Isoniazid , effect metabolism

Increased hepatitis incidence, decreased isoniazid effects in chronic alcohol use due to increased metabolism... 

Isoniazid appears to cause a dual interaction. During administration, it inhibits the activity of cytochrome P450 isoenzyme CYP2E1, the enzyme involved in the metabolism of chlorzoxazone. Shortly after stopping isoniazid, the metabolism of chlorzoxazone is increased, possibly because of induction of CYP2E1, although this effect was only evident in the slow acetylators. ... 

Interesting information stems from studies of the hepatotoxic effect of the concomitant administration of rifampicin, another antituberculostatic drug (and a potent inducer of cytochrome P450) often used in combination with isoniazid. Rifampicin alone is not hepatotoxic but increases significantly the incidence of hepatitis in patients simultaneously dosed with isoniazid. In human volunteers (6 slow and 8 rapid acetylators), daily administration of rifampicin increased the release of hydrazine from isoniazid [180], In slow acetylators, the proportion of the dose metabolized to hydrazine increased... 

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. 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

Estazolam potentiates the CNS depressant effects of phenothiazines, narcotics, antihistamines, MAOIs, barbiturates, alcohol, general anesthetics, and TCAs. Use with cimetidine, disulfiram, oral contraceptives, and isoniazid may diminish hepatic metabolism and result in increased plasma concentrations of estazolam and increased CNS depressant effects. Fleavy smoking (more than 20 cigarettes/day) accelerates estazolam s clearance. Theophylline antagonizes estazolam s pharmacological effects. 

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). 

Williams SE, Wardman AG, Taylor GA, Peacock M, Cooke NJ. Long term study of the effect of rifampicin and isoniazid on vitamin D metabolism. Tubercle 1985 66(l) 49-54. 

Ethionamide This structural analog of isoniazid is believed not to act by the same mechanism. It is effective after oral administration, and is widely distributed throughout the body, including the CSF. Metabolism is extensive. Ethionamide [e thye on AM ide] can inhibit acetylation of isoniazid (Figure 33.7). The urine is the main route of excretion. Adverse effects that limit its use include gastric irritation, hepatotoxicity, peripheral neuropathies, and optic neuritis. Isoniazid... 

Correct choice = D. Isoniazid reacts with pyri-doxine (vitamin Be), which can cause a deficiency of this vitamin, isoniazid readily penetrates into infected cells and therefore is effective against bacilli growing intracellulariy. Isoniazid inhibits the metabolism of phenytoin. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

Isoniazid inhibits monoamine oxidase, and hence reduces tyramine metabolism this effect is enhanced by co-administration of other monoamine oxidase inhibitors... 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

ISONIAZID ANTI FUNG ALS -ITRACONAZOLE, KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE i levels of these azoles, with significant risk of therapeutic failure Isoniazid is a known inhibitor of CYP2E1 and is likely to induce other CYP isoenzymes to varying degrees, usually in a time-dependent manner Avoid co-administration of ketocon-azole or voriconazole with isoniazid. Watch for inadequate therapeutic effects of itraconazole. Higher doses of itraconazole may not overcome this interaction, so consider the use of less lipophilic fluconazole, which is less dependent on CYP metabolism... 

Bender DA (1980) Effects of benserazide, carbidopa and isoniazid administration on tryptophan-nicotinamide nucleotide metabolism in the rat. Biochemical Pharmacology 29, 2099-2104. 

Despite these advances in our understanding of the risk factors that predispose to isoniazid-induced hepatotoxicity/ it remains unclear whether age/ the predominant risk factor (Table 16.3)/ exerts its effects either on isoniazid metabolism or on protective mechanisms that as yet remain undefined. Clearly/ more work is needed in this area/ especially because understanding the biochemical basis of these risk factors plays a central role in developing guidelines for using isoniazid for chemoprophylaxis of tuberculosis (35). 

B14. Biehl, J. F., and Vilter, R. W., Effect of isoniazid on vitamin Bg metabolism its possible significance in producing isoniazid neuritis. Proc. Soc. Exptl. Biol. Med. 85, 389-392 (1954). 

Isoniazid inhibits the metabolism of phenytoin, carbamazepine and ethosuximide, increasing their effect. 

---