Isoniazid hepatotoxicity

The metabolic fate of isoniazid and iproniazid, two isonicotinoylhydra-zides, has been extensively studied, and it has been shown that metabolic hydrolysis represents an important step in their toxification. Isoniazid (4.269) is employed as a first-line tuberculostatic drug, but prolonged therapy is associated in 1 -2% of patients with significant hepatotoxicity. Isoniazid can be metabolized by either of two primary pathways, hydrolysis and direct -acetylation. Isonicotinic acid (4.271), the product of hydrolysis, can be formed either di-... 

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. 

Polypharmacy For example, NSAIDs if used with other hepatotoxic drugs increase the risk of hepatotoxicity. Isoniazid with rifampicin or pyrazinamide... 

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity Isoniazid... 

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. 

Hepatotoxicity is a higher risk when isoniazid is given to those who chronically drink large amounts of alcohol avoid isoniazid in this group if possible, otherwise monitor LFTs. 

Concurrent administration of rifampin is recommended at doses of 10 to 20 mg/kg/day (maximum 600 mg/day) for children and 600 mg/day for adults. The addition ofpyrazinamide (children and adults, 15 to 30 mg/kg/ day maximum in both, 2 g/day) to the regimen of isoniazid and rifampin is now recommended. The duration of concomitant pyrazinamide therapy should be limited to 2 months to avoid hepatotoxicity. 

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. 

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. 

P. Gurumurthy, M. S. Krishnamurthy, O. Nazereth, R. Parthasarathy, G. R. Sarma, P. R. Somasundaram, S. P. Tripathy, G. A. Ellard, Lack of Relationship between Hepatotoxicity and Acetylator Phenotype in Three Thousand South Indian Patients during Treatment with Isoniazid for Tuberculosis , Am. Rev. Respir. Dis. 1984, 129, 58-61. 

A. Noda, K.-Y. Hsu, H. Noda, Y. Yamamoto, T. Kurozumi, Is Isoniazid-Hepatotoxicity Induced by the Metabolite Hydrazine , Sangyo IkaDaigaku Zasshi 1983, 5, 183-190. 

Aminosalicylic acid is a bacteriostatic that inhibits most tuberculous mycobacteria, hi terms of tuberculostatic activity it is inferior to isoniazid and streptomycin. It is nephro-and hepatotoxic, and is rarely used. A synonym of this drug is apacizin. 

Serum chemistry markers play an important role in hepatotoxicity evaluation in human and animal safety studies. The classic markers of hepatotoxicity are alanine aminotransferase (ALT), aspartate aminotrasnferase (AST) and alkaline phosphatase (ALP) [124—127]. Drug-induced hepatotoxicity can be difficult to assess in some circumstances. Hepatotoxic responses can be intrinsic (predictable, dose-related) or idiosyncratic (unpredictable, non-dose-related). ALT, AST and ALP are generally not useful for predicting idiosyncratic responses. The administration of some drugs, such as isoniazid, can lead to a high incidence of ALT elevation, but are tolerated by most patients without severe hepatotoxicity. Adverse drug reactions can be masked... 

Changes in serum ALT may not aWays be indicative ofa true hepatotoxic response. Mild dose-related ALT elevations (2x to 3x ULN) are observed in some patients taking lovastatin as a result of an adaptive response [139]. As another example, isoniazid, an anti-tuberculosis agent, leads to a high incidence of ALT and AST elevations, but is tolerated chronically without severe hepatotoxicity. This suggests that more specific and sensitive biomarkers are still needed to predict serious liver injury. 

Tayal, V. et al. (2007) Hepatoprotective effect of tocopherol against isoniazid and rifampicin induced hepatotoxicity in albino rabbits. Indian Journal of Experimental Biology, 45 (12), 1031-1036. 

Isoniazid can induce a wide variety of potentially serious adverse reactions. Some hepatotoxicity can manifest itself as transient elevations of liver enzymes and this occurs in 10-20% of patients. Progressive and potentially fatal liver damage is age dependent with a very low incidence below the age of... 

Treatment of latent tuberculosis infection (LTBI) with isoniazid (INH) is very effective in preventing persons infected with M. tuberculosis from developing tuberculosis, regardless of HIV-1 serostatus. Several recent studies have shown that rifampicin and pyrazinamide taken for 2 months is as effective as 6-12 months of INH for the prevention of active TBC in HIV-1 seropositive persons although more hepatotoxicity is seen. 

Isoniazid is acetylated to acetyl isoniazid by A-acetyl-transferase, an enzyme in fiver, bowel, and kidney. Individuals who are genetically rapid acetylators will have a higher ratio of acetyl isoniazid to isoniazid than will slow acetylators. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this is not proved. The slow or rapid acetylation of isoniazid is rarely important clinically, although slow inactivators tend to develop peripheral neuropathy more readily. Metabolites of isoniazid and small amounts of unaltered drug are excreted in the urine within 24 hours of administration. 

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. 

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

Hydrazines. The hydrazines have only historic significance. The entire group of MAOIs was discovered through the euphoric side effect of isoniazid (8.36, isonicotinyl-hydrazide), a successful antituberculotic drug introduced in 1952. Iproniazid (8.37) is the corresponding isopropyl derivative. All of the hydrazides are highly hepatotoxic, and are no longer available. 

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. 

Figure 7.24 Metabolism of isoniazid. The acetylhydrazine released by the hydrolysis of acetylisoniazid is further metabolized to a reactive intermediate thought to be responsible for the hepatotoxicity.

The role of acetylhydrazine in isoniazid hepatotoxicity is complex, as the production of the toxic intermediate involves several steps. Further study has indicated that acetylhydrazine is detoxified by further acetylation to diacetlhydrazine (Fig. 7.24) and that isoniazid may interact with acetylhydrazine metabolism. It is therefore clear that the relative rates of production, detoxication, and activation of acetylhydrazine are very important determinants of the hepatotoxicity of isoniazid. 

The role of hydrazine in isoniazid hepatotoxicity, if any, remains to be clarified. 

Thus, the hepatotoxicity of iproniazid and isoniazid may involve the alkylation or acylation of tissue proteins and other macromolecules in the liver. How these covalent interactions lead to the observed hepatocellular necrosis is at present not understood. 

Both these substituted hydrazine drugs may cause liver damage after therapeutic doses. With isoniazid, a mild hepatic dysfunction may occur in 10% to 20% of patients and a more severe type in less than 1%. Both isoniazid and iproniazid yield hydrazine metabolites (acetylhy-drazine and isopropylhydrazine, respectively), which are responsible for the hepatotoxicity after activation by cytochrome P-450. Isoniazid undergoes acetylation, which in humans is polymorphic. Slow acetylators are more at risk from the hepatotoxicity because acetylhy-drazine is detoxified by acetylation. 

Metabolism of isoniazid, especially acetylation by liver/V-acetyltransferase, is genetically determined (see Chapter 4 Drug Biotransformation). The average concentration of isoniazid in the plasma of rapid acetylators is about one third to one half of that in slow acetylators and average half-lives are less than 1 hour and 3 hours, respectively. Rapid acetylators were once thought to be more prone to hepatotoxicity, but this has not been proved. More rapid clearance of isoniazid by rapid acetylators is of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose. 

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