2012/10/05 19:16

Genetic Variations Revealed by the Effects of Drugs

Among the best known examples of drugs that have been responsible for revealing genetic variation in response are isoniazid, succinylcholine, primaquine, coumarin anticoagulants, certain anesthetic agents, the thiopurines, and debrisoquine.

1. Debrisoquine Metabolism

Debrisoquine is a drug that was used frequently in the past for the treatment of hypertension. There is a bimodal distribution in the response to the drug in the general population. Approximately 5% to 10% of persons of European origin are poor metabolizers, being homozygotes for an autosomal recessive gene with reduced hydroxylation activity.

Molecular studies revealed that the gene involved in debrisoquine metabolism is one of the P450 family of genes on chromosome 22, known as CYP2D6. The mutations responsible for the poor metabolizer phenotype are heterogeneous; 18 different variants have been described.

CYP2D6
variation is important because this enzyme is involved in the metabolism of more than 20% of prescribed drugs, including the β-blockers metoprolol and carvedilol, the antidepressants fluoxetine and imipramine, the antipsychotics thioridazine and haloperidol, the painkiller codeine, and the anti-cancer drug tamoxifen.

2.
For many years, quinine was the drug of choice in the treatment of malaria. Although it has been very effective in acute attacks, it is not effective in preventing relapses. In 1926 primaquine was introduced and proved to be much better than quinine in preventing relapses. However, it was not long after primaquine was introduced that some people were found to be sensitive to the drug. The drug could be taken for a few days with no apparent ill effects, and then suddenly some individuals would begin to pass very dark, often black, urine. Jaundice developed and the red cell count and hemoglobin concentration gradually fell as a consequence of hemolysis of the red blood cells. Affected individuals usually recovered from such a hemolytic episode, but occasionally the destruction of the red cells was extensive enough to be fatal. The cause of such cases of primaquine sensitivity was subsequently shown to be a deficiency in the red cell enzyme glucose 6-phosphate dehydrogenase (G6PD).


3.
Coumarin Metabolism
Coumarin anticoagulant drugs, such as warfarin, are used in the treatment of a number of different disorders to prevent the blood from clotting (e.g., after a deep venous thrombosis). Warfarin is metabolized by the cytochrome P450 enzyme encoded by the CYP2C9 gene, and two variants (CYP2C9*2 and CYP2C9*3) result in decreased metabolism. Consequently, these patients require a lower warfarin dose to maintain their target international normalized ratio range and may be at increased risk of bleeding.

4.
Succinylcholine Sensitivity
Curare is a plant extract used in hunting by certain South American Indian tribes that produces profound muscular paralysis. Medically, curare is used in surgical operations because of the muscular relaxation it produces. Succinylcholine, also known as suxamethonium, is another drug that produces muscular relaxation, though by a different mechanism from curare. Suxamethonium has the advantage over curare that the relaxation of skeletal and respiratory muscles and the consequent apnea (cessation of breathing) it induces is only short-lived. Therefore it is used most often in the induction phase of anesthesia for intubation. The anesthetist, therefore, needs to maintain respiration by artificial means for only 2 to 3 minutes before it returns spontaneously. However, about one patient in every 2000 has a period of apnea that can last 1 hour or more after the use of suxamethonium. It was found that the apnea in such instances could be corrected by transfusion of blood or plasma from a normal person. When a suxamethonium-induced apnea occurs the anesthetist has to maintain respiration until the effects of the drug have worn off.
Succinylcholine is normally destroyed in the body by the plasma enzyme pseudocholinesterase. In patients who are highly sensitive to succinylcholine, the plasma pseudocholinesterase in their blood destroys the drug at a markedly slower rate than normal, or in some very rare cases is entirely deficient. Succinylcholine sensitivity is inherited as an autosomal recessive trait due to mutations of the CHE1 gene, and genetic testing may be offered to the relatives of a patient in whom a genetic predisposition has been identified.

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