engleski

The role of pharmacogenetics in management of cardiovascular disease

Individual variation in response to drug ranges from failure to respond to drug reactions and drug to drug interactions when several drugs are taken simultaneously. The clinical consequences range from patient discomfort through serious clinical illness to the occasional fatality. Recent studies have revealed that 1 of 15 (6.7%) hospital admissions is due to adverse drug reaction, and 1 of 300 (0.3%) drug reactions has fatal outcome. This figure ranks adverse drug reactions between the fourth and sixth leading causes of death in hospital patients. The potential risk factors for drug inefficacy or toxicity include biological factors (gender, age, renal and liver function, or other disease factors), lifestyle (smoking, alcohol consumption, diet, drug-drug interaction), and inherited factors. However, of greater importance are inherited factors that affect the kinetics and dynamics of numerous drugs. Genetic variation in genes for drug-metabolizing enzymes, drug receptors, and drug transporters has been associated with individual variability in the efficacy and toxicity of drugs. There is a relationship between genetic predisposition of an individual and his ability to metabolize a drug. Differences in drug metabolism can lead to severe toxicity or therapeutic failure due to changed ratio between the drug dose and concentration of pharmacologically active substance in the blood, as the result of genetic modifications. Genetic polymorphism based on drug metabolism ability is associated with three phenotype classes. The phenotype of extensive drug metabolizer (EM) is characteristic of normal population. EM alleles behave in a dominant way. Individuals with EM phenotype are either homozygous or heterozygous for the wild-type allele. The poor metabolizer phenotype (PM) is associated with the accumulation of specific drug substrates in the body, and is inherited as a recessive autosomal trait due to mutation and/or deletion of both alleles responsible for phenotypic expression. Individuals with PM phenotype are either homozygotes or multiple heterozygotes for mutant alleles. The ultraextensive metabolizer phenotype (UEM) is characterized by enhanced drug metabolism due to gene amplification inherited as an autosomal dominant trait. Individuals with ultrarapid phenotype are prone to therapeutic failure because the drug concentrations at normal doses are by far too low. Five to 20% of patients can belong to one of these risk groups, depending on the population studied. Most of the works on this topic have concentrated on the cytochrome P450 enzyme (CYP), which is a highly polymorphic enzyme that plays a key role in metabolizing the majority of drugs in the human body...

pharmacogenetics; cardiovascular disease

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