Isoniazid dosage

The distribution is clearly bimodal (which means, it has two separate peaks). People with a plasma level of more than 2.5 mg/1 are deemed slow acetylators . This is actually a genetic trait that follows Mendelian inheritance, and it is obviously important for the individual adjustment of isoniazid dosage. It is the classical but by no means single example of genetic variation in drug metabolism. The study of phenomena of this type is called pharmacogenetics , and there actually is a scientific journal of that name. 

An unusual adverse effect of thiacetazone was reported from Thailand (52<=). This report gave details of gynaecomastia which developed in 7 patients undergoing ambulatory treatment with 300 mg of isoniazid and 150 mg of thiacetazone daily. The reaction developed between 2 and 9 months after starting treatment and was reversed by the withdrawal of thiacetazone without any change in isoniazid dosage. 

Antacids also have clinically significant drug interactions with tetracycline, ferrous sulfate, isoniazid, quinidine, sul-fonylureas, and quinolone antibiotics. Antacid-drug interactions are influenced by antacid composition, dose, dosage schedule, and formulation. 

Isoniazid Adults S mg/kg (300 mg) Children 1 0-1 S mg/kg (300 mg) Asymptomatic elevation of aminotransferases, clinical hepatitis, fatal hepatitis, peripheral neurotoxicity, CNS system effects, lupus-like syndrome, hypersensitivity, monoamine poisoning, diarrhea LFT monthly in patients who have preexisting liver disease or who develop abnormal liver function that does not require discontinuation of drug Dosage adjustments may be necessary in patients receiving anticonvulsants or warfarin... 

Intended for use concomitantly with other antituberculosis agents in pulmonary infections caused by capreomycin-susceptible strains of Mycobacterium tuberculosis, when the primary agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli. Administration and Dosage... 

Only a few well-documented drug combinations with phenytoin may necessitate dosage adjustment. Coadministration of the following drugs can result in elevations of plasma phenytoin levels in most patients cimetidine, chloramphenicol, disulfiram, sulthiame, and isoniazid (in slow acetylators). Phenytoin often causes a decline in plasma carbamazepine levels if these two drugs are given concomitantly. 

The incidence and severity of adverse reactions to isoniazid are related to dosage and duration of therapy. Isoniazid-induced hepatitis and peripheral neuropathy are two major untoward effects. 

Isoniazid as a single agent is also indicated for treatment of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly for 9 months. 

Peripheral neuropathy is observed in 10-20% of patients given dosages greater than 5 mg/kg/d, but it is infrequently seen with the standard 300-mg adult dose. Peripheral neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a dosage as low as 10 mg/d. Central nervous system toxicity, which is less common, includes memory loss, psychosis, and seizures. These may also respond to pyridoxine. 

The toxic effects of this anticonvulsant drug, which result from elevated plasma levels, are dose related and are mainly effects on the nervous system (ataxia, drowsiness, nystagmus). The high plasma levels may be due to deficiencies in metabolism as well as excessive dosage. Deficiencies in metabolism may be genetic or due to coadministration of other drugs (e.g., isoniazid, especially in slow acetylators). 

Secondly, the rate of the enzymatic acetylation shows considerable inter-individual variation. This is illustrated in Fig. 2.30c. Shown are the plasma levels of unconjugated (i.e., not yet acetylated) isoniazid in the plasma, 6 hours after intake of a certain dosage of the drug. 

The daily dose of isoniazid is 5 mg/kg, with a maximum of 300 mg/day in adults with normal liver and kidney function. In children, 8-10 mg/kg/day is an appropriate dosage, with a maximum daily dose of 300 mg, since the metabohsm of isoniazid in children is rapid. Untoward effects of isoniazid as a single antituberculosis drug can be evaluated in preventive tuberculosis therapy, since curative regimens usually consist of multiple drugs. 

Desensitization to isoniazid has been attempted in some patients with drug fever or rashes. A procedure of rush desensitization over a few days or a week can be used, starting with 1 mg orally and increasing the dosage every second day (41) or even every few hours. 

Isoniazid inhibits the parahydroxylation of phenytoin. Symptoms of phenytoin intoxication, such as dizziness, incoordination, or excessive sedation, can occur, particularly in patients who are slow acetylators (SEDA-11,271). Dosages of phenytoin should be adjusted according to plasma concentrations (58). 

Slow and rapid inactivators (acetylators) of isoniazid differ in the polymorphic arylamine (V-acetyltransferase type 2 (NAT2) in the U.S., the incidence of slow acetylators is -50%. The serum tj in fast acetylators is 1 hour versus 2-5 hours in slow acetylators, resulting in serum isoniazid levels in fast acetylators that are 30-50% of those in slow acetylators. Because isoniazid is relatively nontoxic, sufficient drug can be administered to fast acetylators to achieve a therapeutic effect. Hepatic insufficiency also increases drug concentrations, and dosage reduction is recommended for slow acetylators in this setting. Slow acetylators rarely may accumulate toxic concentrations if their renal function is impaired. 

The disoovery of MAOIs resulted from a search for derivatives of Isoniazid (isonlootinlo aold hydrazide) (Fig. 21.25) with antitubercular activity. During clinical trials with this hydrazine derivative, a rather consistent beneficial effect of mood elevation was noted in depressed patients with tuberculosis. Although no longer used clinically, iproniazid (Fig. 21.25), the first derivative to be synthesized, was found to be hepatotoxic at dosage levels required for antituberoular and antidepressant activity. The antidepressant activity of iproniazid, however, prompted a searoh for other MAOIs, whioh resulted in... 

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