointestinal transit time

• Presence of other agents – ca in milk reduce
absorption of tetracycline
• Surface area of absorption & local circulation
• Enterohepatic cycling – eg. Chloramphenicol
• Metabolism - eg. propranolol
Bioavailability

•It is a term used to indicate the fractional

extent to which a dose of drug reaches its site
of action or a biological fluid from which the
drug has access to its site of action.
•Drug administered may completely or partially
bioavailable based on the route of
adminstration.
•Bioequivalence - comparable bioavailability
and similar times to achieve peak blood
concentrations.
•Therapeutic equivalence - Two similar drugs
are therapeutically equivalent if they have
comparable efficacy and safety.
Drug interaction during absorption

•Ketoconazole absorption decrease

when administered with histamine H2-
receptor antagonist (e.g nizatidine)
•Caffeine increases absorption of
ergotamine
Drug Distribution
• It is the process by which absorbed drug or drug
directly introduced into the circulation is carried to
various interstitial and cellular fluids.
• Is the delivery of drugs from systemic circulation to
tissues
• The Process occurs by the Diffusion of Free Drug
until equilibrium is established.
• Distribution of drugs is random
 Drug administered
(oral, Iv, rectal…)

Absorption
Storage in tissue
Site of action (eg- body fat)
( receptors…)
distribution

distribution Plasma compartment

Free drug bound drug distribution

distribution
Metabolism
distribution
(eg- liver, GI. Lung…)
Unwanted site
( side effect..)

Excretion
( eg- kidney, lung, sweat…)
 Distribution

•Distribution controls onset, Duration actions,

efficacy and side effect.
•Distribution of drugs is rarely uniform.
•Drugs are simultaneously being eliminated
and distributed, but distribution is usually
faster.
•Tissue distribution is determined by the
partitioning of drug between blood and the
particular tissue
Steps of drug distribution

1.Dilution in blood- The drug has to reach

equilibrium with itself in the blood.
2. Movement into extracellular fluid -
Drugs need to be able to get out from
vascular system.
3. Uptake into cells- The drug must be
able to cross the cell membrane.
Ø Distribution follows two phases:
i. Initial phase: dependent on cardiac
output and blood flow. Well perfused
organs receive most of the drug in this
phase
ii. Second phase: limited by various variables
such as blood flow, lipid solubility, pH,
plasma protein binding
• involves a far larger fraction of body mass than does the
initial phase
•Distribution of drugs in different tissues
depends on different factors:-
• Plasma protein binding
• Tissue uptake (affinity of drugs to tissue)
• Physiological barriers
• Tissue perfusion
• Physico-chemical properties of drugs
§Lipid solubility of the drug
§pka of the drug
I. Plasma protein binding :
•Acidic drugs bind to albumin
•Basic drugs bind to a1-acid glycoprotein
•Plasma protein bound drugs are restricted to
the vascular compartment
•Bound fraction is not available for action,
distribution, metabolism and excretion
•Binding is relatively nonselective as to
chemical structure
• Drug in systemic circulation exist as bound
and unbound form
• Drugs ordinarily bind with plasma protein
in reversible fashion and in dynamic
equilibrium
D + P →[DP] → D + P
• As free drugs leave the systemic circulation
the bound drug dissociate
• Factor affecting drug plasma protein binding:
• Drug affinity for binding site
• Number of binding site
• Since drug binding is saturated process --- ↑ in
site of binding --- ↑ binding
• Drug concentration
• Physicochemical characteristics of drug
• Protein binding is directly relategd to lipophilicity
↑ lipophilicity = ↑ the extent of binding
 Some factor affect the binding of drugs with
albumin:
Age
• Neonate – albumin content is low in new born as
result in increase conc. of unbound drug that primarily
bind to albumin eg. Phenytoin , diazepam
• Elderly -albumin content is lowered result in increase
conc. of unbound drug that primarily bind to albumin
Disease state:
Hyperalbuminemia
Hypoalbuminemia (liver disease )
Hyperbilirubinemia
α1 –acid glycoprotein

Binding site mainly for basic drug like imipramine.

Serum plasma level ↑ in situation such as:
 Stress, injury, trauma
 Cancer, arthritis, myocardial infarction, and Crohn's disease
 Surgery
 In old age AAG level is increase thus decrease conc. of free drug that bind to AAG
 Plasma protein binding is clinically important for those
drugs which have high plasma protein binding and low
excretion
Warfarin
Phenytoin
 Disease state

Disease Influence on Influence on

plasma protein protein drug
binding
Renal failure albumin content Decrease binding of
acidic drug , neutral or
(uremia) basic drug are unaffected

Hepatic failure ↓ albumin

Decrease binding of acidic
drug ,binding of basic drug
is normal or reduced
synthesis depending on AAG level.

Inflammatory state Increase binding of basic

(trauma , burn, ↑ AAG levels drug , neutral and acidic
drug unaffected
infection )
•Class I drugs:
• dose of drug is less than the binding capacity of
albumin
• dose/capacity ratio is low.
• binding sites are in excess of the available drug, and the
bound-drug fraction is high.
• majority of clinically useful agents.
•Class II drugs:
• drugs are given in doses that greatly exceed the
number of albumin binding sites.
• dose/capacity ratio is high, and a relatively high
proportion of the drug exists in the free state, not
bound to albumin.
II. Tissue uptake
 Drugs will not always be uniformly
distributed to and retained by body tissues;
some drug will be either considerably higher
or considerably lower in particular tissues:
due to tissue different affinity
o Adipose tissue : drugs with extreme lipid
solubility e.g barbiturate thiopental
 May result :–
 decrease therapeutic activity
 Prolonged activity
 Toxicity
 Tissue uptake
o Kidneys : contain proteins, methallothionein, that
have high affinity for metals
 Cadmium, Lead, Mercury accumulation -----toxicity
o Eye – drugs which have affinity for retinal pigment,
melanin, accumulate in the eye
Chlorpromazine (other phenothiazine) and chloroquine---
accumulate in eye
o Teeth –TTC accumulation result yellow- brown
discoloration of teeth
o Liver – Chloroquine
o Bone- TTC, Lead, Cisplatin
T TC accumulation may cause dysplasia, poor bone
development
Lead accumulation result bone brittleness (displace Ca2+ )
Slow release of toxic effect may occur from lead and
cisplatin accumulation
Adsorption of drug onto the bone have therapeutic
advantages for the treatment of osteoporosis (sodium
etidronate )
vGenerally tissue accumulation of drug may have
vAdvantageous effect ---(target tissue therapy eg,
iodine: sustained release effect, eg fat depot )
vDisadvantageous effect---mainly toxicity
III.Physiological Barriers
q Blood brain barrier (BBB)
 Transfer of drug to brain is regulated by BBB

Not pass BBB Cross BBB

-- ionized drug --unionized drug
-- Lipid insoluble drugs -- small size drug
-- Bound drug -- unbound drug

 Inflammation such as due to meningitis or encephalitis

increase the permeability of BBB so permeating the passage
of ionized , lipid insoluble drugs.
 Eg:- penicillin and ampicillin – not cross BBB ( highly ionized) but
inflammation– they can pass BBB --used for antibiotic effect
centrally
 Pgp transport system: ↓ the
concentration of some drugs in CNS
 Pump back to systemic circulation
Various approaches to promote crossing BBB:
• Use of Permeation enhancers such as
Dimethyl Sulfoxide.
• Osmotic disruption of the BBB by infusing
internal carotid artery with Mannitol.
• Use of Dihydropyridine Redox system as drug
carriers to the brain ( the lipid soluble
dihydropyridine is linked as a carrier to the
polar drug to form a prodrug that rapidly
crosses the BBB )
qPlacenta barrier
• Placenta is the membrane separating Fetal blood from
the Maternal blood.
• Highly polar and ionized drugs do not cross placenta
readily
• Drugs with high lipid solubility shouldn't be given to
pregnant mother
• E.g. TTC–accumulate in bone and teeth of neonate—
↓development of bone and teeth
• Drug cross PB and cause fetal abnormalities are called
teratogenic drug
IV. Tissue perfusion
• Different tissue have d/t rate and amount
of blood flow
• Highly perfused tissue:- heart, lung, brain,
liver, kidney
• Intermediate perfused tissue:- skeletal
muscle
• Poorly perfused tissue:- skin, bone, nail, fat
tissue
V. Physico-chemical properties of drugs

• Non polar drug diffuse trough membranes more easily

& distribute throughout the body. e.g. Thiopental
• Polar drug are less lipid soluble to diffuse into other
compartments & hence remain in plasma e.g Penicillins
• Pka determine degree of ionization.
• Molecular Size:
Small ions of size < 50 daltons enter the cell through Aq. filled
channels where as larger size ions are restricted unless a
specialized transport system exists for them.
 Miscellaneous Factors

