Embed Size (px)
DESCRIPTION
Principles of Pharmacology: Pharmacodynamics. Dennis Paul, Ph.D. [email protected]. Learning Objectives:. Understand the theoretical basis of drug-receptor interactions. Understand the determinants and types of responses to drug-receptor interactions. - PowerPoint PPT Presentation
Citation preview
Principles of Principles of Pharmacology:Pharmacology:
PharmacodynamicsPharmacodynamics
Dennis Paul, Ph.D.Dennis Paul, Ph.D.
[email protected]@lsuhsc.edu
Learning Objectives:Learning Objectives:
Understand the theoretical basis of drug-Understand the theoretical basis of drug-receptor interactions.receptor interactions.
Understand the determinants and types Understand the determinants and types of responses to drug-receptor of responses to drug-receptor interactions.interactions.
Know the four major families of receptors.Know the four major families of receptors. Define potency and efficacy.Define potency and efficacy. Understand how to compare drug Understand how to compare drug
potency and efficacy.potency and efficacy. Understand the consequences of receptor Understand the consequences of receptor
regulationregulation Understand measures of drug safety. Understand measures of drug safety.
TEXT:TEXT:
CHAPTER 2 – CHAPTER 2 – “PHARMACODYNAMICS: “PHARMACODYNAMICS: Mechanisms of Drug Action and the Mechanisms of Drug Action and the Relationship between Drug Relationship between Drug Concentration and Effect” – Concentration and Effect” – GOODMAN AND GILMAN’S THE GOODMAN AND GILMAN’S THE PHARMACOLOGICAL BASIS OF PHARMACOLOGICAL BASIS OF THERAPEUTICS – 10th edition THERAPEUTICS – 10th edition
Biochemistry:Biochemistry:
L+S LSL+S LS
Biochemistry:Biochemistry:
L+S LSL+S LS
Pharmacology:Pharmacology: L+R LR L+R LR
Biochemistry:Biochemistry:
L+S LS L+S LS (Langmuir (Langmuir equation)equation)
Pharmacology:Pharmacology: L+R LR ResponseL+R LR Response
PharmacodynamicsPharmacodynamics
Drugs:Drugs:
Chemical agents that interact with Chemical agents that interact with components of a biological system components of a biological system to alter the organism’s function. to alter the organism’s function. Examples of such components, sites of Examples of such components, sites of drug action, are enzymes, ion channels, drug action, are enzymes, ion channels, neurotransmitter transport systems, neurotransmitter transport systems, nucleic acids and receptors. Many drugs nucleic acids and receptors. Many drugs act by mimicking or inhibiting the act by mimicking or inhibiting the interactions of endogenous mediators interactions of endogenous mediators with their receptors with their receptors
Receptors:Receptors:
Regulatory proteins that interact Regulatory proteins that interact with drugs or hormones and with drugs or hormones and initiate a cellular responseinitiate a cellular response– Ion channelsIon channels– G-protein coupled receptorsG-protein coupled receptors– Receptor-enzymesReceptor-enzymes– Cytosolic-nuclear receptorsCytosolic-nuclear receptors
Act as transducer proteinsAct as transducer proteins– Receptor-effector signal transductionReceptor-effector signal transduction– Post-receptor signal transduction Post-receptor signal transduction
provides for amplification of the provides for amplification of the signalsignal
Ligand-gated Ion Ligand-gated Ion ChannelsChannels
G-protein coupled G-protein coupled receptorsreceptors
α
β γ
G-protein coupled G-protein coupled receptorsreceptors
α
β γ
Membrane
G-protein coupled G-protein coupled receptorsreceptors
α β γ
Receptor-enzymeReceptor-enzyme
Catalytic site
Binding site
Cytosolic-Nuclear Cytosolic-Nuclear receptorsreceptors
Classical Receptor Classical Receptor Occupancy TheoryOccupancy Theory
KKa a
L+R LRL+R LR Stimulus Stimulus ResponseResponse
KKdd
L: Ligand (Drug)L: Ligand (Drug)R: ReceptorR: ReceptorLR: Ligand-Receptor ComplexLR: Ligand-Receptor Complex
KKaa: Association rate constant: Association rate constantStimulus: initial effect of drug on Stimulus: initial effect of drug on
receptorreceptor
Properties of drugsProperties of drugs
Affinity: The chemical forces Affinity: The chemical forces that cause the drug to that cause the drug to associate with the receptor.associate with the receptor.
