Tuberculosis Flashcards
Why are Mycobacteria resistant to most antibiotics?
- grow more slowly than other bacteria
- dormant, lipid-rich cell wall is impermeable to many agents
- intracellular pathogens residing in macrophages
- combinations of two or more drugs are required
First- line agents
- Isoniazid
- Rifampin
- Pyrazinamide
- Ethambutol
Most active drugs
Isoniazid and Rifampin
4 drugs which are usually combined
Isoniazid
Rifampin
Pyrazinamide - when this is combined it allows the duration of treatment to last 6 months
Ethambutol
Isoniazid
- mechanism of action (4)
- basis of resistance
- bactericidal against growing tubercle bacilli
- penetrates into macrophages and is active against both extracellular and intracellular organisms
- penetrates caseous lesions
- inhibits synthesis of mycolic acid
- prodrug
-katG mutants express high level isoniazid resistance
Isoniazid
- pharmacokinetics (3)
- drug interactions
- readily absorbed from GI tract; diffuses readily into all body fluids and tissues
- acetylation by liver N-acetyl transferase
- rapid and slow acetylators
-reduce the metabolism of phenytoin (increase its blood level and toxicity)
Isoniazid
-unwanted effects
- hepatitis
- peripheral neuropathy
- CNS toxicity
Rifampin
- mechanism of action
- basis of resistance
- binds to beta subunit of bacterial DNA dependent RNA polymerase and thereby inhibits RNA synthesis
- reduced binding to RNA polymerase
Rifampin
- pharmacokinetics (3)
- drug interactions
- well absorbed
- strongly induces most cytochrome P450 isoforms, increases the elimination of numerous drugs
Rifampin
-unwanted effects
-orange color to urine, sweat and tears
Ethambutol
-mechanism of action
-inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB operon; arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall
Ethambutol
- pharmacokinetics
- unwanted effects
- well absorbed, 50% excreted in urine in unchanged form
- retrobulbar neuritis
Pyrazinamide
- mechanism of action
- basis of resistance
- converted to pyrazinoic acid by mycobacterial pyrazinamidase
- pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions
-no cross-resistance with other antimycobacterial drugs
Pyrazinamide
- pharmacokinetics
- unwanted effects
- well absorbed
- hepatotoxicity, hyperuricemia
Streptomycin
- mechanism of action
- pharmacokinetics
- aminoglycozide
- used when an injectable drug is needed or desirable and in the treatment of infections resistant to other drug