• Diet: A Diet high in fats will increase the free fatty acid
levels in circulation thereby affecting binding of acidic
drugs such as NSAIDS to Albumin.
• Obesity: In Obese persons, high adipose tissue content
can take up a large fraction of lipophilic drugs.
• Pregnancy: During pregnancy the growth of the uterus,
placenta and fetus increases the volume available for
distribution of drugs.
• Disease States: Altered albumin or drug – binding
protein conc, Altered or Reduced perfusion to organs
/tissues, Altered Tissue pH
 Redistribution
ü Highly lipid soluble drugs when given by i.v. or by
inhalation initially get distributed to organs with high
blood flow, e.g. brain, heart, kidney etc.
ü Later, less vascular but more bulky tissues (muscles, fat)
take up the drug and plasma concentration falls and drug
is withdrawn from these sites.
ü If the site of action of the drug was in one of the highly
perfused organs, redistribution results in termination of
the drug action.
ü Greater the lipid solubility of the drug, faster is its
redistribution.
 Volume of distribution (Vd)
• Usually referred to as the apparent volume of distribution
• Defined as volume in which the total amount of drug in the
body would be required to be dissolved in order to reflect
the drug concentration attained in plasma.
• Vd is used to quantify the distribution of a drug between
plasma and the rest of the body after oral or parenteral
dosing.
• It has no direct physiological meaning; it is not a ‘real’
volume
 Vd = amount of drug in body
plasma concentration
Having high Vd –high distribution
Vd have inverse relationship with PPB
↑PPB ----- ↓VD
Vd indicate where the drug is
Drug having high PPB and/ or large
molecular weight----mainly found in plasma
( Vd in plasma)
Eg Warfarin, heparin
Low molecular weight & water soluble drug have
Vd at extracellular water (plasma + interstitial fluid)
 E.g. Gentamicin
Low molecular weight & hydrophobic drug—Vd is
in total body water
 E.g. ethanol, phenytoin
Highly lipophilic drug have Vd to adipose tissue
 Eg. thiopental
 Drug interaction during distribution

üWhen two or more drug present to the same

site , competition b/w them for interaction with
same binding site .
üIf one of the drug (A) is bound to such a site ,
then administration of the another drug (B)
having high affinity for same binding site result in
displacement of drugs (A) from its binding site .
This type of interaction is known as displacement
interaction .
üWhere drug (A) here is called as the displaced
drug and drug (B) as the displacer .
Eg. Phenylbutazone displace warferin
Competition b/w drug and normal body
constituent
• The free fatty acids are interact to with a number of drug
that bind primarily to HSA . When free fatty acid level is
increase in several condition – fasting , pathologic –
diabeties , myocardial infraction , alcohol abstinence – the
fatty acid which also bind to albumin influence binding of
several drug
↓binding – diazepam
• Acidic drug like – sod. Salicilate , sod . Benzoate ,
sulfonamide displace bilirubin from its albumin binding site
result in neonate it cross to BBB and precipitate toxicity
 METABOLISM

• Drug Metabolism evolved as a science Post WWII

• Williams R .T – Great Britain
• 1942, worked on the metabolism on TNT with regard to toxicity in
munitions workers
• Developed concept of Phase 1 & Phase 2 Reactions.
• Biotransformation involves metabolic oxygenation, reduction,
or hydrolysis; result in changes in biological activity
(increased or decreased)
• Second phase, conjugation, in almost all cases resulted in
detoxication.
 METABOLISM

•Physiological responses to foreign substances

depends on size
l. Large substances (proteins, viral particles,
bacteria…) evoke an immune response
2. Small substances can be converted into polar
molecules by nonspecific enzymes for excretion
ü First-pass metabolism: liver
METABOLISM

•Drug metabolism studies now

required for drug approval
ü metabolites must be identified
ü metabolites must be shown non-
toxic
 METABOLISM
•It is also called as biotransformation.
•Drug biotransformation is a process by which
drugs are chemically changed in the body as a
result of their interaction with cells or tissues.
•The purpose of biotransformation is to
facilitate excretion of drugs by rendering lipid
soluble drugs more polar (water soluble) or by
conjugating it with highly polar molecules.
 Consequence of BT:
Promotion of renal excretion
Inactivation or decreased activity of parent drug
(most drugs)
Conversion of inactive drug (prodrug) to more
active drug -eg. Levodopa
Prodrug
• Pharmacologically inactive
• Converted rapidly to active metabolite
(usually hydrolysis of ester or amide bond)
• Maximizes the amount of active species that
reaches site of action
Active metabolite/s from an active drug -
e.g. Codeine  morphine
Maintenance of activity – eg diazepam
Conversion of drug to its toxic metabolite
- eg. paracetamole
 Where Do Drug Biotransformation Occur?
Metabolism of drug occur in all body parts
 Lung, GIT, kidney, liver, lungs, blood….
But mainly take place in liver ; b/c it contain large
amount of metabolizing enzyme
• With respect to drug metabolizing reactions, two sub
cellular organelles are quantitatively the most
important: the endoplasmic reticulum and the
cytosol.
üThe phase I oxidative enzymes are almost
exclusively localized in the endoplasmic reticulum.
üPhase II enzymes are located predominantly in the
cytosol
 First-Pass Metabolism
•Following nonparenteral administration of a drug,
a significant portion of the dose may be
metabolically inactivated in either the intestinal
endothelium or the liver before it reaches the
systemic circulation
•Limits oral availability of highly metabolized drugs
 Enzymes responsible for metabolism of drugs

1. Microsomal enzymes. Present in the smooth

endoplasmic reticulum of the liver, kidney and GIT e.g.
• glucuronyl transferase,

• dehydrogenase , hydroxylase and

• cytochrome P450

• flavin-containing monooxygenases

103
 Enzymes….

2. Non-microsomal enzymes: Present in the

cytoplasm, mitochondria of different organs. e.g.

• GST (glutathione-S-transferases )

• SULT (sulfotransferases)

• esterases,

• amidase,

• Hydrolase

104
How BT?

Metabolism in liver involve two steps

Phase I
Phase II
•Generally,
Drug

Phase I
Less polar
metabolite Phase I

Phase II
More polar
metabolite

Excreted
•A great variety of drugs undergo sequential
biotransformation reactions
•In some instances the parent drug may already
possess a functional group that may form a
conjugate directly e.g. isoniazid
qPhase I reaction
§ It is functionalization or non synthetic reaction since it
includes addition or exposure of functional group (-OH,
-COOH, -SH, -O- or NH2 )
§ Introduce or expose a functional group on the parent
drug
§ P ro d u c e m o re re a c t i ve m eta b o l i te s a n d m o re
hydrophilic
§ Generally result in the loss of pharmacological
activity, although there are examples of
retention, enhancement or alteration of activity.
§ Prominent reactions in this category
include :-
§Oxidation:- barbiturates, acetaminophen,
benzodiazepines
§Reduction:- chloramphenicol, methadone
§Hydrolysis:- procaine, oxytocin
•Involve cytochrome P-450 enzyme; not
necessarily for all
Cytochrome P450
• The cytochrome P450 enzyme system is the major
in terms of catalytic versatility and the number of
d r u g s i t m e ta b o l i ze s t o i n a c t i v e o r a c t i v e
metabolites.

• CYP450 is found highly concentrated in liver

endoplasmic reticulum (microsomes).
• Endoplasmic reticulum consists of phospholipid bilayers
organized as tubes
• It has connections to the plasma membrane
• ER membrane localization is ideally suited for its
metabolic function: hydrophobic molecules enter the cell
and become embedded in the lipid bilayer where they
come into direct contact with the phase 1 enzymes.
Once subjected to oxidation, drugs can be conjugated in
the membrane by the UGTs
 Cytochrome P450
• Contain a molecule of heme that is noncovalently
bound to the polypeptide chain (O2)

• CYPs use O2, plus H+ derived from the NADPH, to carry

out the oxidation of substrates
• The reductase serves as the electron source for the
oxidative reaction cycle
Oxidative cycle of CYP

1.oxidized (Fe3+) P450 combines with a drug

substrate to form a binary complex

2. NADPH donates an electron to the flavoprotein

P450 reductase, which in turn reduces the oxidized
P450-drug complex
3. A second electron is introduced from NADPH via
the same P450 reductase, which serves to reduce
molecular oxygen and to form an "activated
oxygen"-P450-substrate complex

4.This complex in turn transfers activated oxygen to

the drug substrate to form the oxidized product

NADPH + H+ + O2 + Drug ® NADP+ + H2O + Oxidized Drug

Types of reactions performed by the Cytochrome P450
system
• Aromatic hydroxylation Phenobarbital, amphetamine
• Aliphatic hydroxylation Ibuprofen, cyclosponine
• Epoxidation Benzo [a] pyrene
• N-Dealkylation Diazepam
• O- Dealkylation Codeine
• S- Dealkylation 6-Methylthiopurine
• Oxidative Deamination Diazepam, amphetamine
• N-Oxidation Chlorpheniramine
• S-Oxidation Chlorpromazine, cimetidine
• Phosphothionate oxidation Parathion
• Dehalogenation Halothane
• Alcohol oxidation Ethanol
 Cytochrome P450

•Categorized into 17 families (CYPs)