Efficacy: The extent of Efficacy: The extent of functional change imparted to functional change imparted to a receptor upon binding of a a receptor upon binding of a drug.drug.
Properties of a Properties of a biological systembiological system Potency:Potency: Dose of drug necessary Dose of drug necessary
to produce a specified effect.to produce a specified effect.– Dependent upon receptor density, Dependent upon receptor density,
efficiency of the stimulus-response efficiency of the stimulus-response mechanism, affinity and efficacy.mechanism, affinity and efficacy.
Magnitude of effect:Magnitude of effect: Asymptotic maximal responseAsymptotic maximal response– Solely dependent upon intrinsic Solely dependent upon intrinsic
efficacy.efficacy.– Also called Also called efficacy.efficacy.
Determinants of Determinants of ResponseResponse Intrinsic Efficacy (Intrinsic Efficacy (εε): Power of a ): Power of a
drug to induce a response.drug to induce a response. Number of receptors in the target Number of receptors in the target
tissue.tissue.
Spare receptorsSpare receptors
Some tissues have more Some tissues have more receptors than are necessary to receptors than are necessary to produce a maximal response.produce a maximal response.– Dependent on tissue, measure of Dependent on tissue, measure of
response and intrinsic efficacy of the response and intrinsic efficacy of the drug.drug.
Active vs Inactive Active vs Inactive statesstates Active states initiate cell Active states initiate cell
signaling.signaling. For any cell, there is an For any cell, there is an
equilibrium between active an equilibrium between active an inactive states. The inactive inactive states. The inactive state usually predominates.state usually predominates.
Each state has its own affinity.Each state has its own affinity.
Classification of a drug Classification of a drug based on drug-receptor based on drug-receptor interactions:interactions: Agonist:Agonist: Drug that binds to receptors and Drug that binds to receptors and
initiates a cellular response; has affinity initiates a cellular response; has affinity and efficacy. Agonists promote the active and efficacy. Agonists promote the active state.state.
Antagonist:Antagonist: drug that binds to receptors drug that binds to receptors but cannot initiate a cellular response, but but cannot initiate a cellular response, but prevent agonists from producing a prevent agonists from producing a response; affinity, but no efficacy. response; affinity, but no efficacy. Antagonists maintain the active-inactive Antagonists maintain the active-inactive equilibrium.equilibrium.
cont.cont.
Partial agonists:Partial agonists: Drug that, no Drug that, no matter how high the dose, cannot matter how high the dose, cannot produce a full response.produce a full response.
Inverse agonist:Inverse agonist: Drug that Drug that binds to a receptor to produce an binds to a receptor to produce an effect opposite that of an agonist. effect opposite that of an agonist. Stabilizes receptors in the Stabilizes receptors in the inactive state.inactive state.
Graded dose-response Graded dose-response curvescurves Individual responses to varying Individual responses to varying
dosesdoses Concepts to remember:Concepts to remember:
– Threshold:Threshold: Dose that produces a Dose that produces a just-noticeable effect.just-noticeable effect.
– EDED5050:: Dose that produces a 50% Dose that produces a 50% of maximum response.of maximum response.
– Ceiling:Ceiling: Lowest dose that Lowest dose that produces a maximal effect.produces a maximal effect.
Dose-response curveDose-response curve
Dose
Resp
on
se
0
20
40
60
80
100
0 200 400 600 800 1000
Dose-response curveDose-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
40
60
80
100
0.1 1 10 100 1000 10000
Dose-response curveDose-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 agonistsFull 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 agonistsFull vs Partial agonists
These terms are tissue dependent These terms are tissue dependent onon– Receptor densityReceptor density– Cell signaling apparatusCell signaling apparatus– Other receptors that are presentOther receptors that are present– Drug historyDrug history
Partial agonists have both agonist Partial agonists have both agonist and antagonist properties.and antagonist properties.
