Lecture Pharmacodynamics
Transcript of Lecture Pharmacodynamics
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PharmacodynamicsPharmacodynamics
Jo G. R. De MeyDept. of Pharmacology
Cardiovascular Research Institute MaastrichtMaastricht University
Nov 20111
PharmacologyPharmacology
Pharmacodynamics
Drug body
Pharmacokinetics Body drug
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Why worry?Why worry?
50 % of the medical profession is relatedto drugs
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DrugsDrugs
A synthetic compound
An endogenous compound
Hormone, neurotransmitter, ...
That influences the function of organs
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Receptors as DrugReceptors as Drug--TargetsTargets
Classification of marketed drugs
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ReceptorReceptor
In physiology
A cell or nerve ending that senses avariable in the environment
In pharmacology
A protein that is acted upon by its ligand
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Learning goalLearning goal
Understand receptor function
Affinity, efficacy
Selectivity
Agonism, antagonism
...
General principles!
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Block 1.2Block 1.2
Effects of exercise (stress) on
CV system
Respiratory system
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Blood pressureBlood pressure
MAP = CO x TPR
MAP = mean arterial pressure
CO = cardiac output
CO = SV x HR
TPR = total peripheral vascular resistance
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ExerciseExercise and CV systemand CV system
Cardiac outputCoronary blood flow
Total peripheral vascular resistance
Venous capcitance
Mediated by noradrenaline and adrenaline
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!!!!!!
Noradrenaline (NA) Norepinephrine
Adrenaline (A) Epinephrine
Effects in some organs but not in other
organs
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RegionalityRegionality
NA and A are drugs (D).
D acts on a receptor (R) on a cell and this
leads to an effect.
D R effect
R on some celltypes but not on others12
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Receptor functionReceptor function
Activation
Binding
D + R DR
D + R* DR*13
ConcentrationConcentration--ResponseResponse
[D] (M) Log[D] (M) Log[D] (M)
DR*/Rt
DR*/Rt
Effect
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Receptor functionReceptor function
Activation
Binding (affinity)
KD
= k-1/k
+1K
DD + R DR
D + R* DR*15
Receptor functionReceptor function
Activation
Binding (affinity)
KD
= k-1/k
+1K
DD + R DR
D + R* DR*
L L
KD 16
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Receptor functionReceptor function
Activation (efficacy, L)
Binding (affinity)
KD
= k-1
/k+1
KD
D + R DR
D + R* DR*
L L
KD 17
Types of drugsTypes of drugs
Agonist
Ligand that displays affinity andefficacy at its receptors
Partial agonist
Ligand that displays affinity and asmall efficacy at its receptors
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Types of drugsTypes of drugs
Agonist
Ligand that displays affinity andefficacy at its receptors
Antagonist
Ligand that displays affinity but noefficacy at its receptors
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Types of drugsTypes of drugs
Antagonist
Ligand that displays affinity but no
efficacy at its receptors
Inverse agonist
Ligand that displays affinity andnegative efficacy at its receptors
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Affinity, Efficacy?Affinity, Efficacy?
Log[D] (M) Log[D] (M)
DR
*/Rt
Ef
fect
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CompetitiveCompetitive AntagonismAntagonism
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CompetitiveCompetitive AntagonismAntagonism
Log [agonist] (M)
Effect
In presence ofIncreasing
[antagonist]
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ReceptorReceptorss!!
Various (sub)types
For various hormones, neurotransmitters,
Ach, NA/A, histamine, insulin, etc
Several thousands / cell
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AdrenergicAdrenergic ReceptorsReceptors
G-protein coupled receptors for NA / A
Note that receptors are named after theirendogenous ligand
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CatecholaminesCatecholamines
NA, A, ISO
Synthesis in:-Post-ganglionic sympathetic nerves-Chromaffin cells of adrenal medulla
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DirectDirect AdrenergicAdrenergic EffectsEffects
Log[D] (M)
Be
ats/min
Log[D] (M)
Con
striction
Log[D] (M)
Relaxation
NA, A, ISO
Heart Artery Airway
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AgonistAgonist--PotencyPotency OrdersOrders
Arterial smooth muscle NA > A >> ISO 1
Cardiomyocyte ISO >> A > NA 1
Airway smooth muscle ISO >> A >> NA 2
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AgonistAgonist--PotencyPotency OrdersOrders
Indicate a relationship between the structure and the activityof a drug. (SAR)
Suggest the existence of different receptors.
Can be confirmed by:- Selective antagonists- Etc
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StructureStructure--ActivityActivity RelationshipsRelationships
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AdrenergicAdrenergic AntagonistsAntagonists
Affinity EfficacyPrazosin 1 >> 1,2 ---
Propranolol 1,2 >> 1 ---
Metoprolol 1 > 2 >> 1 ---
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AdrenalineAdrenaline
Log[D] (M)
Be
ats/min
Log[D] (M)
Con
striction
Log[D] (M)
Re
laxation
Non-selective AR-agonist in absence and presence of1-blocker, -blocker, 1-blocker
Heart Artery Airway
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NoteNote!!
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The examples given in this lecture wereintended to illustrate general principles
Receptors and drugs
The similarities between endogenousand exogenous drugs
Affinity, selectivity and efficacy
NoteNote!!
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Understanding these principles shouldbe helpful for rational pharmacotherapy.
The study of these principles continuesto be the source of novel drugs.
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Thank YouThank You
Very MuchVery Much
Questions?
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