Isoniazid adverse effects

Isoniazid is bactericidal against growing M. tuberculosis. Its mechanism of action remains unclear. (In the bacterium it is converted to isonicotinic acid, which is membrane impermeable, hence likely to accumulate intracellu-larly.) Isoniazid is rapidly absorbed after oral administration. In the liver, it is inactivated by acetylation, the rate of which is genetically controlled and shows a characteristic distribution in different ethnic groups (fast vs. slow acetylators). Notable adverse effects are peripheral neuropathy, optic neuritis preventable by administration of vitamin Be (pyridoxine) hepatitis, jaundice. 

The most commonly observed side effects are GI disturbances and nervous system symptoms, such as nausea, vomiting, headache, dizziness, and fatigue. Hepatitis is a major adverse effect, and the risk is highest in patients with underlying liver diseases and in slow isoniazid acetylators the rate of hepatotoxicity is increased if isoniazid and rifampin are combined. 

Mild hepatic dysfunction, detected as an elevation in serum transaminases, is now well recognized as an adverse effect of isoniazid and occurs in 10% to 20% of patients. Possibly, as many as 1 % of these cases progress to severe hepatic damage, and it has been suggested that this latter, more severe form, of hepa to toxicity may have a different underlying mechanism. However, the greater incidence of hepatotoxicity reported in rapid acetylators has since been questioned. It seems that the incidence of the mild form of isoniazid hepatotoxicity is not related to the acetylator phenotype, but the incidence of the rarer, more severe form is more common in slow acetylators. 

This drug may cause degeneration of peripheral nerves after repeated exposure as a result of the depletion of vitamin B6. This is because isoniazid reacts with pyridoxal to form a hydrazone that inhibits pyridoxal phosphate kinase, so blocking formation of pyridoxal phosphate. As this effect is due to the parent drug, slow acetylators are more at risk, but the adverse effect can be prevented by supplying vitamin B6 to the patient. 

Ethambutol [e THAM byoo tole] is bacteriostatic and specific for most strains of M- tuberculosis and M- kansasii. Resistance is not a serious problem if the drug is employed with other antituberculous agents. Ethambutol can be used in combination with pyrazinamide, isoniazid, and rifampin to treat tuberculosis. Absorbed on oral administration, ethambutol is well distributed throughout the body. Penetration into the central nervous system (CNS) is therapeutically adequate in tuberculous meningitis. Both parent drug and metabolites are excreted by glomerular filtration and tubular secretion. The most important adverse effect is optic neuritis, which results in... 

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... 

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 ANTIVIRALS-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS t adverse effects with didanosine and possibly stavudine Additive side-effects Monitor closely for the development of peripheral neuropathy, but no dose adjustment is required... 

The severe fiver dysfunction also seemed to be more common in slow metabofizers, and it was proposed that this due to a deficiency in detoxication of a metabolite. Monitoring patients with fiver function tests is one way to avoid this adverse effect. There may be other factors as well as the acetylator phenot5rpe that are important, such as other drugs being taken at the same time. Excessive and sustained alcohol intake may also be a factor, as this is quite commonly associated with the occurrence of tuberculosis. Apart from weakening the fiver it will also increase the amount of the enzyme that produces the toxic metabolite of isoniazid. 

Hydralazine has been in use since the 1950s and is usually used in combination with other drugs such as diuretics and P-blockers. In a significant number of patients, and typically after 18 months, adverse effects started to appear. These included joint and muscle pain (arthralgia and myalgia), a rash on the face and inflamed blood vessels (vasculitis). The rash on the face made afflicted patients look wolf-like, which gave rise to the name for the syndrome. Lupus erythematosus (Lupus is Latin for wolf). This disease can be caused by other drugs, such as isoniazid very occasionally and procainamide more frequently. It may also have other, unknown, causes and has some similarities with rheumatoid arthritis. 

