PHARMACOGENETICS
This refers to the influence of genes on the determination of the response to drug therapy. The responses may take the form of an exaggerated physiological response to a drug, resistance to the effect of drugs or an increased frequency of side effects. In some instances pharmacological agents may trigger and precipitate the effects of certain genetic disorders. Other factors which influence the effects of drugs are the ethnic background and specific HLA groups.
Genes affecting drug metabolism
Polymorphism of certain genes can significantly affect the activities
of certain enzymes that are crucial in the metabolism of certain drugs.
Acetylation is critical for the metabolism of many drugs. Polymorphisms
in the rate of acetylation in different patients lead to different effects
for the same drug. If a patient with tuberculosis is treated with isoniazid
and the patient has a phenotype for slow acetylation, the increased levels
of the drug in circulation due to the defect will lead to a peripheral
neuropathy even with conventional doses. On the other hand, a patient on
such treatment, with a phenotype for rapid acetylation will be inadequately
treated due to the rapid breakdown of the drug and reduced blood levels
and may become more prone to a recurrence of tuberculosis.
Pharmacological effects of drugs on diseases
Patients with the X-linked recessive disorder, Glucose - 6 - phosphate
dehydrogenase (G6PD) deficiency, which is seen in a greater frequency in
Mediterranean and African races, remain healthy provided their red cells
are not exposed to any chemical or pharmacological stresses. Such patients
on antimalarial drugs develop haemolysis as an adverse reaction. Many other
drugs and chemicals may precipitate the same reactions.
The gene for malignant hyperthermia is dominant and on chromosome 19. Patients carrying this mutated gene when exposed to the anaesthetic agent halothane, produces muscle spasms and hyperthermia with subsequent acidosis. Tests are available for individuals at risk to verify their state.
Adverse reactions to drugs may be controlled or influenced by genes in the HLA region which in turn influence the immune response. For example patients receiving gold therapy who have the haplotype DRW3 are more likely to have side effects than those who do not have this HLA haplotype.
Another example seen during anaesthesia is succinylcholine sensitivity. In normal individuals the enzyme cholinesterase hydrolyses choline esters which include acetylcholine, and succinylcholine which is a widely used muscle relaxant. Affected individuals are homozygous for a defective cholinesterase gene (atypical cholinesterase allele), which result in an inability to break down succinylcholine. Such people develop prolonged muscle relaxation and apnoea after anaesthesia with succinylcholine. The abnormal cholinesterase can be detected by laboratory tests.