Appendix 10: Pharmacogenetics

Pharmacogenetics refers to the genetic variation in drug response. This could be due to:

(a) Single mutant gene or genetic polymorphism; (b) Polygenic influence.

However the later is not of much significance in Clinical Practice. Variations in drug responses amongst fraternal twins (dizygotic) may be relatively wide when compared to identical (monozygotic) twins. Importance of Pharmacogenetics lies in the development of new drugs from information available from human genome project. It aims at individualizing and improving precision of pharmacotherapy.

When polymorphic DNA sequence variation occurs in the coding region or regulatory regions of genes, it causes variation in gene product through alteration of activity, function or level of expression. The variation to drug response can also be brought about by:

• Metabolic variation;

• Idiosyncratic reaction

As an example, metabolic variation can be best explained by the varied metabolic response exhibited to the antitubercular drug Isoniazid due to the presence of two different phenotypes in a population. These varied phenotypes are expressed as larger or smaller amount of enzyme N-acetylase in liver, and the population being termed as rapid acetylators and slow acetylators, respectively. Some of the pharmacogenetic conditions and the drugs involved are summarized below:

S.No. Pharmacogenetic variation Frequency of occurrence Drugs involved Outcome
1. Acetylator status Varies with race

Isoniazid
slow acetylator
-rapid acetylator
Procainamide
Hydralazine
Sulphas,
Sulphones
Phenelzine


Neuropathy
Hepatotoxicity
SLE
SLE

ADR
ADR
2. Butyrylcholinesterase
enzymes
1: 3000 caucasian Suxamethonium Slower recovery from surgical paralysis
3.

Aromatic hydroxylase

N-oxidation enzyme (aminoxydase)

1.5-9.0%

5%

Debrisoquine

Sparteine

Postural hypotension,

Diplopia, blurred
vision,

4. G-6-PD deficiency Varies with race Antimalarials Primaquine Mepacrine Pamaquine Pentaquine Chloroquine Quinine Proguanil Pyrimethamine Haemolysis
      Cardiovascular drugs
Procainamide
Quinidine
Hydralazine
Thiazide diuretics
 
      Central Nervous System Drugs
Methyldopa
Benzhexol
Phenytoin
 
      Anti-infectives
Dapsone
Sulfacetamide Sulfamethoxypyrimidine
Sulfanilamide Sulfapyridine
Sulfasalazine
Sulfisoxazole
Sulfadiazine
Cotrimoxazole
Trimethoprim Chloramphenicol Ciprofloxacin
Moxifloxacin
Nalidixic acid
Ofloxacin
Norfloxacin
Nitrofurantoin Nitrofurazone
Isoniazid
Furazolidone
Streptomycin
 
      Antineoplastics
Doxorubicin
Rasburicase
 
      Anthelmintics
Niridazole
Stibophen
 
      Analgesics
Acetylsalicylic acid
Antipyrine
 
      Antigout drugs
Probenecid
Colchicine
 
      Antidote
Dimercaprol
Phenylhydrazine
 
      Antimethemoglobinemic Agent
Methylene Blue
 
      Antidiabetics
Glibenclamide
 
      Antihistamines
Diphenhydramine
Tripelennamine
Antazoline
 
      Hormonal contraceptives
Mestranol
 
      Vitamins
Ascorbic acid
Menadione
 
      Diagnostic agent for cancer
Toluidine blue
 
5. Calcium release channel (ryanodine receptor) 1:20,000 Halothane Malignant hyperthermia,
6. Narrow iridocorneal angle 5% US population Corticosteroids Attack of angle closure glaucoma
7. Hb variants Rare Oxidizing agents like quinolones Haemolysis
8. Hepatic porphyrias Rare Haem-containing hepatic oxidizing enzyme inducers like barbiturates, Sulphonamides Sulphanylureas etc. Acute porphyria
(GIT, CNS, CVS
symptoms)
9. Altered receptor or enzyme in liver with increased affinity for vitamin K 2 large pedigrees Warfarin Warfarin resistance
10. Mixed function oxidase in liver microsomes
hydroxylation
d-ethylation
Only 1 small pedigree Dicoumarol
Phenacetin
Dicoumarol sensitivity
Methemoglobinemia
11. N-oxidation enzyme (aminoxydase ) 5% Sparteine Sparteine -induced diplopia, blurred vision, overstimulated uterus
12. Mixed function oxidase 25% Tolbutamide Tolbutamide induced cardiovascular death
13. Cytochrome P450 2D6 Ondansetron Ondansetron Ondansetron
- lesser efficacy in ultrarapid metabolisers
      Tramadol Lesser efficacy of tramadol
      Codeine Codeine - poor analgesia
      Tamoxifen Therapeutic failure of Tamoxifen in poor metabolisers
    ~ 7% caucasians Debrisoquine Poor metabolism of Debrisoquine
14. Cytochrome P450 2C 9 Phenytoin* Decreased hydroxylation of Phenytoin
15. Cytochrome P450 2C9 and Vitamin K epoxide reductase complex subunit 1   Warfarin Longer times to dose stabilisation and higher risk of serious and life threatening bleeding
16. Increased expression of p-glycoprotein Chloroquine, anticancer drugs Development of resistance
17. An enzyme or receptor site with altered affinity for vitamin K Rare Simultaneous administration of inducing agents with warfarin Warfarin resistance
18. Thiopurine methyl transferase enzyme 3% Azathioprine
6- mercaptopurine
Risk of bone marrow suppression
19. Uridine-5-diphosphoglucurosyl transferase 1A1 61% Caucasians
84% Asians
47% African americans
Irinotecan Risk of induction of neutropenia and diarrhoea
20. Dihydropyrimidine dehydrogenase   5-fluorouracil Risk of severe toxicity
21. α-Thalessemia   Artesunate Rise in plasma drug concentration
22. β-Thalessemia   Somatomedin May depress somatomedin activity
* Study carried out in healthy individuals from South India by Rosemary et al (Indian J Med Res 2006, 123: 665-670).