Adverse effects. Isoniazid is in general well tolerated. The most severe adverse effect is liver damage which may range from moderate elevation of hepatic enzymes to severe hepatitis and death. It is probably caused by a chemically reactive meta-bolite(s), e.g. acetylhydrazine. Most cases develop within the first 8 weeks of therapy and liver function tests should be monitored monthly during this period at least. 

Isoniazid is a structural analogue of pyridoxine and accelerates its excretion, the principal result of which is peripheral neuropathy with numbness and tingling of the feet, motor involvement being less common. Neuropathy is more frequent in slow acetylators, malnourished people, the elderly and those with HIV infection, liver disease and alcoholism. Such patients should receive pyridoxine lOmg/d by mouth, which prevents neuropathy and does not interfere with the therapeutic effect some prefer simply to give pyridoxine to all patients. Other adverse effects include mental disturbances, incoordination, optic neuritis and convulsions. 

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). 

Severe local and systemic adverse effects of BCG treatment can be treated successfully with tuberculostatic drugs, to most of which BCG is very susceptible, for up to 6 months (32). The effects of isoniazid on the incidence and severity of adverse effects of intravesical BCG therapy have been analysed in patients who received BCG with (n = 289) and without (n = 190) isoniazid (33). The authors concluded that prophylactic oral administration of isoniazid (300 mg/day with every BCG instillation) caused no reduction in any adverse effect of BCG. In contrast, transient liver function disturbances occurred slightly more often when isoniazid was used. The polymerase chain reaction has been used to monitor BCG in the blood after intravesical BCG instillation (22 patients) as well as after antituberculosis therapy (34). The early and fast diagnosis of BCG in the blood was considered to be potentially valuable in initiating specific early treatment of BCG complications. 

This effect, attributed here to bucillamine, is a rare but well-established adverse effect of penicillamine. Although the patient had also taken isoniazid for pulmonary tuberculosis, that was unlikely to have played a part, since the breast enlargement started earlier and progressed after the isoniazid had been withdrawn. 

Pellagra-associated encephalopathy has been suspected as an adverse effect of isoniazid administration in several patients with tuberculosis. Deficiency of niacin (nicotinic acid) is characterized by dermatitis, diarrhea, and dementia. Other symptoms can occur, such as seizures, hallucinations, spasticity, and glossitis. Pellagra induced by isoniazid is promoted by malnutrition or a vegetarian diet with low intake of the nicotinamide precursors tryptophan and nicotinic acid. Specific supplementation is essential (10). 

Abnormal liver function is the most commonly described adverse effect of isoniazid (23). It may be related to acetylator phenotype. 

Isoniazid is the safest antituberculosis drug for use during lactation (45,46). However, as isoniazid passes into breast milk, a watch must be kept for adverse effects in the infant when a nursing mother is taking isoniazid (47). However, the serum concentrations that occur in children have no therapeutic effect and cannot be considered as a form of preventive chemotherapy in infants of mothers with active tuberculosis. 

Goldman AL, Braman SS. Isoniazid a review with emphasis on adverse effects. Chest 1972 62(l) 71-7. 

Liver damage is the most common adverse effect of pyrazinamide (6). It varies from asymptomatic alteration of hver function detectable only by laboratory tests, through a mild syndrome characterized by fever, anorexia, malaise, hver tenderness, hepatomegaly, and splenomegaly, to more serious reactions with clinical jaundice, and finally the rare form with progressive acute yellow atrophy and death. As most patients take a combined regimen of pjrazinamide with isoniazid and rifampicin, it is difficult to determine which of the three drugs causes the hepatotoxicity it could be due to a combined effect (7). As with isoniazid and rifampicin, hepatic function should initially be monitored every few weeks. 

Chronic alcohohsm is an important risk factor for adverse effects of the rifamycins. In 79 consecutive patients taking rifampicin in combination with isoniazid and another drng, there was a high incidence of acnte chnical liver... 

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