ch02 drug receptor interactions and pharmacodynamics

by Lee Eun Jin

UNIT I:Introduction to Pharmacology

Chapter 2Drug-ReceptorInteractions andPharmacodynamics

Chapter 2: Drug-Receptor Interactions and Pharmacodynamics2

DoseDose EffectEffectEffect site Effect site ConcentrationConcentration

Pharmacokinetics Pharmacodynamics

AbsorptionAbsorption

DistributionDistribution

MetabolismMetabolism

Elimination Elimination

Drug interactionsDrug interactions

Tissue/organ sensitivity Tissue/organ sensitivity (target status)(target status)

What is pharmacodynamics?I. OVERVIEW

Lecture Objectives

To understand the basic concepts regarding pharmacodynamics To define agonist and antagonists and other terms in relation to pharmacodynamics To explain the mechanism of drug receptor interaction Define spare receptors To differentitate between different tyes of antagonism


Action of a drug on the body receptor interactions, mechanisms of therapeutic dose-response phenomena, toxic action.


A drug will not work unless it is bound

PARTICULAR CONSTITUENTS OFCELLS & TISSUES IN ORDER TO

PRODUCE AN EFFECT

PROTEINS LIPIDS DNA


DRUGS THAT ACT WITHOUT BEING BOUND TO ANY OF THE TISSUE CONSTITUENTS

OSMOTIC DIURETICSOSMOTIC PURGATIVESANTACIDSHEAVY METALS CHELATING

AGENTS


Drug Receptor

A macromolecular component of a cell with which a drug interacts to produce a response

Usually a protein


Receptors

Receptors must be biologically important molecules

Receptors must have structural features that permit drug specificity

Receptors must have a drug-binding site and a biologically active site


Characteristics of Characteristics of ReceptorsReceptors

a. specificity a. specificity

b. selectivity of response b. selectivity of response

c. sensitivity c. sensitivity


Molecules capable of serving as Molecules capable of serving as ReceptorsReceptors

Enzymes

Membrane proteins

(glycoproteins, lipoproteins)

Nucleic acids

Complex polysaccharides


Many drugs inhibit enzymes

in the patient (ACE inhibitors)

in microbes (sulfas, Penicillins)

in cancer cells (5-FU, 6-MP)


Types of Protein ReceptorsRegulatory – mediate the action of endogenous

chemicals e.g. hormones, NT , autocoids

Enzymes – may be inhibited or activated e.g. dihydrofolate reductase, receptor for methotrexate

Transport – e.g. Na+ /K+ ATP’ase for digitalis glycosides

Structural – e.g. tubulin,receptor for colchicin


some drugs bind to:

the genome (cyclophosphamide)

microtubules (vincristine)


Non-receptor Mediated EffectsNon-receptor Mediated Effects Interaction with small molecules

(e.g. binding of heavy metals)

Interaction with enzymes

(e.g. sulfonamides, digitalis)

Incorporation into a macromolecule

(e.g. some anticancer agents - purine and pyrimidine analogues)

Nonspecific effects (e.g. membrane perturbation by general anesthetics)


Receptor regulationReceptor regulation

1.1. HomeostasisHomeostasis

2. Up and down regulation 2. Up and down regulation

3. Desensitization 3. Desensitization

4. Tolerance o4. Tolerance or regulationr regulation


agonists desensitize receptors

homologous

(decreased receptor number)

heterologous

(decreased signal transduction

a. Occupation theorya. Occupation theory

D + R D + R DR DR RESPONSE RESPONSE:response is proportional to the fraction of occupied :response is proportional to the fraction of occupied receptors receptors :maximal response occurs when all the receptors are occupied :maximal response occurs when all the receptors are occupied


AriensAriens

response is proportional to the fraction of response is proportional to the fraction of

occupied receptors occupied receptors ANDAND the the intrinsic activity intrinsic activity

Stephenson Stephenson response is aresponse is a FUNCTION FUNCTION of occupancy of occupancy maximum response can be produced maximum response can be produced

