Pharmacogenetics

Pharmacogenetics
• The study of how genetic
determinants affect drug action
Dari : Medical Progress 1979

Distribution
Disintegration

Dissolution

Absorption Extraction
• Drug response:
- contraction of smooth muscle
- relaxation of bronchial muscle
- diuresis
- analgesia
- miosis
- etc.
AGONISTS,ANTAGONISTS AND
EFFICACY
Drugs acting on receptors may be
agonists or antagonists.
Agonists initiate changes in cell
function,producing effects of various
types;antagonists bind to receptors
without initiating such changes.
Agonist potency depends on two
parameters:
- AFFINITY (i.e. a tendency to bind to
receptors) and
- EFFICACY (i.e. ability,once bound,to
initiate changes which lead to effects).
For antagonists,efficacy is zero.
Full agonists (which can produce maxi-
mal effects) have high efficacy;
partial agonists (which can produce
only submaximal effects) have inter-
mediate efficacy.
• Drug action is determined by concen-
tration of drug in the blood or plasma.

• Increased blood drug concentration 

increased drug effect toxic effect.

• Decreased blood drug concentration 

decreased drug effect  no effect.
• Blood/plasma concentration of drug is
determined by:
- drug absorption
- drug distribution
- drug metabolism/biotransformation
- drug excretion
• Drug metabolism is catalysed by meta-
bolizing enzyme.

• Metabolizing enzyme production is

controlled by gene.
• Gene defect  alteration of metaboli
zing enzyme qualitatively and or quan-
titatively  alteration of blood drug
concentration/lead to the appearance
of toxic metabolite,carcinogenic or
mutagenic substances.
Dari : Basic and Clinical Pharmacology, Katzung ,B.G. 8 th. ed. 2001 ,p 59
Enzyme inducer Metabolism 
Phenobarbital Chloramphenicol,barbiturate,
CPZ,cortisol,digitoxin,estradi-
ol,coumarin,quinine,pheny-
toin,phenylbutazone, testo-
sterone.

Rifampin Coumarin,digitoxin,glucocor-
ticoids,methadone,oral con-
traceptives,prednisone,pro-
pranolol,metoprolol,quinidine
Phenylbutazone Aminopyrine,cortisol,
digitoxin.

Phenytoin Cortisol,dexamethasone,
digitoxin,theophylline.

Benzopyrene Theophylline

Griseofulvin Warfarin
Enzyme inhibitor Metabolism ↓

Cimetidine Chlordiazepoxide,diaze-
pam,warfarin

Allopurinol Antipyrine,dicumarol,
Chloramphenicol probenecid,tolbutamide
Isoniazid (INH)

Ketoconazole Cyclosporine,astemizole,
terfenadine
Dicumarol Phenytoin

Disulfiram Antipyrine,ethanol,
phenytoin,warfarin

Phenylbutazone Phenytoin,tolbutamide

Grapefruit juice Alprazolam,atorvastatin

cisapride,cyclosporine,
midazolam,triazolam
 • Perbedaan respons thd obat ok
perbedaan genetic
INH ,Hydralazine,Procainamide,Sulfame-
tazine,Dapson:

Rapid acetylator : Respons thd obat ↓

Toksisitas derivat
N-Acetyl ↑
Sow acetylator : Toksisitas obat ↑
Mekanisme kerja:Perbedaan activitas
Enzyme N-Acetyltransferase
• Debrisoquin, Metoprolol ,Lidocaine :
Hydroxylator extensive: Respons ↓
Hydroxylator lemah : Respons ↑

Mekanisme kerja : Perbedaan activitas

salah satu Cytochrom P450 hepar yang
mengoksidasi Debrisoquin / Spartein.
• S-mefenitoin , Diazepam , Omeprazol :

Hydroxylator extensive: Respons ↓

Hydroxylator lemah : Respons ↑

Mekanisme kerja : Perbedaan activitas

salah satu Cytochrom P450 hepar yang
mengoksidasi S-mefenitoin
• Primaquine ,Chloroquine , Quinine,
Quinidine ,Sulfa ,Sulfon,Nitrofurantoin,
Chloramphenicol,Aspirin , PAS :
Hemoysis pada pemberian bersama
obat – obat yang bersifat oksidator.

Mekanisme kerja: Deficiency Glucosa-6

Phosphate Dehydrogenase
• Halothane , Succinylcholine :

Hyperthermia maligna

Mekanisme kerja : ?