Anti-tuberculous drugs i.e. Pyrazinamide (Z), Isoniazid (H), Rifampicin (R), Ethambutol (B) and Ethionamide have various forms of toxicity varying from mild G.I. disturbances, hypersensitivity reactions to hepatotoxicity. Almost all drugs are hepatotoxic with the exception of streptomycin. 4 Damage to liver ranges from slight asymptomatic increase in aspartate aminotransferase levels to severe frank necrosis. Pyrazinamide which now forms a necessary part of first line of drugs, due to its ability to act intracellularly in acidic environment, 5-7 has been reported to cause hepatitis8-10. The percentage developing hepatitis ranges from 6.611 to 10%6. Hepatitis was so frequent that regular use of pyrazinamide was thought inadvisable. In doses of 30-40mg/kg body weight per day, 8% had increased alaninetransferase12. However none of the patients developed hepatitis with the same dosage in Madras13. Pyrazinamide when used alone in non-alcoholics as a monotherapy showed excellent tolerance. 14 Pyrazinamide-induced hepatitis, however, is generally considered to have high mortality15. The drug also increases the serum uric acid levels causingjoint pains16-19. Isoniazid, a weak amine oxidase inhibitor, is the cheapest and most potent of the antituberculosis drugs which has been associated with severe hepatotoxicity. In one outbreak 19 of 2231 receiving isoniazid prophylactically for positive tuberculin test developed hepatitis; of these 13 developed jaundice and 2 died. 20 Toxicity is higher in older age group and amongst females. Rapid acetylators are said to be more susceptible21. Hepatitis resolves rapidly if the drug is discontinued but when jaundice develops, a mortality of 10% is reported22. Hepatic reactions are mild when isoniazid is used in combination with other antituberculosis drugs in doses not exceeding 30mg/kg/day23,24. Other untoward effects include peripheral neuritis, pyrexial reactions25, cutaneous hypersensitivity26,27 difficulty in starting micturition in males28,29. Peripheral neuritis rarely develops when small doses are used30-34 but is more frequent with larger dosage35-40. Overt reactions are very41,42 low and clinicaljaundice is rare43. Very high dosage produces toxic liver damage in animals44 and humans36. Associated features of hypersen sitivity like rash, fever, leukocytosis and eosinophilia have been reported in a majority of the cases. When used prophylactically it produces a slight rise in aspartate aminotransferase in 10-20% of the cases. Rifampicin can also cause asymptomatic rise in aspartate transferase in 20% cases45 which is usually of bepatic type though cholestatic type is also seen. This often settles in time in spite of the continuation of drug, as the reaction is not of a serious nature. Isoniazid acts synergetically with rifampicin on the liver46 resulting in jaundice and asymptomatic increase in aspartate amino-transaminase levels. 45 In B.T.T.A. studies in 512 patients on 3 different combinations of SHR & E for 9 months, with Zbeing used for the initial2 months as a part of 4 drugs regimens (SHRZ, EHRZ, EHR), 4% showed hepatitis; this frequency was the same as that in the control group. Mean bilirubin increase was 2m mols/L though it did not exceed the normal range47. Hepatitis presented in 3 different ways: (a) asymptomatic but persistently abnormal liver functions, (b) persistently abnormal liver functions with G.I. disturbances, and (c) jaundice. In another study by the same group in 802 patients with no associated disease or alcoholism, 3.6% (29 of 812) showed adverse reaction to R & H regimens, severe enough to warrant discontinuation of treatment. Fourteen of 29 had hepatotoxicity with raised transaminases and 8 had jaundice47. In Arkansas study 11% had adverse reactions of which 4% were major, 3% being hepatitis in R.H. group48. It was concluded that hepatic cirrhosis does not contra indicate the use of R & H or even Z48. In a study amongst alcoholics and patients with altered liver function tests, qualitative and quantitative improvement was observed after 2 months of intensive treatment with R, S, H, Z group and H, S, R, E combinations. Six months regimens studied in United States and Poland showed adverse reactions attributed to rifampicin or isoniazid or both in 5.2% (35/672) cases49. Ethambutol which has replaced PAS causes minimal toxic reactions50 mainly of optic neuropathy causing diminution of visual acuity, narrowing of field of vision and colour blindness and, rarely, hepatitis51,52. Hyperuricaemia responsive to probenicid and not to salicylates unlike that of pyrazinamide53 has also been described54-56. Gouty arthritis attributed to ethambutol has also been reported57. Streptomycin, which is more active in extra cellular alkaline environment58 and acts best on 6 rapidly multiplying bacilli59, is mainly toxic to eight nerve. Vestibular damage i.e. vertigo, ataxia and nystagmus is much more common than auditory disturbances. Hypersensitivity reactions manifested by fever, rash or both usually appear within first 4 weeks of starting the treatment. Adverse reactions of 15% in the present study are similar to early reports when (PAS) was a regular part of therapy, 33,8 but higher than reported in other studies61. Drugs had to be withdrawn in only 0.8% in Lahore study62 compared to 8.5% in ours. Hypersensitivity reactions were very mild in spite of 3 or 4 drugs used in the initial phase of 2 months. Of the 2 patients who complained of itching, one settled, but in the other R had to be withdrawn, and treatment completed with HEZ, followedby EH in continuation phase. Hepatitis that occurred in two cases (4%) is similar to other reports7,10,28. It settled completely, on withdrawal of drugs and treatment was completed by substituting other drugs. In conclusion, antituberculosis combinations used are well tolerated even in the presence of associated anaemia and malnourishment. In most cases there is a slight increase in the serum bilirubin levels in the first 2 weeks though the values remain within normal range, and levels revert back to pre- treatment level, when the therapy is continued. In our opinion, if no associated liver disease is present, frequent estimation of transferases is not essential, since even weekly checks do not provide sufficient warning of impending hepatitis. On first sign of toxicity, i.e., fever, rash or G.I. disturbance, all drugs should be discontinued and transferases checked. Once the liver profile becomes normal, the test doses of most probable offending drug should be tried in turn, offending drug identified and avoided. Drugs producing hepatitis should never be used again. In case of hypersensitivity reactions when no choice is available, desensitization may be tried.
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