ANTI-TUBERCULAR DRUGS

Full: PK + PD + Toxicity + Gyn/OB relevance

1. ISONIAZID (INH / H)

Pharmacodynamics (PD)

• Bactericidal against rapidly dividing TB bacilli
• Inhibits mycolic acid synthesis → disrupts peptidoglycan layer
• Prodrug activated by KatG catalase-peroxidase enzyme
• Greatest action during initial rapid multiplication phase

Mechanism highlights:

• Blocks fatty acid synthesis (InhA)
• Prevents cell wall integrity → cell death

Pharmacokinetics (PK)

• Absorption: excellent oral absorption
• Distribution: penetrates CSF well (useful in TB meningitis)
• Metabolism: hepatic acetylation (N-acetyl transferase)
• slow vs fast acetylators vary toxicity risk
• Excretion: renal metabolites

PK implications:

• Slow acetylators → ↑ risk neuropathy/hepatotoxicity
• Fast acetylators → lower INH levels

Toxicity (key):

• Hepatitis
• Peripheral neuropathy (pyridoxine deficiency)
• Drug-induced lupus
• Hemolysis in G6PD deficiency

OB/Gyn relevance

• Safe in pregnancy
• MUST give pyridoxine
• Safe in breastfeeding

2. RIFAMPICIN (R)

PD

• Bactericidal
• Inhibits DNA-dependent RNA polymerase
• Broad intracellular activity → acts on latent bacilli

PK

• Absorption: oral absorption good
• Distribution: wide including CSF if meninges inflamed
• Metabolism: hepatic enzyme induction
• Excretion: biliary → enterohepatic circulation

PK consequences:

• Strong CYP450 inducer

Toxicity:

• Hepatotoxicity
• Orange body fluids
• Thrombocytopenia

OB/Gyn relevance

• Reduces OCP effect (important counselling)
• Safe in pregnancy
• Suggest vit K if prolonged use near delivery

3. PYRAZINAMIDE (Z)

PD

• Bactericidal in acidic environments
• Works inside macrophage lysosomes
• Converted → pyrazinoic acid

PK

• Absorption: orally good
• Distribution: good CSF penetration
• Metabolism: hepatic
• Excretion: renal metabolites

Toxicity:

• Hepatotoxicity
• Hyperuricemia → gout

OB/Gyn relevance

• WHO: safe in pregnancy
• Monitor liver tests

4. ETHAMBUTOL (E)

PD

• Mainly bacteriostatic
• Inhibits arabinosyl transferase → blocks arabinogalactan in cell wall

PK

• Absorption: oral good
• Distribution: penetrates tissues + CSF when meninges inflamed
• Excretion: renal unchanged

PK implication:

• Dose-adjust in renal failure

Toxicity:

• Optic neuritis → decreased visual acuity, red-green discrimination
• Dose related

OB/Gyn relevance

• Safe in pregnancy, breastfeeding
• Ophthalmic baseline exam helpful

5. STREPTOMYCIN (aminoglycoside)

PD

• Bactericidal
• Bind 30S ribosomal subunit → misreading
• Best for extracellular bacilli

PK

• Absorption: parenteral only (IM/IV)
• Distribution: poor intracellular penetration
• Excretion: renal unchanged

Toxicity:

• Ototoxicity
• Nephrotoxicity

OB/Gyn relevance:

• Contraindicated in pregnancy → fetal ototoxicity
• Avoid in breastfeeding

SECOND-LINE: PK + PD SUMMARY

Fluoroquinolones (levo-/moxi-/ofloxacin)

PD:

• Bactericidal
• Inhibit DNA gyrase/topoisomerase

PK:

• Oral absorption
• Wide distribution
• Renal elimination mainly

OB relevance:

• Avoid in pregnancy if possible

Ethionamide

PD: inhibits mycolic acid synthesis (like INH)

PK: hepatic metabolism

Toxicity: GI upset, hepatitis, hypothyroidism

OB: avoid if possible

Cycloserine

PD: inhibits cell wall synthesis

PK: renal elimination

Toxicity: neurotoxicity, psychosis

OB: avoid

PAS (para-aminosalicylic acid)

PD: folate metabolism interference

PK: renal excretion

Toxicity: GI intolerance, hepatitis, hypothyroidism

Bedaquiline

PD: ATP synthase inhibitor

PK: hepatic metabolism

Toxicity: QT prolongation

GENERAL PHARMACOKINETICS THEMES for first-line drugs

Absorption (oral good):

• INH
• Rifampicin
• PZA
• Ethambutol

Distribution:

• All enter CSF when meninges inflamed
• INH excellent CSF penetration even without inflammation

Metabolism:

• INH + Rifampicin + PZA = hepatic metabolism
• Ethambutol renal

Elimination:

• INH: renal metabolites
• Rifampicin: biliary
• PZA: renal metabolites
• Ethambutol: renal unchanged
• Streptomycin: renal unchanged

PHARMACODYNAMICS THEMES

Cell wall synthesis inhibitors:

• INH – mycolic acids
• Ethambutol – arabinogalactan
• Ethionamide – mycolic acids
• Cycloserine – alanine incorporation
• PAS – folate metabolism

Nucleic acid inhibitors:

• Rifampicin → RNA polymerase
• Fluoroquinolones → DNA gyrase

Protein synthesis inhibitors:

• Streptomycin (30S)
• Amikacin, capreomycin (second-line injectables)

Energy metabolism inhibitors:

• Bedaquiline (ATP synthase)

OBGYN-IMPORTANT TB THEMES

Pregnancy:

• Treat same as non-pregnant EXCEPT avoid streptomycin
• Pyridoxine must be given
• Rifampicin reduces OCP efficacy → contraception counselling

Infertility:

• Genital TB → tubal obstruction, endometrial scarring
• Differential for chronic pelvic pain

Breastfeeding:

• Safe drugs: INH, Rifampicin, Ethambutol, Pyrazinamide

Congenital TB:

• hematogenous spread; serious neonatal disease
• maternal treatment reduces risk

🧠 ANTI-TUBERCULAR DRUGS — MASTER TABLE

(PK + PD + Toxicity + OB/GYN relevance)

🟢 FIRST-LINE ANTI-TB DRUGS (HRZE ± S)

🟡 SECOND-LINE ANTI-TB DRUGS — SUMMARY TABLE

🔵 GENERAL PK THEMES — FIRST-LINE DRUGS

🔴 PHARMACODYNAMIC CLASSIFICATION (EXAM GOLD)

🟣 OB/GYN-IMPORTANT TB THEMES — CONSOLIDATED