Impact of pharmacogenetic factors on the effects of drugs
Pharmacogenetic response - a response to the changing drug, due to hereditary factors. Many of these reactions are undesirable character. If they have been reported in a small number of people, they are called idiosyncrasies. Pharmacogenetic reaction may be direct or indirect.
The number of clinical cases of, for which a direct link between the unusual pharmacological effect of the drug and genetically caused the change of a certain organ or receptor, very little.
The study of the genetic basis of the sensitivity of the human organism to drugs is the subject of pharmacogenetics.
Hereditary factors, determining unusual reactions to drugs, They are mainly biochemical. Most often, this lack of enzymes, catalyzing the biotransformation of drugs (the main mechanism for the development of pharmacogenetic reactions). Atypical reactions to drugs can also be observed in hereditary metabolic disorders.
Atypical pseudocholinesterase - Enzyme, providing hydrolysis of choline esters, and various aliphatic and aromatic acids. With a deficit of cholinesterase (this pathology occurs with a frequency of about 1:2500) reduced ability to inactivate succinylcholine, which leads to prolonged paralysis of the respiratory muscles with the usual doses of the drug.
In the event of prolonged apnea (stop breathing) the application of intravenous succinylcholine fresh donor blood with normal activity pseudocholinesterase.
Among common hereditary defects include nedostatochnosty glucose-6-fosfatdegidrogenazы (G-6-PDG). Carriers such a defect is, at least, 200 million people.
When failure of G-6-PDG taking certain drugs (primaquine, salazosulьfapiridin, sulfonamides, sulfacetamide, phenyl hydrazine, furazolidon) leading to massive destruction of red blood cells (hemolytic crisis) due to falling content of reduced glutathione and destabilization of the membrane (glutathione reductase activity remains normal).
Some drugs have hemolytic effect in people with failure of G-6-PDG only under certain conditions. Contributing factors are infectious diseases (OVRZ, OVG, BVI), failure of the liver and kidneys, diabetic acidosis, etc.. d.
Number of people, whose respective drugs cause hemolysis, It varies in populations of 0 to 15%, and in some areas up 30%.
Failure N-atsetiltransferazы.
Shortly after introduction into medical practice of isonicotinic acid hydrazide (Isoniazid) It was found, that the tolerance of this material by patients varies. Some patients tolerate the drug well, while in others there are serious side effects - headache, dizziness, nausea, vomiting, chest pain, irritability, insomnia, tachycardia, polyneuritis, etc.. d. In an individual sensitivity to isoniazid is unequal intensity of its metabolism. The activity of this enzyme is caused by genetically different individuals and is not the same. It has been found, that after a single dose of isoniazid in some patients excreted in the urine 6-7% administered substance in metabolized form, others - twice. At slow inactivators of isoniazid concentration in the blood is much higher, rapid than.
The percentage ratio between the slow and fast inactivators of isoniazid in the population fluctuates within wide limits. So, slow inactivators are only 5% Eskimos and 45% Americans. The number of fast inactivators in Europe and India reaches 50%, and in Japan - 90-95%.
In appointing isoniazid TB patients must take into account the rate of its metabolism. Ceteris paribus in fast inactivators of isoniazid is used in high doses, than slow inactivators. The latter drug is useful to combine with pyridoxine (Vitamin B6), which prevents polyneuritis and other adverse reactions.
Differences in the rate of metabolism of isoniazid have little effect on the results of the treatment of tuberculosis (but affect the dosing frequency of the drug), however, they greatly affect the incidence of adverse drug reactions. At slow inactivators of isoniazid side effects occur more often. The rate of acetylation can be different not only isoniazid, but sulfadimezin, gidralazina, prazosin.
Other enzymes - catalase - destroys peroxide, formed in the body, and is involved in the metabolism of ethyl and methyl alcohol.
People with gipokatalaziey acatalasemia and especially with highly sensitive to alcohol (and alcohol-containing medicines) because of reduced rate of oxidation of ethanol.