• Sequences > 40% identical
• Identified by Arabic number, CYP1, CYP2
•Further into subfamilies
• sequences >55% identical
• identified by a letter, CYP1A, CYP2D
•May have different, individual isoforms
• Identified by another Arabic number, CYP2D6, CYP3A4
•In humans, 12 CYPs (CYP1A1, 1A2, 2A6,
1B1, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1,
3A4, and 3A5) are known to be
important for metabolism of
xenobiotics
•It is noteworthy that CYP3A4 alone is
responsible for the metabolism of over
50% of the clinically prescribed drugs
metabolized by the liver.
Participation of the CYP Enzymes in Metabolism of
Some Clinically Important Drugs
CYP Examples of substrates
Enzyme
1A1 Caffeine, Testosterone, Warfarin
1A2 Acetaminophen, Caffeine, Phenacetin, Warfarin
2A6 17-Estradiol, Testosterone
2B6 Cyclophosphamide, Erythromycin, Testosterone
2C-family Acetaminophen, Tolbutamide (2C9); Hexobarbital, S-
Warfarin (2C9,19); Phenytoin, Testosterone, R-
Warfarin, Zidovudine (2C8,9,19);
2E1 Acetaminophen, Caffeine, Chlorzoxazone, Halothane
2D6 Acetaminophen, Codeine, Debrisoquine
3A4 Acetaminophen, Caffeine, Carbamazepine, Codeine,
Cortisol, Erythromycin, Cyclophosphamide, S- and R-
Warfarin, Phenytoin, Testosterone, Halothane,
Zidovudine
 Flavin-containing monooxygenases (FMOS)

• Another superfamily of phase 1 enzymes involved in drug

metabolism
• Family of enzymes that catalyze oxygenation of nitrogen,
phosphorus, sulfur
• There are six families of FMOs
• FMOs are considered minor contributors to drug
metabolism.
• Require molecular oxygen, NADPH, flavin adenosine
dinucleotide (FAD)
• FMOs are heat labile and metal-free, unlike CYPs
• FMOs are not induced by any of the xenobiotic or easily
inhibited
Induction & inhibition of drug metabolism

toxicity
 Enzyme Induction

•Enzyme induction is the process by which

exposure to certain substrates (e.g., drugs,
environmental pollutants) results in accelerated
biotransformation
(some substance stimulates the synthesis of
the enzyme or reducing its rate of degradation
and the metabolic capacity is increased -drug
gets metabolized faster)
•Many currently used drugs are well known to
induce their own metabolism or the metabolism
of other drugs. Some examples are the
anticonvulsant medications phenobarbital and
carbamazepine, and even St. John’s Wort.
•Cigarette smoking can cause increased
elimination of theophylline and other compounds.
•Environmental pollutants are also
capable of inducing P450 enzymes.
•exposure to benzo[a]pyrene and other
polycyclic aromatic hydrocarbons induce
CYP1A enzymes
Consequences of Induction

•Increased rate of metabolism

•Decrease in drug plasma concentration
•Enhanced oral first pass metabolism
•Reduced bioavailability
•If metabolite is active or reactive, ↑ drug effects
or toxicity
Therapeutic Implications of Induction

• Most drugs can exhibit decreased efficacy due to

rapid metabolism
• but drugs with active metabolites can
display increased drug effect and/or
toxicity due to enzyme induction
• Dosing rates may need to be increased to maintain
effective plasma concentrations
Inhibition of Drug Metabolism

•Drug metabolism is an enzymatic process

can be subjected to inhibition.

•Drugs and other substances can inhibit the

metabolism of other drugs.
Some types of inhibition
• Competition between substrates for enzyme active site
- Concentration of substrates
- Affinity for binding site (drug with high affinity for an
enzyme will slow the metabolism of any low affinity
drug)
• Irreversible inactivation of enzyme
- Complex with heme iron of CYP450 (cimetidine,
ketoconazole)
- Destruction of heme group (secobarbital)
• Depletion of cofactors for phase II enzymes
 Consequences of Inhibition

•Increase in the plasma concentration of parent drug

•Reduction in metabolite concentration

•Exaggerated and prolonged pharmacological effects

•Increased liklihood of drug-induced toxicity

Therapeutic Implications of Inhibition

• Particularly effects drug prescribing for patients on

multidrug regimens
• Knowledge of the CYP450 metabolic pathway
provides basis for predicting and understanding
inhibition
Esp drug-drug interaction
CYP 3A4 affected drug inducer, inhibitor
Affected drug Inducer Inhibitor
Acetaminophen, alfentanil, amiodarone, Barbiturates, Azamulin,
astemizole, cisapride, cocaine, cortisol, carbamazepine, diltiazam,
cyclosporine, dapsone, diazepam, glucocorticoids, macrolide erythromycin,
dihydroergotamine, dihydropyridines, antibiotics, pioglitazone, fluconazole,
diltiazem, erythromycin, ethinyl estradiol, phenytoin, rifampin grapefruit juice
gestodene, indinavir, lidocaine, (furanocoumarin
lovastatin, macrolides, methadone, s), itraconazole,
miconazole, midazolam, mifepristone ketoconazole,
(RU 486), nifedipine, paclitaxel, ritonavir,
progesterone, quinidine, rapamycin, troleandomycin
ritonavir, saquinavir, spironolactone,
sulfamethoxazole, sufentanil, tacrolimus,
tamoxifen, terfenadine, testosterone,
tetrahydrocannabinol, triazolam,
troleandomycin, verapa
 Phase II reaction

• Also called as conjugation or synthetic reaction

• If not excreted rapidly, the products of phase I
biotransformation undergo phase II conjugation
reaction.
• Phase II reactions are usually the detoxification step.
• The catalytic rates of phase 2 reactions are
significantly faster than the rates of the phse I (CYPs).
Phase II reaction
§ The enzymes involved in phase II reactions are
tranferases. e.g. UDP glucoronide transferase,
c a t a l y s e s t h e c o n j u ga t i o n o f a d r u g w i t h
glucoronide.
§ Involves conjugation of more polar molecule to ↑
water solubility
§ Form highly polar conjugates which are generally
inactive and are rapidly excreted in the urine or
feces
§Leads to the formation of a covalent linkage
b et we e n a f u n c t i o n a l g ro u p o n t h e p a re nt
compound with endegenous substrates (glucuronic
acid, sulfate, amino acids, glutathione or acetate).
§Higher molecular weight conjugated metabolites
are mostly excreted in the bile
• Because the endogenous substrates originate in
the diet, nutrition plays a critical role in the
regulation of drug conjugations

• Phase II reactions require energy (ATP)

• Is a saturable process
• Phase II reactions is the depend on cofactors such as
UDP-glucuronic acid (UDP-GA) and 3’-
phosphoadenosine-5’-phosphosulfate (PAPS)

• All of the phase 2 reactions are carried out in the cytosol

(exception of glucuronidation, endoplasmic reticulum)
•Drug conjugations were believed to be terminal
inactivation "true detoxification" reactions.
•But, this concept must be modified
• Glucuronidation of NSAIDs may lead to the formation
of reactive species responsible for the toxicity of the
drugs.
• Sulfation is known to activate the orally active prodrug
minoxidil into a very efficacious vasodilator
 Types of Phase II reactions

Glucuronide conjugation
Is the most important of the phase 2 reactions in the
metabolism of drugs
• Using UDP- glucuronosyl transferase (UGTs) enzyme
• UGTs are expressed in a tissue-specific and often
inducible fashion in most human tissues, with the
highest concentration of enzymes found in the GI tract
and liver.
• Catalyze the transfer of glucuronic acid from the
cofactor UDP-glucuronic acid to a substrate to
form ß-D-glucopyranosiduronic acids
(glucuronides)

