Isoniazid pyridoxal phosphate

Figure 7.42 Reaction of isoniazid with pyridoxal phosphate to form a hydrazone.

Isoniazid reacts with pyridoxal phosphate to form a hydrazone (Fig. 7.42), which is a very potent inhibitor of pyridoxal phosphate kinase. The hydrazone has a much greater affinity for the enzyme (100—lOOOx) than the normal substratepyridoxal. The result of this is a depletion of tissue pyridoxal phosphate. This cofactor is of importance particularly in nervous tissue for reactions involving decarboxylation and transamination. The decarboxylation reactions are principally affected however, with the result that transamination reactions assume a greater importance. 

In humans, peripheral neuropathy due to isoniazid is influenced by the acetylator phenotype (see chap. 5), being predominantly found in slow acetylators. This is probably due to the higher plasma level of isoniazid in this phenotype. In this case, therefore, acetylation is a detoxication reaction, removing the isoniazid and rendering it unreactive toward pyridoxal phosphate. 

This drug may cause degeneration of peripheral nerves after repeated exposure as a result of the depletion of vitamin B6. This is because isoniazid reacts with pyridoxal to form a hydrazone that inhibits pyridoxal phosphate kinase, so blocking formation of pyridoxal phosphate. As this effect is due to the parent drug, slow acetylators are more at risk, but the adverse effect can be prevented by supplying vitamin B6 to the patient. 

Isoniazid (isonicotinic acid hydrazide), a drug frequently used to treat tuberculosis, can induce a B6 deficiency by forming an iiactive derivative with pyridoxal phosphate. Dietary supplementation with B is, thus, an adjunct to isoniazide treatment. Otherwise, cletary deficiencies in pyridoxine are rare but have been observed in newborn infants fed formulas low in vitamin B6, in women taking oral contraceptives, and in alcoholics. 

Vitamin B6 (pyridoxine, pyridoxamine, and pyridoxal) has the active form, pyridoxal phosphate. It functions as a cofactor for enzymes, particularly in amino acid metabolism. Deficiency of this vitamin is rare, but causes glossitis and neuropathy. The deficiency can be induced by isoniazid, which causes sensory neuropathy at high doses. 

Drug-Coenzyme Interactions Isoniazid and Pyridoxal Phosphate... 

A-39 Deficiency of Vitamin B6 can cause convulsions, lethargy, mental changes retardation, anemia, and skin inflammation. Deficiencies of vitamin Be are rare and usually are related to an overall deficiency of all the B-complex vitamins. Isoniazid (see niacin deficiencies above) and penicillamine (used to treat rheumatoid arthritis and cystinurias) are two drugs that complex with pyridoxal and pyridoxal phosphate resulting in a deficiency in this vitamin. 

Vitamin B6 is required for the formation of pyridoxal phosphate, an important cofactor in nitrogen metabolism. Deficiencies of vitamin B6 are caused by a lack of the vitamin in the diet or by the administration of drugs such as isoniazid, which interfere with its metabolism. Synthesis of neurotransmitters, NAD, and heme are decreased, resulting in neurologic and pellegra-like symptoms and anemia. 

Isoniazid is widely prescribed for tuberculosis. It can chemically react with pyridoxal and pyridoxal phosphate, thus significantly reducing the availability of this coenzyme (Fig. 8.37) (61). Pyridoxinesupplements commonly are recommended to prevent isoniazid-caused... 

Vitamin deficiency can result from treatment with certain drags. Thus, destruction of intestinal microorganisms by antibiotic therapy can produce symptoms of vitamin K deficiency. Isoniazid, used to treat tuberculosis, is a competitive inhibitor of pyridoxal kinase, which is needed to produce pyridoxal phosphate. Isoniazid can produce symptoms of pyridoxine deficiency. To prevent this, pyridoxine is often incorporated into isoniazid tablets. Methotrexate and related folate antagonists act by competitively inhibiting dihydrofolate reductase (Chapter 27). 

Isoniazid causes peripheral neuropathy and liver damage (centrilobular necrosis). The liver damage is caused by a metabolite, acetylhydrazine whereas the peripheral neuropathy is caused by the parent drug interacting with pyridoxal phosphate and thereby interfering with the metabolism of vitamin B6. The genetic factor acetylator phenotype is important in both types of toxicity. Thus... 

Isoniazid, carbidopa, and hydralazine are hydrazine derivatives with therapeutic uses. They form Schiff bases with pyridoxal 5 -phosphate, and rate constants for their formation and hydrolysis have been measured in aqueous solution pH-rate profiles are reported and compared with that of hydrazine itself. 

Although, owing to the wide distribution of vitamin Bg in nature, clinical deficiency symptoms are seldom observed, there is little doubt that pyridoxine is essential in human nutrition. Pyridoxine is absorbed from the gastrointestinal tract and is converted to the active form pyri-doxal phosphate. Absorption is decreased in gastrointestinal diseases and also in subjects taking isoniazid (3). It is excreted in the urine as 4-pyridoxic acid (2). The metabolism of vitamin Bg in human beings has been investigated (56). 

Isoniazid, hydrazine, and the Gyrometria species of mushrooms can decrease the brain concentrations of gamma-aminobutyric acid by inhibiting pyridoxal-5-phosphate activity, resulting in the development of severe seizure activity. The administration of... 

A. Acute overdose. Isoniazid produces acute toxic effects by reducing brain pyridoxal 5-phosphate, which is the active form of vitamin Bg and an essential cofactor for the enzyme glutamic acid decarboxylase. This results in lower CNS levels of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, which leads to uninhibited electrical activity manifested as seizures. INH may also Inhibit the hepatic conversion of lactate to pyruvate, exacerbating the lactic acidosis from seizures. 

Hartnup disease, an autosomal recessive trait that interferes with the absorption of tryptophan, and carcinoid syndrome in which the amino acid is preferentially oxidized to 5-hydroxytryptophan and serotonin. Prolonged treatment with the drug isoniazid, which competes with pyridoxal 5 -phosphate (a vitamin Be-derived coenzyme required in the tryptophan-to-niacin pathway), also reduces the conversion of tryptophan to niacin. Oral contraceptives that contain high doses of estrogen increase tryptophan conversion efficiency (Braidman and Rose 1971). 

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