Slow acetylator, drug reaction

Hydralazine may cause a dose-related, reversible lupus-like syndrome, which is more common in slow acetylators. Lupus-like reactions can usually be avoided by using total daily doses of less than 200 mg. Other hydralazine side effects include dermatitis, drug fever, peripheral neuropathy, hepatitis, and vascular headaches. For these reasons, hydralazine has limited usefulness in the treatment of hypertension. However, it may be useful in patients with severe chronic kidney disease and in kidney failure. 

Mefabo//sm - The half-life of INH is widely variable and dependent on acetylator status. Isoniazid is primarily acetylated by the liver this process is genetically controlled. Fast acetylators metabolize the drug about 5 to 6 times faster than slow acetylators. Several minor metabolites have been identified, one or more of which may be reactive (monoacetylhydrazine is suspected), and responsible for liver damage. The rate of acetylation does not significantly alter the effectiveness of INH. However, slow acetylation may lead to higher blood levels of the drug, and thus to an increase in toxic reactions. 

An interesting example of racial differences in drug conversion is seen in the metabolism of the antitubercular, isoniazid. It is inactivated by an acetylation reaction. Slow acetylation leads to toxicity (lupus, drowsiness, nausea, cyanosis). Free isoniazid also inhibits the action of phenytoin (an anticonvulsive) and results in phenytoin toxicity. Normal acetylation has a half-life of 45-80 minutes while a "slow acetylator" shows a 140-200 min half-life. The U.S. population shows a 50/50 distribution of "slow" versus "fast" acetylators. 44-55% of American Causasians and blacks are "slow". 

Orientals are fast acetylators. Separation of individuals into either rapid or slow acetylators is determined by variation at a single autosomal locus and constitutes one of the first discovered genetic polymorphisms of drug metabolism. In general, Eskimos are fast acetylators, while Jews and white North Africans are slow. The half-life of the acetylation reaction for isoniazid in fast acetylators is approximately 70 minutes, whereas in the slow acetylators this value is in excess of 3 hours. 

In contiast, slow acetylators appear to show a greater incidence of systemic lupus erytiiematosus following administration of hydrazine (hugs tiian do rapid acetylators as this toxic reaction is related to the parent drug. 

Race and ethnicity may also be risk factors for ADRs. Prior personal or family history of ADRs may be predictive of future adverse reactions. Genetic polymorphisms for many metabolic reactions are described in Chapter 13 and have been well documented (45). Prescribing some medications without regard to genetic differences in metabolism can result in therapeutic failures or drug toxicity (45, 46). For example, differences in acetylator phenotype can alter the metabolism of some drugs and influence the risk of certain adverse reactions. Slow acetylators, for example, may be more likely than rapid acetylators to develop he pa to toxicity from isoniazid treatment. The biochemical basis for this difference is described in Chapter 16. 

One common polymorphism in the United States is for N-acetyltransferase, an enzyme involved in phase II reactions. N-acetyltransferase catalyzes the acetylation of aromatic amines and hydrazines, and other classes of xenobiotics. People characterized as slow acetylators have relatively low N-acetytransf-erase activity. Consequently, slow acetylators are more sensitive to the toxic effects of certain types of drugs, including sulfa drugs. In addition, a study of workers exposed to benzidine in the dye industry suggested a link between the slow acetylator phenotype and the development of bladder cancer. 

Answer D Procainamide is metabolized by N-acetyltransferase (a phase II drug metabolism reaction) to form iY- ace t yl - pro e ain am i de (NAPA), which itself has antiarrhythmic activity. Patients who are classified as slow acetylators may develop SLE-like symptoms when treated with procainamide. Other drugs metabolized via N-acetyltrans-ferase, including isoniazid and hydralazine, have also been associated with lupus-like symptoms in slow acetylators. 

Acetylation is a very common metabolic reaction which occurs with amino, hydroxyl or sulfhydryl groups. The acetyl group is transferred from acetyl-coenzyme A 2ind the reaction is catalysed by acetyltransferases. An important aspect of this kind of substitution is the genetic polymorphism of one acetyltransferase in humans, who are divided into fast and slow acetylators. In a few cases, the conjugates are further metabolized to toxic compounds, as is seen with isoniazid. Some evidence exists that acetylation of the antitubercular isoniazid leads to enhanced hepatotoxicity of the drug. ° Acetylation followed by hydrolysis and cytochrome P-450-dependent oxidation yields free acetyl radicals or acylium cations which may acetylate the nucleophilic macromolecule functions (Fig. 32.16). 

This is a vasodilator drug, which causes SLE in a significant proportion of patients. Several predisposing factors have been identified dose (>25 mg) duration of therapy (mean 18 months) acetylator phenotype (slow) HLA type (DR4) and gender (females males, 4 1). Antinuclear antibodies and antihydralazine antibodies are detected in serum. This causes a type III immune reaction. Mechanism is unclear but may involve interference with the development and maturation of T cells in the thymus, leading to an alteration of tolerance... 

There could be alternate models than those used in the above discussions of the elimination processes. For instance, a model of acetylation, where the binding equilibria of drugs with serum protein and liver tissues are slow reactions and compete with each other for drugs, would result in a different expression than Equation 14. However, analyses of the rates of acetylation and excretion for various test organisms, which are physicochemically as well as statistically reasonable, are only possible with the present models. The propriety of using these models would be further proved by the following discussions on the time of duration. 

Carbachol is an example of a direct-acting parasympathetic drug in which the stability of ACh is increased by replacement of the acetyl function by the acyl-like group—the car-bamyl ester—which has considerable resistance to hydrolysis. Although enzymatic hydrolysis of carbachol occurs, the reaction is so slow that for practical purposes it may be considered insignificant. 

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