Hepatitis isoniazid

The incidence of adverse reactions appears to be higher when larger doses of isoniazid are prescribed. Adverse reactions include hypersensitivity reactions, hematologic changes, jaundice, fever, skin eruptions, nausea, vomiting, and epigastric distress. Severe, and sometimes fatal, hepatitis has been associated witii isoniazid tiierapy and may appear after many months of treatment. Peripheral neuropathy (numbness and tingling of the extremities) is the most common symptom of toxicity. 

ISONIAZID. Severe and sometimes fatal hepatitis may occur with isoniazid therapy. The nurse must carefully monitor all patients at least monthly for any evidence of liver dysfunction. It is important to instruct patients to report any of tlie following symptoms anorexia, nausea, vomiting, fatigue, weakness, yellowing of Hie skin or eyes, darkening of Hie urine, or numbness in the hands and feet. 

Because they are hepatically cleared, isoniazid and rifampin do not require dose modification in renal failure.31,36,39 Pyrazinamide and ethambutol typically are reduced to three times weekly to avoid accumulation of the parent drug (ethambutol) or metabolites (pyrazinamide).28,31 Renally cleared TB drugs include the aminoglycosides (e.g., amikacin, kanamycin, and streptomycin), capreomycin, ethambutol, cycloserine, and lev-ofloxacin.28,31,33,39 Dosing intervals need to be extended for... 

Isoniazid Adults S mg/kg (300 mg) Children 1 0-1 S mg/kg (300 mg) Asymptomatic elevation of aminotransferases, clinical hepatitis, fatal hepatitis, peripheral neurotoxicity, CNS system effects, lupus-like syndrome, hypersensitivity, monoamine poisoning, diarrhea LFT monthly in patients who have preexisting liver disease or who develop abnormal liver function that does not require discontinuation of drug Dosage adjustments may be necessary in patients receiving anticonvulsants or warfarin... 

Elevations of serum transaminase concentrations generally are not correlated with the residual capacity of the liver to metabolize drugs, so these markers cannot be used directly as guides for residual metabolic capacity. Hepatically cleared TB drugs include isoniazid, rifampin, pyrazinamide, ethionamide, and p-aminosalicylic acid.39 Ciprofloxacin is about 50% cleared by... 

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... 

Recently, the role of hydrazine in the mechanism of isoniazid hepatotox-icity was confirmed by Sarich et al. [181]. Using a model of isoniazid-in-duced hepatotoxicity in rabbits, they found that hydrazine plasma concentrations correlated significantly with plasma argininosuccinic acid lyase, a sensitive marker of hepatic necrosis. In contrast, no correlation was found between plasma levels of isoniazid or acetylisoniazid and the markers of induced hepatic necrosis. 

The hepatic injury caused by iproniazid could also be due to the formation of the toxic metabolite hydrazine by A-dealkylation followed by hydrolysis. Indeed, A-dealkylation is a main route in the metabolism of iproniazid, with plasma levels of hydrazine in rabbits three- to sixfold higher than after isoniazid [188],... 

J. R. Mitchell, U. P. Thorgiersson, M. Black, J. A. Timbreb, W. R. Snodgrass, W. Z. Potter, D. J. Jollow, H. Keiser, Increased Incidence of Isoniazid Hepatitis in Rapid Acetylators Possible Relation to Hydrazine Metabobtes , Clin. Pharmacol. Ther. 1975, 18, 70-79. 

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. 

Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur or develop even after many months of treatment. The risk of developing hepatitis is... 

Treat patients with tuberculosis who have hepatitis attributed to isoniazid with appropriate alternative drugs. Reinstitute isoniazid after symptoms and laboratory abnormalities have become normal. Restart the drug in very small doses gradually increase doses and withdraw immediately if there is any indication of recurrent liver involvement. 

Previous isoniazid-associated hepatic injury or other severe adverse reactions. 

