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Patients with cardiovascular disease, like other patient groups, vary in their response to drugs. This is true both in terms of the response of their disease to treatment and their ability to tolerate medication. Several factors contribute to this variability, including differences in body mass, co-existent renal disease, concomitant drug treatment, and the heterogeneous nature of the disease. The Human Genome Project and the general focus of clinical science on genetic determinants of disease has increased interest in the role of genetic factors in determining an individual's response to drugs. Pharmacogenetics is a growing discipline concerned with the effect of genetic variation on the response to drugs and the extent to which drug treatment can be tailored to the individual according to their genetic makeup.
The idea that the dose of a drug should be adjusted according to the patient's genotype is not new. It is well recognised that polymorphism in genes encoding P450 enzymes, N-acetyltransferase, and other key enzymes of drug metabolism are responsible for major inter-individual differences in blood concentrations of certain drugs. Clinically, poor metabolisers may be slow to activate and respond inadequately to some pro-drugs, or exhibit reduced clearance and increased effects from some pharmacologically active agents, particularly when the latter have a steep dose-response curve or a narrow therapeutic index. For example, the principle route of metabolism of flecainide and propafenone is via cytochrome P450 2D6 and multiple alleles have been identified that impair the activity of the enzyme. Patients with poor CYP450 2D6 activity demonstrate higher blood concentrations of flecainide and propafenone and have more side effects for a given dose than those with normal enzyme activity.1 , …