Isoniazid elimination

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. 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

Disulfiram is rapidly and completely absorbed from the gastrointestinal tract however, a period of 12 hours is required for its full action. Its elimination rate is slow, so that its action may persist for several days after the last dose. The drug inhibits the metabolism of many other therapeutic agents, including phenytoin, oral anticoagulants, and isoniazid. It... 

Another cause of toxicity with diphenylhydantoin can be the result of interactions with other drugs such as isoniazid. This drug is a noncompetitive inhibitor of the aromatic hydroxylation of diphenylhydantoin. Consequently, the elimination of diphenylhydantoin is impaired in the presence of isoniazid, and the plasma level is greater than anticipated for a normal therapeutic dose. Furthermore, it was found that there was a significant correlation... 

Figure 2.8 Clonidine 23 was designed as a nasal decongestant but it turned out to be a potent antihypertensive drug. Clinical tests revealed the antidepressant activity of iproniazid 24, an isopropyl analog of the antituberculosis drug isoniazid 25. D-Penicillamine 26 was originally used to treat Wilson s disease, to eliminate an excess of copper ions later it was recognized to have beneficial effects in rheumatoid arthritis.

Peripheral neuropathy has been observed as a complication in tuberculosis therapy with isonicotinic acid hydrazide (isoniazid), especially when large doses have been employed (B14). This complication of isoniazid therapy has been largely eliminated by simultaneous administration of pyridoxine. These observations have prompted studies on the urinary excretion of xanthurenic acid as an index of the antipyridoxine activity of isoniazid. The excretion of an excess of vitamin Be as such... 

Individuals also vary widely in their elimination kinetics of isoniazid, procainamide, and other substrates of N-acetyltransferase (NAT2). Peripheral neuropathy associated with the use of isoniazid, an antituberculosis drug, first surfaced more than 40 years ago. It is now known that the slow acetylator phenotype represents approximately 40-50% of Caucasians, and results in decreased clearance of drug with increased potential for associated toxicities. 

These can interfere with vitamin processing in the intestinal tract, tie up the vitamin preventing it from being used, or possibly promote elimination of the vitamin. Examples include isoniazid-pyridoxine, phenobarbital-cholecalciferol, methotrexate-folic acid, phenytoin-folicacid. 

In nearly all patients, isoniazid and rifampin do not require dose modification in renal failure. They are eliminated primarily by the liver." " " In the unlikely event that peripheral neuropathies develop, the frequency of isoniazid dosing may be reduced. Pyrazinamide and ethambutol typically require a reduction in dosing frequency from daily to three times weekly " (Table 110-6). 

Antituberculosis drugs that rely on hepatic clearance for most of their elimination include isoniazid, rifampin, pyrazinamide, ethionamide. 

Probenecid acts at the luminal side of the renal tubular cell. Thus, it must use the organic acid secretory system to enter the lumen of the tubule, because it is not filtered. Drugs such as aspirin and isoniazid (as well as most (3-lactam antibiotics, and a host of other drugs that are organic acids) also use the organic acid secretory system for transport into the nephron, in their elimination. Thus, there is competition for transport, which may result in a decrease in drug elimination and subsequent increase in plasma levels of the concurrent drug, as well as a decrease in the efficacy of probenecid. 

Answer E. Cimetidine is an inhibitor of the hepatic cytochrome P450 isoform that metabolizes phenytoin, consequently i its clearance and thus T its elimination half-life. The hepatic metabolism of many other drugs can be inhibited by cimetidine, possibly necessitating dose reductions to avoid toxicity, including beta blockers, isoniazid, procainamide, metronidazole, tricyclic antidepressants, and warfarin. 

Phenytoin The oral bioavailability of phenytoin is variable because of differences in first-j>ass metabolism. Phenytoin metabolism is nonlinear elimination kinetics shift from first-order to zero-order at moderate to high dose levels. The drug binds extensively to plasma proteins (97-98%), and free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete for binding (eg, sulfonamides, valproic acid). The metabolism of phen)Toin is enhanced in the presence of inducers of liver metabolism (eg, phenobarbital, rifampin) and inhibited by other drugs (eg, cimetidine, isoniazid). Fos-phenytoin is a water-soluble prodrug form of phen)Toin that is used parenterally. 

Antimicrobial drugs that are eliminated via hepatic metabolism or biliary excretion include erythromycin, cefoperazone, clindamycin, doxycycline, isoniazid, ketoconazole, and nafcillin. The answer is (C). 

D. Enhancement of Elimination Enhancement of elimination is possible for a number of toxins, including manipulation of urine pH to accelerate renal excretion of weak acids and bases. For example, alkaline diuresis is effective in toxicity due to fluoride, isoniazid, fluoroquinolones, phenobarbital, and salicylates. Urinary acidiflcation may be useful in toxicity due to weak bases, including amphetamines, nicotine, and phencyclidine, but care must be taken to avoid acidosis and renal failure in rhabdomyolysis. Hemodialysis or hemoperfusion enhances the elimination of many toxic compounds, including acetaminophen, ethylene glycol, formaldehyde, lithium, methanol, procainamide, quinidine, salicylates, and theophylline. Cathartics such as sorbitol (70%) may decrease absorption and hasten removal of toxins from the gastrointestinal tract. 

A molecule of streptomycin and a molecule of isoniazid by means of a strong double bond between C and N with the elimination of a mole of water. The hyberdised molecule exhibits a significant potentiated antibacterial and tuberculosstatic agent. 

D. Pharmacokinetics. Disulfiram is rapidly and completely absorbed, but peak effects require 8-12 hours. Although the elimination half-life is 7-8 hours, clinical actions may persist for several days. Disulfiram is metabolized in the liver it inhibits the metabolism of many other dmgs, including isoniazid, phenytoin, theophylline, warfarin, and many benzodiazepines. (See also Table 11-59.)... 

Wanwimolruk S, Kang W, Coville PF, Viriyayudhakon S, Thitiarchakul S. K ked enhancement by rifampicin and lack of effect of isoniazid on the elimination of quinine in man. BrJ CUnPharmacol( 995) 40,87-91. 

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