Treatment of Tuberculosis PDF

# Treatment of Tuberculosis ## Antituberculosis Drugs ### First Line Drugs (FLDs) #### First Line Oral (FLO) Drugs 1. Isoniazid (INH/H) 2. Rifampicin (R) 3. Pyrazinamide (Z) 4. Ethambutol (E) ## Isoniazid - Isonicotinic acid hydrazide (INH) - Structurally related to pyridoxine (vita...

# Treatment of Tuberculosis ## Antituberculosis Drugs ### First Line Drugs (FLDs) #### First Line Oral (FLO) Drugs 1. Isoniazid (INH/H) 2. Rifampicin (R) 3. Pyrazinamide (Z) 4. Ethambutol (E) ## Isoniazid - Isonicotinic acid hydrazide (INH) - Structurally related to pyridoxine (vitamin B6) - Prodrug activated in M. tuberculosis by KatG, a catalase-peroxidase. - Inhibits cell wall by inhibiting mycolic acid synthesis - Bactericidal to actively growing bacilli - Acts on both intracellular and extracellular bacilli ### Mechanism of Resistance - Mutation in catalase peroxidase gene - Mutation in the promoter gene inhA ### PK - Penetrates most body fluids and accumulates in caseated lesions - Acetylated in the liver by N-acetyltransferase; acetyl isoniazid is eliminated faster than isoniazid ### Uses: - Combined with RIF, PZA, EMB for treatment - Used alone for prophylaxis ### Adverse Effects - Allergic Reaction - Metabolites of INH may be hepatotoxic (↑ with Age, daily alcohol consumption, drug abuse) - INH can inhibit mammalian pyridoxal kinase and enhance pyridoxine excretion - Peripheral neuropathy with high dose - Minimized by the coadministration of pyridoxine. - Inhibits the metabolism of other drugs, especially diphenylhydantoin. ### Drug Interactions - AlOH inhibits absorption of INH - Alcohol increases risk of hepatitis - Inhibits the metabolism of phenytoin and carbamazepine ## Rifampicin, rifapentine, rifabutin - Rifamycin derivative, Inhibits DNA-dependent RNA polymerase - Bactericidal against intra- and extracellular bacilli - Also active against M. leprae, Staph. Aureus, N. meningitis, H. influenza, Brucella, and Legionella - Rifapentine and rifabutin are analogs of rifampin ### Resistance - Develops rapidly if used alone - Results from point mutation in rpoB gene ### PK - Well absorbed orally; significantly protein bound - Excreted mainly thru liver and bile (Enterohepatic circulation) - Induces hepatic microsomes - decrease half-lives of drugs such as anticonvulsants, antiretrovirals etc. ### Adverse effects - Mainly hepatitis (Dose-dependent and reversible) - Nausea and vomiting, dizziness, fatigue, fever, jaundice, and an orange color to urine and other excretions. ### Drug interactions: - Enzyme inducer - Accelerates metabolism of many drugs e.g. oral contraceptives, anticoagulants, protease inhibitors ## Ethambutol (Myambutol) - Inhibits arabinosyl transferases involved in cell wall biosynthesis - Tuberculostatic - Resistance due to mutation in emb B gene ### Adverse effects: - Reversible retrobulbar neuritis (impaired visual acuity, red-green colour discrimination) - Mild GI disturbances; Decreases urate secretion and may precipitate gout ## Pyrazinamide - Derivative of nicotinamide - Prodrug that is converted to pyrazinoic acid by bacterial pyrazinamidase enzyme. - Bactericidal - Inactive at neutral pH, but it inhibits tubercle bacilli in the acidic (pH 5) phagosomes of macrophages. - Mutation in pcnA gene (encodes pyrazinamidase enzyme) - Adrs: hepatotoxicity, vomiting, anorexia. Not used in pregnancy ### Adverse Effects - Hepatotoxicity is the major adverse effect - Inhibits urate excretion and can precipitate acute episodes of gout. - Acts on extracellular tubercle bacilli. ## Second Line Drugs (SLDS) ### Second Line Oral (SLO) Drugs 1. Fluoroquinolones - Levofloxacin (Lfx) - Moxifloxacin (Mfx) - Gatifloxacin (Gfx) 2. Ethionamide (Eto) 3. Prothionamide (Pto) 4. Cycloserine (Cs) 5. Terizidone (Trz) 6. Para-aminosalicylic Acid (PAS) 7. Thiacetazone (Taz) 8. Rifabutin/Rifapentine ## Antituberculosis Agents | MIC (meg/ml) | Mechanism of Action | Geme(s) Imvolved in Resistance | Role in Resistance | |---|---|---|---| | 0.01-0.25 | Inhibition of mycolic acid synthesis and other multiple effects on DNA, lipids, carbohydrates, and NAD metabolism | katG, inha, ahpC | Prodrug conversion, Drug target, Marker of resistance | | 0.5-2 | Inhibition of RNA synthesis | rpoB | Drug target | | 16-100* | Inhibition of membrane energy and transport| pcnA | Prodrug conversion | | 1-5 | Inhibition of arabinogalactan synthesis | embCAB | Drug target | | 2-8 | Inhibition of protein synthesis| rpsL, rrs (16S rRNA)| Drug target, Drug target | | 2-4 | Inhibition of protein synthesis | rrs (16S rRNA) | Drug target | | 0.5-2.5 | Inhibition of DNA synthesis | gyrA or gyrB | Drug target | | 10 | Inhibition of mycolic acid synthesis | etal or ethA, inha | Prodrug conversion, Drug target | | 1-8 | Inhibition of folate pathway and mycobactin synthesis (7) | thyA (thymidylate synthase)? | Drug target | ## Tuberculosis Treatment | | Tuberculosis | Treatment | |------|--------------------------------------|-----------------------------------| | 1 | Latent TB Infection (Chemoprophylaxis) | Daily INH for 9 months | | 2 | Category 1 (New or previously untreated cases) | 2HRZE + 4HR | | 3 | Category 2 (Previously treated cases; relapses and treatment defaults) | 2HRZES + I HRZE + 5HRE | | 4 | Treatment failure and special cases: | | | | a. Resistance (or intolerance) to H | 6 RZE + Q (for extensive disease) | | | b. Resistance (or intolerance) to R | 12 HZEQ + S (for ext. disease) | | | c. Intolerance to Z | 2 HRE + 7 HR |