Pharmacodynamics

Dr. Tarun Arora

Associate Professor
Department of Pharmacology, LHMC
Pharmacodynamics

•(1) How the drugs act

•on the body?
•(2) The mechanism of action
•of drug and its effects.
Pharmacodynamics

•The mechanism of action

represents the interaction
between drug molecules and
biological structures of the
organism.
Pharmacodynamics

•The effect represents the

final results from the drug
action.
•The effect can be observed
and measured, but not the
action.
SITES OF DRUG ACTION

•They can be divided

into:
•specific and
•non-specific
Non-specific action have:
• osmotic diuretics Mannitol

• Osmotic laxative drugs

• Duphalac
• MgSO4
• Anti-acids (antacids)
NaHCO3
Specific action

•It is connected with

interaction of the drug with
specific site(s) on the cell
membrane or inside the cell.
MOLECULAR ASPECTS OF SPECIFIC
DRUG ACTION

•How drugs act?

Main specific targets for drug
actions are:
• DNA
• microbial organelles
• target macroproteins
(including enzymes)
 DNA

Alkylating agents bind covalently to

sites
within the DNA such as N7 of guanine
 Microbial organelles

Doxycycline Penicillins Nystatin

Rifampicin
 Target macroproteins

• receptors (> 150 types with

many subtypes)
• ion channels
• enzymes
• carrier molecules
(Transporters)
P. Ehrilch
(1854-1915)

“Corpora non
agunt nisi fixata”
(a drug will not
work unless it is
bound).
A. Receptors

•are the regulatory

macroproteins –sensitive
elements in the system of
chemical communications that
coordinates the function of
the different cells in the body.
Receptors bind to
• Endogenous ligands (such as):
- neurotransmitters (mediators)
- hormones
- autacoids (tissue mediators)
- growth factors
- inhibitory factors, etc.
• Exogenous ligands:
- many (but not all) drugs
- some other xenobiotics
The main receptor ligands are
• agonists - activate the receptors
• antagonists - block the receptors
Agonist and antagonist
Types of interaction between drug
and receptors
• The interaction between the ligand and the
receptor does not involve covalent bonds but
weaker, reversible forces commonly, such as:
• Ionic bonding
• Hydrogen bonding
• Hydrophobic bonding
• Van der Waals forces.
3-D structure of receptors and
ligands
• The receptors have a three-
dimensional organization in
space and require the different
aspects of a ligand to be
presented in the correct 3-D
configuration (like fitting a
hand into the glove).
Affinity, intrinsic activity
(efficacy) and selectivity
 Affinity: Drug binding to receptor is said to have affinity and producing the
effect (intrinsic activity) is called as coupling.

 Intrinsic activity: Maximal response produced by a dose of drug is called as

efficacy.

 Selectivity: A drug binding to single type of receptor will be highly selective. E.g.
Alpha1 blockers, beta2 agonists, etc.
3-D structure of drug

• Both affinity (defined by dissociation

constant kd) and intrinsic activity are
primarily determined by chemical structure
of drug.
• Selectivity is also primarily determined by
chemical structure of drug.
Types of Receptors

Receptors

Physiological (regulatory) Silent Spare

Constitutive Orphan Targeted

Physiological:
• Receptors mediating the effects of drugs similar to
exerted by endogenous substances such as
neurotransmitters (GABA, glutamate, epinephrine,
etc.), hormones and autocoids (histamine,
prostaglandins) are called as regulatory proteins.
• Drugs acting on such receptors are called agonists.
• Majority of drugs act through these receptors.
Types of agonists
o Primary agonist: An agonist binding at same site as that of endogenous
substance and leads to maximal response after full occupation of receptors
e.g. Ach, NA, Dopamine.
o Allosteric or Allotopic agonist: An agonist binding to a site different from
primary agonist e.g. BZDs, Barbiturates.
o Partial agonist: Agonists which have effect less than agonist even after full
occupation of receptors. E.g. buprenorphine, aripiprazole,etc. Partial
agonists act as antagonists in presence of endogenous agonists. Partial
agonists lead to submaximal response even after full occupation of receptors
Orphan Receptors
 These are receptors which have no endogenous ligand.
• Orphan drugs are those drugs which are used in treatment of rare
diseases (affecting less than 1 in 5000 people in India, 1 in 2 lac
people in USA) such as myasthenia gravis, alpha-1 antitrypsin
deficiency, wilsons disease, etc.
• Complete list of drugs and orphan diseases used in India can be
downloaded from ORDI website (Organisation for rare diseases
India)
Silent Receptors

