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(lanjutan)Fathiyah Safithri

Laboratorium Farmakologi

Fakultas Kedokteran Universitas Muhammadiyah Malang2010

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Model of simpleoccupancy theory

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0

20

40

60

80

100

0 200 400 600 800

Graded Dose-Effect Curve

%o

fEffect

[Drug]

EC50

Maximal effect

Showing progressively

increasing effect with

increasing dose.

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Log concentration [A]

%o

fEffect

Full agonist

Log dose-effect curve

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GRADED DOSE-

RESPONSE CURVEED50

ED50

From Nierenberg W and Melmon KL. Introduction to Clinical Pharmacology in Cli nical Pharmacology: Basic Principles in

Therapeutics, Third edition, 1992, Melmon KL et al., editors, p 1-51, McGraw Hill.

intensity

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Graded Dose-Effect Analysis

Identify the therapeutic dose/concentration

Define site of drug action (receptor)

Classify effect produced by drug-receptorinteraction (agonist, antagonist)

Compare the relative potency and efficacy ofdrugs that produce the same effect

Assess mechanism of drug interactions

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QUANTAL DOSE-RESPONSE CURVE

Frequency

Distribution

Cumulative

Frequency

Distribution

From Ross EM andGilman AG.

Pharmacodynamics:

mechanisms of drug action

and the relationship

between drug

concentration and effect..

in Goodman and Gilmans

The Pharmacological Basis

of Therapeuti cs. 7th

edition,1985, Pages 35-48.

Macmillan Publishing

Company.

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Emax & ED50

Log concentration [A]

Response

Emax

Emax

ED50 ED100

I I I I I I I I

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Receptor Binding

The dose-response relationship (from C.D. Klaassen, Casarett and Doulls Toxicology, 5th ed., New York: McGraw-Hill, 1996).

%B

ound

Concentration of Ligand

Kd

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Drug-Receptor Interactions

k1k2

Drug

Receptor

Effect

Drug-Receptor

Complex

Effect = Maximal effect [Drug]KD + [Drug]

(KD = k2/k1)

Ligand-binding

domain

Effector domain

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From Ross EM and Gilman AG. Pharmacodynamics: mechanisms of drug action and the relationship between drug

concentration and effect.. in Goodman and Gilmans The Pharmacological Basis of Therapeutics. 7th edition, 1985, Pages 35-48.

Macmillan Publishing Company.

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1) Affinity for the receptor.

Affinity is related to potency.

Measure of how avidly a drug binds to its receptor

Equilibrium constant KDKA conc. of drug that produces 50% of response

2) Efficacy once bound to the receptor.

Efficacy refers to the maximal effect the drug can

elicit.

Intrinsic activity

Ability of a drug to elicit a response from a receptor

Drugs are described based on themagnitude of two properties:

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[D](concentration units)

[DR]/RT

0.01 0.10 1.00 10.00 100.000.00

0.25

0.50

0.75

1.00Kd=1

kd=5

Kd=0.5

Compounds Have Different Affinities for the Same Recepto

Compare the ED50s

equal efficacies

Differ In Potency

PARTIAL AGONISTS

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[D](concentration units)

%M

aximalEffe

ct

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

PARTIAL AGONISTSEven though drugs may occupy the same of receptors, the

magnitude of their effects may differ.

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Morphine

Aspirin

From Nierenberg W and Melmon KL. Introduction to Clinical Pharmacology in Clinical Pharmacology: Basic Principles in

Therapeutics, Third edition, 1992, Melmon KL et al., editors, p 1-51, McGraw Hill.

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Agonists and Antagonists

AGONIST - Has affinity for receptor and efficacy.

(efficacy intrinsic activity)ANTAGONIST - Has affinity but no efficacy.

Competitive Antagonist

Noncompetitive Antagonist

Partial Agonist or Partial Antagonist - Has affinity but lowerefficacy than full agonist.

Examples of typical curves...

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Effect of competitive

antagonists

Log [A]

Respo

nse

Increasing concentrations

of competitive antagonist

Agonist alone

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Competitive Antagonism ShiftsThe Agonist D-R Curve

(Potency)

Drug Concentration (log scale)

AG + ANTAG alone

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Effect of irreversible antagonists

Log [A]

Respo

nse

Agonist aloneLow dose

High dose

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Noncompetitive Antagonism (NC ANT)

Decreases AgonistEfficacy

Log Drug Concentration

%M

axresponse AG alone

AG + NC ANT

AG + higher dose NC ANT

Types of Receptor Antagonists

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Competitive Noncompetitive

Types of Receptor Antagonists

From Taylor, P and Insel PA. Molecular Basis of Pharmacological Selectivity, in Principles of Drug Action, W Pratt and P Taylor, editors, p

1-103,1990, Churchill Livingstone

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Agonist + AntagonisAgonist +

Antagonist Non Compt

Efek antagonis Efek antagonis

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7127

700

200

70

20

127

Kontraksi otot polos akb.

pemberian :

A. AgonisB. Agonis + Antagonis

11 2 3

2

5

4

3

6

5

4

Ag Ag+Antg

3

4

5

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Log (kosentrasi)

%

Efek

0

10

20

30

40

50

60

70

80

90

100

-8 -7 -6 -5 -4 -3

A

B

C

Jelaskan perbandingan potensi

dan efficacy obat A, B, C.

