Antimycobacterials

Question 1

Isoniazid

Answer 1

• mechanism: inhibits synthesis of mycolic acids, which are in mycobacterial cell walls
• kinetics: oral, readily diffuses into all body tissues and fluids when absorbed from GI
• clinical: Mycobacterium tuberculosis
• toxicity/interactions: neurotoxicity (peripheral neuritis, restlessness, muscle twitching, and insomnia), hepatotoxicity; can reduce the metabolism of phenytoin, increasing its blood level and toxicity
• misc: usually, TB therapy is 4-drug regimen (RIPE)=rifampin, isoniazid, pyrazinamide, and ethambutol (or streptomycin is used instead of ethambutol)

Question 2

Pyrazinamide

Answer 2

• mechanism: converted to pyrazinoic acid (active form) by mycobacterial pyrazinamidase–> disrupts mycobacterial cell membrane metabolism and transport functions
• kinetics: oral
• clinical: Mycobacterium tuberculosis
• toxicity/interactions: nongouty polyarthralgia, hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, and hyperuricemia
• misc: should be avoided in pregnancy

Question 3

Rifampin

Answer 3

• mechanism: inhibits DNA-dependent RNA polymerase by binding to its beta subunit
• kinetics: oral (well absorbed and can go into CNS), undergoes enterohepatic recirculation
• clinical: Mycobacterium tuberculosis, staphylococci, pneumococci
• toxicity/interactions: light-chain proteinuria, rashes, thrombocytopenia, nephritis, harmless orange color to urine, sweat, and tears; flu-like symptoms; induces most cytochrome P450 isoforms (1A2, 2C9, 2C19, 2D6, and 3A4)–> increase elimination of many other drugs

Question 4

Ethambutol

Answer 4

• mechanism: inhibits arabinosyl transferases involved in the synthesis of arabinogalactan, a component of mycobacterial cell walls
• kinetics: oral (well absorbed and can go into CNS)
• clinical: Mycobacterium tuberculosis
• toxicity/interactions: visual disturbances such as decreased visual acuity, red-green color blindness, optic neuritis, and possible retinal damage

Question 5

Streptomycin

Answer 5

-seen in aminoglycosides but also an antimycobacterial drug used to treat mycobacterium tuberculosis

Question 6

Cycloserine

Answer 6

• mechanism: blocks the incorporation of D-Ala into the pentapeptide side chain of the peptidoglycan
• kinetics: oral
• clinical: Mycobacterium tuberculosis (2nd line drug)
• toxicity/interactions: peripheral neuropathy, CNS dysfunction (depression and psychotic reactions)
• misc: only given if TB is resistant to first-line agents

Question 7

Dapsone

Answer 7

• mechanism: inhibitor of folate synthesis: competitively inhibit dihydropteroate synthase b/c it’s structurally similar to PABA
• kinetics: oral; tends to be retained in skin, muscle, liver, and kidney
• clinical: Mycobacterium leprae
• toxicity/interactions: hemolysis may occur in patients with G6PDH deficiency, methemoglobinemia, GI intolerance, fever, pruritus, rashes
• misc: usually given with rifampin and/or clofazimine to prevent dapsone resistance