Pharm of TB - Fitzpatrick Flashcards
(34 cards)
What are the 4 front line TB drugs?
- Isoniazid
- Rifampin
- Ethambutol
- Pyrazinamide
When should Anti-TB drugs be discontinued?
- If serum bili is = or > 3mg/dL or serum transaminases are more than 5x ULN.
(Isoniazid, Rifampin and pyrazinamide)
Four common symptoms of active pulmonary TB
- a bad cough that lasts 3 weeks or longer
- Pain in the chest
- Coughing up blood or sputum
- sweating at night
What are the three main goals with TB treatment?
- Eradicate M.tuberculosis infection
- Prevent emergence of drug resistance
- Prevent relapse of infection
What is the standard therapy for ACTIVE TB?
In two phases:
Intense phase: Isoniazid, rifampin, Ethambutol, and pyrazinamide for 8 weeks.
Continuation phase with Isoniazid and Rifampin until week 26
What is the purpose of using 4 drugs at the same time for active TB?
avoid drug resistance
What drug is used as first line drug for Active TB in hospitalized pts who cannot tolerate oral drugs?
Streptomycin (aminoglycoside)
what effect does INH have on mycobacteria?
INH is a chemical relative of pyridoxine that disrupts mycolic acid synthesis that is narrow spectrum for mycobacteria tuberculosis and is BACTERICIDAL in growing mycobacteria
True or False: INH is given as an inactive oral drug that is activated by pt’s liver enzymes and then attack mycobacteria
False. Enzymes in M. Tuberculosis converts INH into an pharmacologically active metabolite
what mycobacterial enzyme converts INH into its active metabolite? what does the active metabolite then block?
Catalase peroxidase (KatG). it then inhibits InhA and KasA
Isoniazid resistance mechanisms
- Depletion of KatG
- Overexpression/mutation of InhA and KasA
Explain how INH can cause hepatotoxicity
- 90% of INH excreted as N-acetyl-INH, and this is normal
- Pts who are slow acetylators, only about 65% INH is excreted as N-acetyl INH. THe other 35% gets further broken down into N-acetyl hydrazine and isonicotiic acid. N acetyl hydrazine gets ruther broken down to reactive metabolytes by CYP450. These reactive metabolites are what causes the hepatotoxicity.
Hepatoxicity due to INH risk is increased in what pt population?
Slow acetylators
-Age, alcoholism, drug abuse, liver disease, drugs (enzymes inducers)
How does INH cause Neuropathy?
INH reacts covalently with pyridoxal-5-phosphate, enhancing its urinary excretion and depleting the pools of pyridoxines required as cofactors for neurotransmitter synthesis- esp the inhibitory neurotransmitter GABA. This is why seizure occurs with isoniazid.
Slow acetylators depeltes it faster and thus slow acetylors would get both the hepatoxicity and the neuropathy side effects more than normal.
what ethnicity are slow acetylators of INH? Fast acetylators?
Slow:
- Caucasians
- Blacks
- Hispanics
Fast: Asians
what are the two major AE of INH?
- Hepatotoxicity (elevated LFTs, jaundice, hepatitis)
- Neurologic: peripheral neuritis (paresthesias), convulsions
what is the MOA of Rifampin?
- Inhibits prokaryotic DNA dependent RNA polymerase (broad specturm).
- Bactericidal even on slow growing bacteria
How is resistance acquired with rifampin?
- mutation of RNA polymerase
- Drug permeability
What AE are seen with rifampin?
- stains things red/orange.. urine, sweat, contact lenses
- strong inducer of CYP450
- increases metabolism of other drugs thus lowering systemic drug levels
- RIfampan can increase clearance of Oral contraceptives and thus thus increase unplanned pregnancy
- Increase clearance of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors.
In pt with HIV/AIDS what TB drugs should be substituted?
Use Rifabutin instead of Rifampin
what is the MOA of pyrazinamide (PZA)?
- uncertain– probably disrupts mycolic acid biosynthesis.
What toxicities are seen with PZA?
Hepatotoxicity in 15% and Gout
If a pt cannot take PZA due to whatever reason, how should the TB treatment plan be altered?
Take only INH, RIF and EMB daily for 2 months and the total treatment duration extended
what is the MOA of ethambutol?
Inhibitors arabinosyl transferases and cell wall synthesis.
Resistance = mutation of arabinosyl transferase
