Treatment of Adverse Drug Reactions of Anti-TB Drugs

MD Examination Answer — 15 Marks

INTRODUCTION

CLASSIFICATION OF ADRs OF ANTI-TB DRUGS

1. Minor reactions — manageable without stopping the drug
2. Major reactions — require drug discontinuation and substitution

I. ISONIAZID (INH / H)

A. Peripheral Neuropathy

• Mechanism: INH competes with pyridoxine (Vitamin B6), causing relative deficiency → impaired synthesis of neuronal lipids
• Features: Paresthesia, numbness, burning of hands and feet
• Risk factors: Slow acetylators, malnutrition, alcoholics, diabetes, HIV, pregnancy, elderly
• Treatment:
  • Prevention: Pyridoxine 10–25 mg/day given with INH to all high-risk patients (Harrison's recommendation)
  • If neuropathy develops: Increase pyridoxine to 100–200 mg/day
  • INH need not be stopped for mild neuropathy if pyridoxine is given
  • Discontinue INH if severe or progressive despite pyridoxine

B. Drug-Induced Hepatitis (DILI)

• Most serious ADR of INH; potentially fatal if unrecognized
• Incidence increases with: age >35 years, concurrent rifampicin use, daily alcohol consumption, pre-existing liver disease
• Monitoring: Check ALT + bilirubin at baseline; monthly ALT if hepatic risk factors present
• Treatment:
  • Monitor for symptoms: nausea, vomiting, RUQ pain, fatigue, jaundice, dark urine
  • Stop INH (and Z, R, other hepatotoxics) if:
    • ALT ≥ 5× ULN (asymptomatic), OR
    • ALT ≥ 3× ULN with symptoms
  • Obtain viral hepatitis serologies
  • Withhold alcohol
  • Rechallenge: Once liver enzymes normalize, R and H may be sequentially reintroduced. Z is often not re-introduced. Alternative protocols exist
  • If INH cannot be tolerated: Use an alternative regimen (e.g., rifampicin-based regimen without INH)

C. CNS Effects

• Seizures (especially in overdose), psychosis, memory impairment
• Treatment: Pyridoxine is the antidote for INH-induced seizures (gram-for-gram replacement in overdose); benzodiazepines may be used adjunctively

D. Hypersensitivity Reactions

• Drug fever, skin rash, lupus-like syndrome (SLE)
• Treatment: Stop INH; antihistamines/corticosteroids for rash; do not rechallenge if SLE-like syndrome

II. RIFAMPICIN (R)

A. Hepatotoxicity

• Primarily cholestatic pattern (elevated bilirubin + alkaline phosphatase)
• Treatment:
  • Discontinue R if total bilirubin reaches jaundice levels (usually >2× ULN)
  • May attempt reintroduction after normalization
  • If rifampicin not tolerated: substitute with a fluoroquinolone (Q) — e.g., levofloxacin or moxifloxacin

B. Orange-Red Discolouration of Body Fluids

• Urine, tears, sweat, saliva turn orange-red
• Treatment: Reassurance; no drug modification needed; warn patient in advance, especially contact lens wearers

C. Drug Interactions (CYP450 Induction)

• Rifampicin is a potent inducer of CYP450 and phase II enzymes
• Decreases efficacy of: oral contraceptives, warfarin, antiretrovirals (protease inhibitors, NNRTIs), corticosteroids, phenytoin, theophylline
• Treatment:
  • Increase doses of affected co-medications
  • Switch to rifabutin (40% less potent CYP inducer) in HIV patients on ART
  • Use alternative contraception

D. Flu-Like Syndrome (Intermittent High-Dose)

• Fever, chills, myalgia, bone pain (particularly with intermittent dosing)
• Treatment: Switch to daily dosing; consider dose reduction; may use NSAIDs symptomatically

E. Thrombocytopenia / Haemolytic Anaemia

• Immune-mediated; more common with intermittent dosing
• Treatment: Stop rifampicin permanently; do not rechallenge (risk of serious anaphylaxis)

