Pharmacodynamics

Collected and Prepared

By
S.Bohlooli, PhD
Presented by
Sylvan S.R, M.Farm., Apt.
 LOCUS OF ACTION TISSUE
“RECEPTORS” RESERVOIRS
Bound Free Free Bound

ABSORPTION Free Drug EXCRETION

SYSTEMIC
Bound Drug CIRCULATION

BIOTRANSFORMATION
Molecular pharmacology :
 Molecular pharmacology is concerned with studies of
basic mechanisms of drug actions on biological
systems.
 The idea that drugs act upon specific sites (receptive
substance) began with John New Port Langley (1852-
1926) of Cambridge.
 However the word ‘receptor’ is given by Paul Ehrlich
(1854- 19 15).
 The receptor concept which forms a key note in the
development of molecular pharmacology became
firmly established by the quantitative work of Alfred
Joseph Clark (1885-1941), a professor of
pharmacology at Kings College London.
Receptor (key element)
 In addition to its usefulness for explaining
biology, the receptor concept has important
practical consequence for
 The development of drugs
 Arriving at therapeutic decisions in clinical
practice.
Receptors:

 Largely determine the quantitative relations

between dose or concentration of drug and
pharmacologic effects

 Are responsible for selectivity of drug action

 Mediate the actions of pharmacologic

antagonists
Macromolecular nature of drug receptors

 Regulatory proteins

 Enzymes

 Transport proteins

 Structural proteins
Quantitative aspects of
drug-receptor interaction
 Drug-Receptor Interactions Obey
the Law Of Mass Action

At equilibrium
k1
D  R  DR  effect
k2

By law of mass action:

[ D ].[ R ].k1  [ DR ].k 2

Therefore:

k2 [ D ].[ R ]
 KD 
k1 [ DR ]
 [ D].[ R ]
KD 
[ DR]

Total number of receptors: Rt = [R] + [DR]

[R] = Rt – [DR]

[ D].( Rt  [ DR]) [ D].Rt  [ D].[ DR]

KD  
[ DR] [ DR]

After rearrangement:

[ D].Rt [ DR] [ D]
[ DR ]  
K D  [ D] Rt K D  [ D]
 When [D] = KD
[DR] = 0.5
RT
1.00

0.75
[DR]/Rt

[ DR] [ D]
0.50 
Rt K D  [ D]

0.25

0.00
0 5 10 15 20

[D]
KD
Receptor Binding
% Bound

KD

Concentration of Ligand
The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).
 Relation between drug
dose & clinical response
Drugs are described based on the
magnitude of two properties:
1. Affinity for the receptor. Affinity is related to
potency.

2. Efficacy once bound to the receptor.

Efficacy refers to the maximal effect the drug
can elicit.
Agonists and Antagonists

 AGONIST - Has affinity for receptor and efficacy.

 ANTAGONIST - Has affinity but no efficacy.

 Competitive Antagonist
 Noncompetitive Antagonist

 Partial Agonist or Partial Antagonist –

 Has affinity but lower efficacy than full agonist.
Receptor ligand types
Full Agonists (i.e., equal efficacies) that
Differ In Potency:

A
B C
% Max Response

Compare the EC50s

Drug Concentration (log scale)

Agonists That Differ in Efficacy

A
% Max response
B

Log Drug Concentration

 Full and partial agonist occupancy and response relationship

100

Response
(full agonist) Occupancy
(both)
Response(%)

50

Response
(partial Agonist)

0.0
0.01 0.1 1.0 10.0
Concentration (umol/l)
 Inverse agonist
Inverse agonist can exist where an appreciable level of
activation may exist even when no ligand is present
For example: receptors for benzodiazepines, cannabinoids
and dopamine

Under such condition it may be possible for a ligand to

reduce the level of activation. such drugs are known as
inverse agonist
Competitive Antagonism Shifts The
Agonist D-R Curve (Potency)

AG + ANT
% Max Response

AG alone

EC50 EC50

Drug Concentration (log

scale)
Noncompetitive Antagonism Decreases
Agonist Efficacy

AG alone
% Max response

AG + NC ANT

AG + higher dose
NC ANT

Log Drug Concentration

 Spare receptor

Receptors
Emax are said to be ‘spare’ for a given pharmacological
response when the maximal response can be elicited by an
agonist at a concentration that not result
Agonist with in occupancy of the
Agonist with
Agonist
full complement of available noncompetitive
receptors noncompetitive
Respones(%)

alone
antagonist in antagonist in
presence of spare absence of
receptor spare receptor

Log Concentration
Antagonist like to bind to Agonist like to bind to
receptor in R and R” state receptor in R’ state and
without any preference and shifts the equilibrium
makes no shifts in net toward more LR’ and
equilibrium makes effect
R R’
L L Effect
No effect

LR LR’
Inverse agonist has
more affinity to receptor Partial agonist has a little more
in R state and shifts the affinity for receptor in R’ states
equilibrium toward more than R state and makes partial
LR and make negative effect
response than resting
state.
Possible mechanism for the partial agonist phenomenon.
 Desensitization and Tachyphylaxis

Changes in receptor
Desensitization
Tolerance Loss of receptor
Refractoriness How? Exhaustion of mediators
Drug resistance Increased metabolic degradation
Physiological adaptation
Active extrusion of drug from cells
Drug Antagonism

Propranolol &
Pharmacologic norepinephrine

Dimercaprol &
Chemical heavy metals

Pharmacokinetic
Phenobarbital &
warfarine

Physiologic
Epinephrine &
histamine
Signaling mechanism
&
drug action
Type of receptors
 Ligand gated ion channels

 G protein coupled receptors

 Ligand-Regulated Transmembrane Enzymes

Including Receptor Tyrosine Kinases

 Cytokine Receptors

 Intracellular receptors
Ligand gated ion channel (iontropic
receptors)
 -amino butyric acid (GABA)
 Glycine
 Aspartate
 Glutamate
 Acethylcholine
 Serotonin
Ligand gated ion channel (iontropic receptors)
ions

Hyper polarization
or
depolarization

Cellular effects
G protein coupled receptors
 Adernocorticotropic hormone
 Acetylcholine
 Angiotensin
 Catecholamines
 Chrionic gonadotropin
 Follicle stimulating hormone
 Glucagon
 Histamine
 Luteinizing Hormone
 Seretonin
 Vasopressin
 Ions G protein coupled receptors

R E
G G
+ - + -

Change in Second messengers

excitability

Ca2+ release Protein other

phosphorylation

Cell effects
Kinase linked receptors
 Ligand -regulated transmembrane enzyme
including receptor tyrosine kinases
 Insulin
 Epidermal growth factor (EGF)
 Platelet-derived growth factor (PDGF)
 Arterial natriuretic factor (ANF)
 Transforming growth factor (TGF- )
 Cytokine receptors
 Growth hormone
 Erythropoietin
 Interferones
Kinase linked receptors

R/E

Protein
phosphorylation

Gene transcription

Protein synthesis

Cellular effects
 Nuclear receptors

Nucleus

R
Gene
transcription

Protein synthesis

Cellular effects
Well Established Second Messengers

 Cyclic Adenosine Monophosphate (cAMP)

 Calcium and Phosphoinositides
 Cyclic Guanosine Monophosphate (cGMP)
 
Good Luck