PHARMACODYNAMICS

• In Greek
Pharmacon = Drug
Dynamics = Action/Power
It covers all the aspects relating to “What a drug
does to the body” i.e. Mechanism of action

• Action: How and Where the effect is produced is

called as Action.

• Effect: The type of response producing by drug.

 Site of Drug Action

• Where:

1. Extra cellular
2. Cellular
3. Intracellular
 Types of Drug Action
EFFECT (Type of responses):-
1.Stimulation
2.Inhibition/Depression
3.Replacement
4.Irritation
5.Cytotoxic
 Mechanism of Action of Drugs
• Drug act either by receptor or by non
receptor or by targeting specific genetic
changes.
Majority of drugs acts by (HOW)

Receptor mediated Non receptor mediated

 Receptor Mediated action
• Drug produce their effect through interacting
with some chemical compartment of living
organism c/s Receptor.

• Receptors are macromolecules

• Most are proteins
• Present either on the cell surface, cytoplasm or
in the nucleus
 Receptors
• Most drugs exert their effects
by interacting with receptors.

• RECEPTORS
• It is defined as a macromolecule or binding site located on
cell surface or inside the effector cell that serves to
recognize the signal molecule/drug and initiate the
response to it, but itself has no other function, e.g.
Muscarinic (M type) and Nicotinic (N type) receptors of
Cholinergic system
“LOCK & KEY” model of RECEPTORS
 RECEPTOR MEDIATED
MECHANISM
• Receptor: It is a membrane bound or intracellular
macromolecular protein which is capable of binding the
specific functional groups of the drug or endogenous
substance.

• Binding of a drug with its receptor results in the

formation of drug receptor complex (DR) which is
responsible for triggering the biological response.

Drug +Receptor → (Drug Receptor complex) → Bilogical effect

 Ligand binding
domain

Transduction of
signal into response

Receptor Functions : Two essential functions

• 1. Recognization of specific ligand molecule (Ligand
binding domain)

• 2. Transduction of signal into response (Effector domain)

Drug(D) +Receptor® Drug receptor complex Response

Drug receptor interaction:-

1. Selectivity:- Degree of complimentary co relation
between drug and receptor.
Ex:- Adrenaline Selectivity for α, ß Receptor

2. Affinity:- Ability of drug to get bound to the receptor.

3. Intrinsic activity (IA) or Efficacy:- Ability of drug to

produce a pharmacological response after making the
drug receptor complex.
 Drug – Receptor occupation theory – Clark`s
equation (1937)
• Drugs are small molecular ligands (pace of cellular function
can be altered)
• Drug (D) and receptor (R) interaction governed by “law of
mass action”
• Effect (E) Is the direct function of the Drug-Receptor complex
K1
D+R DR E (direct function of DR complex)
K2

• But DR complex may not be sufficient to elicit E (response)

• D must be able to bring a conformational change in R to get E
• Affinity and Intrinsic activity (IA)
 Receptor occupation theory –
contd.
• Affinity: Ability to bind with a Receptor
• Intrinsic activity (IA): Capacity to induce
functional change in the receptor
• Competitive antagonists have Affinity but no IA
• Therefore, a theoretical quantity (S) – denoting
strength was interposed
K1
D+R K2
DR S E
 Drug classification
(on the basis of affinity & efficacy)
Response No response
• Partial agonist :These drug have full affinity to
receptor but with low intrinsic activity (IA=0 to 1).
• These are only partly as effective as agonist

(Affinity is lesser when comparison to agonist)

Ex: Pindolol, Pentazocine
• Inverse agonist: These have full affinity
towards the receptor but intrinsic activity is
zero to -1 i.e., produces effect is just
opposite to that of agonist.

Ex:- ß-Carboline is inverse agonist for

Benzodiazepines receptors.
 Some Common Terms
• Agonist: An agent which activates a
receptor to produce an effect similar to a
that of the physiological signal molecule,
e.g. Muscarine and Nicotine

• Antagonist: an agent which prevents the

action of an agonist on a receptor or the
subsequent response, but does not have
an effect of its own, e.g. atropine is a
muscarinic receptor antagonist.
•Inverse agonist: an agent which activates receptors
to produce an effect in the opposite direction to that
of the agonist, e.g. DMCM (β Carboline) in
Benzodiazepine receptors

•Partial agonist: An agent which activates a receptor

to produce submaximal effect but antagonizes the
action of a full agonist, e.g. opioids

•Ligand: (Latin: ligare – to bind) - any molecule

which attaches selectively to particular receptors or
sites
 Receptor families

Four types of receptors families

1. Ligand-gated ion channels (inotropic

receptors)
2.G-protien coupled receptor (Metabotropic
receptors)
3. Enzymatic receptors (tyrosine kinase)
4.Intracellular receptors
 Characteristics of receptor families
Ligand G-protein Enzymatic Nuclear
gated coupled

Location Membrane Membrane Membrane Intracellular

Effector Ion channel Ion Channel Enzyme Gene

or enzyme
coupling Direct G-protein Direct Via DNA

Example Nicotinic Muscarinic Insulin Steroid ,

hormone
Signal transduction mechanism
• Ligand gated ion channels / Ion gated receptors:-
Localized on cell membrane and coupled directly to an
ion channel.
Ion

