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 |
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 |
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 |
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Central Nervous System Drugs Methyldopa Benzhexol Phenytoin |
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Anti-infectives Dapsone Sulfacetamide Sulfamethoxypyrimidine Sulfanilamide Sulfapyridine Sulfasalazine Sulfisoxazole Sulfadiazine Cotrimoxazole Trimethoprim Chloramphenicol Ciprofloxacin Moxifloxacin Nalidixic acid Ofloxacin Norfloxacin Nitrofurantoin Nitrofurazone Isoniazid Furazolidone Streptomycin |
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Antineoplastics Doxorubicin Rasburicase |
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Anthelmintics Niridazole Stibophen |
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Analgesics Acetylsalicylic acid Antipyrine |
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Antigout drugs Probenecid Colchicine |
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Antidote Dimercaprol Phenylhydrazine |
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Antimethemoglobinemic Agent Methylene Blue |
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Antidiabetics Glibenclamide |
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Antihistamines Diphenhydramine Tripelennamine Antazoline |
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Hormonal contraceptives Mestranol |
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Vitamins Ascorbic acid Menadione |
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Diagnostic agent for cancer Toluidine blue |
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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). |