Isoniazid clinical importance

A clinically important example of microsomal enzyme inhibition is the interaction between the drugs isoniazid and diphenylhy dan loin. Termination of the pharmacological activity of diphenylhydantoin depends on microsomal metabolism (figure 7.54). This may be inhibited... 

Commonly used drugs (other than isoniazid) affected by NAT2 polymorphism were procainamide, hydralazine, dapsone, and sulfonamides with an increase of side effects in all cases. A selective substrate of NATl is -aminosalicylic acid (PAS), but its genetic variation was never clinically important (52). Because of such lack of importance, more attention is often paid to the fact that various industrial chemicals with carcinogenic potential, and mutagenic heterocyclic amines, are substrates of both N-acetyltransferases (53). The presence or absence of these transferases will determine some incidences of cancer (54). Attempts have been made to ascribe cancer incidences in different populations to acetyltransferase differences (55). 

Miller RR, Porter J, Greenblatt DJ. Clinical importance of the interaction of phenytoin and isoniazid a report from the Boston Collaborative Drug Surveillance Program. Chest 1979 75(3) 356-8. 

Acetylation of drugs is also associated with genetically determined interindividual and interethnic differences. Differences in isoniazid toxicity between Asians and Caucasians are due to acetylation enzyme polymorphism. The majority (78%-93%) of Chinese and East Asians are fast acetylators, whereas only 50% of whites and African Americans are fast acetylators (Weber 1987). This is clinically important, because several psychoactive compounds (e.g., caffeine, clonazepam, nitrazepam, and phenelzine) are metabolized through acetylation (Sjoqvist et al. 1997). 

Clinically important, potentially hazardous interactions with albuterol, alcohol, clonidine, corticosteroids, danazol, diuretics, epinephrine, estrogens, isoniazid, lithium, oral contraceptives, pentamidine, phenothiazines, propranolol, somatropin, terbutaline, thyroid... 

Clinically important, potentially hazardous interactions with amprenavir, aprepitant, bedomethasone, buprenorphine, calcium, chloramphenicol, cimetidine, dobazam, clorazepate, cyclosporine, cyproterone, darunavir, dasatinib, delavirdine, dexamethasone, diazoxide, disulfiram, dopamine, fesoterodine, fluconazole, flunisolide, fluoxetine, fosamprenavir, ginkgo biloba, hydrocortisone, imatinib, indinavir, influenza vaccines, isoniazid, isradipine, itraconazole, lacosamide, lapatinib, lopinavir, meperidine, methylprednisolone, midazolam, mivacurium, nelfinavir, nilotinib, nilutamide, phenylbutazone, piracetam, posaconazole, prednisolone, prednisone, primrose, ritonavir, rivaroxaban, sage, saquinavir, solifenacin, St John s wort, sucralfate, telithromycin, temsirolimus, teniposide, ticlopidine, tizanidine, tolvaptan, triamcinolone, uracil/tegafur, vigabatrin... 

Clinically important, potentially hazardous interactions with aluminum, aminophylline, carbamazepine, carbimazole, cyclosporine, daclizumab, diuretics, etoposide, etretinate, grapefruit juice, indomethacin, isoniazid, itraconazole, ketoconazole, licorice, live vaccines, methotrexate, naproxen, oral contraceptives, pancuronium, phenobarbital, phenytoin, rifampicin, troleandomycin... 

Clinically important, potentially hazardous interactions with amiodarone, amprenavir, anisindione, antacids, anticoagulants, aprepitant, atazanavir, atovaquone, beclomethasone, buprenorphine, corticosteroids, cortisone, cyclosporine, cyproterone, dabigatran, dapsone, darunavir, delavirdine, dexamethasone, dicumarol, digoxin, eszopiclone, flunisolide, fosamprenavir, gadoxetate, gestrinone, halothane, imatinib, isoniazid, itraconazole, ketoconazole, lapatinib, lorcainide, methylprednisolone, midazolam, nelfinavir, nifedipine, oral contraceptives, phenylbutazone, prednisone, protease inhibitors, pyrazinamide, ramelteon, ritonavir, saquinavir, solifenacin, sunitinib, tacrolimus, telithromycin, temsirolimus, tipranavir, tolvaptan, trabectedin, triamcinolone, triazolam, voriconazole, warfarin, zaleplon... 

Isoniazid may increase the metabolism of enflurane, isoflurane or sevoflurane and thereby increase plasma-fluoride concentrations. However, this does not seem to have resulted in clinically important renal impairment. 

