Download pdf - Pharmacodynamic2-UNMUL 2007

7/29/2019 Pharmacodynamic2-UNMUL 2007

1/37

Pharmacodynamics

(continued)


2/37

Model of simple

occupancy theory


3/37


4/37


5/37

Receptor Binding

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

%Bound

Concentration of Ligand

Kd


6/37

Dose-Effect and Log Dose-Effect Curves

Dose Log Dose

Effect

ED50


7/37

k1

D + R DRk2

EFFECT

HUBUNGAN DOSIS DENGANINTENSITAS EFEK

menurut teori pendudukan reseptor (receptor

occupancy), intensitas efek obat berbanding lurus

dengan fraksi reseptor yang diduduki atau

diikatnya, dan intensitas efek mencapai maksimal

bila seluruh reseptor diduduki oleh obat.Dan oleh karena interaksi obat reseptor ini analog

dengan interaksi substrat enzim, maka disini

berlaku persamaan Michaelis-Menten:


8/37

Emax [D]

Kd + [D]=E

Persamaan Michaelis-Menten:

Dimana :

E = Intensitas efek obat

Emax = efek maksimal

[D] = kadar obat bebasKD = K2/K1 = konstanta disosiasi

kompleks obat-reseptor

Bila KD = [D], maka:

E =Emax [D]

[D] +[D]= .Emax

Ini berarti 50% reseptor diduduki oleh obat


9/37

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.


10/37

Drugs are described based on the

magnitude of two properties:

1)Affinity for the receptor. Affinity is related topotency.

2) Efficacy once bound to the receptor.

Efficacy refers to the maximal effect the drug

can elicit.


11/37[D]

(concentration units)

[DR]/R

T

0.01 0.10 1.00 10.00 100.000.00

0.25

0.50

0.75

1.00

Kd=1

kd=5

Kd=0.5

Compounds Have Different Affinities for the Same Receptor

Compare the ED50s

equal efficacies

Differ In Potency

RT = total # of receptors


12/37[D](concentration units)

%M

aximalEffect

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.


13/37

Agonists and Antagonists

AGONIST - Has affinity for receptor and efficacy.

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

Competitive Antagonist

Noncompetitive Antagonist

Partial Agonist or Partial Antagonist - Has affinity butlowerefficacy than full agonist.

Examples of typical curves...


14/37

70000

000000o

0000

200000

000

70

20

7127

2000

700

200

70

20

127

Kontraksi otot polos

akb. pemberian :

A. AgonisB. Agonis + Antagonis

11 2 3

2

5

4

3

6

5

4

A B


15/37

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, p1-103,1990, Churchill Livingstone


16/37

Competitive Antagonism Shifts The

Agonist D-R Curve( Potency)

Drug Concentration (log scale)

AG + ANTAG alone


17/37

Noncompetitive Antagonism (NC ANT)

Decreases AgonistEfficacy

Log Drug Concentration

%

Maxresponse

AG alone

AG + NC ANT

AG + higher dose

NC ANT


18/37

Agonist + AntagonisAgonist +

Antagonist Non Compt

Efek antagonis Efek antagonis


19/37

GRADED DOSE-

RESPONSE CURVEED50

ED50

From Nierenberg W and Melmon KL. Introduction to Clinical Pharmacology in Clinical Pharmacology: Basic Principles inTherapeutics, Third edition, 1992, Melmon KL et al., editors, p 1-51, McGraw Hill.

intensity


20/37

QUANTAL DOSE-

RESPONSE CURVE

Frequency

Distribution

Cumulative

FrequencyDistribution

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 Basisof Therapeutics. 7th edition,

1985, Pages 35-48.Macmillan Publishing

Company.


21/37

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.


22/37

Therapeutic and Toxic Effects are

Dose-Related: Phenobarbital

Sleep Death

Dose of Phenobarbital

ED50 LD50


23/37

Therapeutic Index (TI)

LD50

ED50

LD50

ED50

= > 1Obat Ideal :


24/37

Factors Affecting Drug Response

Resistance: used in context of antimicrobialdrugs.

Tolerance: a decrease in drug responseduring repeated administration.

Tachyphylaxis: acute development oftolerance due to rapid repeated admin. ofsome drugs.


25/37

Receptor Regulation

Supersensitization or Up-regulation

1. Prolonged/continuous use of receptor blocker

2. Inhibition of synthesis or release ofhormone/neurotransmitter - Denervation

Desensitization or Down-regulation

1. Prolonged/continuous use of agonist

2. Inhibition of degradation or uptake of agonist

Homologous vs. Heterologous

DYNAMICS OF RESEPTOR


26/37

DYNAMICS OF RESEPTOR

RESEPTOR REGULATION

REGULATION HOMEOSTASIS

*DESENSITIZATION

*DOWN REGULATION

*SUPERSENSITIZATION

*UP REGULATION

SIFAT REGULASI HOMOLOG

HETEROLOG CROSS-TALK


27/37


28/37

Mekanisme terjadinya desensitisasi adrenoseptor

REGULASI HOMOLOG


29/37

REGULASI HOMOLOG


30/37

Desensitization

Homologous: affecting responses

elicited only by the stimulated receptor.

Heterologous: acting on several

receptors or on a pathway common to

many receptors.


31/37

MECHANISM

DESENSITISATION PHOSPHORILATION

SEKUESTRATIONBARK, ARRESTIN, PKA

DOWN REGULATION c-AMP

mRNA receptor


32/37

REGULASI HETEROLOG


33/37

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


34/37

The anticoagulant heparin and its antagonist,

protamine.

Chelating agents EDTA, penicillamine, and

dimercaprol bind toxic metals (lead, copper, and

mercury).

Antacids act by neutralizing gastric acid

Incorporation into a macromolecule (e.g. some

anticancer agents - purine and pyrimidine analogues)

Nonspecific effects (e.g. membrane perturbation

by general anesthetics)

Non-receptor Mediated Effects

Mana yang lebih efficacy ?


35/37

Mana yang lebih efficacy ?

Mana yang lebih potent ?

C I


36/37

Case I

Jika anda sebagai dokter mendapat informasi daripabrik obat untuk pengobatan astma sepertipada gambar A & B.

Data apa yang didapat untuk potensi obat &efficacy pada gambar A & B ?

CASE II


37/37

CASE II

Jika anda sebagaidokter akanmemilih obatdengan profil

seperti gambar A& B.

Obat mana yanglebih aman

menurut anda (A atau B) &alasannya ?
http://animat%28%27chart06%27%29/