• Metabolites are sensitive to cleavage by ß-

glucuronidase
• The generation of glucuronides can be formed through
alcoholic & phenolic hydroxyl groups, carboxyl, sulfuryl,
and carbonyl moieties, as well as through primary,
secondary, and tertiary amine linkages.
• Two family UGT1 & UGT2
• Both families involved in the metabolism of drugs and
xenobiotics
• UGT2 family have greater specificity for endogenous
substances (steroids)
•From a clinical perspective, the expression of
UGT1A1 assumes an important role in drug
metabolism
•Bilirubin is the breakdown product of heme
• Bilirubin is hydrophobic must be metabolized further by
glucuronidation to assure its elimination
• Glucuronidation of bilirubin by UGT1A1 is the rate-limiting
step in assuring efficient bilirubin clearance, and this rate
can be affected by both genetic variation and competing
substrates (drugs)
•Based upon their physicochemical properties,
glucuronides are excreted
• By the kidneys into the urine
• By active transport processes through the apical surface
of the liver hepatocytes bile ducts
duodenum for excretion with components of the bile
• Enterohepatic recirculation
Drug examples: Chloramphenicol (CAF),
morphine , Aminosalicylic acid (ASA),
diazepam, sulfathiazole, meprobamate,
digitoxin, digoxin
Acetylation reaction
Use cytosolic N-acetyltransferases (NATs)
Metabolism of drugs and environmental agents that
contain an aromatic amine or hydrazine group
NATs are among the most polymorphic of all the human
xenobiotic drug-metabolizing enzymes
There are two functional NAT genes in humans, NAT1
and NAT2
 Mutations have been identified in the NAT1 gene as the
NAT2 gene
• Slow acetylation patterns are attributed mostly to
polymorphism in the NAT2 gene
• Drug metabolism through acetylation, confirming an
individual's phenotype can be important.
• The adverse drug response in a slow acetylator resembles
a drug overdose
• Reducing the dose
• ↑ dosing interval is recommended
• E.g hydralazine (vasodilator) drug, is metabolized by
NAT2. The administration of therapeutic doses of
hydralazine to a slow acetylator can result in extreme
hypotension and tachycardia
• Tissue-specific expression patterns of NAT1 and NAT2 have
a significant impact on the fate of drug metabolism and
the potential for eliciting a toxic episode.
• NAT1 seems to be ubiquitously expressed among most
human tissues, whereas NAT2 is found in liver and the GI
tract.
• NAT2 fast acetylators are able to efficiently metabolize and
detoxify bicyclic aromatic amine through liver-dependent
acetylation.
•Slow acetylators (NAT2 deficient) accumulate
bicyclic aromatic amines,
• Substrates for CYP-dependent N-oxidation. These N-OH
metabolites are eliminated in the urine.
• In tissues such as bladder epithelium, NAT1 is highly
expressed and can efficiently catalyze the N-hydroxy
acetylation of bicyclic aromatic amines, leads to de-
acetylation and the formation of the mutagenic
nitrenium ion
• Drug examples: isoniazid (INH), hydralazine, sulfonamides
Sulphate conjugation
Use sulfotransferase (SULTs) enzyme
Conjugate sulfate derived from PAPS to the hydroxyl
groups of aromatic and aliphatic compounds
SULT1, SULT2 and SULT4 families
SULTs play an important role in normal human
homeostasis
SULT1 family isoforms are considered to be the major
forms involved in drug metabolism
 SULT1A1 being the most important and displaying extensive diversity in its
capacity.
• SULT1 family have been recognized as phenol SULTs
(phenolic molecules such as acetaminophen, minoxidil,
and 17- ethinyl estradiol)
• Both SULT1C2 and SULT1C4 are expressed abundantly
in fetal tissues and decline in abundance in adults
(little is known about their substrate specificities)
• Drug metabolism through sulfation may generate of
chemically reactive metabolites
Methyl conjugation
Use methyl transferase
Drugs and xenobiotics can undergo O-, N-, and S-
methylation
Humans express three N-methyltransferases, one
catechol-O-methyltransferase (COMT) a phenol-O-
methyltransferase (POMT), a thiopurine S-
methyltransferase (TPMT), and a thiol
methyltransferase (TMT).
Use S-adenosyl-methionine (SAM; AdoMet) as the
methyl donor
Eg:- catecholamine, histamine
• From a clinical perspective, the most important MT may
be TPMT, which catalyzes the S-methylation of aromatic
and heterocyclic sulfhydryl compounds, including the
thiopurine drugs azathioprine (AZA), 6-mercaptopurine
(6-MP), and thioguanine
Glutathione conjugation
Use glutathione transferase
Glutathione protect cells from reactive compounds
Glutathione exists in the cell as oxidized (GSSG) or
reduced (GSH), and the ratio of GSH:GSSG is critical in
maintaining a cellular environment
•Two forms GST - cytosolic and the microsomal
forms.
• Cytosolic forms have more importance in the
metabolism of drugs and xenobiotics
• Microsomal GSTs are important in the endogenous
metabolism of leukotrienes and prostaglandins
•GST activities in cancerous tissues have been linked
to the development of drug resistance toward
chemotherapeutic agents
 Metabolism of drugs to toxic products

•Metabolism is not always safe process

•Toxic reactions may not be apparent at low
levels of exposure to parent compounds
•At higher dose toxic pathway may prevail,
resulting in overt organ toxicity or carcinogenesis
 Metabolism of drugs to toxic products
Paracetamole
• Glucuronidation and sulfation (95% of the total excreted
metabolites)
The alternative P450-dependent GSH conjugation pathway
accounts for the remaining 5%
Paracetamole Phase I NAPQI( highly reactive) Phase II
detoxification
• But at high concentration of paracetamole, since
glutathione are limited more NAPQI (N-acetyl-p-
benzoquinone imine)------cause hepatotoxicity
METABOLISM OF DRUGS TO TOXIC PRODUCTS
 Clinical relevance of drug
metabolism
• Dose and frequency of administration required to achieve
effective therapeutic blood and tissue levels vary in
different patients
• Individual differences in drug distribution and rates of
drug metabolism and elimination
•Drug metabolism affected by:-
• Genetic factors and nongenetic variables such as age,
sex, liver function, body temperature, nutritional and
environmental factors such as concomitant exposure to
inducers or inhibitors of drug metabolism.
Genetic Factors
• Genetic Polymorphism = demonstrably different forms
or levels of enzyme(s) in distinct population
• Defined by >1% incidence in population.
e.g. lower levels or non-functional P450’s
- “poor metabolizers” toxicity.
higher P450 levels.
- “fast metabolizers” therapeutic failure.
• Inter-individual or interracial differences.
•Clear Example: CYP2D6!
• CYP2D6 is extensively studied, the gene for CYP2D6 is
highly polymorphic
• It’s expression leads to 4 phenotypes (phenotype is
the expression of genetic make-up)
• Poor metabolizers (PM)- Poorly active or inactive enzyme
• Intermediate metabolizers (IM)- Normal enzyme in
diminished amounts
• Extensive metabolizers (EM)- Normal enzyme (fully
functional), normal amts.
• Ultrarapid metabolizers (UM)- Massive amounts of enzyme.
•Inter-racial Differences
• 5-10% Caucasians (European) => PM’s
• 1-2% SE-Asian (descent) => PM’s
• 1/3 of individual in Ethiopians & Saudi
Arabians => UM’s
=> Potential consequences?
- PM’s toxicity
- UM’s failure
- => Codeine is metabolized much faster to morphine,
often resulting in undesirable adverse effects of
morphine, such as abdominal pain = UM’S.
- Therapeutic failure = PM’S
Diet & Environmental Factors
• Diet and environmental factors contribute to individual
variations in drug metabolism
• Charcoal-broiled foods & cruciferous vegetables are known
to induce CYP1A enzymes,
• Grapefruit juice is known to inhibit the CYP3A
• Cigarette smokers
Age & Sex
• Very Young
• Not fully ‘metabolically competent.’
– Chloramphenicol toxicity in newborns (Gray Baby
Syndrome) due to poor glucuronidation (virtually no
Phase-2 enzymes).
• Fetus: CYP3A Sub-family only (poor metabolism
overall).
• Elderly
• Diminished metabolism and excretion.
• Diminished enzyme induction.
•Sex
• Differences probably hormonally based
• N-Demethylation of erythromycin F>M.
• Propranolol oxidation M>F.
• Pregnancy – induction of certain drug
metabolizing enzymes occurs in second and third
trimester
Diseases Affecting Drug Metabolism
• Liver Disease – Cirrhosis, Alcoholic liver disease,
jaundice, carcinoma
• Major location of drug metabolizing enzymes
• Dysfunction can lead to impaired drug metabolism-decreased
enzyme activity
• First pass metabolism effected – may inc 2-4 x bioavailiability
• Results in exaggerated pharmacological responses and
adverse effects
• Cardiac failure causes decreased blood flow to the liver
 Drug interaction during metabolism

• Enzyme induction (rifampin - ↑ metabolism of cyclosporine)

