Isonicotinoylhydrazide

Uses

Isonicotinoylhydrazide is used for the treatment of all forms of tuberculosis in which organisms are susceptible.

Isonicotinoylhydrazide is also used to associated treatment for these conditions: Active Tuberculosis, Mycobacterium kansasii infection, Late phase Tuberculosis

How Isonicotinoylhydrazide works

Isonicotinoylhydrazide is a prodrug and must be activated by bacterial catalase. Specficially, activation is associated with reduction of the mycobacterial ferric KatG catalase-peroxidase by hydrazine and reaction with oxygen to form an oxyferrous enzyme complex. Once activated, isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.

Dosage

Isonicotinoylhydrazide dosage

Adult:

• Active tuberculosis: 5 mg/kg/day. Max: 300 mg/day or 15 mg/kg up to 900 mg/day, 2 or 3 times wkly.
• Latent tuberculosis: 300 mg/day for 6 mth. Nontuberculous mycobacterial infections 5 mg/kg/day for at least 12 mth of culture-negative sputum. Max: 300 mg/day.

Child:10-15 mg/kg/day, max 300 mg/day q 12-24 hourlyWith directly observed biweekly therapy, dosage is 20-30 mg/kg, max 900 mg/dose twice weekly

Side Effects

Peripheral neuropathy (dose-related incidence, 10-20% incidence with 10 mg/kg/d), Loss of appetite, Nausea, Vomiting, Stomach pain, Weakness 1-10%, Dizziness, Slurred speech, Lethargy, Progressive liver damage (increases with age; 2.3% in pts > 50 yo), Hyperreflexia, Agranulocytosis, Anemia, Megaloblastic anemia, Thrombocytopenia, Systemic lupus erythematosus, Seizure

Toxicity

LD₅₀ 100 mg/kg (Human, oral). Adverse reactions include rash, abnormal liver function tests, hepatitis, peripheral neuropathy, mild central nervous system (CNS) effects. In vivo, Isonicotinoylhydrazide reacts with pyridoxal to form a hydrazone, and thus inhibits generation of pyridoxal phosphate. Isonicotinoylhydrazide also combines with pyridoxal phosphate; high doses interfere with the coenzyme function of the latter.

Precaution

Renal or hepatic impairment; convulsive disorders; history of psychosis; patients at risk of neuropathy or pyridoxine deficiency eg, diabetic, alcoholic, malnourished, uraemic, infected with HIV. Careful monitoring of hepatic function is necessary for black and hispanic women. Check hepatic function before and during treatment. Pregnancy and lactation.

Interaction

Inhibit the hepatic metabolism of antiepileptics (e.g. carbamazepine, ethosuximide, primidone, phenytoin), benzodiazepines (e.g. diazepam, triazolam), chlorzoxazone, theophylline, disulfiram, sometimes leading to increased toxicity. Increased metabolism of enflurane, resulting in potentially nephrotoxic levels of fluoride. Increased concentrations and enhanced effects or toxicity of clofazimine, cycloserine and warfarin. Reduced absorption with Al-containing antacids. Increased risk of peripheral neuropathy with zalcitabine and stavudine.

Food Interaction

• Administer vitamin supplements. Vitamin B6 (pyridoxine) should be given with isoniazid to prevent deficiency.
• Avoid alcohol. Avoid drinking alcoholic beverages such as unpasteurized beer; unless approved by your physician, as they may contain tyramine. Consuming alcohol may also increase the risk of isoniazid induced hepatitis and neuropathy.
• Avoid chocolate. Chocolate contains caffeine, which should be limited during isoniazid therapy.
• Avoid histamine-containing foods and supplements. Histamine-containing foods (e.g., skipjack, tuna, other tropical fish) can cause headaches, sweating, palpitations, flushing, and hypotension.
• Avoid tyramine-containing foods and supplements. Tyramine-containing foods include cheese, red wine, fava beans, pickled food, cured food, and alcoholic beverages.
• Limit caffeine intake.
• Take on an empty stomach. Take at least 1 hour before or 2 hours after meals.
• Take separate from antacids. Taking this medication with antacids can reduce absorption.

[Moderate] ADJUST DOSING INTERVAL: Administration with food significantly reduces isoniazid absorption, increasing the risk of therapeutic failure or resistance.

The mechanism is unknown.

GENERALLY AVOID: Concomitant administration of isoniazid with foods containing tyramine or histamine may decrease the metabolism of tyramine and histamine, increasing the risk of symptoms relating to tyramine- and

The proposed mechanism is isoniazid-mediated inhibition of monoamine oxidase (MAO) and diamine oxidase (DAO), enzymes responsible for the metabolism of tyramine and histamine, respectively.

MANAGEMENT: Isonicotinoylhydrazide should be administered on an empty stomach, one hour before or two hours after meals.

Patients should be advised to avoid foods containing tyramine (e.g., aged cheese, cured meats such as sausages and salami, fava beans, sauerkraut, soy sauce, beer, or red wine) or histamine (e.g., skipjack, tuna, mackerel, salmon) during treatment with isoniazid.

Corticosteroids and antihistamines may be considered if histamine intoxication is suspected.

Isonicotinoylhydrazide Alcohol interaction

[Moderate] GENERALLY AVOID:

Alcoholic patients have been shown to have a higher incidence of isoniazid-induced hepatotoxicity.

The mechanism has not been established.

Patients should be counseled to avoid the combination of alcohol and isoniazid and clinicians should be aware of the risk for increased hepatotoxicity in these patients.

Isonicotinoylhydrazide Drug Interaction

Moderate: duloxetine, duloxetine, adalimumab, adalimumab, acetaminophen, acetaminophen, cholecalciferol, cholecalciferolUnknown: diphenhydramine, diphenhydramine, omega-3 polyunsaturated fatty acids, omega-3 polyunsaturated fatty acids, pregabalin, pregabalin, cyanocobalamin, cyanocobalamin, pyridoxine, pyridoxine, ascorbic acid, ascorbic acid

Isonicotinoylhydrazide Disease Interaction

Major: hepatotoxicity, liver disease, peripheral neuropathyModerate: hemodialysis, renal dysfunction

Elimination Route

Readily absorbed following oral administration; however, may undergo significant first pass metabolism. Absorption and bioavailability are reduced when isoniazid is administered with food.

Half Life

Fast acetylators: 0.5 to 1.6 hours. Slow acetylators: 2 to 5 hours.

Elimination Route

From 50 to 70 percent of a dose of isoniazid is excreted in the urine within 24 hours.

Pregnancy & Breastfeeding use

Pregnancy Category C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Lactation: distributed into milk but safe for nursing infants

Contraindication

Acute liver disease or history of hepatic damage during INH therapy; hypersensitivity.

Innovators Monograph

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