Isoniazid toxicity

Administer vitamin B6 (pyridoxine) in the setting of isoniazid toxicity... 

Rifampicin is an enzyme inducer and can increase the incidence and severity of isoniazid-induced hepatitis. Carbamazepine is an enzyme induction agent and interacts with isoniazid, increasing its hepatotoxicity. Isoniazid toxicity is associated with fast acetylator genotype. Although his phenotype was unknown, the interaction with carbamazepine increases risk of this toxicity. 

Genetics Genetic differences in drug metabolising enzymes may predispose certain patients to hepatotoxicity. For example, the hlack and Hispanic population may he more prone to isoniazid toxicity Genetics may play a role in diclofenac hepatotoxicity... 

Liver damage usually appears 1-2 months after the start of therapy. In children, raised liver enzymes are common during the first few months of treatment, but withdrawal is seldom necessary. A careful watch should be kept for early symptoms of isoniazid-induced hepatitis, such as malaise, fatigue, nausea, and epigastric distress. The dangers of continuing isoniazid after the onset of symptoms of toxicity have been highlighted (30). The earhest symptoms of isoniazid toxicity should be clearly described to the patient, particularly to hepatitis B carriers, who may be more susceptible to hepatotoxicity (26). 

Acute poisoning with isoniazid in children (48) and adults (13,26,35) causes recurrent seizures, profound metabolic acidosis, coma, and even death. In adults, toxicity can occur with the acute ingestion of as little as 1.5 g of isoniazid. Doses larger than 30 mg/kg often produce seizures and 80-150 mg/kg or more can be rapidly fatal. The first signs and symptoms of isoniazid toxicity usually appear 0.5-2.0 hours after ingestion, by which time peak absorption occurs (49), and include nausea, vomiting, slurred speech, dizziness, tachycardia, and urinary... 

Gilhotra R, Malik SK, Singh S, Sharma BK. Acute isoniazid toxicity—report of 2 cases and review of literature. Int J Clin Pharmacol Ther Toxicol 1987 25(5) 259-61. 

Acetylation of drugs is also associated with genetically determined interindividual and interethnic differences. Differences in isoniazid toxicity between Asians and Caucasians are due to acetylation enzyme polymorphism. The majority (78%-93%) of Chinese and East Asians are fast acetylators, whereas only 50% of whites and African Americans are fast acetylators (Weber 1987). This is clinically important, because several psychoactive compounds (e.g., caffeine, clonazepam, nitrazepam, and phenelzine) are metabolized through acetylation (Sjoqvist et al. 1997). 

This polymorphism (NAT2) was discovered almost 50 years ago after differences were observed to isoniazid toxicity in tuberculosis patients (66). Subsequently, the differences in isoniazid toxicity were attributed to genetic variability in NAT2, a cytosolic phase II conjugation enzyme primarily responsible for deactivation of isoniazid (67). Indeed, the polymorphism was termed the "isoniazid acetylation polymorphism" for many years until the importance of the polymorphism in the metabolism and disposition of other drugs and chemical carcinogens was fully appreciated (65). 

A study found that aminosalicylic acid significantly increased the plasma levels of isoniazid at 4 and 6 hours after administration by 32% and 114%, respectively in fast acetylators of isoniazid, and by 21% and 39%, respectively in slow acetylators. The half-life of isoniazid was increased from 1.32 to 2.89 hours in fast acetylators and from 3.05 to 4.27 hours in slow acetylators (see Genetic factors , (p.4), for more information about acetylator status). The effects were probably due to the inhibition of isoniazid metabolism by aminosalicylic acid. There seem to be no reports of isoniazid toxicity arising from this interaction, but the manufacturers of isoniazid warn that adverse effects are more likely in the presence of aminosalicylic acid. ... 

The mechanism of isoniazid-induced neurotoxicity is believed to be reduced concentrations of GABA by inhibition of pyridoxine (vitamin Be) metabolism. Human studies describing white matter changes in isoniazid toxicity have also corroborated a potential toxic effect on myelin. Rapid resolution of diffusion-restricted lesions in this patient suggested a similar process of intramyeUnic edema. In addition, the half-Ufe of isoniazid was 3.9 hours, suggestive of the slow acetyla-tor phenot, with increased susceptibility to adverse effects of 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. 

