Tuberculosis

Question 1

What is the mechanism of action of Isoniazid (INH)?

Answer 1

• Prodrug activated by catalase-peroxidase (KatG) in mycobacteria.
• Forms a complex with NAD⁺ that inhibits enoyl-ACP reductase (InhA) and KasA.
• Disrupts synthesis of mycolic acids, key cell wall components → bactericidal.

Question 2

Describe the pharmacokinetics of INH.

Answer 2

• Well absorbed orally.
• Distributes to CSF, placenta, and lesions.
• Hepatic metabolism by acetylation.
• Excreted renally.

Question 3

What are the ADRs of INH?

Answer 3

• Hepatitis (age-dependent).
• Peripheral neuropathy (due to pyridoxine deficiency).
• CNS toxicity (rare): seizures, irritability.
• Rash, lupus-like syndrome.

Question 4

What causes resistance to INH?

Answer 4

• KatG gene mutation → prevents activation.
• InhA mutation → reduces drug binding.
• Increased efflux.
• No cross-resistance.

Question 5

What are the key drug interactions of INH?

Answer 5

• ↓ Absorption with antacids.
• ↑ Levels of phenytoin, carbamazepine, warfarin.
• Rifampicin induces its metabolism.

Question 6

What is the mechanism of action of Rifampicin?

Answer 6

• Binds to β-subunit of DNA-dependent RNA polymerase (rpoB gene).
• Inhibits initiation of transcription → halts RNA and protein synthesis.
• Bactericidal for intra- and extracellular bacilli.

Question 7

Describe the pharmacokinetics of Rifampicin.

Answer 7

• Good oral absorption (↓ with food).
• Distributed widely including CSF.
• Hepatic metabolism; induces CYP450.
• Excreted in bile.

Question 8

What are the ADRs of Rifampicin?

Answer 8

• Hepatotoxicity.
• Flu-like syndrome.
• GI upset.
• Orange-red discoloration of urine and tears.

Question 9

What causes resistance to Rifampicin?

Answer 9

• Mutation in rpoB gene of RNA polymerase.
• No cross-resistance among rifamycins.

Question 10

What are the key drug interactions of Rifampicin?

Answer 10

• Potent CYP450 inducer → ↓ efficacy of OCPs, warfarin, corticosteroids.
• Interacts with fluconazole, theophylline, antiretrovirals.

Question 11

What is the mechanism of action of Pyrazinamide?

Answer 11

• Prodrug converted to pyrazinoic acid by pyrazinamidase (pncA).
• Disrupts membrane potential and energy metabolism in acidic pH.
• Effective in intracellular macrophages.

Question 12

What are the ADRs of Pyrazinamide?

Answer 12

• Hepatotoxicity.
• Hyperuricemia → gout.
• Arthralgia, myalgia.
• Nausea, vomiting.

Question 13

What is the mechanism of action of Ethambutol?

Answer 13

• Inhibits arabinosyl transferase (embB gene).
• Prevents polymerization of arabinogalactan → disrupts mycolic acid incorporation.
• Bacteriostatic.

Question 14

What are the ADRs of Ethambutol?

Answer 14

• Optic neuritis → visual acuity loss, red-green color blindness.
• Rash, fever.
• No hepatotoxicity; safe in pregnancy.

Question 15

What are the fluoroquinolones used as second-line anti-TB drugs?

Answer 15

• Levofloxacin, Moxifloxacin, Ofloxacin
• Moxifloxacin > Levo > Ofloxacin > Ciprofloxacin (in potency)
• Act on DNA gyrase; bactericidal
• Resistance: mutation in DNA gyrase
• Indications: MDR-TB, XDR-TB

Question 16

What is the mechanism and use of Ethionamide?

Answer 16

• Similar to INH; inhibits mycolic acid synthesis
• Active against intra- and extracellular TB bacilli
• Bactericidal; good tissue penetration
• ADRs: GI upset, metallic taste, rash, neurological effects
• Indications: MDR-TB, MAC

Question 17

What is the mechanism and ADR of Cycloserine?

Answer 17

• Inhibits bacterial cell wall synthesis (D-alanine racemase)
• Bacteriostatic
• ADR: CNS toxicity (headache, psychosis, seizures)
• Indications: MDR-TB

Question 18

What is Para-aminosalicylic acid (PAS) and how is it used?

Answer 18

• Folate synthesis inhibitor; analogue of PABA
• Bacteriostatic; delays resistance development
• Competes for INH acetylation
• ADRs: GI upset, hypothyroidism, hepatotoxicity
• Indications: resistant TB

Question 19

What is Terizidone and when is it used?

Answer 19

• Derivative of cycloserine (di-imine structure)
• Less neurotoxic
• Indications: MDR-TB, genitourinary TB

Question 20

What is Rifapentine and how is it different from Rifampin?

Answer 20

• Long-acting rifamycin; used in continuation phase and TPT
• Similar ADRs and interactions as rifampin
• Dose: 600 mg once/twice weekly
• Not used in intensive phase

Question 21

What are the injectable second-line anti-TB drugs?

Answer 21

Amikacin:
- Less vestibular toxicity than streptomycin
- ADRs: nephrotoxicity, ototoxicity

Streptomycin:
- Cidal; acts on extracellular bacilli
- ADRs: ototoxicity, nephrotoxicity
- Resistance develops fast

Question 22

What is the mechanism and use of Bedaquiline?

Answer 22

• Inhibits mycobacterial ATP synthase → ↓ energy production
• Bactericidal; acts on dormant and active bacilli
• ADR: QT prolongation, hepatotoxicity, arthralgia
• Used in both shorter and longer MDR-TB regimens

Question 23

What is the role of Delamanid?

Answer 23

• Nitroimidazole; prodrug activated by nitroreductase
• Inhibits mycolic acid synthesis
• Acts on replicating and dormant TB bacilli
• ADR: QT prolongation, nausea
• Used in MDR/XDR-TB

Question 24

Describe Linezolid in TB treatment.

Answer 24

• Inhibits 50S ribosomal subunit → protein synthesis inhibition
• Bacteriostatic; active on both intra/extracellular bacilli
• ADRs: myelosuppression, peripheral and optic neuropathy
• Indication: longer MDR-TB regimens

Question 25

What is Pretomanid and where is it used?

Answer 25

- Component of BPaLM regimen (with Bdq + Lzd + Mfx) - Kills both replicating and dormant bacilli - ADRs: hepatotoxicity, anemia, QT prolongation, neuropathy - Used in MDR/XDR-TB

Question 26

What is Clofazimine and its use in TB?

Answer 26

- Binds DNA; anti-leprosy drug repurposed for TB - Bacteriostatic - ADRs: skin discoloration, GI upset, optic neuritis (rare) - Used in longer MDR-TB regimens