• Enzyme inhibition (cimetidine - ↓ metabolism of warfarine)
Interactions between Drugs & Endogenous Compounds
• Drugs may compete for the same endogenous substrates,
and the faster-reacting drug may effectively deplete
endogenous substrate levels and impair the metabolism of
the slower-reacting drug.
• Drug excretion is the elimination (passage out) of a
systemically absorbed drug from the body in the
form of metabolites or unchanged drug.
• It is a process of drug transfer from the
internal to the external environment
FThe kidneys are the main organ of excretion of
drugs and their metabolites.
FOther routes of drug elimination:
Ø Lungs (Exhaled air): for volatile substances
volatile anesthetics, alcohol
ØSweat: for volatile oils, rifampin
ØBile and colon (for conjugated large molecular
weight drug or metabolite)
ØSaliva
ØTears
ØMilk – Metronidazole, Phenytoin
ØFeces: mefloquine, purgatives – liquid paraffin
Renal excretion
• Principal organ for most drug removal especially
for water soluble (responsible for excreting water
soluble substances) and non volatile drug
• The amount of drug or its metabolites ultimately
present in urine is the cumulative effect of:
• Glomerular filtration
• Tubular secretion
• Tubular reabsorption
Glomerular filtration
FDepends on:
FMolecular size, shape, protein binding rate of
blood flow, and influence glomerular filtration
FExtent of filtration depend on glomerular
filtration rate and fraction of unbound drug (Fu)
ØPlasma protein binding: for a drug to be filtered
through the glomerulus, it should not bind to plasma
proteins.
 Passive tubular reabsorption
• The reabsorption of water result increased concentration of
drug in luminal fluid. So the concentration gradient thus
facilitate movement of drug out of tubular lumen
• Drugs should be in their non-ionized form to undergo passive
reabsorption.
 However reabsorption of drug affected by:
Lipid solubility
Ionization of drug
 So the rate /amount of passive diffusion depend on
PH of urine ( since drug are weak base/acid)
• Changes in urinary pH affects the excretion of
drugs:
ØAcidic drugs are excreted in alkaline urine
ØBasic drugs are excreted in acidic urine
 Effect of PH on urinary drug elimination have
important medical application
Toxicity management by facilitating excretion
For weak acid drug toxication—alkalinizing the
urine ---bicarbonate administration
For weak base drug toxication---acidification
the urine ----ammonium administration
 Generally reabsorption of drug mainly take place
by passive diffusion, however there is active
reabsorption also.
Active secretion
 Active secretion need energy and carrier
Important in drug excretion b/c charged and
cations are often strongly bound to plasma
protein and therefore are not readily available
for excretion by filtration. However since protein
binding is reversible ,they are excreted by active
secretory system.
Active secretion
Since it use carrier it is saturable and
competitive (inhibited by drugs which use
the same transport mechanism).
Have clinical importance
Prolonging duration of action---by ↓tubular
secretion
Eg ; penicillin ----main mechanism of excretion is
ATS-----have short duration of action----to prolong
its action----coadministration of Probencid----
compete for same carrier
 Generally the rate of urinary drug excretion
will depend on:
Drug volume of distribution
Degree of protein binding
Glomerular filtration rate
Tubular fluid PH
Extent of back-diffusion of unionized form
Extent of active tubular secretion of
compound
P o s s i b l y, e x t e n t o f a c t i v e t u b u l a r
reabsorption
Biliary excretion
Mainly for conjugated drugs
Enterohepatic recirculation is common
Highly conjugated drug excreted in the bile ----then to
GIT---GI flora and enzyme (such as -glucuronidase)
hydrolyze-----reabsorbed
Pulmonary excretion
Mainly for drugs that are volatile and gas
ØAny volatile material, irrespective of its route of
administration, has the potential for pulmonary
excretion
ØThe rate of loss of gases depends on the rate of
respiration and pulmonary blood flow, degree of
solubility(blood) of the gas in blood
 Eg; ethanol and NO
Drug interaction during excretion

•Excretion
• Probencid - ↓ secretion of penicillin
•

• Is also known as saturable, dose- or concentration-dependent,

nonlinear, and Michaelis-Menten elimination.
• For drugs that exhibit capacity-limited elimination (eg,
phenytoin, ethanol), clearance will vary depending on the
concentration of drug that is achieved
• Most drug elimination pathways will become saturated if the
dose is high enough.
ü Flow-dependent elimination
• In contrast to capacity-limited drug elimination, some
drugs are cleared very readily by the organ of elimination,
so that at any clinically realistic concentration of the drug,
most of the drug in the blood perfusing the organ is
eliminated on the first pass of the drug through it.
• The elimination of these drugs will thus depend primarily
on the rate of drug delivery to the organ of elimination.
• Such drugs can be called "high-extraction" drugs since
they are almost completely extracted from the blood by
the organ
Dosage forms of drugs
• A dosage form of a drug is the form of preparation
designed for administration to the body for the
purpose of diagnosis, prophylaxis and treatment.
• After development of a specific chemical entity for
its pharmacological effects, it is formulated in a form
that is suitable for administration and even efficacy
and for the stability of the drug itself.
• There are different dosage form designs intended for
the various routes of administration.
Solid dosage forms
FTablets:
Øtablets are solid dosage forms containing the active
ingredient with suitable diluents
ØThey may be coated or uncoated.
ØCoating is intended to mask the contents of the tablet
§ Enteric coated: intended for intestinal medications without
getting disintegrated in the stomach.

§ Non-enteric coated: intended to mask the unpleasant odour

and taste of a drug.
FCapsules
ØAre solid dosage forms which the solid or liquid drug is
enclosed in a hard or soft soluble gelatin shell to mask its
bad taste and odor. They are intended for internal use.

FSuppositories
ØAre solid dosage forms with various sizes and shape for
administration into body cavities (rectum, vagina, and
urethra)
Semi-solid dosage forms
FSyrups
ØSyrups are semi-solid, viscous, sticky preparations
containing medicinal substance dissolved in a concentrated
sugar solution.
FOintments
ØAre semi-solid preparations containing the medicinal agent
intended for use for application on skin or mucous
membranes
FCreams
ØCreams are emulsions for external use as protective or
emollients to soften and sooth.
FPastes
ØAre semi-solid dosage forms of heavy consistency.
Liquid dosage forms
FSolutions

ØAre liquid preparations prepared by dissolving

active medicinal substance in a solvent. It can be
for internal or external use.

ØFor internal use solutions

§ Injectables, Tinctures, Elixirs,
ØInjectables are sterile preparations for parenteral
route. They may be labeled as
§ “for injection”: a sterile powder prepacked in a vial which
on the addition of a suitable vehicle forms a clear solution.
§ “injection”: a ready made sterile liquid preparation in an
ampoule or vial.
§ “sterile suspension”: a ready made suspension for
parenteral uses, but not for intravenous or intrathecal
injection.
§ “sterile for suspension”: a sterile powder prepacked in a
vial which on addition of a sterile vehicle is made into a
suspension for parenteral uses, but not for intravenous or
intrathecal injection.
ØFor external use solutions
§ Drops: are aqueous preparations intended for topical
administration to the nose, throat, eye or ear.

§ Gargles: are aqueous solution used to treat disease of the

pharynx or nasopharynx

§ Enemas: are aqueous solutions to be placed in the rectum

to evacuate the bowel or to bring about local or systemic
therapeutic action.
FSuspensions
ØSuspensions are preparations containing drugs,
uniformly dispersed with the help of a dispersing
agent. Every suspension should have a label “shake
well before use”
ØSuspensions include
§ Mixtures: preparation of any solid material suspended in a
liquid, and intended for internal use.
§ Lotion: an aqueous suspension to be applied without friction,
for soothing, cleansing or antiseptic action on the skin
Time course of drug action
Plasma Drug Levels
ü Clinical significance of plasma drug levels—there is usually
direct correlation between therapeutic and toxic responses and
plasma drug levels.
üTwo plasma drug levels defined
a. Minimum effective concentration (MEC) – is defined
as the plasma drug level below which therapeutic effect
will not occur.
b. Toxic concentration – the plasma drug level at which
toxic effects begin is termed as toxic concentration.
üDrug Half-Life – is also called elimination half-life.
üTime required for amount of drug in the body to decrease
by 50 %.
Therapeutic range—Objective of drug
dosing(between MEC and toxic levels).
• Single-Dose Time Course
 Repeated administration
• Steady State
• steady-state concentration eventually will be achieved when a
drug is administered at a constant rate.
• At this point, drug elimination will equal the rate of drug
availability.
• This concept also extends to regular intermittent dosage
• During each interdose interval, the concentration of drug rises
with absorption and falls by elimination.
• At steady state, the entire cycle is repeated identically in each
interval.
Dosage regimen
FD o s a ge re g i m e n i s a syste m at i c way o f d r u g
administration. There are two types: constant and
variant dosing

FVariant dosing includes

ØA loading dose in one or a series of doses that may be given
at the onset of therapy with the aim of achieving the target
concentration rapidly.

Ø It is desirable if the time required to attain steady state by

the administration of drug at a constant rate (four elimination
half lives) is long relative to the temporal demands of the
condition being treated.
§Use of loading dose has significant disadvantages
I. Sensitive individuals may be exposed abruptly to a toxic
concentration of a drug.

II. If the drug has long half-life. It takes long time for the
concentration to fall if the level achieved was excessive

III. Loading doses tend to be large, and they are often

given parenterally and rapidly; this can be particularly
dangerous if toxic effects occur as a result of action of
the drug at sites that are in rapid equilibrium with
plasma.
§Maintenance dose: is a dose administered to maintain
the target concentration of a drug. The amount is
equivalent to daily excreted dose.
Pharmacodynamics
 Pharmacodynamics studies the physiological and
biochemical effects of drugs and their mechanism of
action
Study of action of drugs to the body: mechanism
of action of the drug
 Mainly concerns on the interaction of the drug
with receptors
 Drugs interact with receptors to produce their
characteristic effects.
 Drugs potentially are capable of altering both the
extent and rate at which any bodily function proceeds
 Drugs do not create effects but instead modulate
intrinsic physiological functions.
 What are receptors?
Receptors are functional macromolecular
components of the organism
Receptors are the macromolecular component
of the cell to which a drug bind to produce its
effect.
Are mainly protein molecule whose function is
to recognize and respond to endogenous
chemicals and xenobiotics
Functions of the receptors :
• Propagation of signal from outside to inside the cell.
• Amplify the signal.
• Adapt to short and long term changes.

NB: There are drugs which don’t need receptors to

produce an action, eg Mg(OH)2 antacid
RECEPTOR FAMILIES
CHANNEL LINKED (IONOTROPIC) : The cell
surface has a selective ion channel like Na, K ,
Ca , or Cl .

•O n s e t o f a c t i o n t h ro u g h t h e s e t y p e s o f
receptors is fastest – milliseconds.