Laboratory tests Because there is a higher frequency of isoniazid-associated hepatitis among certain patient groups, obtain transaminase measurements prior to starting and monthly during preventative therapy, or more frequently as needed. If any of the values exceed 3 to 5 times the upper limit of normal, temporarily discontinue isoniazid and consider restarting therapy. 

Isoniazid (child 10 mg/kg up to) 300 mg orally, for 6 months 15 mg/kg orally, for 6 months 15 mg/kg orally, for 6 months Hepatic enzyme elevation Hepatitis Peripheral neuropathy CNS (mild) Drug interactions Hepatitis risk increases with age and alcohol consumption. Pyridoxine can prevent peripheral neuropathy... 

Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the latter drugs inhibit the hepatic metabolism of phenytoin. A reduction in phenytoin dose can alleviate the consequences of these drug-drug interactions. 

The incidence and severity of adverse reactions to isoniazid are related to dosage and duration of therapy. Isoniazid-induced hepatitis and peripheral neuropathy are two major untoward effects. 

A minor asymptomatic increase in liver aminotransferase is seen in 10 to 20% of patients, whereas fatal hepatitis is seen in fewer than 1% of isoniazid recipients. Risk factors for hepatitis include underlying liver disease, advanced age, pregnancy, and combination therapy with acetaminophen. Early recognition and prompt discontinuation of the drug is recommended to prevent further damage to the liver. 

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. 

PAS is readily absorbed from the GI tract and is widely distributed throughout body fluids except cerebrospinal fluid. It penetrates tissues and reaches high concentrations in the tuberculous cavities and caseous tissue. Peak plasma levels are reached within 1 to 2 hours of drug administration, and the drug has a half-life of about an hour. PAS is primarily metabolized by hepatic acetylation. When combined with isoniazid, PAS can function as an alternative substrate and block hepatic acetylation of isoniazid, thereby increasing free isoniazid levels. Both the acetylated and unaltered drug are rapidly excreted in the urine. The concentration of PAS in urine is high and may result in crystalluria. 

Thiacetazone is active against many strains of M. tuberculosis. It is not marketed in the United States. However, because of its low cost, it is used as a first-line agent in East Africa, especially in combination with compounds such as isoniazid. The most common side effects of thiacetazone include GI intolerance and development of rashes. It causes significant ototoxicity, especially when coadministered with streptomycin. Life-threatening hypersensitivity reactions, such as hepatitis, transient marrow aplastic syndromes, neutropenia, and thrombocytopenia, have been reported. 

Contraindications Acute hepatic disease, history of hypersensitivity reactions or hepatic injury with previous isoniazid therapy... 

Rare reactions include hepatotoxicity (risk is increased when rifampin is taken with isoniazid), hepatitis, blood dyscrasias, Stevens-Johnson syndrome, and antibiotic-associated colitis. 

Estazolam potentiates the CNS depressant effects of phenothiazines, narcotics, antihistamines, MAOIs, barbiturates, alcohol, general anesthetics, and TCAs. Use with cimetidine, disulfiram, oral contraceptives, and isoniazid may diminish hepatic metabolism and result in increased plasma concentrations of estazolam and increased CNS depressant effects. Fleavy smoking (more than 20 cigarettes/day) accelerates estazolam s clearance. Theophylline antagonizes estazolam s pharmacological effects. 

Isoniazid metabolites and a small amount of unchanged drug are excreted, mainly in the urine. The dose need not be adjusted in renal failure. Dose adjustment is not well defined in patients with severe preexisting hepatic insufficiency... 

Isoniazid Inhibits synthesis of mycolic acids, an essential component of mycobacterial cell walls Bactericidal activity against susceptible strains of M tuberculosis First-line agent for tuberculosis treatment of latent infection less active against other mycobacteria Oral, IV hepatic clearance (half-life 1 h) reduces levels of phenytoin Toxicity Flepatotoxic, peripheral neuropathy (give pyridoxine to prevent)... 

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