Pharmacodynamics
Collected and Prepared
By
S.Bohlooli, PhD
LOCUS OF ACTION
“RECEPTORS”
Bound
ABSORPTION
Free
TISSUE
RESERVOIRS
Free
Bound
Free Drug
Bound Drug
SYSTEMIC
CIRCULATION
BIOTRANSFORMATION
EXCRETION
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 (18521926) 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 ]. k 1  [ DR ]. k 2
Therefore:
k2
k1
 KD 
[ D ].[ R ]
[ DR ]
KD 
[ D ].[ R ]
[ DR ]
Total number of receptors: Rt = [R] + [DR]
[R] = Rt – [DR]
KD 
[ D ].( R t  [ DR ])

[ D ]. R t  [ D ].[ DR ]
[ DR ]
[ DR ]
After rearrangement:
[ DR ] 
[ D ]. R t
[ DR ]
K D  [D]
Rt

[D]
K D  [D]
When [D] = KD
[DR]
= 0.5
RT
1.00
[DR]/Rt
0.75
[ DR ]
0.50
Rt

[D]
K D  [D]
0.25
0.00
0
5
10
[D]
KD
15
20
% Bound
Receptor Binding
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
Compare the EC50s
Drug Concentration (log scale)
Agonists That Differ in Efficacy
A
% Max response
B
C
Log Drug Concentration
Full and partial agonist occupancy and response relationship
100
Response(%)
Response
(full agonist)
Occupancy
(both)
50
Response
(partial Agonist)
0.0
0.01
0.1
Concentration (umol/l)
1.0
10.0
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 alone
EC50
AG + ANT
EC50
Drug Concentration (log scale)
Noncompetitive Antagonism Decreases
Agonist Efficacy
% Max response
AG alone
AG + NC ANT
AG + higher dose
NC ANT
Log Drug Concentration
Spare receptor
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
in occupancy
of the
Agonist
with
Agonist
with
Agonist
full complement
of availablenoncompetitive
receptors
noncompetitive
alone
Respones(%)
Emax
Receptors
antagonist in
presence of spare
receptor
Log Concentration
antagonist in
absence of
spare receptor
Antagonist like to bind to
receptor in R and R” state
without any preference and
makes no shifts in net
equilibrium
Agonist like to bind to
receptor in R’ state and
shifts the equilibrium
toward more LR’ and
makes effect
R
R’
L
L
Effect
No effect
LR
LR’
Inverse agonist has
more affinity to receptor
Partial agonist has a little
in R state and shifts the
more affinity for receptor in R’
equilibrium toward more
states than R state and makes
LR and make negative
partial effect
response than resting
state.
Possible mechanism for the partial agonist phenomenon.
Desensitization and Tachyphylaxis
Desensitization
Tolerance
Refractoriness
Drug resistance
Changes in receptor
Loss of receptor
How?
Exhaustion of mediators
Increased metabolic degradation
Physiological adaptation
Active extrusion of drug from cells
Drug Antagonism
Pharmacologic
Chemical
Propranolol &
norepinephrine
Dimercaprol &
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
R
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
G protein coupled receptors
Ions
R
+
G
Change in
excitability
Ca2+ release
-
+
G
E
-
Second messengers
Protein
phosphorylation
Cell effects
other
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