lecture pharmacodynamics

7/29/2019 Lecture Pharmacodynamics

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PharmacodynamicsPharmacodynamics

Jo G. R. De MeyDept. of Pharmacology

Cardiovascular Research Institute MaastrichtMaastricht University

[email protected]

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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Activation

Binding (affinity)

KD

= k-1/k

+1K

DD + R DR

D + R* DR*15


Activation

Binding (affinity)

KD

= k-1/k

+1K

DD + R DR

D + R* DR*

L L

KD 16


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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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Agonist

Ligand that displays affinity andefficacy at its receptors

Antagonist

Ligand that displays affinity but noefficacy at its receptors

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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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1 1 2


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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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lecture pharmacodynamics

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