Isoniazid Rifampicin

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... 

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. 

Streptomycin (Boxes 20-B, 20-H) was introduced into clinical use against tuberculosis in about 1943. However, resistant mutants always survived until newer drugs were developed. Isonicotinylhydrazide (isoniazid) is especially effective in combinations with suitable antibiotics and other drugs.8 The four-drug combination isoniazid, rifampicin (Box 28-A), pyrazinamide, and ethambutol is often used. Nevertheless, bacteria resistant to all of these have developed. 

In the treatment of tuberculosis, resistant strains of M. tuberculosis (multidrug-resistant tuberculosis, MDRTB) present a growing problem, so that new antituber-culotic agents are required which act according to a different mechanism to that of standard agents such as isoniazid, rifampicin, pyrazinamide, and ethambutol. The more modern fluoroquinolones are of particular interest, and in particular moxifloxacin, which has powerful in vitro and in vivo activity and, in contrast to sparfloxacin and clinafloxacin, is not photo toxic [191]. 

The interaction of rifampicin with diazepam has been reviewed (54). The mean half-life of diazepam fell from 58 to 14 hours in seven patients who took isoniazid, rifampicin, and ethambutol (55). 

Drugs that are considered to be absorbed to a lesser degree with food include antibiotics (ampicillin, penicillins G and VK, isoniazid, rifampicin, lincomycin, nafcillin, tetracyclines), methyldopa and levodopa (to be... 

Acid-fast bacilli Mycobaazerium tubercu/osis isoniazid + rifampicin pyrazinamidc a quinolone or cycloserine or capreomycm or... 

Meningeal tuberculosis. It is essential to use isoniazid and pyrazinamide which penetrate well into the CSF. Rifampicin enters inflamed meninges well but noninflamed meninges less so. An effective regimen is isoniazid, rifampicin, pyrazinamide and streptomycin. Treatment may need to continue for much longer than modem short-course chemotherapy for pulmonary tuberculosis. 

Drugs include phenytoin, gold, penicillins, hydralazine, isoniazid, rifampicin, penicillamine, probenecid, sulphonamides. 

As a rule, a regimen of two, three, or four of the five first-line antituberculosis drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin) is used in tuberculosis (1). The 6-month short-course regimen consists of isoniazid, rifampicin, and pyrazinamide for 2 months, followed by isoniazid and rifampicin for 4 months (1). It may be advisable to include ethambutol in the initial phase when isoniazid resistance is suspected or if the prevalence of primary resistance to isoniazid is over 4% in new cases. A 9-month regimen consisting of isoniazid and rifampicin is also highly successful (1). Treatment should always include at least two drugs to which the mycobacteria are susceptible. 

Hepatotoxicity is the most important adverse effect of antituberculosis drug therapy. Isoniazid, rifampicin, and pyrazinamide are the main culprits. There is wide variability in the risk of hepatotoxic reactions reported from different parts of the world or in different populations (for example African-American women in the postpartum period) (SEDA-24, 353). 

Enhanced hepatotoxicity of conventional antituberculosis regimens has been reported in recipients of orthotopic hver transplants, which is not unexpected, because of bouts of organ rejection (25). The authors recommended ofloxacin for these patients on the basis of favorable outcome in six cases. A conventional antituberculosis induction regimen was used initially until hepatotoxicity developed in all six patients. Thereafter they were treated with a combination of ofloxacin and ethambutol, with apparent cure in all. It should be noted that most of the patients took isoniazid + rifampicin for almost 2 months, which is the usual period when hepatotoxic reactions occur. Perhaps one should evaluate substitution of rifampicin with ofloxacin from the very beginning in order to minimize hepatotoxicity, as well as interference with ciclosporin leading to graft rejection noted in an earlier study (26). 

Hwang SJ, Wu JC, Lee CN, Yen FS, Lu CL, Lin TP, Lee SD. A prospective clinical study of isoniazid-rifampicin-pyrazinamide-induced liver injury in an area endemic for hepatitis B. J Gastroenterol Hepatol 1997 12(1) 87-91. 

There was no statistical difference between patients who received different forms of treatment for suppurative lymphadenitis 36 patients received erythromycin, 21 isoniazid, and 21 isoniazid + rifampicin (90). When lymphadenitis developed rapidly (within 2 months), the incidence of spontaneous drainage and suppuration was reported to be significantly higher than in patients with slowly developing processes. Total surgical excision is recommended in these rapidly evolving cases. 

Barbiturates which induce Uver drug-metaboUzing enz)mes increase the rate of metabolism of isoniazid, rifampicin, or combined antituberculosis treatment, since they may result in accelerated breakdown of these drugs (52). 

Rifampicin is rarely used as monotherapy. The risk of hepatotoxicity appears to be very low in patients with normal liver function, especially if rifampicin is given continuously. When given with isoniazid, rifampicin can cause a fulminant liver reaction. This may be attributable to enhancement of isoniazid hepatotoxicity as a result of enzyme induction by rifampicin. In some cases, jaundice occurred within 6-10 days after beginning isoniazid plus rifampicin (52). High serum transaminase activities, disturbances of consciousness, and centrilobular necrosis were found. All the patients recovered. 

Pessayre D. Present views on isoniazid and isoniazid-rifampicin hepatitis. Agressologie 1982 23(A) 13-5. 

The current approach is to treat tuberculosis in two phases an initial phase where a combination of three drugs is used to reduce the bacterial level as rapidly as possible, and a continuation phase in which a combination of two drugs is employed. Front-line drugs are isoniazid, rifampicin, streptomycin and ethambutol. Pyrazinamide, which has good meningeal penetration, and is thus particularly useful in tubercular meningitis, may be used in the initial phase to produce a highly bactericidal response. 

First line drugs used to treat tuberculosis include isoniazid, rifampicin and pyrazi-namide with streptomycin and ethambutol as secondary drugs. 

Isoniazid-induced fulminant liver failure occurred in a 16-year-old girl taking carbamazepine and clonazepam, within 5 days of starting isoniazid, rifampicin and pyrazinamide. She recovered with supportive measures and later tolerated the antiepileptics with concurrent rifampicin and pyrazinamide. Isoniazid hepatotoxicity has also occurred in a 74-year-old woman and a 10-year-old boy" taking carbamazepine, shortly after treatment with isoniazid, rifampicin, and ethambutol, with or without pyrazinamide, was started. 

Gronhagen-Riska C, Hellstrom P, Fr5seth B (1978) Predisposing factors in hepatitis induced by isoniazid-rifampicin treatment of tuberculosis. Am Rev Respir Dis 118 461 Groopman JE, Soloff L, Tessler S (1978) Hepatitis from isoniazid and rifampin. N Engl J Med 298 1316... 

In a retrospective study in Brazil in 319 patients who underwent liver transplant and survived more than 1 month tuberculosis was identified in five women, mean age 40 years [ST f. None received chemoprophylaxis before or after liver transplant. Two had disseminated tuberculosis, two had pulmonary disease, and one had extrapulmonary disease. Cultures were positive in four. Four patients received isoniazid, rifampicin, and... 

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