The nurse monitors the patient taking isoniazid for toxicity. The most common symptom of toxicity is... 

Acetaminophen may alter blood glucose test results, causing falsely lower blood glucose values. Use with the barbiturates, hydantoins, isoniazid, and rifampin may increase the toxic effects and possibly decrease the therapeutic effects of acetaminophen. The effects of the loop diuretics may be decreased when administered with acetaminophen. Hepatotoxicity has occurred in chronic alcoholics who are taking moderate doses of acetaminophen. 

Certain medications (e.g., cimetidine, diltiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefazodone, propoxyphene, and verapamil) added to carbamazepine therapy may cause carbamazepine toxicity. 

Frequency 45-65% of Caucasians and African Americans 10-15% of Asians Slow inactivation of drugs such as isoniazid (for tuberculosis), dapsone (for leprosy), and hydralazine (for high blood pressure), leading to toxicity from the drug at doses well tolerated in people with rapid acetylator phenotype Clinical consequences depend on the specific side effects of the drugs... 

Increased risk of hydralazine-induced lupus, increased levels of isoniazid with an increased risk of neurotoxicity, increased risk of bladder cancer in individuals exposed to aromatic amines Increased risk of serious toxicity to mercaptopurine and azathioprine... 

The mechanism of toxification of isoniazid was investigated in rats pretreated with inducers or inhibitors of microsomal enzymes or an inhibitor of acylamidases. In animals pretreated with the acylamidase inhibitor bis(4-nitrophenyl) phosphate, isoniazid and acetylisoniazid produced less liver necrosis than in control animals. The treatment had no effect on the necrosis due to acetylhydrazine [173], In animals pretreated with inducers of microsomal cytochrome P450 such as phenobarbital, acetylisoniazid, and acetylhydrazine caused markedly increased necrosis, while pretreatment with cytochrome P450 inhibitors decreased necrosis. In contrast, the toxicity of isoniazid and hydrazine was not modified by phenobarbital pretreatment. From these observations, Trimbell et al. [173] concluded that the hydrolysis of acetylisoniazid is a prerequisite for hepatotoxicity, and that microsomal enzymes transform acetylhydrazine, the product of hydrolysis, to a toxic species. 

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],... 

Isoniazid, the hydrazide of isonicotinic acid was introduced into medical practice for treating tuberculosis in 1953. Isoniazid exhibits bactericidal action on Mycobacterium tuberculosis. It inhibits the synthesis of mycoUc acid, an important component of the cell membrane of mycobacteria. Mycolic acid is specific only to mycobacteria, and it is the cause of the selective toxicity of the drag with respect to these microorganisms. 

Mefabo//sm - The half-life of INH is widely variable and dependent on acetylator status. Isoniazid is primarily acetylated by the liver this process is genetically controlled. Fast acetylators metabolize the drug about 5 to 6 times faster than slow acetylators. Several minor metabolites have been identified, one or more of which may be reactive (monoacetylhydrazine is suspected), and responsible for liver damage. The rate of acetylation does not significantly alter the effectiveness of INH. However, slow acetylation may lead to higher blood levels of the drug, and thus to an increase in toxic reactions. 

Lactation The small concentrations of isoniazid in breast milk do not produce toxicity in the nursing newborn therefore, do not discourage breastfeeding. However, because levels of isoniazid are so low in breast milk, they cannot be relied upon for prophylaxis or therapy in nursing infants. 

Toxic effects are usually encountered with higher doses of isoniazid the most frequent are those affecting the nervous system and the liver. 

Mycobacterium tuberculosis Add streptomycin or ethambutol as a fourth drug in a regimen containing isoniazid (INH), rifampin, and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH or rifampin resistance is very low. Streptomycin also is indicated for therapy of tuberculosis when one or more of the above drugs is contraindicated because of toxicity or intolerance. 

Intended for use concomitantly with other antituberculosis agents in pulmonary infections caused by capreomycin-susceptible strains of Mycobacterium tuberculosis, when the primary agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or the presence of resistant tubercle bacilli. Administration and Dosage... 

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