Blocker

Agonist
Receptor
Receptor
Na+2
Permeation of
Hyper polarization or
ion is blocked
depolarization

No cellular effect
Cellular effect
• Ex: Nicotinic cholinergic receptor
 G-protein coupled receptors
• Membrane bound, which are coupled to
effector system through GTP binding
proteins called as G-proteins

Bound to inner face of

plasma membrane (2nd
messenger)
 Varieties of G-protein
G-protein Receptor for Signaling pathway/
Effector
Gs ß adrenegic, AC— cAMP
H,5HT,Glucagon
Gi1,2,3 α2 adrenergic, Ach, AC— cAMP,
Open K+
Gq Ach Phospholipase-C,
IP3’cytoplasmic Ca+2
Go Neurotransmitters Not yet clear
in brain
 G-protein effector systems

• 1.Adenylase cyclase : cAMP system

• 2.Phospholipase –C: Inositol phosphate

system

• 3. Ion channels
cAMP system
Phospholipase-C system
How do GPCRs cause a change in cellular activity?
• An activated GPCR must interact with another protein called a guanine-
nucleotide binding protein (G protein)
• G proteins are made up of three subunits ( they are ‘heterotrimeric’):
α (alpha), β (beta) and γ (gamma)
Agonist-bound
Receptor


GDP
GTP
  
 

GTP
GDP

• The GPCR-G protein interaction activates the G protein by causing

GTP to exchange for GDP on the G protein α subunit
 Receptor-G protein-Effector signalling
Agonist-bound
Receptor

GTP
GDP

  
GTP
 

GDP

The α-βγ complex immediately

dissociates (into α-GTP + free βγ   
subunits) and each can then interact
with effector proteins (second GTP
messenger-generating enzymes,
or ion channels)

EFFECTOR EFFECTOR
RECEPTOR (GPCR) G PROTEIN EFFECTOR

Effectors can be ENZYMES:

ADENYLYL CYCLASE
ATP cyclic AMP

PHOSPHOLIPASE C Receptor Effector

PIP2 IP3 + DAG G protein

PHOSPHOINOSITIDE 3-KINASE (PI3K)

PIP2 PIP3

cGMP PHOSPHODIESTERASE
cyclic GMP 5’-GMP

or ION CHANNELS:

VOLTAGE-OPERATED Ca2+ CHANNELS (VOCCs)

G PROTEIN-REGULATED INWARDLY-RECTIFYING
K+ CHANNELS (GIRKs)
Agonist-stimulated regulation of adenylyl cyclase

Agonist

s
AC
  s
GDP GTP

Examples:
ATP cyclic AMP
Gs-coupled receptors
β-adrenoceptors
D1 dopamine receptors
H2 histamine receptors
Cyclic AMP-dependent protein kinase (PKA)
Gi coupled receptors
Epacs (guanine nucleotide exchange factors)
α2-adrenoceptors
D2 dopamine receptors Cyclic-nucleotide-gated ion channels (CNGs)
μ-opioid receptors
 RECEPTOR (GPCR) G PROTEIN EFFECTOR

Effectors can be ENZYMES:

ADENYLYL CYCLASE
ATP cyclic AMP

PHOSPHOLIPASE C Receptor Effector

PIP2 IP3 + DAG G protein

PHOSPHOINOSITIDE 3-KINASE (PI3K)

PIP2 PIP3

cGMP PHOSPHODIESTERASE
cyclic GMP 5’-GMP

or ION CHANNELS:

VOLTAGE-OPERATED Ca2+ CHANNELS (VOCCs)

G PROTEIN-REGULATED INWARDLY-RECTIFYING
K+ CHANNELS (GIRKs)
Agonist-stimulated regulation of phospholipase C
Agonist
PLC PIP2 DAG

  q q
P
GDP GTP P PKC

P P
P

IP3
P

IP3 receptor

Examples:
Ca2+
Gq-coupled receptors
α1-adrenoceptors
M1 muscarinic receptors
H1 histamine receptors Endoplasmic reticulum
 Ion channel regulation
• G-protein coupled receptors can control
the functioning of ion channel by don't
involving any second messenger
• Ex:- In cardiac muscle
 Enzymatic receptors
• These receptor are directly linked tyrosine kinase.
• Receptor binding domain present in extra cellular
site.
• Binding of a ligand to an extracellular domain
activates or inhibits this cytosolic enzyme activity.
• Produce conformational changes in intra cellular
Ex:- Insulin receptors
Enzymatic receptors
Extra cellular receptor
binding domain

Intra cellular
changes
e.g. Tyrosine kinase receptor
 Intracellular receptors
• Receptor is entirely intracellular
• Ligand must diffuse into the cell to interact
with the receptor
• Ligand must have sufficient lipid solubility to
move across the target cell membrane.
• The time course of activation and response
of these receptors is much longer.
• E.g. steroid receptors
 Intracellular receptors
Increase RNA
polymerase activity

Unfolds the receptor and

expose normally masked
DNA binding site
 Receptor regulation theory
• Receptors are in dynamic state.

