Isoniazid mechanism

The cell walls of mycobacteria contain three structures peptidoglycan, an arabinogalactan polysaccharide and long chain hydroxy fatty acids (mycolic acids) which are all covalently linked. Additional non-covalently attached lipid components found in the wall include glycolipids, various phospholipids and waxes. The lipid-rich nature of the mycobacterial wall is responsible for the characteristic acid-fastness on staining and serves as a penetration barrier to many antibiotics. Isoniazid and ethambutol have long been known as specific antimycobacterial agents but their mechanisms of action have only recently become more clearly understood. 

Pierattelli R, L Banci, NA Eady, J Bodiguel, JN Jones, PCE Moody, EL Raven, B Jamart-Gregoire, K A Brown (2004) Enzyme-catalyzed mechanism of isoniazide activation in Class I and Class III peroxidases. J Biol Chem 279 39000-39009. 

The answer is a. (Hardman, p 1157. Katzung, p 804J Isoniazid inhibits mycobacterial cell-wall synthesis by inhibiting my colic acid synthesis by a mechanism that is not fully understood. 

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. 

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. 

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. 

Pharmacology Aminosalicylic acid is bacteriostatic against Mycobacterium tuberculosis. It inhibits the onset of bacterial resistance to streptomycin and isoniazid. The mechanism of action has been postulated to be inhibition of folic acid synthesis (but without potentiation with antifolic compounds) or inhibition of synthesis of the cell wall component, mycobactin, thus reducing iron uptake by M. tuberculosis. 

Isoniazid (INH) is a synthetic derivative of isonico-tinic acid. It has bactericidal activity against both intra- and extra-cellular mycobacteria. It also displays anti-bacterial activity in caseous lesions, but only in proliferating cells. Losing genes which code for catalase and peroxidase is the major mechanism through which resistance occurs. Single mutations can rapidly result in such resistance if isoniazid is used alone. Its mechanism of action is presumably based on inhibition of the synthesis of mycolic acids, unique and essential components of the mycobacterial cell wall. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

The most common mechanism of isoniazid resistance is the mycobacteria s formation of mutations in catalase-peroxidase KatG, the enzyme that is responsible for activation of isoniazid. Another resistance mechanism is through a missense mutation related to the inhA gene involved in mycolic acid biosynthesis. 

Ethionamide (Trecator) is a derivative of isonicotinic acid and is chemically related to isoniazid. It is a secondary agent used in combination when primary agents are ineffective or contraindicated it is a bacteriostatic antituberculosis agent. Its exact mechanism of action is unknown but is believed to involve inhibition of oxygen-dependent mycolic acid synthesis. It is thought that mutations in the region of the (tnhA) gene that are involved in mycolic acid synthesis can cause both isoniazid and ethionamide resistance. 

Isoniazid possibly exerts its action by inhibiting the synthesis of mycolic acid which is an essential component of mycobacterial cell wall. It is also postulated that the ability of isoniazid to suppress the formation of DNA and RNA and also inhibition of various oxidative mechanisms may be responsible for its action. 

Only a very few therapeutic agents, in marked contrast to the large number of entities that contain a pyrimidine ring, are based on the pyrazine ring. One of those, the anti-tubercular antibiotic pyrazinamide (68-6), probably acts by a similar mechanism as its pyridine parent, isoniazide. The tonnage chemical ort/zo-phenylene diamine (68-2) provides a convenient route to pyrazines. Thus condensation of that diamine with glyoxal (68-1) leads to quinoxaline (68-3). Treatment of the heterocycle with... 

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. 

Although isoniazid has been in use for about 45 years, the enzyme that it inhibits has been recognized only recently. It is a specific NADH-depen-dent enoyl reductase involved in synthesis of mycolic acids.h/1 The isoniazid must be activated by action of a bacterial catalase-peroxidaseh This enzyme may convert the drug to a reactive radical that combines with a NADH-derived radical to form an adduct in the active site of the enzymes. One possible reaction sequence follows.11 However, the mechanisms are not clear. 

Isoniazid (INH, Laniazid, Nydrazid, other names) is one of the primary drugs used to treat tuberculosis.24,61 Although the exact mechanism of action is unknown, this drug appears to interfere with several enzymatic pathways involving protein, lipid, carbohydrate, and nucleic acid metabolism in susceptible bacteria. Adverse reactions to isoniazid are common, and patients may develop disorders such as hepatitis and peripheral neuropathies. 

Isoniazid is bactericidal for growing tubercle bacilli, is absorbed orally, and is metabolized by acetylation. It is a structural analogue of pyridoxine and may cause pyridoxine deficiency, peripheral neuritis and, in toxic doses, pyridoxine-responsive convulsions. Its mechanism of action is not known. 

Polasek TM, Elliot DJ, Somogyi AA, et al. An evaluation of potential mechanism-based inactivation of human drug metabolizing cytochromes P450 by monoamine oxidase inhibitors, including isoniazid. Br J Clin Pharmacol 2006 61(5) 570-584. 

Mechanism of action Isoniazid, often referred to as INH, is believed to target the enzyme responsible for assembly of mycolic acids into the outer layer of the mycobacteria, a structure unique to these organisms. Mycolic acids account for the acid-fastness of the mycobacteria this property is lost after exposure to isoniazid. 

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... 

In the treatment of tuberculosis, resistant strains of M. tuberculosis (multidrug-resistant tuberculosis, MDRTB) present a growing problem, so that new antituber-culotic agents are required which act according to a different mechanism to that of standard agents such as isoniazid, rifampicin, pyrazinamide, and ethambutol. The more modern fluoroquinolones are of particular interest, and in particular moxifloxacin, which has powerful in vitro and in vivo activity and, in contrast to sparfloxacin and clinafloxacin, is not photo toxic [191]. 

METFORMIN ISONIAZID 1 efficacy of antidiabetic drugs Isoniazid causes hyperglycaemia, the mechanism being uncertain at present Monitor capillary blood glucose closely t doses of antidiabetic drugs may be needed... 

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