Pharmacology of Tuberculosis Drugs

Pharmacology of Drugs Used in the Management of Tuberculosis

• Learning Objectives:
  • Differentiate between first-line and second-line TB drugs, including MDR-TB drugs.
  • Describe the mechanism of action for each TB drug.
  • Identify adverse effects of each TB drug.
  • Understand the pharmacokinetics and drug interactions of first-line TB drugs.
  • Identify drugs associated with drug-induced liver injury.
  • Identify treatment periods and agents for TB prophylaxis in close contacts.
  • Understand the use of the TB vaccine.
  • Outline drugs used for TB management in HIV-positive patients and pregnant women.

Tuberculosis (TB) Pathogenesis

• Airborne infectious disease caused by Mycobacterium tuberculosis.
• Spread through air droplets during active respiratory disease.
• Primary infection is asymptomatic, with bacteria proliferating in macrophages.
• Symptoms include fever, night sweats, persistent cough, bloody phlegm, chest pain, and shortness of breath.

Treatment

• Goal: Prevent death, relapse, and transmission of active TB and development of drug resistance.
• Challenges: Mycobacterium resistance to antibiotics, the presence of lipid-rich mycobacterial cell walls, and the dormant state of mycobacterial cells.
• Diagnosis:
  • Latent TB infection: TB skin test and blood test.
  • TB disease: Medical history, physical examination, chest X-ray, and Xpert/culture.

First-line TB Drugs

• General principles: Use correct drugs for adequate duration, directly observed therapy (DOT), and achieve treatment completion and compliance.

• Effective First-line Drugs with Acceptable Toxicity:

  • Isoniazid (H)
  • Rifampicin (R)
  • Pyrazinamide (Z)
  • Ethambutol (E)

• Intensive Phase: HRZE (2 months) -- Eradicate tubercle bacilli, clinical improvement

• Continuation Phase: HR (4 months) -- Eliminate remaining bacilli, prevent relapse

• Dosing: Varied based on age (Tables 1 and 2 in the presentation)

Severe/Complicated TB

• Treatment duration is 9 months for TB meningitis, bone/joint TB, and miliary TB, using the HRZE phase followed by the HR phase.

Isoniazid (INH)

• Mechanism of action (MOA): Inhibits mycolic acid synthesis.
• Clinical use: Mycobacterium tuberculosis, non-tuberculosis mycobacteria, TB chemoprophylaxis.
• Pharmacokinetics (PK): Undergoes N-acetylation in the liver—fast acetylators may need higher doses; slow acetylators have longer half-lives.
• Drug interactions: Antacids decrease absorption; inhibits cytochrome P450 - increases plasma concentrations of phenytoin, carbamazepine, and warfarin.
• Adverse effects: Hepatotoxicity, neurotoxicity.

Rifampicin

• MOA: Binds to the β-subunit of DNA-dependent RNA polymerase, inhibiting RNA synthesis
• PK: Highly protein-bound, oral bioavailability decreased by food and first-pass metabolism, half-life is 2-5 hrs, rapid metabolism in liver, well distributed.
• Clinical uses: Mycobacterium Tuberculosis, Mycobacterium Leprae (Leprosy infections), brucellosis, and resistant staphylococcal infections.
• Drug interactions: A potent inducer of cytochrome P450 enzymes—interacts with protease inhibitors, non-nucleoside reverse transcriptase inhibitors, warfarin, oral contraceptives, phenytoin, fluconazole, oral hypoglycemic agents, theophylline, and digoxin.
• Adverse effects: Gastrointestinal issues (N, V, D, anorexia), rash, hypersensitivity reactions, hepatitis, red-orange discoloration of fluids (tears, urine, sweat).

Rifabutin

• Related to rifampicin and less potent inducer of cytochrome P450 than rifampicin
• PK: Half-life 36 hours. Liver metabolism.
• Clinical uses: Mycobacterium tuberculosis; prophylaxis in Mycobacterium avium complex (MAC) infections.

Rifapentine

• Antimicrobial rifamycin derivative with similar spectrum of activity to rifampicin.
• PK: Half-life 14-16 hours; liver metabolism, primarily eliminated via biliary excretion.
• Clinical Uses: TB preventive treatment (3HP). Three months of isoniazid and rifapentine administered once weekly.

Pyrazinamide

• MOA: Converted to pyrazinoic acid by mycobacterial pyrazinamidase. Inhibits cell wall synthesis
• PK: Widely distributed; half-life 9-10 hours
• Clinical uses: Highly specific for Mycobacterium tuberculosis.
• Drug interactions: Allopurinol, probenecid, diuretics
• Adverse effects: Hepatotoxicity (hepatitis, liver damage), hyperuricemia, joint pain.

Ethambutol

• MOA: Inhibits arabinosyltransferase (polymerization of arabinogalactan required for cell wall synthesis).
• PK: Widely distributed, half-life 3-4 hours, primarily eliminated by urinary excretion, crosses the blood-brain barrier (BBB).
• Clinical Uses: Mycobacterial infections.
• Adverse effects: Ocular toxicity, retrobulbar neuritis, hyperuricemia, joint pain.

MDR-TB

• Resistance to rifampicin and isoniazid, potentially other drugs.
• Second-line drugs are expensive, less effective, and have more side effects.
• DOT (directly observed therapy) is essential and duration depends on regimens and resistance levels.

Drug-Induced Hepatitis

• Increased risk in patients with chronic infectious hepatitis, pre-existing liver disease, MDR-TB, alcohol consumption, concurrent use of hepatotoxic drugs, HIV infection, or older age.

• First-line agents: Pyrazinamide, isoniazid, rifampicin

• Second-line agents: Ethionamide, para-aminosalicylic acid, bedaquiline

• Monitoring: Stop treatment if ALT is over 3x or 5x the normal limit. Monitor ALT regularly (e.g., every 3 days).

TB Preventive Treatment (TPT)

• Options include 3HP (isoniazid + rifapentine, once weekly), 3RH (rifampicin + isoniazid, daily), 6H (isoniazid, daily), or 12H (isoniazid, daily).

BCG Vaccine

• Bacille Calmette-Guérin (BCG)
• Live vaccine from bovine tubercle bacillus.
• Stimulates immune system.
• Used for TB skin testing and blood tests.
• Contraindications: Immunosuppression (HIV, immunocompromised), pregnancy

TB and HIV Infection

• Co-treatment is crucial, with short courses of standard treatment and HIV-infected patients monitored.
• Introduce ART (Antiretroviral Therapy) as soon as TB therapy is stable.
• Drug interactions may occur.

Pregnancy and Lactation

• Initiate standard treatment, either drug-sensitive or drug-resistant TB.
• Second-line agents safety in pregnancy is not yet determined.
• Maximum therapeutic doses should not be exceeded
• Aminoglycosides are contraindicated.

Recommended Textbooks

• Basic & Clinical Pharmacology (Lange, 15th Edition).
• Goodman & Gilman's The Pharmacological Basis of Therapeutics (13th Edition).
• SAMF (South African Medicines Formulary, 14th Edition)。

Test your knowledge on the pharmacology of drugs used in the management of tuberculosis. This quiz covers first-line and second-line TB drugs, their mechanisms of action, adverse effects, pharmacokinetics, and the specific considerations for treating special populations. Assess your understanding of TB management, including drug interactions and prophylaxis strategies.