Role of genetic polymorphism
Any pharmacogenetic reactions are based on genetic polymorphism, which arose evolutionarily. The human genome encodes more than thirty families of enzymes responsible for drug metabolism.
The key group consists of hepatic enzymes — cytochromes P450, represented by numerous allelic variants. The mechanism of their influence is as follows: genetic polymorphism leads to differences in the amino acid sequences of proteins, which naturally alters enzyme specificity and activity. As a result, an individual response to drugs is formed. The fate of most administered drugs is determined by the complex interaction of multiple genes simultaneously.
Clinical examples of pharmacogenetic reactions
Differences in metabolism are clearly manifested when standard drugs are prescribed:
- Isoniazid and N-acetyltransferase. When treating tuberculosis with isoniazid, a subset of patients exhibits an autosomal recessive trait: they are "slow acetylators." Their liver enzymes cannot timely attach an acetyl group to drug components. Due to delayed elimination 6 hours after a standard dose, the serum concentration of the drug rises critically, leading to toxic damage to peripheral nerves.
- Acetylsalicylic acid and coagulopathies. Prescribing this drug to patients with hereditary hemostasis defects (e.g., hemophilia or von Willebrand disease — an autosomal dominant disorder with spontaneous bleeding) causes an aberrant reaction. There is a high risk of massive gastrointestinal bleeding and cerebral hemorrhage.
- Suxamethonium and serum cholinesterase. The neuromuscular blocker suxamethonium causes respiratory arrest resembling curare poisoning. Normally, it is rapidly degraded by serum cholinesterase (normal allele E_u). However, in compound heterozygotes E_sE_f or homozygotes E_s, the pathological effect is fully manifested: enzymatic activity is absent, the drug is not cleaved, and prolonged apnea occurs (up to 1 hour). The patient requires mechanical ventilation. Pathological alleles are present in 3–4% of Europeans, are extremely rare in Africans, but are very common among Alaska Natives.
Genetic basis of pharmacokinetics
The fate of any pharmacological substance in the body goes through a series of consecutive stages, each of which is controlled by genes encoding specific and non-specific enzymes. The main pharmacokinetic factors include:
- Drug absorption;
- Distribution (to organs, tissues, individual cells, and intracellular organelles);
- Interaction with receptors;
- Biotransformation and metabolism;
- Excretion.
Pharmacogenomics: individualization of treatment
Pharmacogenomics is a branch of pharmacology that investigates the body's response characteristics based on the decoded genome of a specific patient.
Its main goals are to individualize therapeutic measures. By analyzing genomic information, physicians can understand drug compatibility, predict hypersensitivity in individuals, precisely select dosage, choose a safe alternative, and determine the optimal route of administration. For example, treatment with leptin demonstrates efficacy exclusively in patients whose obesity is caused by a mutation in the leptin gene itself.
Briefly: answers to topical questions
Which cytochrome P450 isoenzymes play the main role in the metabolism of most drugs?
The CYP3A4 isoenzyme plays a key role in drug metabolism: it participates in the metabolism of antiviral agents and is the primary enzyme for drug metabolism in the intestinal wall. The CYP2C19 isoenzyme participates in the metabolic activation of clopidogrel.
What toxic effects does isoniazid cause in patients with the slow acetylator phenotype?
In patients with the slow acetylator phenotype, isoniazid is eliminated slowly, so its serum concentration increases significantly 6 hours after a standard dose. This can cause adverse reactions, including peripheral neuropathy.
In which hereditary hemostasis defects does the administration of acetylsalicylic acid cause massive bleeding?
The use of acetylsalicylic acid causes massive bleeding in hemophilia and von Willebrand disease.
Against the background of these biochemical hemostasis defects, an aberrant reaction to the drug occurs, which can trigger:
- Gastrointestinal bleeding.
- Cerebral hemorrhage.
Such complications are associated with the pronounced antiplatelet effect of acetylsalicylic acid, which is strictly contraindicated in such patients because it critically exacerbates the existing hemorrhagic syndrome.
For memorization: Isoniazid Impairs nerves in "slow" acetylators.
Class and exam questions
What is the main difference between pharmacogenetics and pharmacogenomics?
Pharmacogenetics studies the influence of hereditary factors on the body's response to drugs in general. Pharmacogenomics, on the other hand, uses information about a patient's specific genome for personalized drug selection and dosing.
Why does suxamethonium cause prolonged apnea in some people?
In patients with homozygous carriage of the pathological allele (E_s), serum cholinesterase activity is completely absent. The enzyme does not break down suxamethonium, leading to respiratory arrest lasting up to an hour and requiring mechanical ventilation.
What is the role of cytochromes P450?
This is a key group of hepatic enzymes responsible for drug metabolism. Their genetic polymorphism alters amino acid sequences and enzyme activity, determining an individual's response to medications.
What else to study on this topic
- Molecular mechanisms of hepatic cytochrome P450 polymorphism
- Inheritance patterns of pathological serum cholinesterase alleles
- Pathogenesis of peripheral neuropathy during isoniazid use
- Von Willebrand disease: genetics and pharmacological risks
- Genetic control of drug biotransformation and excretion
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