Information on this interaction is limited, and it is not established. The clinical importance of the modest reductions in isoniazid levels with aluminium hydroxide in one study is uncertain, but likely to be small. However, aluminium/magnesium hydroxide did not interact, and neither did didanosine chewable tablets. 

Prednisolone can lower plasma isoniazid levels, but this may not be clinically important... 

The clearance of a single 600-mg intravenous dose of isoniazid was reduced by 21%, from 16.4 to 13 L/hour, in 6 healthy subjects after they took propranolol 40 mg three times daily for 3 days. It is suggested that propranolol reduces the clearance of isoniazid by inhibiting its metabolism (acetylation) by the liver. However, as the increase in isoniazid levels is likely to be only modest this interaction is probably of little clinical importance. 

Direct information seems to be limited to these reports, but the interactions appear to be of clinical importance. Monitor the serum phen5doin levels and increase the dosage appropriately if rifampicin alone is started. Reduce the dosage if the rifampicin is stopped. If both rifampicin and isoniazid are given, the outcome may depend on the isoniazid acetylator status of the patient. Those who are fast acetylators will probably also need an increased phenytoin dosage. Those who are slow acetylators may need a smaller phenytoin dosage if toxicity is to be avoided. All patients should be monitored very closely as, unless acetylator status is known, the outcome is unpredictable. 

The interaction with phenytoin and isoniazid alone is well documented, well established, clinically important and potentially serious. About 50% of the population are slow or relatively slow metabolisers of isoniazid, but not all of them develop serum phenytoin levels in the toxic range. The reports indicate that somewhere between 10 and 33% of patients are at risk. This adverse interaction may take only a few days to develop fully in some patients, but several weeks in others. Therefore concurrent use should be very closely monitored, making suitable dosage reductions as... 

Information is limited but the interactions appear to be established. Their clinical importance is uncertain but be alert for the need to decrease the dosages of diazepam and triazolam if isoniazid is started. There seems to be no direct information about other benzodiazepines, but those undergoing high first-pass extraction and/or liver microsomal metabolism may interact similarly. Oxazepam and clotiazepam appear not to interact. 

The interaction between haloperidol and rifampicin would appear to be established and clinically important. Be alert for any evidence of reduced haloperidol effects if rifampicin alone is used, and possibly increased effects if isoniazid alone is used. Adjust the haloperidol dosage if necessary. 

Antituberculous treatment with rifampicin, isoniazid and etham-butol has been shown to increase the non-renal clearance of cimetidine by about 50%. This is probably due to enzyme induction caused by rifampicin. However, the total clearance is unchanged and so this interaction would appear to be of little clinical importance. ... 

The increase in chlorzoxazone levels is established, and occurs in both slow and fast acetylators of isoniazid, although the increase in levels is slightly greater in slow acetylators. In practical terms this means that it may be necessary to reduce the chlorzoxazone dosage in some patients if they take isoniazid. Monitor concurrent use carefully. The rebound increase in chlorzoxazone clearance in slow acetylators on stopping isoniazid was short-lived and is probably of little clinical importance. 

Isoniazid is acetylated to acetyl isoniazid by A-acetyl-transferase, an enzyme in fiver, bowel, and kidney. Individuals who are genetically rapid acetylators will have a higher ratio of acetyl isoniazid to isoniazid than will slow acetylators. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this is not proved. The slow or rapid acetylation of isoniazid is rarely important clinically, although slow inactivators tend to develop peripheral neuropathy more readily. Metabolites of isoniazid and small amounts of unaltered drug are excreted in the urine within 24 hours of administration. 

Quinolones are important recent additions to the therapeutic agents used against M. tuberculosis, especially in MDR strains. Clinical trials of ofloxacin in combination with isoniazid and rifampin have indicated activity comparable to that of ethambutol. In addition, quinolones, particularly ciprofloxacin, are used as part of a combined regimen in HIV-infected patients. 

Thus, the importance of enzyme induction is that it may alter the toxicity of a foreign compound. This can have important clinical consequences and underlie drug interactions. Thus, the antitubercular drug rifampicin is thought to increase the hepatotoxicity of the drug isoniazid, and alcohol may increase susceptibility to the hepatotoxicity of... 

Rifampicin toxicity is becoming of greater importance in the treatment of leprosy. Several studies have recently been reported in which rifampicin was used in combination with Isoprodian, a combination of dapsone, isoniazid and prothionamide. The commonest adverse effects observed on this combination are gastrointestinal disturbances and mild hepatitis, manifested either as abnormalities in biochemical parameters or clinically by jaundice. One case of exfoliative dermatitis was reported from a trial carried out in South India (35 ). 

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