WITHOUT 100% occupation, WITHOUT 100% occupation,

i.e. tissues have i.e. tissues have spare receptorsspare receptors


Schematic representation of the relationship Schematic representation of the relationship between threshold, receptor between threshold, receptor reserve, reserve, receptorreceptor occupancy, biological stimulus occupancy, biological stimulus and biological responseand biological response


BIOLOGICAL STIMULUSBIOLOGICAL STIMULUS

0%0%TRETHOLDTRETHOLD BIOLOGICAL RESPONSEBIOLOGICAL RESPONSE

100%100%RECEPTOR RESERVERECEPTOR RESERVE

Threshold EffectThreshold EffectMax Max EffectEffect

PERCENT RECEPTOR OCCUPANCYPERCENT RECEPTOR OCCUPANCY

Receptors are said to be sparespare

for a given pharmacological response

when the maximal response can be elicited

by an agonist at a concentration that does

not result in occupancy of the full complement

of available receptors


Spare receptors More receptors available than

needed

to elicit maximum response allow maximal response without total

receptor occupancy – increase sensitivity of the system

Agonist has to bind only a portion of receptors for full effect


Some terminologies regarding drug receptor interaction

Affinity

Efficacy

Potency

Ligand


Affinity: measure of propensity of a drug to bind receptor; the attractiveness of drug

and receptor

Efficacy: Potential maximum therapeutic response that a drug can produce.

Potency: Amount of drug needed to produce an effect.


Ligand:

Molecules that binds to a receptor


Classification of Ligands Classification of Ligands a.a. agonist agonist

b. partial agonistb. partial agonist

c. antagonist c. antagonist

pharmacological vs. physiological vs. chemical pharmacological vs. physiological vs. chemical

pharmacological antagonistspharmacological antagonists

- - competitive competitive

surmountable surmountable

- - noncompetitive noncompetitive



kk11

kk22

DrugDrug

ReceptorReceptorEffectEffect

Drug-Receptor Drug-Receptor ComplexComplex

Ligand-binding Ligand-binding domain domain

Effector domain Effector domain

Drug(Ligand) Receptor interactionLangley (1878)

EffectD+R DRk1

k2


- Primary way for drug to produce an action

non-specific receptors

neurotransmitters

hormones enzymes transport systems

• ion channels • active transporters, e.g. uptake blockers

Drug Receptor interaction

Targets of drug action


III. MAJOR RECEPTOR FAMILIES

Figure 2.2Transmembrane signaling mechanisms. A. Lignad binds to the extracellular domain of a

ligand-gated channel. B. Ligand binds to a domain of the serpentine receptor, which is coupled to G protein. C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor.


III. MAJOR RECEPTOR FAMILIESG-protein coupled receptors triggers an increase (or, less

often, a decrease) in the activity of adenylyl cyclase.


III. MAJOR RECEPTOR FAMILIESMechanism of intracellular receptors (e.g. nuclear receptors).


III. DESENSITIZATION OF RECEPTORS

- Receptor structure change

- Receptor inactivation (protein inhibitors, modifications)

- Down regulation of receptor byendocytosis or degradation


What is a receptor “agonist”?

Any drug that binds to a receptor and stimulates the functional activities

e.g.: adrenaline (epinephrine)

Receptor

Epinephrine

Cell

Effect

agonist

Drugs that cause a responseDrugs that interact with and activate receptors;

They possess both affinity and efficacyTypes Full agonists An agonist with maximal efficacy (response)

has affinity plus intrinsic activityPartial agonists

An agonist with less then maximal efficacy

has affinity and less intrinsic activity


Agonists differing in potency and maximum efficacy


PARTIAL AGONISTS - EFFICACYEven though drugs may occupy the same # of receptors, the magnitude of their effects may differ.


[D] (concentration units)

% M

axim

al E

ffec

t

0.01 0.10 1.00 10.00 100.00 1000.000.0

0.2

0.4

0.6

0.8

1.0

Partial agonist

Full Agonist

Partial agonist


What is a receptor “antagonist”?

Any drug which can influence a receptor and produce no response

e.g.: propranolol (a beta blocker)

epinephrine

propranololHey, you’rein my way!

