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isoniazid; isonicotinic acid hydrazide (INH, Nydrazid, Hyzyd, Laniazid, Niazid)

Tradename: Nydrazid, INH. (isonicotinic acid hydrazide). Indications: 1) treatment of active & latent tuberculosis [9] 2) prophylaxis for tuberculosis exposure Dosage: Tuberculosis: 10-20 mg/kg up to 300 mg PO QD. Tabs: 50,100, 300 mg. Syrup: 50 mg/5 mL. Injection: 100 mg/mL (10 mL vials) Dosage adjustment in renal failure: - none, dose after hemodialysis Pharmacokinetics: 1) rapid & complete absorption after oral administration 2) distributed to most body tissues including CSF 3) metabolized by liver 4) eliminated in urine 5) 1/2 life dependent upon acetylation status of patient a) rapid acetylators 1-1.5 hours b) slow acetylators 2-2.5 hours c) prolonged in liver impairment (8-17 hours ESRD) 6) 50-100% removed by hemodialysis Monitor: - liver function tests baseline & monthly if a) >= 35 years of age b) regular alcohol consumption c) IV drug users d) women of minority groups, especially post-partum [7,11,12] - Canadian guidelines: LFTS periodically in all patients [12] Adverse effects: 1) common (> 10%) - peripheral neuritis - give supplemental pyridoxine 25 mg PO QD - loss of appetite - nausea/vomiting - stomach pain - weakness 2) less common (1-10%) - hepatotoxicity, hepatitis (1-2.5%), 0.6% [8,10] - dizziness, slurred speech, lethargy, hyperreflexia 3) uncommon (< 1%) - blood dyscrasias, fever, skin rash, arthralgia, seizures, mental depression, psychosis, - ocular adverse effects optic neurpathy, blurred vision, loss of vision 4) other - lupus-like syndrome [5] Overdose: 1) decreases synthesis of GABA, resulting in CNS stimulation 2) symptoms include nausea, vomiting, dizziness, slurred speech, coma, seizures & metabolic acidosis 3) treatment: GI decontamination followed by activated charcoal. Pyridoxine slowly IV in weight equivalent to ingested isoniazid, or empirically 5 g IV over 30 min as 5-10% solution Drug interactions: 1) antacids & aluminum salts may delay & decrease INH absorption; take 2 hours apart 2) alcohol increases risk of hepatotoxicity 3) INH inhibits metabolism of carbamazepine & phenytoin 4) disulfiram in combination may cause altered mental status 5) corticosteroids in combination enhance metabolism of INH 6) ketoconazole levels are decreased with INH; SHOULD NOT BE TAKEN TOGETHER 7) phenobarbital may increase metabolism of INH 8) p-aminosalicylate, procainamide, chlorpromazine increase INH t1/2 9) INH may enhance metabolism of theophylline 10) INH inhibits cyt P450 CYP1A2 & CYP2C9 -> may increase levels of drugs metabolized by cyt P450 CYP1A2 & CYP2C9 Test interactions: -> chemical interferences -> isoniazid may increase plasma ammonia levels Laboratory: 1) specimen: a) serum, plasma (heparin, EDTA) b) stable for up to 1 month at 40 degrees C c) N-acetylisoniazid is extremely unstable, even when frozen 2) methods: GLC, HPLC, color, fluorometry 3) interferences: a) color method is insensitive & cumbersome b) pyrazinamide & p-aminosalicylic acid (high conc.) can interfere Mechanism of action: 1) inhibits synthesis of mycolic acid, a component of mycobacterial cell wall 2) bacteriostatic or bactericidal depending upon bacterial replication rate & concentration

Interactions

drug interactions

Related

cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2) cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10)

General

anti-tuberculous agent hydrazine pyridine

Properties

MISC-INFO: elimination route LIVER KIDNEY 1/2life 45-80 HOURS 140-200 HOURS therapeutic-range 1-7 UG/ML toxic-range >20 UG/ML protein-binding <5% elimination by hemodialysis + peritoneal dialysis + pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996.
  2. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 133
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  5. Medical Knowledge Self Assessment Program (MKSAP) 11, 17. American College of Physicians, Philadelphia 1998, 2015
  6. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  7. Prescriber's Letter 8(8):48, 2001
  8. Journal Watch 25(17):137-38, 2005 Fountain FF, Tolley E, Chrisman CR, Self TH. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic. Chest. 2005 Jul;128(1):116-23. PMID: 16002924
  9. CDC & American Thoracic Society http://www.thoracic.org/adobe/statements/latenttb1-27.pdf
  10. Chalasani N et al. for the Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008 Dec; 135:1924. PMID: 18955056
  11. deprecated reference
  12. Prescriber's Letter 17(7): 2010 Recommended Lab Monitoring for Common Medications Liver Function Test Scheduling Detail-Document#: 260704 (subscription needed) http://www.prescribersletter.com

Component-of

isoniazid/pyrazinamide/rifampin (Rifater) isoniazid/rifampin (Rifamate)