THERAPEUTIC INDEX AN INDEX OF SAFETY

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THERAPEUTIC INDEX AN INDEX OF SAFETY

Hypnosis Death

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Therapeutic and Toxic Effects are

Dose-Related: Phenobarbital

Sleep Death

Dose of Phenobarbital

ED50 LD50

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Therapeutic Index (TI)

TI (preclinical) LD50ED50

clinical TI TD50

ED50

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0

20

40

60

80

100

70 80 90100 200 300

Therapeutic and Toxic Effects

Dose

%

Responding

Therapeutic

Toxic

ED99

TD1ED50TD50

Indices

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Therapeutic Indices

Therapeutic Ratio =TD50

ED50= 2.5

Certain Safety Factor=TD1

ED99= 1.3

Standard Safety Margin =TD1 - ED99

ED99X 100 = 31%

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Therapeutic indices are calculated from dose-effect

curves in order to quantify the relative safety of a drug.

Using these curves we can calculate a therapeuticratio using the TD50 and ED50. The TD50/ED50 ratio for

the drug shown on the previous graph is about 2.5,

which means that about 2.5 times as much drug willcause a toxic effect in half the subjects as is needed to

produce a therapeutic in the same proportion of

subjects. However this ratio of toxic to therapeutic

dose may not hold across the entire dose range if the

dose-effect curves are not parallel.

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The aim of drug therapy is to achieve the desiredtherapeutic effect in all patients without the producingtoxicity in any. A ratio that uses thelowest toxic andhighest therapeutic doses is more realistic and consistent

with this aim. The certain safety factor (CSF) is the ratioofTD1/ED99. A CSF > 1 indicates that the dose effective in99% of the population is less than that which would be toxicin 1%. If the CSF < 1, there is overlap between themaximally effective and minimally toxic doses.

Unlike the therapeutic ratio this measure is independent ofthe shapes of the quantal dose-effect curves for thetherapeutic and toxic effects.

The Standard Safety margin uses the same extremes and

derives the percentage by which the ED99 has to beincreased before the TD1 is reached.

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Receptor Regulation

Supersensitization or Up-regulation

1. Prolonged/continuous use of receptor blocker

2. Inhibition of synthesis or release of

hormone/neurotransmitter - Denervation

Desensitization or Down-regulation

1. Prolonged/continuous use of agonist

2. Inhibition of degradation or uptake of agonist

Homologous vs. Heterologous

Uncoupling vs. Decreased Numbers

DYNAMICS OF RESEPTOR

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RESEPTOR REGULATION

REGULATION HOMEOSTASIS

*DESENSITIZATION

*DOWN REGULATION

*SUPERSENSITIZATION

*UP REGULATION

SIFAT REGULASI HOMOLOG

HETEROLOG CROSS-TALK

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From Taylor, P and Insel PA. Molecular Basis of Drug Action, in Principles of Drug Action, 3rd edition, W Pratt and P Taylor,

editors, p 103-200, 1990, Churchill Livingstone

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Desensitization

Homologous: affecting responses

elicited only by the stimulated

receptor.

Heterologous: acting on several

receptors or on a pathway common tomany receptors.

REGULASI HOMOLOG

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REGULASI HETEROLOG

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C f V i bilit i D

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Causes of Variability in Drug

ResponseThose related to the biological system

1. Body weight and size2. Age and Sex

3. Genetics - pharmacogenetics

4. Condition of health5. Placebo effect

C f V i bilit i D

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Causes of Variability in Drug

Response Those related to the conditions of administration

1. Dose, formulation, route of administration.

2. Resulting from repeated administration of drug:

drug resistance; drug tolerance-tachyphylaxis; drug allergy

3. Drug interactions:

chemical or physical;

GI absorption;

protein binding/distribution;

metabolism (stimulation/inhibition);

excretion (ph/transport processes);

receptor (potentiation/antagonism);

changes in pH or electrolytes.

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Monitoring Dose-Effect Level

Molecular (e.g, enzyme inhibition)

Cellular (in vitro tissue culture, blood cells)

Tissue or organ (in vitro orin vivo)

Organism

Endpoint used to measure effect may be different ateach level

Overall effect = sum of multiple drug effects and

physiological response to drug effects

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Endpoints to Monitor Drug Effect

LEVEL ENDPOINTMolecular Farnesyltransferase inhibition

Cellular Proliferation rate, apoptosis

Tumor Response (change in tumor size)

Organism Survival, quality of life

Farnesyltransferase Inhibitors for Cancer