Pharmacodynamics

Jo G. R. De Mey Dept. of Pharmacology Cardiovascular Research Institute Maastricht Maastricht University

j.demey@maastrichtuniversity.nl

Pharmacology
Pharmacodynamics Drug body Pharmacokinetics Body drug

Nov 2011

Why worry?
50 % of the medical profession is related to drugs

Drugs
A synthetic compound An endogenous compound
Hormone, neurotransmitter, ...

That influences the function of organs

Receptors as DrugDrug-Targets Classification of marketed drugs

Receptor

In physiology
A cell or nerve ending that senses a variable in the environment

In pharmacology
A protein that is acted upon by its ligand

Learning goal

Block 1.2

Understand receptor function

Affinity, efficacy Selectivity Agonism, antagonism ...

Effects of exercise (stress) on

CV system Respiratory system

General principles!
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Blood pressure

Exercise and CV system

MAP = CO x TPR
MAP = mean arterial pressure CO = cardiac output CO = SV x HR TPR = total peripheral vascular resistance
Cardiac output Coronary blood flow Total peripheral vascular resistance Venous capcitance

Mediated by noradrenaline and adrenaline

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!!!

Regionality
NA and A are drugs (D).

Noradrenaline (NA)
Norepinephrine

Adrenaline (A)
Epinephrine

D acts on a receptor (R) on a cell and this leads to an effect. D R effect

Effects in some organs but not in other organs

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R on some celltypes but not on others

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Receptor function
Activation Binding

ConcentrationConcentration -Response

DR*/Rt

D + R*

DR*
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DR*/Rt

[D] (M)

Log[D] (M)

Effect Log[D] (M)

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D+R

DR

Receptor function
Activation Binding (affinity) KD = k-1/k+1 D+R KD DR

Receptor function
Activation Binding (affinity) KD = k-1/k+1 D+R L

KD DR L KD DR*
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D + R*

DR*
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D + R*

Receptor function
Activation (efficacy, L) Binding (affinity) KD = k-1/k+1 D+R L D + R* KD

Types of drugs
Agonist Ligand that displays affinity and efficacy at its receptors Partial agonist Ligand that displays affinity and a small efficacy at its receptors
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KD DR L DR*
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Types of drugs
Agonist Ligand that displays affinity and efficacy at its receptors Antagonist Ligand that displays affinity but no efficacy at its receptors
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Types of drugs
Antagonist Ligand that displays affinity but no efficacy at its receptors Inverse agonist Ligand that displays affinity and negative efficacy at its receptors
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Affinity, Efficacy?

Competitive Antagonism

DR*/Rt

Log[D] (M)

Effect Log[D] (M)

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Competitive Antagonism

Effect
In presence of Increasing [antagonist]

Receptors!
Various (sub)types
For various hormones, neurotransmitters, Ach, NA/A, histamine, insulin, etc

Several thousands / cell

Log [agonist] (M)

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Adrenergic Receptors
G-protein coupled receptors for NA / A Note that receptors are named after their endogenous ligand

Catecholamines
Synthesis in: -Post-ganglionic sympathetic nerves -Chromaffin cells of adrenal medulla

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NA, A, ISO

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Direct Adrenergic Effects

Heart Artery Airway

AgonistAgonist -Potency Orders

Constriction

Relaxation

Arterial smooth muscle Cardiomyocyte Airway smooth muscle Log[D] (M)

NA > A >> ISO ISO >> A > NA ISO >> A >> NA

1 1 2

Beats/min

Log[D] (M)

Log[D] (M)

NA, A, ISO

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AgonistAgonist -Potency Orders

StructureStructure -Activity Relationships

Indicate a relationship between the structure and the activity of a drug. (SAR) Suggest the existence of different receptors. Can be confirmed by: - Selective antagonists - Etc

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Adrenergic Antagonists
Heart

Adrenaline
Artery Airway

Constriction

Prazosin Propranolol Metoprolol

Relaxation

Beats/min

Affinity 1 >> 1,2 1,2 >> 1 1 > 2 >> 1

Efficacy -------

Log[D] (M)

Log[D] (M)

Log[D] (M)

Non-selective AR-agonist in absence and presence of 1-blocker, -blocker, 1-blocker

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Note! Note !

Note! Note !

The examples given in this lecture were intended to illustrate general principles Receptors and drugs The similarities between endogenous and exogenous drugs Affinity, selectivity and efficacy
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Understanding these principles should be helpful for rational pharmacotherapy. The study of these principles continues to be the source of novel drugs.

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Thank You Very Much

Questions?

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