principles of pharmacology: pharmacodynamics dennis paul, ph.d. [email protected]
TRANSCRIPT
Learning Objectives:
Understand the theoretical basis of drug-receptor interactions.
Understand the determinants and types of responses to drug-receptor interactions.
Know the four major families of receptors.
Define potency and efficacy. Understand how to compare drug
potency and efficacy. Understand the consequences of
receptor regulation Understand measures of drug safety.
Biochemistry:
L+S LS
Biochemistry:
L+S LS (Langmuir equation)
Pharmacology:L+R LR
Biochemistry:
L+S LS
Pharmacology:L+R LR Response
Pharmacodynamics
Drugs:
Chemical agents that interact with components of a biological system to alter the organism’s function. Examples of such components, sites of drug action, are enzymes, ion channels, neurotransmitter transport systems, nucleic acids and receptors. Many drugs act by mimicking or inhibiting the interactions of endogenous mediators with their receptors
Receptors:
Regulatory proteins that interact with drugs or hormones and initiate a cellular response– Ion channels– G-protein coupled receptors– Receptor-enzymes– Cytosolic-nuclear receptors
Act as transducer proteins– Receptor-effector signal transduction– Post-receptor signal transduction
provides for amplification of the signal
Mg++
Ca++
Na+
Na+
K+
Ligand-gated Ion Channels
Mg++
Ca++
Ca++
Na+
Na+
Na+Na+
Na+
Mg++
Ca++
K+
Ligand-gated Ion Channels Mg++
Ca++
Ca++
Na+
Na+
G-protein coupled receptors
NH3+
COOH-
GTP
agb
G-protein coupled receptors
NH3+
COOH-
GDP
agb
Receptor-enzyme
Catalytic site
Receptor-enzyme
Catalytic site
Cytosolic-Nuclear receptors
Cytosolic-Nuclear receptors
Classical Receptor Occupancy Theory
Ka
L+R LR Stimulus Response
KdL: Ligand (Drug)R: ReceptorLR: Ligand-Receptor ComplexKa: Association rate constantStimulus: initial effect of drug on
receptor
Properties of drugs
Affinity: The chemical forces that cause the drug to associate with the receptor.
Efficacy: The extent of functional change imparted to a receptor upon binding of a drug.
Properties of a biological system Potency: Dose of drug
necessary to produce a specified effect.– Dependent upon receptor density,
efficiency of the stimulus-response mechanism, affinity and efficacy.
Magnitude of effect: Asymptotic maximal response– Solely dependent upon intrinsic
efficacy.– Also called efficacy.
Determinants of Response Intrinsic Efficacy (ε): Power of a
drug to induce a response. Number of receptors in the target
tissue.
Spare receptors
Some tissues have more receptors than are necessary to produce a maximal response.– Dependent on tissue, measure of
response and intrinsic efficacy of the drug.
Active vs Inactive states Receptors in an active state
initiate cell signaling. For any cell, there is an
equilibrium between receptors in active and inactive states. The inactive state usually predominates.
Each state has its own affinity.
Classification of a drug based on drug-receptor interactions: Agonist: Drug that binds to receptors
and initiates a cellular response; has affinity and efficacy. Agonists promote the active state.
Antagonist: drug that binds to receptors but cannot initiate a cellular response, but prevent agonists from producing a response; affinity, but no efficacy. Antagonists maintain the active-inactive equilibrium.
cont.
Partial agonists: Drug that, no matter how high the dose, cannot produce a full response.
Inverse agonist: Drug that binds to a receptor to produce an effect opposite that of an agonist. Stabilizes receptors in the inactive state.
Graded dose-response curves Individual responses to varying doses Concepts to remember:
– Threshold: Dose that produces a just-noticeable effect.
– ED50: Dose that produces a 50% of maximum response. (EC50: blood concentration that produces a 50% of max response)
– Ceiling: Lowest dose that produces a maximal effect.
Dose-response curve
Dose
Resp
on
se
0
20
40
60
80
100
0 200 400 600 800 1000
Dose-response curve
Dose
Resp
on
se
0
20
40
60
80
100
0.1 1 10 100 1000 10000
= Agonist
0
20
40
60
80
100
0.1 1 10 100 1000 10000
= Agonist
0
20
40
60
80
100
0.1 1 10 100 1000 10000
= Agonist
0
20
40
60
80
100
0.1 1 10 100 1000 10000
= Agonist
0
20
40
60
80
100
0.1 1 10 100 1000 10000
= Agonist
0
20
40
60
80
100
0.1 1 10 100 1000 10000
= Agonist
0
20
40
60
80
100
0.1 1 10 100 1000 10000
= Agonist
0
20
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60
80
100
0.1 1 10 100 1000 10000
Dose-response curve
Dose
Resp
on
se
0
20
40
60
80
100
0.1 1 10 100 1000 10000
Ceiling
ED50
Threshold
ED50
Full vs Partial agonists
0
20
40
60
80
100
0.1 1 10 100 1000 10000
Full Agonist
Partial Agonist
Dose
% E
ffect
Full vs Partial agonists
These terms are tissue dependent on– Receptor density– Cell signaling apparatus– Other receptors that are present– Drug history
Partial agonists have both agonist and antagonist properties.