III. PYRAZINAMIDE (Z)

A. Hepatotoxicity

• Most hepatotoxic of first-line drugs at higher doses; now less common at standard doses
• Risk factors: Age, active liver disease, HIV, low albumin
• Treatment:
  • Same protocol as INH hepatotoxicity
  • Stop Z if ALT ≥ 5× ULN (or ≥ 3× ULN with symptoms)
  • Z + R combination for LTBI is no longer recommended due to unacceptable hepatotoxicity rates
  • Z is typically NOT reintroduced after drug-induced liver injury

B. Hyperuricaemia / Gout

• Pyrazinoic acid (active metabolite) inhibits renal tubular secretion of urate
• Hyperuricaemia is common but clinical gout is rare
• Treatment:
  • Asymptomatic hyperuricaemia: No treatment required — manage conservatively
  • Symptomatic gout: NSAIDs (avoid aspirin); colchicine
  • Avoid allopurinol during active TB treatment (may worsen rash)
  • Z can usually be continued with conservative management

C. Arthralgia / Myalgia

• Non-gouty arthralgia is common
• Treatment: NSAIDs (aspirin or ibuprofen); dose may be reduced if severe

IV. ETHAMBUTOL (E)

A. Optic Neuritis (Most Important ADR)

• Ethambutol inhibits arabinosyl transferase in the retinal neurons
• Features: Decreased visual acuity, loss of red-green colour discrimination, central scotoma
• Risk factors: High doses, prolonged use, renal impairment (reduced drug clearance)
• Treatment:
  • Baseline visual acuity and colour vision test before starting ethambutol
  • Monthly visual screening during therapy
  • Stop ethambutol immediately upon any visual change
  • Vision usually recovers after stopping, but may take months
  • Recovery is generally good if caught early; irreversible if delayed
  • Peripheral neuropathy may precede ocular toxicity — repeat eye examination if it occurs
  • Dose adjustment required in renal impairment

B. Peripheral Neuropathy

• Less common than with INH
• Treatment: Dose reduction or drug discontinuation; pyridoxine supplementation

C. Hyperuricaemia

• Reduced uric acid excretion; usually mild
• Treatment: Caution in gout patients; NSAIDs if symptomatic

V. STREPTOMYCIN (S) — Second-line but still used

A. Ototoxicity (VIII cranial nerve)

• Vestibular damage (dizziness, ataxia) more common than cochlear damage (hearing loss)
• Treatment: Stop streptomycin; irreversible if not caught early; audiometry monitoring

B. Nephrotoxicity

• Tubular damage → rise in creatinine, electrolyte disturbances
• Treatment: Stop drug; hydration; avoid other nephrotoxins (NSAIDs, aminoglycosides)
• Contraindicated in pregnancy (causes foetal ototoxicity)

VI. SECOND-LINE DRUGS — KEY ADRs AND TREATMENT

VII. DRUG-INDUCED LIVER INJURY (DILI) — GENERAL MANAGEMENT PROTOCOL

1. Identify the offending drug (INH, R, or Z — all hepatotoxic)
2. Stop all potentially hepatotoxic drugs (H + Z + R)
3. Substitute a non-hepatotoxic regimen: streptomycin + ethambutol + fluoroquinolone as a bridging regimen
4. Monitor LFTs until ALT < 2× ULN
5. Sequential rechallenge:
   • Reintroduce R first → wait 3–7 days → check LFTs
   • Then add H → wait 3–7 days → check LFTs
   • Z is usually not reintroduced given the severity of reaction
   • If any drug causes recurrence, that drug is permanently excluded

VIII. MONITORING FRAMEWORK — HARRISON'S TABLE (Abbreviated)

IMPORTANT PRINCIPLES

1. Prevention is better than cure — Pyridoxine 10–25 mg/day with every INH-containing regimen prevents neuropathy
2. Directly Observed Therapy (DOT) improves adherence and enables early detection of ADRs
3. Monthly clinical monitoring is mandatory for all TB regimens
4. Rechallenge after DILI is feasible for R and H but not Z in most cases
5. Patient education about ADR symptoms (jaundice, visual blurring, tingling) empowers early reporting
6. Dose adjustment in renal impairment is essential — especially for ethambutol and streptomycin