 Drugs binding to plasma proteins (albumin or α1 acid

glycoprotein) that result in no therapeutic effect.
 Represent storage sites of drugs or sites of drug
action loss.
Spare Receptors
 These receptors mediate the maximal effect of an agonist even after
irreversible blockade of 99% of receptors.
 So clearly these receptors act as contingency plan of body to protect against
emergent consequences of irreversible blockade. E.g. even after giving large
doses of propranolol, our heart can still respond to sympathetic stress e.g.
exercise and produce similar tachycardia as in absence of propranolol.
 These effects are usually the consequence of prolonged secondary
messenger generation by receptors.
Constitutive Receptors and Inverse agonists
 Receptors which are continuously in active state in
absence of ligand. E.g. COX-1 receptors in stomach, H3
receptors in neurons, COX-2 in kidney, GABAA receptors,
etc.
• Inverse agonist: Drugs which act on constitutive receptors
in absence of endogenous ligand to inhibit their activity
and produce effects opposite to agonists. E.g. β-carboline,
pimavanserin at 5-HT2A receptors
Targeted Receptors
• Some receptors are being targeted by specific
ligands owing to structural or chemical or
genomic sequence similarity and produce
therapeutic effects while avoiding toxicity to
nearby cells.
• E.g. antibody drug conjugates like gemtuzumab
ozagamicin, radioactive iodine therapy, α1A
blockers like tamsulosin, etc.
Receptor families
• There are 4 main types of receptors,
according to their molecular structure
and the nature of receptor-effector
linkage.
• The location of type 1, 2 and 3
receptors is on (into) the cell
membranes; type 4 - into the cell
nucleus or cytoplasm.
Four types of receptors families

•1. Receptors with intrinsic ion

channels.
•2. G-protien coupled receptor
•3. Enzymatic receptors
•4. Intracellular receptor
 G-protein-coupled receptors
(Largest Family)

• All comprise 7 membrane-spanning segments

(serpentine or hepta-helical). One of the
intracellular loops is larger than the others and
interacts with G-protein.
G-Proteins
• The G-protein is a membrane protein comprising 3
subunits (a, b, g).
• Categorization of G-proteins into Gs, Gi, Gq, G0 and G12/13 is based on α
subunit of G-protein.
• The alpha-subunit possesses GTPase-activity.
• •When the agonists occupy a receptor, the alpha-
subunit dissociates and is then free to activate a
target (effector):
- enzyme (AC, GC, PLC)
- Ca2+ ion channels
• AC (adenylate cyclase) catalyses formation of the
intracellular messenger (cAMP).
• cAMP activates various protein kinases (PKA and
others) which control cell function in many
different ways by causing phosphorylation of
various enzymes, carriers and other proteins.
Adrenaline acting through Gs
protein
• Adrenaline (b1&b2)
• Out
Gs AC
• In

ATP cAMP

PKA Effects
Functioning of GPCR
Enzymatic receptors (Tyrosine-
kinase linked)
• Incorporate tyrosine kinase in their
intracellular domain.
• These receptors are involved mainly in
events controlling phosphorylation, cell
growth and differentiation.
• Examples :
• Insulin receptor
• ANP receptor
• growth factors rec.
Tyrosine-kinase linked receptors
Nuclear or cytoplasmic
receptors
• They are nuclear or cytoplasmic
proteins, so ligands must first enter
cells.
• Receptors have DNA-binding domain.
• Stimulation of these receptors
increase protein synthesis by the
activation of DNA transcription.
Cytoplasmic receptors
Intranuclear receptors
• Examples are:
• Cytoplasmic: steroid receptors
(mineralo, Gluco and sex steroids),
vitamin D
• Nuclear: thyroid receptors and retinoid
receptors

• Slowest acting class of receptors.

