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Questions and Answers
What is the mechanism of action (MOA) of Pyrazinamide?
What is the mechanism of action (MOA) of Pyrazinamide?
Which of the following is NOT a second-line drug for MDR-TB?
Which of the following is NOT a second-line drug for MDR-TB?
Which drug is primarily used to monitor liver function during TB treatment?
Which drug is primarily used to monitor liver function during TB treatment?
What is the main adverse effect associated with Ethambutol?
What is the main adverse effect associated with Ethambutol?
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For individuals at risk of developing TB, what is one option for preventive treatment (TPT)?
For individuals at risk of developing TB, what is one option for preventive treatment (TPT)?
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What is a common adverse effect shared by both Pyrazinamide and Ethambutol?
What is a common adverse effect shared by both Pyrazinamide and Ethambutol?
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Which BCG vaccine characteristic is true regarding its administration?
Which BCG vaccine characteristic is true regarding its administration?
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What is one of the main criteria for reintroducing rifampicin in the treatment of TB?
What is one of the main criteria for reintroducing rifampicin in the treatment of TB?
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In co-infected patients with TB and HIV, when should ART be initiated?
In co-infected patients with TB and HIV, when should ART be initiated?
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What is the mechanism of action of rifampicin?
What is the mechanism of action of rifampicin?
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Which of the following statements about rifampicin's pharmacokinetics is correct?
Which of the following statements about rifampicin's pharmacokinetics is correct?
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Which of the following is NOT a clinical use of rifampicin?
Which of the following is NOT a clinical use of rifampicin?
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What adverse effect is associated with rifampicin?
What adverse effect is associated with rifampicin?
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Which drug is a less potent inducer of cytochrome P450 compared to rifampicin?
Which drug is a less potent inducer of cytochrome P450 compared to rifampicin?
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How is pyrazinamide activated in the body?
How is pyrazinamide activated in the body?
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What is the main route of elimination for rifapentine?
What is the main route of elimination for rifapentine?
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Which of the following conditions is treated with the combination of isoniazid and rifapentine?
Which of the following conditions is treated with the combination of isoniazid and rifapentine?
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Which statement accurately describes the mechanism of action of isoniazid?
Which statement accurately describes the mechanism of action of isoniazid?
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What is the primary goal of the treatment regimen for active tuberculosis?
What is the primary goal of the treatment regimen for active tuberculosis?
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In the context of pharmacokinetics, what characterizes fast acetylators of isoniazid?
In the context of pharmacokinetics, what characterizes fast acetylators of isoniazid?
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What adverse effect is commonly associated with isoniazid use?
What adverse effect is commonly associated with isoniazid use?
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Which of the following drugs is NOT included in the first line TB regimen?
Which of the following drugs is NOT included in the first line TB regimen?
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What is a key feature of the continuation phase in TB treatment?
What is a key feature of the continuation phase in TB treatment?
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Which type of drug interaction is associated with isoniazid?
Which type of drug interaction is associated with isoniazid?
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In severe or complicated TB cases, how long is the treatment duration typically recommended?
In severe or complicated TB cases, how long is the treatment duration typically recommended?
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What role does the TB vaccine play in tuberculosis management?
What role does the TB vaccine play in tuberculosis management?
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What distinguishes the first line TB drugs from second line TB drugs?
What distinguishes the first line TB drugs from second line TB drugs?
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Study Notes
Pharmacology of Drugs Used in the Management of Tuberculosis
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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.
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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
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General principles: Use correct drugs for adequate duration, directly observed therapy (DOT), and achieve treatment completion and compliance.
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Effective First-line Drugs with Acceptable Toxicity:
- Isoniazid (H)
- Rifampicin (R)
- Pyrazinamide (Z)
- Ethambutol (E)
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Intensive Phase: HRZE (2 months) -- Eradicate tubercle bacilli, clinical improvement
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Continuation Phase: HR (4 months) -- Eliminate remaining bacilli, prevent relapse
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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
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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.
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First-line agents: Pyrazinamide, isoniazid, rifampicin
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Second-line agents: Ethionamide, para-aminosalicylic acid, bedaquiline
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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)。
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Description
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.
