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30 Cards in this Set
- Front
- Back
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Major drugs used in TB
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isoniazid (INH)
rifampin ethambutol pyrazinamide stretomycin |
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Mechanism of isoniazid
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-structural congener of pyridoxine
- inhibits mycolic acids, characteristic components of mycobacterial cell walls |
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Association with high-level resistance of INH
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deletion in the katG gene that codes fro a catalase-peroxidase involved in the bioactivation of INH
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Association with low-level resistance of INH
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deletions in the inhA gene that encodes the "target enzyme," an acyl carrier protein reductase
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Pharmacokinetics of INH
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-well absorbed orally and penetrates cells to act on intracellular mycobacteria
-liver metabolism is by acetylation and under genetic control |
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Various INH half-lives
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"fast acetylators": 60-90 minutes
"slow acetylators": 3-4 hours |
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INH Toxicity
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neurotoxic effects: peripheral neuritis, restlessness, muscle twitching, insomnia
-hepatotoxic: abnormal LFTs, jaundice, and hepatitis - hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency |
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Relief of toxicity effects
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administration of pyridoxine
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Mechanism of Rifampin
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-bactericidal against M tuberculosis
-inhibits DNA-dependent RNA polymerase in M tuberculosis |
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Pharmacokinetics of Rifampin
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-orally: well absorbed and distributed to most body tissues, including the CNS
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Clinical uses of Rifampin
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-always used in combination
- can be used as the sole drug in treatment of latent TB in INH-intolerant patients or in close contacts of patients with INH-resistant strains |
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Toxicity of Rifampin
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-light-chain proteinuria
-may impair antibody responses -skin rashes, thrombocytopenia, nephritis, liver dysfunction |
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Rifampin interactions
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-strongly induces liver drug-metabolising enzymes and enhances theh elimination rate of many drugs, including anticonvulsants, contraceptive steroids, cyclosporine, ketoconazole, methadone, terbinafine, and warfarin
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Mechanisms of action of Ethambutol
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-inhibits arabinosyl transferases involved in the synthesis of arabinogalactan
* resistance occurs rapidly if the drug is used alone |
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Pharmacokinetics of Ethambutol
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-well absorbed orally and distributed to most tissues, including the CNS
-large fraction unchanged in the urine -must reduce dose in renal impairment |
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Mechanisms of action of Pyrazinamide
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-unknown
- bacteriostatic action requires metabolic conversion via pyrazinamidases present in M tuberculosis |
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Pharmacokinetics of Pyrazinamide
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-well absorbed orally and penetrates tissues well, including CNS
- metabolized to pyrazinoic acid, and both are excreted in urine |
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Toxicity of Pyrazinamide
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40% of patients develop nongouty polyarthralgia
-hyperuricemia but is asymptomatic -myalgia, GI irritation, maculopapular rash, hepatic dysfunction, porphyria, photosensitivity reactions **Contraindicated in pregnancy |
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Streptomycin for use in TB
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aminoglycoside more often used now due to increasing drug-resistance
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Alternative drugs with antimycobacterial activity
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Amikacin: must be used in combination
Ciprofloxacin and ofloxacin: active against TB that is resistant to first-line agents (always use in combo) Ethionamide: congener of INH; tox= GI irritation and neurologic effects p-Aminosalicylic acid: primary resistance is common; tox includes Gi irritation, peptic ulceration, hypersensitivity reactions, effects on kidney, liver, and thyroid function -capreomycin: ototoxicity, renal dysfunction -cycloserine: peripheral neuropathy, CNS dysfunction |
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Anti-TB drug regimen
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initial 3-drug regimen of INH, rifampin, and pyrazinamide
-if organisms susceptible, stop pyrazinamide after 2 months |
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Alternative regimens
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INH + rifampin for 9 months
INH and ETB for 18 months |
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treatment for TB resistant to only INH
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6 months RIF + pyrazinamide + ethambutol or streptomycin
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most active drug against M. leprae
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dapsone (diaminodiphenylsulfone)
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Mechanism of action of sulfones
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-inhibition of folic acid synthesis
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How to ameliorate resistance
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administer with rifampin and/or clofazimine
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Pharmacokinetics of dapsone
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oral administration, penetrates tissues well, undergoes enterohepatic cycling, eliminated in the urine as acetylated metabolites
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adverse effects of dapsone
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Gi irritation, fever, skin rashes, methemoglobinemia, hemolysis (G6PD deficiency)
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prophylaxis in patients with CD4 counts less than 50/uL against Mycobacterium avium
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clarithromycin or azithromycin with or without rifabutin
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Treatment of MAC infections
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combination of drugs, azithromycin or clarithromycin with ethambutol and rifabutin
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