Transcript Pharmacodynamics
Pharmacodynamics
Collected and Prepared By S.Bohlooli, PhD
LOCUS OF ACTION “RECEPTORS
”
Bound Free TISSUE RESERVOIRS Free Bound ABSORPTION Free Drug Bound Drug SYSTEMIC CIRCULATION EXCRETION 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
D
R k
1
k
2
DR
effect
By law of mass action: [
D
].[
R
].
k
1 [
DR
].
k
2 Therefore:
k
2
K D k
1 [
D
].[
R
] [
DR
]
K D
[
D
].[
R
] [
DR
] Total number of receptors: R t = [R] + [DR] [R] = R t – [DR]
K D
[
D
].(
R t
[
DR
] [
DR
]) [
D
].
R t
[
D
[
DR
] ].[
DR
] After rearrangement: [
DR
]
K
[
D D
].
R t
[
D
] [
DR
]
R t K D
[
D
] [
D
]
When [D] = K D [DR] = 0.5
R T 1.00
0.75
0.50
0.25
0.00
0
K D
5
[
DR
]
R t K D
[
D
] [
D
]
10 [D] 15 20
Receptor Binding
K D 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 B C Log Drug Concentration
100 Full and partial agonist occupancy and response relationship 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 AG + ANT
EC 50 EC 50
Drug Concentration (log scale)
Noncompetitive Antagonism Decreases Agonist
Efficacy
AG alone AG + NC ANT AG + higher dose NC ANT Log Drug Concentration
Spare receptor
Receptors 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 full complement of available receptors alone antagonist in Agonist with noncompetitive antagonist in presence of spare receptor absence of spare receptor Log Concentration
Antagonist like to bind to receptor in R and R” state without any preference and makes no shifts in net equilibrium L R No effect Agonist like to bind to receptor in R’ state and shifts the equilibrium toward more LR’ and R’ makes effect L Effect LR LR’ Inverse agonist has more affinity to receptor in R state and shifts the Partial agonist has a little more affinity for receptor in R’ equilibrium toward more LR and make negative states than R state and makes partial effect response than resting state.
Possible mechanism for the partial agonist phenomenon.
Desensitization and Tachyphylaxis Desensitization Tolerance Refractoriness Drug resistance How?
Changes in receptor Loss of receptor Exhaustion of mediators Increased metabolic degradation Physiological adaptation Active extrusion of drug from cells
Drug Antagonism Pharmacologic Chemical Pharmacokinetic Physiologic Propranolol & norepinephrine Dimercaprol & heavy metals Phenobarbital & warfarine 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
Ions
G protein coupled receptors
+ G R Change in excitability
E
+ G Second messengers Ca 2+ release Protein phosphorylation other 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)