•Nicotinic cholinergic receptors, GABA-A and

NMDA receptors.
G PROTEIN LINKED (METABOTROPIC) : These
are cell membrane receptors which are linked to
effector mechanisms through G-proteins.
•Effector mechanisms includes adenylyl cyclase,
phospholipase C, channel regulation
•Onset of response in seconds.
•Eg : adrenergic receptors, histamine receptors
E N Z Y M E L I N K E D : T h e s e c e l l m e m b ra n e
receptors are enzymatic in nature
•Insulin, atrial natriuretic peptide (ANP) acts
through this receptors.
•Onset of response in minutes.
INTRACELLULAR RECEPTOR : These includes
•Steroids, Thyroxine and Vit–D
•It takes days to produce its actions
• Mechanism of intracellular receptors (e.g. nuclear receptors).
 Effectors

•Def: molecules that translate the drug receptor

interaction into a change in cellular activity.
•Ex: adenylyl cyclase.
•Some receptors are also effectors in that a single
molecule may incorporate both the drug binding
site and the effector mechanism, e.g., the
tyrosine kinase effector of the insulin receptor.
 Signaling Mechanisms

• Five major types of transmembrane sig­naling

mechanisms for receptor-effector systems have been
defined
Known transmembrane signaling mechanisms
Signaling Mechanisms
Receptors that are intracellular

• Some drugs, especially more lipid-soluble or

diffusible agents (eg, steroid hormones, nitric oxide)
may cross the membrane and combine with an
intracellular receptor that affects an intracellular
effector molecule.

• No specialized trans­membrane signaling device is

required.
Glucocorticoid MOA
Signaling Mechanisms
Receptors located on membrane-spanning enzymes:

• Drugs combine with a receptor on the extracellular

portion of enzymes and modify their intracellular
activity.

• For example, insulin acts on a tyrosine kinase that is

located in the membrane.
Mechanism of activation of the epidermal growth factor (EGF)
receptor, a representative receptor tyrosine kinase.
Signaling Mechanisms
Receptors located on membrane-spanning molecules that
bind separate intracellular tyrosine kinase molecules
• These receptors have extracellular and intracellular domains and
form dimers.

• After receptor activation by an appropriate drug, the tyrosine

kinase molecules (Janus kinases; JAKs) are activated, resulting in
phosphorylation of "STAT" molecules (signal transducers and
activators of tran­scription).

• STAT dimers then travel to the nucleus, where they regulate

transcription.
Cytokine receptors
Signaling Mechanisms
Receptors located on membrane ion channels

• Receptors that regulate membrane ion channels may

directly cause the opening of an ion channel
Ex: acetylcholine at the nicotinic receptor

• Or, modify the ion channel's response to other agents

Ex: benzodiazepines at the GABA channel.
The nicotinic acetylcholine receptor
Signaling Mechanisms
Receptors linked to effectors via G proteins

• A very large number of drugs bind to receptors that

are linked by coupling proteins to intracellular or
membrane effectors.
• Example: the sympathomimetic drugs, which
activate or inhibit adenylyl cyclase by a multistep
process: activation of the receptor by the drug
results in activation of G proteins that either
stimulate or inhibit the cyclase.
• G-protein coupled receptors triggers an increase (or, less often,
a decrease) in the activity of adenylyl cyclase.
 Table 2-1. G proteins and their receptors and effectors
G Protein Receptors for: Effector/Signaling Pathway
β-Adrenergic amines, glucagon,
Gs histamine, serotonin, and many ↑ Adenylyl cyclase , ↑ cAMP
other hormones
α2-Adrenergic amines,
Several, including:
acetylcholine (muscarinic),
Gil, Gi2, Gi3 ↓ Adenylyl cyclase , ↓ cAMP
opioids, serotonin, and many
Open cardiac K+ channels , ↓ heart rate
others
Odorants (olfactory
Golf ↑ Adenylyl cyclase , ↑ cAMP
epithelium)
Neurotransmitters in brain (not
Go Not yet clear
yet specifically identified)

Acetylcholine (eg, muscarinic),

↑ Phospholipase C, ↑ IP3,
Gq bombesin, serotonin (5-HT1C),
↑ diacylglycerol, cytoplasmic Ca2+
and many others

Photons (rhodopsin and color

↑ cGMP phosphodiesterase
Gt1, Gt2 opsins in retinal rod and cone
(phototransduction)
cells)
 Some Characteristics of Receptors
A. Receptor Regulation
• Sensitization or Up-regulation
1. Prolonged/continuous use of receptor blocker
2. Inhibition of synthesis or release of
hormone/neurotransmitter - Denervation
• Desensitization or Down-regulation
1. Prolonged/continuous use of agonist
2. Inhibition of degradation or uptake of agonist
B. Spare receptors
l More receptors available than
needed to elicit maximum
response
Øallow maximal response
without total receptor
occupancy – increase
sensitivity of the system
ØAgonist has to bind only a
portion of receptors for full
effect
Spare Receptors

• Mechanisms of spare receptor:

1) The effect of the drug­ receptor interaction may
persist for a much longer time than the interaction itself.
2) The actual number of receptors may exceed the
number of effector molecules available.
• The presence of spare receptors increases sensitivity to
the agonist.
Drug action in relation to the level of biological
organization

•Levels of drug action

- Biological molecules Subcellular
structures Cells Organized cells
intact organism
• Biological molecules
- Receptors, enzymes, transport systems, molecular
components of the genetic apparatus, acceptor sites
Drug action at subcellular structures
• Mitochondria (closantel)
• Microtubules (Vinca alkaloids)
• Lysosomes (Chloroquine, cortisone, indomethacin)
• Vesicles (reserpine, amphetamine)
• Cell membrane (drugs can act on receptors, transporters,
or affect membrane permeability)
Drug action on cells, tissue, and intact organism
• Cells:
- Fundamental units of biological organization
- Understanding effects of drug is an essential part of the full
characterization of the pharmacological activity
- Concept of receptor deduced from such action on nerve cells,
effector cells of muscular or secretory tissues
• Tissue/organs: techniques of investigation are limited or
action may be on many cells than on a particular cell
• Intact organism: action on homeostatic mechanisms
 How drug work

•Most drug by interacting with endogenous protiens

Ø Some antagonize, block or inhibit endogenous
proteins
Ø Some activate endogenous proteins
Ø A few have unconventional mechanisms of action
 HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT
ENDOGENOUS PROTEINS?

• Antagonists of Cell Surface Receptors

• Antagonists of Nuclear Receptors
• Enzyme Inhibitors
• Ion Channel Blockers
• Transport Inhibitors
• Inhibitors of Signal Transduction Proteins
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

•
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

Extracellular Unbound Endogenous Activator (Agonist) of Receptor

Compartment

Cell Membrane
Inactive Cell Surface Receptor

Intracellular
Compartment
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

Extracellular Bound Endogenous Activator (Agonist) of Receptor

Compartment

Cell Membrane
Active Cell Surface Receptor

Intracellular
Compartment

Cellular Response
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

Displaced Endogenous Activator (Agonist) of Receptor

Extracellular
Compartment Bound Antagonist of Receptor (Drug)

Cell Membrane

Inactive Cell Surface Receptor Upon being Bound

Intracellular
Compartment
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

• Most antagonists attach to binding site on receptor for

endogenous agonist and sterically prevent endogenous
agonist from binding.
üIf binding is reversible - Competitive antagonists
üIf binding is irreversible - Noncompetitive antagonists
• However, antagonists may bind to remote site on
receptor and cause allosteric effects that displace
endogenous agonist or prevent endogenous agonist
from activating receptor. (Noncompetitiveantagonists)
HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS?

Displaced Endogenous Activator (Agonist) of Receptor

Extracellular Bound Antagonist of Receptor

Compartment

Cell Membrane

Active Receptor Inactive Receptor

Intracellular
Compartment

Allosteric Inhibitor
ARE DRUGS THAT ANTAGONIZE CELL SURFACE
RECEPTORS CLINICALLY USEFUL?

Some important examples:

Angiotensin Receptor Blockers (ARBs) for high blood
pressure, heart failure, chronic renal insufficiency
(losartan [Cozaar®]; valsartan [Diovan®])

Beta-Adrenoceptor Blockers for angina, myocardial

infarction, heart failure, high blood pressure,
performance anxiety (propranolol [Inderal®]; atenolol
[Tenormin®])
HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?

Unbound Endogenous Activator

(Agonist) of Nuclear Receptor

Inactive Nuclear Receptor

in cytosolic compartment

DNA

Nucleus
Intracellular
Compartment

Inactive Nuclear Receptor

in nuclear compartment
HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?

Active Nuclear Receptor

Bound Endogenous Activator
(Agonist) of Nuclear Receptor
DNA

Modulation of Nucleus
Transcription

Intracellular
Compartment
HOW DO DRUGS WORK BY ANTAGONIZING
NUCLEAR RECEPTORS?

