Isoniazid antitubercular action

Isoniazid (INH) [Antitubercular Agent] Uses Rx prophylaxis of TB Action Bactericidal interferes w/ mycolic acid synth, disrupts cell wall Dose Adults. Active TB 5 mg/kg/24 h PO or IM (usually 300 mg/d) or DOT 15mg/kg... 

The first inhibitors of flavin-dependent MAO that were developed for clinical use were hydrazines and hydrazides. The chance discovery that the antitubercular drug, 4-pyridine carboxylic acid hydrazide (isoniazid, 40), was also a potent MAO inhibitor led to the development of the related drug, iproniazid (41), used for the treatment of depressive illness. Although this compound demonstrated remarkable antidepressant action, its clinical value was seriously compromised by side effects [19]. 

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". 

The positive effects of the monoamine oxidase inhibitor isoniazid and the amine reuptake blocker imipramine were both discovered by accident. Isoniazid was being used as an antitubercular drug when patients reports of elation led Nathan Kline to test and to demonstrate its antidepressant power. Ronald Kuhn had synthesized imipramine, a tricyclic molecule, as a possible me-too analog of chlorpromazine. When Kuhn found that it had little or no antipsychotic potential, he tried it out on depressives, and voila They got better. After a while, that is. As with isoniazid, imip-ramine s antidepressant action was evident only after one to four weeks of administration. 

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