Isonicotinic Acid Hydrazide
Pharmacology: Isoniazid is a bactericidal agent active against organisms of the genus Mycobacterium, specifically M. tuberculosis, M. bovis and M. kansasii. It is a highly specific agent, ineffective against other microorganisms. The mode of action is unknown but the drug is firmly bound to actively growing, sensitive, tubercle bacilli and does not affect these organisms when they are in the metabolic resting state.
When used alone in the treatment of tuberculosis, resistant strains emerge very rapidly; when combined with other antituberculosis agents the emergence of resistant strains may be delayed or prevented. When isoniazid is used alone in the prophylaxis of tuberculosis, the development of resistance does not appear to be a major problem.
Pharmacokinetics: Isoniazid is rapidly and almost completely absorbed, and peak blood levels are reached in about 1 to 2 hours. Bioavailability is reduced when isoniazid is administered with food. It diffuses readily into all body fluids (including cerebrospinal, pleural, and ascitic), tissues, organs, and excreta (saliva, sputum and feces).
Isoniazid is metabolized by the liver mainly by acetylation and dehydrazination. The N-acetylhydrazine metabolite is believed to be responsible for the hepatotoxic effects seen in patients treated with isoniazid. The rate of acetylation is genetically determined. Approximately 50% of blacks and Caucasians are slow inactivators; the majority of Inuit and Orientals are rapid inactivators. The half-life in fast acetylators is 1 to 2 hours while in slow acetylators it is 2 to 5 hours. Elimination is largely independent of renal function, however the half-life may be prolonged in liver disease. The rate of acetylation has not been shown to significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood concentrations with chronic administration of the drug, with an increased risk of toxicity. Isoniazid and its metabolites are excreted in the urine with 75 to 95% of the dose excreted in 24 hours. Small amounts are also excreted in saliva, sputum and feces. Isoniazid is removed by hemodialysis and peritoneal dialysis.
Indications: Used in conjunction with other antituberculosis agents in the treatment of pulmonary and extrapulmonary tuberculosis and alone in the prophylaxis of tuberculosis.
Patients who develop severe hypersensitivity reactions to isoniazid, including drug-induced hepatitis; acute liver disease of any etiology.
Warnings: Severe and sometimes fatal hepatitis associated with isoniazid therapy may occur and may develop even after months of treatment. Serum AST levels become elevated in about 10 to 20% of patients, usually during the first few months of therapy, but it can occur at any time. Usually enzyme levels return to normal despite continuance of the drug, but in some cases progressive liver dysfunction occurs. The risk of developing hepatitis is increased with pre-existing liver disease, increasing age, concurrent use of other hepatotoxic medications and excessive or chronic use of alcohol. Patients given isoniazid should be carefully monitored and interviewed regularly. Patients should be instructed to report immediately any of the prodromal symptoms of hepatitis, such as fatigue, weakness, malaise, anorexia, nausea or vomiting. If symptoms and signs suggestive of hepatic damage are detected, an alternative agent should be used since continued use of isoniazid in these patients may cause a more severe form of liver damage. If isoniazid must be reinstituted, this should be done only after symptoms and laboratory abnormalities have cleared. Therapy should be reinitiated in very small and gradually increasing doses, and withdrawn immediately if there is any indication of recurrent liver involvement.
Precautions: Isoniazid may cause mild or severe hepatic dysfunction (see Warnings).
Hypersensitivity reactions, including rash, fever, lymphadenopathy or vasculitis have occurred rarely and usually develop within 3 to 7 weeks of starting therapy. If these signs or symptoms occur, isoniazid should be discontinued and reinstituted very gradually, if necessary, after the reaction resolves.
Optic neuritis has been reported as a rare complication. Periodic ophthalmoscopic examinations during isoniazid therapy are recommended when visual symptoms occur.
It is believed that isoniazid competes with pyridoxyl phosphate for the enzyme apotryptophanase which may lead to symptoms of pyridoxine (vitamin B6) deficiency. Pyridoxine administration can prevent and reverse peripheral neuropathy complicating isoniazid use. Prophylactic pyridoxine administration (e.g., 10 to 50 mg/day) should probably be given routinely in individuals predisposed to develop peripheral neuropathies secondary to isoniazid therapy (e.g., patients who are malnourished, pregnant, alcoholic, diabetic, HIV-infected, or patients receiving higher doses of isoniazid).
Drug Interactions : Because the chemotherapy of tuberculosis involves the use of at least 2 drugs, the possible adverse reactions of each drug should be borne in mind as well as the potential for drug interactions.
Aluminum Hydroxide Gel: Decreases gastrointestinal absorption of isoniazid; isoniazid should be administered at least 1 hour before the antacid.
Anticonvulsants: Isoniazid inhibits hepatic metabolism of carbamazepine and phenytoin, resulting in increased anticonvulsant concentrations and toxicity in some patients. If isoniazid and carbamazepine or phenytoin are administered concurrently, serum concentrations of the anticonvulsant should be monitored, the patient observed for evidence of toxicity and the dosage of the anticonvulsant should be reduced accordingly.