Competitive Antagonist: both the drug and its antagonist compete for the same site of the receptor Non-competitive Antagonist: the drug and its antagonist do not compete for the same site

NOT change the receptor Interact with the receptor but do

Have affinity but NO efficacy

Block the action of other drugs

Effect only observed in presence of agonist


Types of Antagonists

Competitive(Surmountable)decrease apparentPotency

Noncompetitivedecrease apparent maximum efficacy


Competitive Antagonist

competes with ________for receptor

surmountable with increasing agonist concentration

displaces agonist dose response curve to

the ___________(dextral shift)

reduces the apparent affinity of the __________.


Noncompetitive Antagonist

drug binds to receptor and stays boundirreversible – does not let go of receptor

produces slight dextral shift in the agonist DR curve in the low concentration range

but, as more and more receptors are bound (and essentially destroyed),

the agonist drug becomes incapable of eliciting a maximal effect


AGONIST VS ANTAGONIST


What happen when you increase agonist concentration even higher


How do non competitive antagonist affect receptor function



Monitoring drug responsesMonitoring drug responses

LevelLevel Molecular (e.g., enzyme inhibition, receptor Molecular (e.g., enzyme inhibition, receptor

binding assay)binding assay) Cellular (Cellular (in vitroin vitro tissue culture, blood cells) tissue culture, blood cells) Tissue or organ (Tissue or organ (in vitroin vitro or or in vivoin vivo)) Animal disease modelAnimal disease model

Endpoint used to measure the effect may be different Endpoint used to measure the effect may be different at each levelat each level

Overall effect = Sum of multiple drug effects and Overall effect = Sum of multiple drug effects and physiological responses to drug effectsphysiological responses to drug effects


Endpoints to monitor drug effectsEndpoints to monitor drug effects

LEVEL ENDPOINT

Molecular Farnesyltransferase inhibition

Cellular Proliferation rate, Apoptosis

Tumor Response (Change in tumor size)

Organism Survival, Quality of life

Farnesyltransferase inhibitors for cancerFarnesyltransferase inhibitors for cancer


IV. DOSE-RESPONSE RELATIONSHIPS

Figure 2.6The effect of dose on the

magnitude of pharmacologic response.

Panel A is a linear graph.

*Effect =*Effect =EffectEffectMaxMax • [Drug] • [Drug]

KKDD + [Drug] + [Drug]

*EC50=drug dose that shows fifty percent of maximal response.



Figure 2.6The effect of dose on the

magnitude of pharmacologic response.

Panel B is a semi-logarithmic plot of the

same data.


Determinants of Drug Activity

1. Potency: the amount of drug to produce an effect of a given magnitude

2. Efficacy: the maximal response (effect) produced by drug

Bio

logi

c ef

fect

Log dose

potency

efficacy

0

50

100

Bio

logi

c ef

fect

(%)

Log dose (mg)

1 10 100

MorphineCodeine

Aspirin



Figure 2.7Typical dose-response

curve for drugs showing differences in potency and efficacy.



Figure 2.9Effects of drug antagonists.



Figure 2.10Effects of partial agonists.

-1 0 1 2

RE

SPO

NS

E

Full Agonist

Partial Agonist

Antagonist

Log([A]/KA)


Therapeutic Index

Therapeutic index =

toxic dose(LD50)/effective dose(EC50)

This is a measure of a drug’s safety• A large number = a wide margin of safety• A small number = a small margin of safety

V. QUANTAL DOSE-RESPONSE RELATIONSHIPS




(Continued overleaf)




Walter Straub (1874-1944)“There is only a quantitative difference between a drug

and a poison”

Summary (T or F)

Pharmacodynamics is the study of absorption, distribution,

metabolism and elimination of drug. Some drugs can act without binding to a receptor spare receptors allow maximum response without full receptor occupancy Efficacy is the amount of drug needed to produce an effect. Affinity is the attractiveness between 2 drug molecules. Agonist are the drugs that block the response. Partial agonist has affinity and maximum efficacy. Antagonist has efficacy but no affinity. Competitive antagonist decreases potency Non competitive antagonist decreases efficacy



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ch02 drug receptor interactions and pharmacodynamics

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