Maximal response manifests in days.
Ionotropic receptors (ion-channel
incorporating)
• These receptors are involved mainly in
fast synaptic transmission.
• •They are proteins containing several
transmembrane segments arranged
around a central channel.
• •Ligand binding and channel opening
occur on a millisecond time-scale.
• Fastest acting class of receptors
Ionotropic receptors
•Examples:
•nACh-receptors
•GABAA-receptors
•5-HT3-receptors, etc.
Nicotinic receptors: 5 subunits
GABAA receptors: 5 subunits
(Pentameric)
Quantification of pharmacodynamics of
drug-receptor interaction
 This is mainly done by analyzing the types of drug-receptor
interaction.
• States of receptor
• Receptors exist in three states viz.
• Active state denoted by Ra: Favored by agonists (Full and partial)
• Inactive state denoted by Ri : Favored by agonists (inverse and partial)
• Constitutive state: Favored by inverse agonists
Drug-receptor coupling reaction
• Drug [D] + Receptor [R] K1→ [DR] → [DR] effect or response
K2
• K2
Drug-receptor response
 At any time, response depends on equilibrium between drug and receptor complex (DR).
 Agonists bind preferentially to Ra state of receptors and shift equilibrium to right.
 Partial agonists (PA) bind to Ra receptors but less than that of agonists and remaining
receptors exist in Ri state. Therefore, response of partial agonists is always less than that
of agonists at same occupation of Ra.
 Inverse agonists (IA) only bind to Ri state and therefore act opposite to agonists by
suppressing activity of constitutively active receptors and hence equilibrium shifts to left.
• Antagonists bind equally to Ra and Ri state, therefore net response is zero
Pharmacodynamic parameters of drug-receptor interaction
Affinity
 1. Affinity: It is determined by Kd or equilibrium dissociation constant value. This value is
determined as below:

Kd = Rate of backward reaction/rate of forward reaction = K2 / K1 = [D] [R]/[DR] = 1/Ka

where Ka is affinity or rate forward constant

 Therefore, higher the Kd value, lower is the affinity of drug to it’s receptor.
 Also f = [D]/Kd + [D]
o where f – fractional occupancy of receptor, D-Drug concentration
 Therefore, when [D] = Kd, f = 0.5 which means 50% occupancy of receptors at half the
maximal concentration.

Important:

All drugs whether agonist, partial agonist, inverse agonist or antagonist have affinity for receptor.
Efficacy (intrinsic activity)
 2. Intrinsic activity: It is measure of efficacy or effect produced by
drug.
o It’s value lies between -1 to +1.
o Agonists have value +1,

o Partial Agonists have value between 0 and 1,

o inverse agonists have value between 0 and -1

o while antagonists have value 0.

Dose response curve (DRC)
• When a drug is administered, it produces a response
and this response shows alteration with change in dose.
 The change can be plotted with dose as abscissa and
response as ordinate.
 The resulting curve is known as DOSE RESPONSE
• CURVE.
DOSE-RESPONSE
RELATIONSHIPS
• Most drugs produce graded dose-
related effects, which can be
plotted as a dose response curve.
• Such curves are often hyperbolic
(a), but they can be conveniently
plotted on semi-logarithmic paper
to give sigmoidal shape (b).
Dose-response curves
• The method of plotting dose-response curves
facilitates quantitative analysis of:
• full agonists, which produce graded responses up
to maximum
value;
• antagonists, which produce no response on their
own but antagonize the response to an agonist;
• Partial agonists, which produce some response
but to a lower maximum than that of a full
agonist and antagonize its effect.
DRC of Full agonists A & B and Partial
agonist C
Types of DRC

•These are of two types:

•Graded Dose response curve
•Quantal dose response curve
Graded Dose response curve
• The dose response curve rises steeply at first, but after that it
become steady as the dose is increased.
•  Curve is popularly known as hyperbolic or exponential curve.