Cycloserine: In combination with isoniazid may result in increased cycloserine CNS side effects such as dizziness or drowsiness.
Disulfiram: Coordination difficulties and psychotic episodes have occurred in patients receiving isoniazid and disulfiram; concurrent administration of the drugs should be avoided.
Ketoconazole: Concentrations may be decreased by isoniazid, possibly decreasing the antifungal effect.
Rifampin: Hepatotoxicity has been reported to occur more frequently when rifampin and isoniazid are given concurrently. The incidence may be higher in slow isoniazid acetylators, those receiving high doses of isoniazid or those with pre-existing liver disease.
Others: In addition, isoniazid may cause inhibition of metabolism of the following: acetaminophen, corticosteroids, diazepam, oral anticoagulants, primidone and theophyllines. The patient should be observed for increased effect or toxicity of these agents.
Pregnancy: Although safe use of isoniazid during pregnancy has not been definitely established, isoniazid has been used to treat clinical tuberculosis in pregnant women. If a risk vs. benefit analysis results in a decision to use isoniazid during pregnancy, prophylactic pyridoxine supplementation is recommended.
Prophylactic isoniazid therapy is best postponed until after delivery, unless the woman is likely to have been recently infected or has other high risk medical conditions such as HIV infection.
Lactation: No adverse effects have been reported, but there is a potential risk of peripheral neuritis or hepatic damage. Breast-fed infants should be carefully observed for evidence of adverse effects.
Adverse Effects: Toxic effects are usually encountered only with higher doses of isoniazid, and their incidence is reportedly higher in slow inactivators. The incidence of adverse effects at a dose of 10 mg/kg has been reported to be approximately 15%.
CNS: Peripheral neuropathy (occurs most often in the malnourished and is usually preceded by paresthesias of the feet and hands) is the most common (see Precautions). Convulsions, toxic encephalopathy, optic neuritis and atrophy, and toxic psychosis may occur rarely.
Gastrointestinal: nausea, vomiting, epigastric distress.
Hepatic: elevated serum aminotransferases (ALT, AST) and bilirubin concentrations (10 to 20%), hepatitis with or without jaundice. Isoniazid-associated, occasionally severe and sometimes fatal hepatitis is generally considered an unpredictable hypersensitivity reaction (see Warnings).
Hematologic: agranulocytosis, hemolytic, sideroblastic or aplastic anemia; thrombocytopenia; eosinophilia.
Hypersensitivity: fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, vasculitis. Hypersensitivity reactions usually occur in the first 3 to 7 weeks of therapy (see Precautions).
Metabolic and Endocrine: pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, gynecomastia.
Miscellaneous: rheumatic syndrome and systemic lupus erythematosus like syndrome.
tag_OverdoseOverdose: Symptoms: Manifestations of isoniazid overdosage usually become apparent within 30 minutes to 3 hours following ingestion. Nausea, vomiting, dizziness, slurring of speech, blurring of vision and visual hallucinations (including bright colors and strange designs), are among the early manifestations. With marked overdosage, respiratory distress and CNS depression, progressing rapidly from stupor to profound coma, are to be expected, along with severe, intractable seizures. Severe metabolic acidosis, acetonuria and hyperglycemia are typical laboratory findings.
Treatment: Treatment of overdosage consists of establishment of an airway, controlling of seizures with diazepam or barbiturates, i.v. injection of large doses of pyridoxine (e.g., a gram-for-gram dose equivalent to the amount of isoniazid ingested). See Vitamin B6 General Monograph. If seizures are under control and ingestion occurred within the past 2 to 3 hours, gastric lavage should be performed. I.V. sodium bicarbonate may be used to correct metabolic acidosis if necessary. Forced osmotic diuresis should be used to increase renal clearance over several hours, with monitoring of fluid intake and output. Hemodialysis or peritoneal dialysis may be helpful in severe cases.
Dosage: Isoniazid is given orally, as a single daily dose. Absorption is optimal if taken on an empty stomach but it may be taken with food if gastrointestinal irritation occurs.
Treatment of Tuberculosis: In conjunction with other agents, the adult dose is 5 to 10 mg/kg/day, to a maximum of 300 mg, for a minimum of 6 months. When intermittent therapy regimens are used, the adult dose of isoniazid is 15 mg/kg 2 or 3 times weekly, to a maximum of 900 mg per dose.
Children: 10 to 20 mg/kg once daily to a maximum of 300 mg. Intermittent therapy in children: 20 to 40 mg/kg 2 or 3 times weekly, to a maximum of 900 mg per dose.
Prophylaxis of Tuberculosis: Isoniazid is generally used alone for preventive therapy, for a period of 6 to 12 months. Adults: 300 mg once daily. Children: 10 to 15 mg/kg once daily, to a maximum of 300 mg.
For high-risk individuals who are likely to be noncompliant and whose prophylactic therapy needs to be directly observed, a dose of 15 mg/kg twice weekly, to a maximum of 900 mg per dose, may be considered as an alternative to daily therapy.
ISONIAZID General Monograph,INH Isonicotinic Acid Hydrazide Isonicotiny lhydrazide Antimycobacterial