Displaced Endogenous Activator

(Agonist) of Nuclear Receptor
Bound Antagonist
of Receptor (Drug)

Inactive Nuclear Receptor

In Cytosolic Compartment
DNA

Nucleus

Intracellular
Inactive Nuclear Receptor
Compartment In Nuclear Compartment
ARE DRUGS THAT ANTAGONIZE NUCLEAR
RECEPTORS CLINICALLY USEFUL?

Some important examples:

• Mineralocorticoid Receptor Antagonists for edema

due to liver cirrhosis and for heart failure
(spironolactone [Aldactone®])

• Estrogen Receptor Antagonists for the prevention

and treatment of breast cancer
(tamoxifen[Nolvadex®])
HOW DO DRUGS WORK BY INHIBITING
ENZYMES?

• Enzymes catalyze the biosynthesis of products

from substrates.

• Some drugs bind to enzymes and inhibit

enzymatic activity.

• Loss of product due to enzyme inhibition

mediates the effects of enzyme inhibitors.
 ARE DRUGS THAT INHIBIT ENZYMES
CLINICALLY USEFUL?

Some important examples:

• Cyclooxygenase Inhibitors for pain relief,

particularly due to arthritis (aspirin; ibuprofen
[Motrin®])
•• HMG-CoA Reductase Inhibitors for
hypercholesterolemia (atorvastatin [Lipitor®];
pravastatin [Pravachol®])
•• Angiotensin Converting Enzyme (ACE) Inhibitors
for high blood pressure, heart failure, and chronic
renal insufficiency (captopril [Capoten®]; ramipril
[Altace®])
ARE DRUGS THAT BLOCK ION CHANNELS
CLINICALLY USEFUL?

Some important examples:

• Calcium Channel Blockers (CCBs) for angina and

high blood pressure (amlodipine [Norvasc®];
diltiazem [Cardizem®])

• Sodium Channel Blockers to suppress cardiac

arrhythmias (lidocaine [Xylocaine®]; amiodarone
[Cordarone®])
ARE DRUGS THAT INHIBIT TRANSPORTERS
CLINICALLY USEFUL?

Some important examples:

• Selective Serotonin Reuptake Inhibitors (SSRIs) for

the treatment of depression (fluoxetine [Prozac®];
fluvoxamine [Luvox®])

• Inhibitors of Na-2Cl-K Symporter (Loop Diuretics)

in renal epithelial cells to increase urine and
sodium output for the treatment of edema
(furosemide [Lasix®]; bumetanide [Bumex®])
ARE DRUGS THAT INHIBIT SIGNAL
TRANSDUCTION PROTEINS CLINICALLY
USEFUL?
Some important examples:
•
• Type 5 Phosphodiesterase Inhibitors for erectile
dysfunction (sildenafil [Viagra®])
• Tyrosine Kinase Inhibitors for chronic myelocytic
leukemia (imatinib [Gleevec®])
• This is a major focus of drug development
HOW DO CHEMICALS WORK BY ACTIVATING CELL
SURFACE RECEPTORS?

• Cell surface receptors exist to transmit chemical

signals from the outside to the inside of the cell.

• Some chemicals bind to cell surface receptors and

trigger a response.

• Chemicals in this group are called receptor agonists.

• Some agonists are actually the endogenous chemical

signal, whereas other agonists mimic endogenous
chemical signals.
HOW DO DRUGS WORK BY ACTIVATING
ENDOGENOUS PROTEINS?

• Agonists of Cell Surface Receptors

(e.g. alpha-agonists, morphine agonists)

• Agonists of Nuclear Receptors

(e.g. HRT for menopause, steroids for inflammation)

• Enzyme Activators
(e.g. nitroglycerine (guanylyl cyclase), pralidoxime)

• Ion Channel Openers

(e.g. minoxidil (K) and alprazolam (Cl))
HOW DO CHEMICALS WORK BY UNCONVENTIONAL
MECHANISMS OF ACTION?

• Disrupting of Structural Proteins

e.g. vinca alkaloids for cancer, colchicine for gout

• Covalently Linking to Macromolecules

e.g. cyclophosphamide for cancer

• Reacting Chemically with Small Molecules

e.g. antacids for increased acidity

• Binding Free Molecules or Atoms

e.g. drugs for heavy metal poisoning
HOW DO DRUGS WORK BY UNCONVENTIONAL
MECHANISMS OF ACTION (Continued)?

• Being Nutrients
e.g. vitamins, minerals

• Exerting Actions Due to Physical Properties

e.g. mannitol (osmotic diuretic), laxatives

• Working Via an Antisense Action

e.g. fomivirsen for CMV retininitis in AIDS

• Being Antigens
e.g. vaccines

• Having Unknown Mechanisms of Action

e.g. general anesthetics
DRUG-RECEPTOR INTERACTIONS

•Most drug-receptor interaction

Ø Revisable
Ø Weak chemical bonds
•Irrevesible drug-receptor intraction
Ø Not common
Ø Strong chemical bond (covalent)
Ø Usually undesirable
Ø E.g asprin
Relation between drug concentration and
response
• Response increase as dose increase
• Response increment diminish as dose increase &
reached at point no further increase in response
Relationship between ligand concentration and
occupancy
• Assumptions of the law of mass action
- All receptors are equally accessible to ligand
- No partial binding occurs; receptors are either free of
ligand or bound with ligand
- Ligand is not altered by binding
- Binding is reversible
Drug(Ligand)  Receptor interaction
• Ligand + Receptor ligand-receptor response
complex
k1
• Ligand + Receptor ligand-receptor
k2
• At equilibrium
[ligand].[receptor].k1 [ligand.receptor].k2
• Rearrange the equation to define the equilibrium dissociation
constant kD
[ligand].[receptor] = k2 = KD
[ligand. Receptor] k1
• If RT = total # of receptors, then
RT = [R] + [DR]
• Replace [R] by (RT-[DR]) and rearrange:

=
=

• DR =drug bound to receptor

• RT = maximum binding of receptor
• C = drug concentration
• Dose response data are often presented as a plot of the
drug effect (ordinate) against the logarithm of the dose or
concentration (abscissa)
• This mathematical maneuver transform hyperbolic curve
into sigmoid curve.
• KD= represents the concentration of free drug at which
half-maximal binding is observed & characterizes the
receptor’s affinity for binding
Overlapping a log concentration-occupancy curve on a log
concentration-response curve reveals three scenarios:

FIdentical occupancy and response curves

FK D = EC 50 meaning half maximal response at half
maximal occupancy
FMaximum response at full occupancy only
FMaximum response attained at sub-maximal occupancy
FKD > EC50
FThis occurs because the transducer mechanism is very effective
at converting drug-response interaction in to response.
FScenario 3
Dose-Response Relationships
FIs the relationship between intensity of drug effect and drug
dosage (drug level)
FHas two components
ØDose-plasma concentration relationship
ØPlasma concentration-response relationship

FQuantification of drug level at the site of action is difficult

and hence either the dose administered or its plasma
concentration are considered during quantification.
Graded Dose-Response Relationships
• Grade response
• Dose administered to single subject
• The relationship between dose and response is a
continuous one
• Used to characterization of the action of drug (potency
& IA)
• The efficacy (Emax) and potency (EC50) parameters are
derived from these data.
Morphine

Aspirin
Quantal Dose-Response Relationships
• Quantal response
• Influence of the magnitude of the dose on the proportion of
a population that responds.

• Is all or none phenomena

• Employed to study toxicity of a drug

• Useful for determining doses to which most of the

population responds.
Quantal Dose-Response Relationships
• The Plot of the fraction of the population that
responds at each dose of the drug versus the log of
the dose administered

• The median effective (ED50), median toxic (TD50) ,and

median lethal doses (LD50) are extracted from
experiments carried out in this manner.
FACTORS GOVERNING DRUG ACTION

• Affinity is a measure of the tightness with which a

drug binds to the receptor.

• Intrinsic activity is a measure of the ability of an

agonist that is bound to the receptor to generate an
activating stimulus and produce a change in cellular
activity.
Efficacy
• Efficacy (often called maximal efficacy): is the maximal
effect (Emax) an agonist can produce if the dose is taken
to very high levels.

• Efficacy is determined mainly by the nature of the

receptor and its associated effector system.

• It can be measured with a graded dose-response curve

• By definition, partial agonists have lower maximal

efficacy than full agonists.
Potency
• Potency denotes the amount of a drug needed to produce a given
effect.

• In graded dose-response measurements, the effect usually chosen

is 50% of the maximal effect ( EC50).

• Potency is determined mainly by the affinity of the receptor for the

drug.

• In quantal dose-response measurements ED50, TD50, and LD50 are

typical potency variables (median effective, toxic, and lethal doses,
respectively, in 50% of the population studied).

• Potency can be determined from either graded (EC50) or quantal

dose-response curves (ED50, TD50, and LD50), but the numbers
obtained are not identical.
•Drug potency does not necessarily mean
therapeutic superiority.