•  Such a curve can be shown by plotting dose (Log) against

percent response.
Graded DRC
Advantages of Graded DRC
• Important:

 Log doses are used, as response to a drug increases in exponential manner to

increases in small doses of drug and hence large number of doses can be
plotted on X-axis.
 It is easy and quick measure of assessing the sensitivity of an individual to
very small doses of drug.
 Log plasma concentration curves become straight line between 20% to 80% of
maximum dose which is easier to quantitate (sigmoidal in shape) than curves
which are concave or convex (if log doses are not used).
Parameters derived from log dose-response curve
I. Potency: It is defined as dose or plasma concentration required to obtain 50% of maximal
effect, denoted by EC50 on X-axis of DRC.

Important:

 Potency is determined by both affinity and efficacy.

 Farther the DRC is located on right side of one drug, lesser will be potency of second drug.

II. Efficacy: It is determined by maximum response (Emax) on dose response curve.

Important:

 Efficacy is determined by coupling process (intrinsic activity) only.

 Efficacy is more important parameter for choosing one drug over another drug for a clinical
response.

Slope: It indicates the change in magnitude of response with small changes in dose.
Michel-Mentons Kinetics
• V=Vmax*C/Km+C, Enzymatic reaction
• In drug –receptor response, this equation is represented by
• E=Emax*C/KDorKm+C
• Now when Km=C, then
• E=0.5Emax
• Therefore, when Km=EC50, half the maximal response is produced.
• EC50 or Km is measure of potency, i.e. dose required to produce half
the maximal response.
Drug A is more potent than B
Drug A is less effective than B
Other parameters derived from
graded DRC
I. Therapeutic range: This is range of plasma concentration which lies between plasma
concentration producing therapeutic effect and toxic effect. Usually it is calculated
between EC50 and TC50. Narrower the therapeutic range, more unsafe is drug.

II. Drug selectivity: It is determined by closeness of EC50 values on dose response curves
for two actions of same drug. Closer the DRC, more likely drug is acting through same
receptors in different organs.

• Antagonism: The type of antagonism whether competitive or non-competitive can be

known from DRC as described further
Quantal dose response curve

 This is plotted between different doses of a drug and percentage or

proportion of population showing a fixed end response. So
importantly here, response is all or none phenomena i.e. percentage
of population showing it or not.
 Most important use of such type of DRC is calculation of therapeutic
index of drug.
Therapeutic index
• Median effective dose(ED50 ).
•  Is a dose of the drug that gives a response equals to 50% of the

maximal response.
• Median lethal dose(LD50 ).
• Is the dose of a drug required to produce toxicity in 50 % of patients.

• Therapeutic index: LD50/ED50

• Drugs with higher therapeutic index are safer.
THERAPEUTIC INDEX(TI)
• It is a measure of the relative safety of a drug for a particular
treatment.
•  Therapeutic index = LD50 / ED50

•  Large value - a wide margin of safety. Eg:Penicillin

•  Small value - a narrow margin of safety Eg: warfarin

ANTAGONISM
•When one drug decreases or
abolishes the action of another.
•Effect of drug A+ B < Effect of
drug A+ Effect of drug B
Types of Drug antagonist
• Physical antagonism
• Chemical antagonist.
• Physiological antagonist.
• Pharmacological antagonist (Most commonly exploited)

• Competitive Non-Competitive
• (Irreversible)
• Equilibrium Non-equilibrium Pseudo-reversible
(Reversible) (irreversible)
Physical Antagonism
• Based on physical property.

• Examples
 Charcoal adsorbs alkaloids and can prevent their absorption,
used in alkaloid poisoning.
Chemical Antagonism
 Two drugs react chemically and form an inactive product.

• Examples
• KMnO4 oxidizes alkaloid used for gastric lavage in
poisoning.
• Antacids neutralise gastric acid
• Protamine sulfate (basic) neutralises heparin (acidic)
Physiological Antagonism
Two drugs acting on different receptors by different
mechanism, have opposite effect on the same physiological
function.