• The affinity of the response to drugs is not fixed.

It alters according to situation.

• Receptor down regulation:

Prolonged use of agonist

Receptor number and sensitivity

Drug effect

Ex: Chronic use of salbutamol down regulates ß2 adrenergic receptors.

• Receptor up regulation:
Prolonged use of antagonist

Receptor number and sensitivity

Drug effect

• Ex:- propranolol is stopped after prolong

use, produce withdrawal symptoms. Rise
BP, induce of angina.
Agonist: Both the high affinity as well as
intrinsic activity (IA=1)
These drug trigger the maximal biological response or
mimic effect of the endogenous substance.
Ex:- Methacholine is a cholinomimetic drug which
mimics the effect of Ach on cholinergic receptors.
 Types of agonism
• Summation :- Two drugs eliciting same
response, but with different mechanism and their
combined effect is equal to their summation.
(1+1=2)

Aspirin Codiene

Prostaglandins Opiods receptor

Analgesic+ Analgesic+

++
 Types of agonism
• Additive: combined effect of two drugs acting by
same mechanism
Aspirin

PG PG

Analgesic+ Analgesic+

++
• Synergism (Supra additive):- (1+1=3)

The combined effect of two drug effect is

higher than either individual effect.
Ex:-
1.Sulfamethaxazole+ Trimethoprim
2. Levodopa + Carbidopa.
 Types of antagonism
Antagonism: Effect of two drugs is less than sum of the
effects of the individual drugs.
1. Chemical antagonism
Ex: -heparin(-ve) protamine +ve, Chelating agents
1. Physiological /Functional antagonism
Acting on different receptors
e.g. Histamine (Histamine receptor), Epinephrine (beta receptor)

1. Pharmacokinetic antagonism
2. Pharmacological antagonism
I. Competitive ( Reversible)
II. Non competitive (Irreversible)
 Pharmacokinetic antagonism
• One drug affects the absorption,
metabolism or excretion of other drug and
reduce their effect.

Ex:-Warfarin in presence of phenobarbitone,

warfarin metabolism is increased, it effect
is reduced.
 Pharmacological antagonism

• Pharmacodynamic antagonism between two

drugs acting at same receptors.
• Two important mechanism according to which
these antagonists

»1.Reversible(Competitive)
»2.Irreversible(Non)
 Reversible antagonism
(Competitive antagonism)
• These inhibition is commonly observed
with antagonists that bind reversibly to the
same receptor site as that of an agonist.

• These type of inhibitions can be overcome

by increasing the concentration of agonist

• Ex:- Atropine is a competitive antagonist of

Ach.
 Irreversible Antagonism
• It occurs when the antagonist dissociates
very slow or not at all from the receptors
result that no change when the agonist
applied.
• Antagonist effect cannot be overcome
even after increasing the concentration of
agonist
 Non receptor mediated action
• All drugs action are not mediated by receptors.
Some of drugs may act through chemical action
or physical action or other modes.

» Chemical action
» Physical action (Astringents)
» Being protoplasmic action (antiseptics)
» Formation of antibody (Vaccines)
» Targeting specific genetic changes.
 Dose
• It is the required amount of drug in weight,
volumes, moles or IU to provide a desired effect.

• In clinical it is called as Therapeutic dose

• In experimental purpose it is called as effective

dose.

• The therapeutic dose varies from person to

person
Single dose:
1.Piperazine (4-5g) is sufficient to eradicate round
worm.
2.Single IM dose of 250mg of ceftriaxone to treat
gonorrhoea.

Daily dose:
It is the quantity of a drug to be administered in
24hr, all at once or equally divided dose.
1.10mg of cetrizine (all at once) is sufficient to
relive allergic reactions.
2.Erythromycin is 1g per day to be given in 4
equally divided dose (i.e., 250mg every 6 hr)
• Total dose: It is the maximum quantity of the
drug that is needed the complete course of the
therapy.

Loading dose:- It is the large dose of drug to be

given initially to provide the effective plasma
concentration rapidly. The drugs having high Vd
of distribution.
Chloroquine in Malaria – 600 mg Stat
300mg after 8 hours
300 mg after 2 days.
Maintenance dose:- Loading dose normally
followed by maintenance dose.
• Needed to maintain the steady state
plasma concentration attained after giving
the loading dose.
Therapeutic index:
• Margin of safety
• Depend upon factor of dose producing
desirable effect  dose eliciting toxic
effect.

LD 50
Therapeuti c index 
ED 50

• TI should be more than one

 Therapeutic window:
Optimal therapeutic range of plasma
concentrations at which most of the patients
experience the desired effect.
Therapeutic range Therapeutic window
Sub optimal

optimal
Toxic
• Cyclosporine – 100-400ng/ml
• Carbamazapine- 4-10µg/ml
• Digoxin- 0.8-2ng/ml
• Lithium- 0.8-1.4 mEq/L
• Phenotoin – 10-20µg/ml
• Qunindine- 2-6µg/ml