Inverse Agonist
Dose
% E
ffect
-40
-20
0
20
40
60
80
100
1 1 0 1 0 0 1 0 0 0 1 0 0 0 0
Full agonist
Partial agonist
Inverse agonist
Relative Potency
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A B
Dose
Eff
ec
t
Relative Potency
Dose
Eff
ec
t
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A B
Relative Potency
=ED50B/ED50A
320/3.2=100
Relative Efficacy
0
20
40
60
80
100
0.1 1 10 100 1000 10000
Relative Efficacy
Antagonists
Competitive: Antagonist binds to same site as agonist in a reversible manner.
Noncompetitive: Antagonist binds to the same site as agonist irreversibly.
Allosteric: Antagonist and agonist bind to different site on same receptor
Physiologic: Two drugs have opposite effects through differing mechanisms
= Agonist = Antagonist
0
20
40
60
80
100
120
-10.5 -10 -9.5 -9 -8.5 -8 -7.5 -7 -6.5 -6
= Agonist = Antagonist
0
20
40
60
80
100
120
-11 -10 -9 -8 -7 -6
= Agonist = Antagonist
0
20
40
60
80
100
120
-11 -10 -9 -8 -7 -6
= Agonist = Antagonist
0
20
40
60
80
100
120
-11 -10 -9 -8 -7 -6
= Agonist = Antagonist
0
20
40
60
80
100
120
-11 -10 -9 -8 -7 -6
= Agonist = Antagonist
0
20
40
60
80
100
120
-11 -10 -9 -8 -7 -6
= Agonist = Antagonist
0
20
40
60
80
100
120
-11 -10 -9 -8 -7 -6
Competition
0
200
400
600
800
1000
1200
-11 -10 -9 -8 -7 -6
ID50 or IC50
log [antagonist]
Eff
ect
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
Competitive antagonists
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A CB
Dose
Resp
on
se
Noncompetitive antagonists
Dose
Resp
on
se
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A
C
B
Allosteric and Physiologic antagonists Response can be irregular
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric Antagonism
Allosteric antagonists 1
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A
Dose
Resp
on
se
Allosteric antagonists 2
Dose
Resp
on
se
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A
C
B
Quantal Dose-Response Curves
Also known as concentration-percent or dose-percent curves
Used when the dose of a drug to produce a specified effect in a single patient is measured (individual effective dose or concentration.)
The percent of subjects responding at a dose is plotted.
Quantal Dose-Response Curves
1 3.2 10 32 100 320 1000 32000
10
20
30
40
50
60
70
80
90
100
DosePerc
en
t R
esp
on
ders
Cumulative Quantal Dose-Response Curves
1 3.2 10 32 100 320 1000 32000
20
40
60
80
100
120
DosePerc
en
t R
esp
on
ders
Cumulative Quantal Dose-Response Curves
1 10 100 1000 100000
20
40
60
80
100
120
DosePerc
en
t R
esp
on
ders
Receptor regulation
Reduced responsivity: Chronic use of an agonist can result in the receptor-effector system becoming less responsive
– eg. alpha-adrenoceptor agents used as nasal decongestants
Myasthenia gravis: decrease in number of functional acetylcholine nicotinic receptors at the neuromuscular junction.
Receptor regulation
Increased responsivity: Chronic disuse of a receptor-effector system can result in an increased responsiveness upon re-exposure to an agonist.
– Denervation supersensitivity at skeletal muscle acetylcholine nicotinic receptors
– Thyroid induced upregulation of cardiac beta-adrenoceptors
– Prolonged use of many antagonists (pharmacological as well as functional) can result in receptor upregulation
Receptor Upregulation
Most receptors are internalized and degraded or recycled with age and use.
Antagonists slow use-dependent internalization
Inverse agonists stabilize the receptor in the inactive state to prevent internalization.
The cell continues to produce receptors.
Desired vs undesired effects: Indices of drug safety. Safety Index Therapeutic Index
“Potency means nothing. I can always give a bigger pill.”
J. Hunter
Safety index: LD1/ED99
-20
0
20
40
60
80
100
0.00
010.
001
0.01 0.
1 1 10 100 1K 10
K10
0K
Sleep Death
LD1
ED99
Therapeutic index: LD50/ED50
-20
0
20
40
60
80
100
0.00
010.
001
0.01 0.
1 1 10 100 1K 10
K10
0K
Sleep Death
Safety Index vs. Therapeutic Index
1 10 100 1000 10000 1000000
20
40
60
80
100
Dose
Perc
en
t Eff
ect
LethalityDesired Effect
LD50ED50 ED99 LD1
Safety Index
Therapeutic Index