Hepatotoxicity of antiTB agents

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Hepatotoxicity of anti-TB agents

• Ri ??? Nov 11, 2002

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Diagnosis of TB

• Symptoms / signs
• Sputum smear
• Sputum culture
• CXR
• TST
• PCR

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Treatment of Active tuberculosis

• S/S dyspnea, fever, cough with sputum, and night
  sweating
• CXR S1, S2, S6 radiological change
• S/C or S/S acid-fast bacilli
• HERZ 2 months HER 4 months
• HER 9 months

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Treatment of PPD reactors

• 5-mm immunocompromised, close contact of TB pt,
  typical CXR change
• 10-mm high-prevalence group
• 15-mm low-prevalence group
• INH for 612 months
• RIF PZA for 2 months
• (X) Underlying liver disease
• (X) Prior INH-associated liver disease

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Risk of Reactivation TB

• Recent TST result change
• CXR definite findings
• Exposure to active TB
• Immunocompromised

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First-line Anti-TB Drugs

• Isoniazid(INH) Duracrin 100mg/tab
• Ethambutol(EMB) Myambutol 400mg/tab
• Rifampin(RIF) Mycobutin 150mg/cap
• Pyrazinamide(PZA) Pyramide250mg/tab
• Streptomycin 1g/vial
• Rifinah 300mg/tab (INH 150 RIF 300)

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Isoniazid (INH)

• Inhibit the synthesis of mycolic acids
• Metabolized in the liver
• Inhibit cytochrome P-450 system
• Side effects
• Hepatotoxicity
• Peripheral neuritis pyridoxine support
• Rashes and skin eruptions

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Risk of Isoniazid Hepatitis

• Risk factors old age, alcoholism
• lt20 y/o rare
• 20 34 y/o lt 0.3
• 35 49 y/o lt1.2
• gt50 y/o lt2.3

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INH Hepatotoxicity

• Incidence 10 20 (asymptomatic)
• Liver enzymes ? 2 to 3 times generally occur lt
  first 2 months
• Usually ? even if therapy is continued
• Liver disease occurred in 0.4 patients

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Follow-up

• Routine monitoring of LFTs not recommened
• Routine monitoring of serum transaminase levels
  is suggested in patients with risk factors
• Fulminant hepatic failure rare

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Rifampin (RIF)

• Inhibit RNA polymerase
• Metabolized in the liver
• Induce cytochrome P-450 system
• Side effects
• Urine, sweat, and tears may become red-orange in
  color
• Hepatitis
• GI upset, leucopenia or thrombocytopenia

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RIF Hepatotoxicity

• Prevalence 10 to 15
• Transient hepatic enzymes ? usually within the
  first 8 weeks
• Overt hepatotoxicity lt 1

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Pyrazinamide (PZA)

• Mechanism unknown
• Side effects
• Hepatotoxicity
• Gout
• Arthralgia and myalgia

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PZA Hepatotoxicity

• The risk of drug-induced hepatitis is dependent
  upon dosage.
• Symptomatic hepatitis 1 (combined with INH)

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Ethambutol (EMB)

• Inhibit arabinogalactan
• Side effects
• Optic neuritis or other visual disturbances
• Gout
• GI upset

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EMB Hepatotoxicity

• Not remarkable!

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Streptomycin

• Binds to the 30S ribosomal subunit
• Side effects
• Ototoxicity
• Nephrotoxicity usually reversible

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Streptomycin Hepatotoxicity

• Not remarkable!

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Second-line Anti-TB Drugs

• Para-aminosalicyclic acid
• Ethionamide
• Capreomycin sulfate
• Cycloserine
• Kanamycin
• Amikacin
• Quinolones

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Management of Hepatotoxicity

• Hepatocellular toxicity
• GOT or GPT gt 5 times
• Related to INH?RIF or PZA
• DC all drugs and re-add
• Cholestatic toxicity
• Bilirubin?
• Related to RIF
• DC all drugs and re-add

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Time to Change Drugs

• Significant adverse effect
• Drug resistance
• Persistent positive sputum culture or smear
• CXR findings deteriorate

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Modified Regimen

• Substitution of PZA with streptomycin in a 4-drug
  regimen
• More gradual reintroduction of drugs and a slower
  dose titration schedule
• 45 patients with antitubercular drug- induced
  liver disease.
• Original regimen (Group 2 n25)
• Modified regimen (Group 1 n20)

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Modified Regimen

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Result

• Recurrence of hepatotoxicity
• Group 1 0 / 20
• Group 2 6 / 25 (24) .
• Five of these 6 patients subsequently were
  retreated with the Group 1 regimen and each was
  cured without recurrence.

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Result

• A safe and effective retreatment strategy for
  patients who develop hepatotoxicity (Tahaoglu et
  al, 2001)

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Summary

• INH, RIF, and PZA may induce liver enzyme level
  ?
• Fulminant hepatitis or hepatic failure is rare
• Routine monitoring of lab data is controversial
• Recommend in patients of risk factors

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• Thank You for Your Attention !