Usual regimen: INH/rifampin/pyrazinamde and either ethambutol or streptomycin (4 drug combo)

Prophylaxis: INH for 12 mos.

Primary drugs: INH, pyrazinamide, rifampin, ethambutol, streptomycin

MOA: Uncertain, but INH does inhibit synthesis of mycolic acid, a component of the cell wall.

Selectivity: INH is only effective against mycobacteria. Bactericidal.

Resistance: Develops rapidly. Mutants decrease catalase and peroxidase, increase mycolic acid synthesis, cleave off the hydrazine group from the drug with hydrazide enzyme (most common), or survive with less mycolic acid in their cell wall.

Pharmacokinetics: Acetylation occurs in the liver and is different between fast and slow acetylators. The slow inactivator is homozygous recessive. One of the toxicities of INH is pyroxidine (B6) deficiency and slow acetylators are more likely to suffer. Also, INH inhibits the metabolism of phenytoin, which can lead to toxicity in slow acetylators. Acetyl-INH is excreted in the urine.

Toxicity: Peripheral neuropathy reversed by vitamin B6 (due to drug competing with B6 for enzyme apotrytophanase); hepatitis seen during prophylactic use in those over 35 yrs old.

Therapeutic place: Treatment is aimed at the active state of Tb. Also used for prophylaxis.

MOA: Unknown, but interferes with mycolic acid and RNA synthesis.

Toxicity: Optic neuritis (color blindness), loss of visual acuity, and retrobulbar neuritis.

Therapeutic place: M. tuberculosis, M. bovis.

Contraindicated: In children under 5 yrs old.

MOA: Rifampin inhibits DNA-dependent RNA polymerase ( subunit).

Spectrum: M. tuberculosis and G(+) organisms.

Toxicity: Turns body fluids orange (not harmful).

Pharmacokinetics: Rifampin induces p450 enzymes, thereby decreasing the half-lives of a number of drugs.

Pyrazinamde – Can cause liver damage and uric acid retention.

Second-line drugs: Cycloserine, viomycin, kanamycin, capreomycin, PAS, ethionamide

Cycloserine – Cell wall inhibitor, CNS toxicity.

Capreomycin – Renal and oxtotoxicity.

PAS – Bad shits.

INH-Rifampin – Hepatotoxicity.

Rifampin-oral contraceptives – Decreased effectiveness of contraceptive.

Category: Pharmacology Notes