Inverse AgonistInverse 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 PotencyRelative Potency
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A B
Dose
Eff
ec
t
Relative PotencyRelative Potency
Dose
Eff
ec
t
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A B
Relative PotencyRelative Potency
=ED=ED5050B/EDB/ED5050AA
320/3.2=100320/3.2=100
Relative EfficacyRelative Efficacy
0
20
40
60
80
100
0.1 1 10 100 1000 10000
Relative Efficacy
AntagonistsAntagonists
Competitive:Competitive: Antagonist binds to Antagonist binds to same site as agonist in a reversible same site as agonist in a reversible manner.manner.
Noncompetitive:Noncompetitive: Antagonist binds to Antagonist binds to the same site as agonist irreversibly.the same site as agonist irreversibly.
Allosteric:Allosteric: Antagonist and agonist Antagonist and agonist bind to different site on same receptorbind to different site on same receptor
Physiologic:Physiologic: Two drugs have Two drugs have opposite effects through differing opposite effects through differing mechanismsmechanisms
= 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
CompetitionCompetition
0
200
400
600
800
1000
1200
-11 -10 -9 -8 -7 -6
IC50
log [antagonist]
Eff
ect
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
= Agonist = Antagonist
Competitive Competitive antagonistsantagonists
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A CB
Dose
Resp
on
se
Noncompetitive Noncompetitive antagonistsantagonists
Dose
Resp
on
se
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A
C
B
Allosteric and Allosteric and Physiologic Physiologic antagonistsantagonists Response can be irregularResponse can be irregular
Allosteric AntagonismAllosteric Antagonism
Allosteric AntagonismAllosteric Antagonism
Allosteric AntagonismAllosteric Antagonism
Allosteric AntagonismAllosteric Antagonism
Allosteric antagonists Allosteric antagonists 11
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A
Dose
Resp
on
se
Allosteric antagonists Allosteric antagonists 22
Dose
Resp
on
se
0
20
40
60
80
100
0.1 1 10 100 1000 10000
A
C
B
Receptor regulationReceptor regulation
Reduced responsivity: Chronic Reduced responsivity: Chronic use of an agonist can result in use of an agonist can result in the receptor-effector system the receptor-effector system becoming less responsivebecoming less responsive
– eg. alpha-adrenoceptor agents eg. alpha-adrenoceptor agents used as nasal decongestantsused as nasal decongestants
Myasthenia gravis: decrease in Myasthenia gravis: decrease in number of functional number of functional acetylcholine nicotinic receptors acetylcholine nicotinic receptors at the neuromuscular junction. at the neuromuscular junction.
Receptor regulationReceptor regulation
Increased responsivity: Chronic Increased responsivity: Chronic disuse of a receptor-effector system disuse of a receptor-effector system can result in an increased can result in an increased responsiveness upon re-exposure to responsiveness upon re-exposure to an agonist.an agonist.
– Denervation supersensitivity at skeletal Denervation supersensitivity at skeletal muscle acetylcholine nicotinic receptorsmuscle acetylcholine nicotinic receptors
– Thyroid induced upregulation of cardiac Thyroid induced upregulation of cardiac beta-adrenoceptorsbeta-adrenoceptors
– Prolonged use of many antagonists Prolonged use of many antagonists (pharmacological as well as functional) (pharmacological as well as functional) can result in receptor upregulationcan result in receptor upregulation
Receptor UpregulationReceptor Upregulation
Most receptors are internalized Most receptors are internalized and degraded or recycled with age and degraded or recycled with age and use.and use.
Antagonists slow use-dependent Antagonists slow use-dependent internalizationinternalization
Inverse agonists stabilize the Inverse agonists stabilize the receptor in the inactive state to receptor in the inactive state to prevent internalization.prevent internalization.
The cell continues to produce The cell continues to produce receptors.receptors.
Desired vs undesired Desired vs undesired effects: Indices of drug effects: Indices of drug safety.safety. Safety IndexSafety Index Therapeutic IndexTherapeutic Index
Safety index: LDSafety index: LD11/ED/ED9999
-20
0
20
40
60
80
100
0.00
010.
001
0.01 0.
1 1 10 100 1K 10
K10
0K
Sleep Death
LDLD11
EDED9999
Therapeutic index: Therapeutic index: LDLD5050/ED/ED5050
-20
0
20
40
60
80
100
0.00
010.
001
0.01 0.
1 1 10 100 1K 10
K10
0K
Sleep Death