Examples
Glucagon & insulin on blood sugar
Histamine and Adrenaline on bronchial airways
Ach and NA on blood vessels
Pharmacological Antagonism
• Reversible : Competitive equilibrium type
• Pseudo-reversible: Competitive type
• Irreversible: Competitive non-equilibrium type
and non-competitive type
Competitive Antagonist
• Reversible or equilibrium type
• Both antagonist and agonist compete for same binding site on receptor.
Therefore, structures of both should be similar.
• Bond formed between antagonist and receptor is weak e.g. Van der
waals or H-bond.
• The antagonist effect can be overcome by increasing the agonist
concentration.
• Log DRC is shifted to Right in presence of antagonist.
• Km value is increased and Emax or efficacy remains same.
• Examples: Most antagonists belong to this class viz. muscarinic or
adrenergic blockers, histaminergic blockers, opioid antagonists, etc.
B is competitive antagonist
Competitive Non-equilibrium
Type
• Both bind at same site on receptor but bond formed is covalent and
hence antagonist does not dissociate from receptor.
• Antagonism cannot be overcome by increasing dose of agonist.
• Log DRC is not shifted in presence of antagonist. Therefore Km
remains same.
• Emax is reduced.
• E.g. Dibenamine at α1 adrenergic receptors
Log DRC is not shifted
Competitive pseudo-reversible Type
• Seen due to lesser receptor occupancy by antagonist or presence of
spare receptors.
• Log DRC is initially shifted to right i.e. Km is increased but with higher
doses, Emax is reduced and Km becomes static.
• E.g. Phenoxybenzamine at α receptors and methylsergide at 5-HT
receptors.
• Organophosphates inhibiting acetylcholinesterase and methotrexate
inhibiting DHFRase
Initial increase in Km, then Emax is
reduced
Non-competitive or irreversible type
• Both bind to receptor at different sites, therefore structures are
dissimilar.
• Antagonist prevents binding of agonist to its site.
• Log DRC resembles competitive non-equilibrium type.
• Km remains same while Emax is reduced.
Only Emax is reduced
COMBINED EFFECT OF DRUGS
•When two or more drugs are given
simultaneously or directly after each
other, they may be either indifferent
to each other or exhibit synergism or
antagonism
Drug summation (1+1=2)
• Effect of two drugs acting through different
mechanisms is equal to effect of each drug.
• Example aspirin + codeine as analgesic
Drug addition (1+1=2)
• Effect of two drugs acting through same mechanisms
is equal to effect of each drug.
• Example: Aspirin+Diclofenac
Drug synergism (supra-
additiveness)(1+1=4)
• Effect of two drugs acting through different
mechanisms is more than effect of each drug.
• Example: Trimethoprim + sulfamethaxozole, Levodopa
+ carbidopa, etc.
REGULATION OF RECEPTORS
• Receptor down regulation: or Tolerance
• Prolonged use of agonist
• Decrease in Receptor number and sensitivity (Tolerance)
• Happens in days, can be overcome by increase in dose
• Drug effect is decreased
 Ex: Chronic use of salbutamol down regulates ß 2
• adrenergic receptors
• Tolerance to analgesic effect of morphine, etc
Tachyphylaxis or acute tolerance
• Doses of drugs given in quick succession leads to receptor
desensitisation (either exhaustion of secondary messengers or
receptor involution).
• Happens in hours, cannot be overcome by increase in dose

• Usually seen with indirectly acting sympathomimetics like ephedrine,

tyramine, amphetamine or with Nitrates (Monday disease)
Receptor up regulation: or Super sensitivity

• Prolonged use of antagonist

• Increase in Receptor number and sensitivity
• Drug effect is increased
•  Eg:- if timolol is stopped after prolong use, produce withdrawal
symptoms. Rise in iop.
•  Sudden withdrawal of beta blockers leads to hypertension.
Factors affecting drug response
• In the clinical situation dose-response curves are
influenced by many factors including
• genetic, as well as
• age, weight, nutrition;
• psychological and social
• factors (that strongly influence compliance and
placebo effect).
•Thank You