•Other factors such as adverse drug reactions

associated with the drug need to be
considered.
 Factors that modify drug effect and drug dosage
ØBody weight
ØAge
§ Infants
• Small volume of body fluid compartment
• Incomplete development of the BBB
• Undeveloped renal system
• Undeveloped enzyme system
§ Old people: deteriorated body functions
ØSex
§ Women respond faster due to their relative small body size
ØRoute of administration
ØTime of administration
ØPhysiological variables: fluid and electrolyte balance,
acid-base status, blood flow and body temperature.
ØTolerance to drugs (It is the requirement of higher dose
than usual dose to produce the effect)
ØPathological factors that alter pharmacokinetics and
Pharmacodynamic parameters. Special attention is given
to renal and hepatic problems
ØGenetic factors
ØEmotional factors
ØEnvironmental
§More of a hypnotic drug is required to induce
hypnosis during day time than during night
§More dose of antihypertensive drug is required to
lower blood pressure in cold weather than in hot one.
ØNutritional state
§Starvation causes decreased protein synthesis (drug
metabolizing enzymes), hence enhanced drug effect.
Therapeutic Index, Therapeutic Window
• The therapeutic index
- is the ratio of the TD50 (or LD50) to the ED50.
- It is determined from quantal dose-response curves.
- It represents an estimate of the safety of a drug, since a very safe
drug might be expected to have a very large toxic dose and a small
effective dose.

• The therapeutic window

- a more clinically relevant index of safety
- describes the dosage range between the minimum effective
therapeutic concentration or dose, and the minimum toxic
concentration or dose.
Clinical selectivity: beneficial vs toxic effects
of drugs

•No drug causes only a single, specific effect

• Drug may bind more than one receptor

• Biochemical processes controlled by receptor

may take place in multiple cell type
Effect mediated by identical receptors in the
same tissue
• Clinically, most serious toxicities occur in this manner
• Pharmacological extension of therapeutic actions of drug

• Reduced primarily through careful control of drug dosage &

monitoring of blood concentration
Effect mediated by identical receptors in D/t
tissue
• Many drug produce desirable & side effect by acting on single
receptor in d/t tissue

• Strategies to reduce toxicity

• Administration at lowest effective dose (monitoring)
• Use in combination of with other drugs that achieve a similar physiological
effect but through a d/t mechanism (allows lower dose)
• Altered route of administration
Effects mediated by d/t receptors
• Often, receptors exist as multiple isoforms with distinct ligand
selectivity, tissue expression patterns & physiological function
• Drugs may exhibit affinity for multiple isoforms
• Example: adrenergic receptors

• Strategies to reduce toxicity

• Administration at lowest effective dose
• Drug combinations
• Route of administration
 Classification of Ligands

ØIn view of binding, ligands can be

§Agonists: It binds to the receptors and it will

activate the receptor.
§Has both affinity and intrinsic activity (A=1 &
IA=1). Eg. morphine, epinephrine
§e.g.: adrenaline (epinephrine)
§Antagonist: binds to the receptor but it will
not activate the receptor.
§Has affinity but no intrinsic activity (A=1 & IA=0).
Eg : atenolol, metoprolol, Prazosin, propranolol
(a beta blocker)
 §Partial agonist/antagonist: It activates the receptor and
produce sub maximal response.
§Has affinity bit with sub maximal intrinsic activity (A=1 &
0<IA<1)
§ It antagonizes the action of pure agonist
vNB: Partial agonist act as competitive antagonist in presence
of an agonist
v Even though drugs may occupy the same # of receptors,
the magnitude of their effects may differ.
When each of the agonist and partial agonist is used alone and response is
measured, occupancy of all the receptors by the partial agonist produces a lower
maximal response than does similar occupancy by the full agonist.
§Inverse agonist: this phenomenon is evident in only
some receptors which are activated spontaneously
with out ligand binding (A=1 & -1<IA<0)

§Some antagonist (so called inverse agonist) reduce

receptor activity below basal levels observed in the
absence of bound ligand.
Pharmacological vs. physiological vs.
chemical antagonism
Physiologic Antagonists
• A physiologic antagonist is a drug that binds to a different
receptor, producing an effect opposite to that produced by
the drug it is antagonizing.
• Example: the antagonism of the bronchoconstrictor action
of histamine (mediated at histamine receptors) by
epinephrine's bronchodilator action (mediated at beta
adrenoceptors ).
 Chemical Antagonists

• A chemical antagonist is a drug that interacts directly

with the drug being antagonized to remove it or to
prevent it from reaching its target.

• A chemical antagonist does not depend on interaction

with the agonist's receptor .

• Examples:
- Dimercaprol, a chelator of lead and some other toxic
metals.
- Pralidoxime, which combines avidly with the
phosphorus in organophos­phate cholinesterase
inhibitors.
Pharmacologic Antagonists
• Types of agonist- antagonist interaction at receptors
A. Reversible antagonism
1. Competitive antagonism
2. Non-competitive antagonism
B. Irreversible antagonism

Reversible antagonism
-Is reversible since week bond b/n receptor & antagonist
Competitive Pharmacologic Antagonists
•Competitive antagonists are drugs that bind to
the receptor in a reversible way without
activating the effector system for that receptor.
•In the presence of a competitive antagonist, the
log dose-response curve is shifted to higher
doses but the same maximal effect is reached.
•The effects of competitive antagonists can be
overcome by adding more agonist.
•Competitive antagonists increase the ED50
Changes in agonist concentration-effect curves produced by a competitive
antagonist
• Non-competitive antagonism

• Binding site for antagonist is different from

agonist

• Antagonist cannot be overcome by ↑ increasing

agonist concentration

• ↓ maximal response
• Produces slight dextral shift in the agonist DR curve
in the low concentration range

• But, as more and more receptors are bound (and

essentially destroyed), the agonist drug becomes
incapable of eliciting a maximal effect
Irreversible pharmacological antagonist

• Irreversible antagonist

•Strong covalent bond

•Irreversibly inactivate the receptor

•↓ maximal response
 Irreversible pharmacological antagonist
• Irreversible pharmacological antagonist causes a
downward shift of the maximum, with no shift of the
curve on the dose axis unless spare receptors are present.

• Irreversible antagonists cannot be overcome by adding

more agonist.

• Irreversible antagonists do not increase ED50 (unless spare

receptors are present).
 E

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Drug interactions
ØDrug-drug interaction – modulation of pharmacological
activity one drug by concomitant/prior administration of
another drug

ØInteraction occurs at two stages

§At pharmacokinetic level

üA t t h e l e v e l o f a b s o r p t i o n , d i s t r i b u t i o n ,
biotransformation or excretion

§At Pharmacodynamic level

üAt the level of receptors and beyond

Types of drug interaction

• Type of interaction
• Additive (e.g carbachol + acetyl choline)
• Synergetic (e.g ethanol + carbon tetrachlorid)
• Potentiation (e.g isopropanol + carbon tetrachlorid)
• Antagonism ( e.g insulin + glucagon)
Types Therapy
ØPhysiotherapy
ØPsychotherapy
ØDrug therapy
§ Chemotherapy: drugs used against microbes,
parasites, cancer cells
§ Pharmacotherapy: application of drugs for their
action on various body parts. It could be
ü Symptomatic treatment
ü Curative treatment…

The type of therapy depends on the nature of disease

or illness
Drug adverse effects and drug toxicities

ØThese are effects not favorable to the patient

ØExpected adverse effects
§ Side effects: effects observed at therapeutic dose
§ Toxic effects: effects observed at larger concentrations
üAcute toxicity: acute administration of larger
doses.
üChronic toxicity: usually with prolonged and
repeated use of a drug.

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ØUnexpected adverse effects
§Hypersensitivity reactions: abnormal response due
to antigenic nature of some drugs
üAllergy
üAnaphylaxis: extreme sensitivity to antigenic
substance and subsequent circulatory collapse
§Idiosyncratic reactions: an abnormal reactivity to a
chemical that is peculiar to a given individual.
Management of toxicity

ØD O S E o f a d r u g d e te r m i n e s w h e t h e r i t h a s
medicinal or toxic effects

ØPoisons affect adversely one or more vital body

functions and only few poisons have specific
antidotes.
General procedures in the management of
poisoning
oLife support
üThe first step is to recognize and treat life threatening
conditions (ABCD)
oDrug identification
üMore detailed evaluation to make a specific diagnosis
oDecontamination
üShould be undertaken simultaneously with initial
stabilization, diagnostic assessment, and laboratory
evaluation
 ü Termination of exposure to the toxic substance
§Allowing to fresh air
§Washing of the eyes and skin
ü Prevention of further absorption of ingested poison
§Induction of emesis
§Use of adsorbent
§Induction of purgation
oSpecific antidotes
• e.g. Atropine antidote Anticholinesterases
oEnhancing elimination of toxins
- Hemodialysis or urinary alkalinization
 Experimental pharmacology
Stages of New Drug Development
• Is an expensive and lengthy process
• The testing of new drugs has two principal steps:
1. Preclinical testing
2. Clinical testing

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Phase 1
üEffects of the drug as a function of dosage are established in a small number
of healthy volunteers.
üGoal is to find the maximum tolerated dose
Phase 2
üThe drug is studied in patients with the target disease to determine its
efficacy
Phase 3
üThe drug is evaluated in much larger numbers of patients with the target
disease to further establish safety and efficacy
Phase 4
üMonitoring the safety of the new drug under actual conditions of use in
large numbers of patients