TB Drugs Flashcards
What factors make TB so difficult to treat?
- Impermiable cell wall (mycolic acid)
- Intrinsic Resistance re efflux pumps
- Inaccessible when latent because it is intracellular
- Slow growing so antimetabolites, anti DNA, anti RNA dont work as well
- Latent vs Active infection
What four medicaitons
comprise the standard treatment for TB?
Think RIPE
Rifampin
Isoniazid
Pyrazinamide
Ethambutal
What is the sequence and duration of standard treatment for latent and active TB?
Latent: INH x 9 months or RIF x 4 months
Active: Rifampin, Isoniazid, Pyrazinamide
(plus Ethambutal if suspect INH resistance)
X 2 months
Then RIF and INH x 4 mo if not INH resistant
Why are the RIPE drugs given initially for 2 months?
To culture INH and RIF for resistance
To destroy any TB that is resistant to INH or RIF
What are MDR-TB and XDR-TB and how are they treated?
MDR = multi-drug resistant: resistant to INH and RIF
Tx: 4-6 drugs x 18 mos based on evidence of susceptibility
XDR = extensive drug resistant: resistant to 4+ medications
Tx: $500K!!
What is the MoA and Resistance of Isoniazid?
MoA: bacteriocidal; inhibits mycolic acid synthesis; able to penetrate inside macrophages to get to the TB
Resistance: deletion/mutation of KatG that activates it
Overexpression of its target: InhA
How is isoniazid metabolized and how does this affect dosing?
Metabolized in the host from Isoniazid (INH) to N-acetyle INH by NAT2.
Fast acetylators (Inuit, Japanese)
Slow acetylators (Euro- and African-Americans, Egyptians): buildup of INH leads to toxic metabolites leading to hepatotoxicity and peripheral neuropathy and SLE
How can Isoniazid lead to peripheral neuropathy?
It outcompetes for B6/pyridoxine
(especially in slow acetylators).
Tx: give supplemental B6
What are the drug drug interactions re Isoniazid
HUGE!
Induces CYP for some medications (acetaminophen)
Inhibits CYPs for many others (warfarin, diazepam, phenytoin)
What is the MoA and primary resistance re Pyrazinamide?
MoA: analog of Nicotinamide inhibits Fatty Acid Synthase I and thereby inhibits cell membrane synthesis.
Prodrug that is inactive at neutral pH but converted to by mycobacteria pncA (acidic) into active.
Resistance: pncA mutations
What are the key adverse effects of Pyrazinamide?
Hepatotoxicity
Hyperuricemia leading to gout sx
Arthralgia
What is the MoA of Ethambutal?
MoA: inhibits mycobacteria arabinosyl transferase from polymerizing cell wall leading to holes in cell wall
What are the key adverse effects of Ethambutal?
Optic neuritis (1%, rare): decreased vision and red/green color blindness. Warn them about this!
Also: fever, rash.
What is the MoA and primary resistance re Rifampin?
MoA: penetrates macrophages, binds to bacterial DNA dependent RNA polymerase (rpoB) but not eukaryote version.
Thus is inhibits RNA synthesis.
Resistance: mutation of rpoB
What is an odd side effect of Rifampin?
It can turn tears and urine reddish orange and can permanently stain contact lenses and permanent lenses.
Warn your patient!
Also: N, V, fever, rash, and liver disease (re alcoholics)
What are the drug drug interactions re Rifampin and what comorbidity does this affect?
It induces hepatic CYPs causing therapeutic failure of HIV protease inhibitors, methodone, warfarin, OCPs.
This makes it hard to treat the 500,000 patients
who have both TB and HIV
Treat with Rifabutin instead.
Bedaquiline is reserved for a special group of patients.
Who are they?
Patients with MDR-TB (multi-drug resistant)
They take Bedaquiline with three or more additional meds. x 24 weeks ($30K)!!
What medication cannot be taken with Bedaquiline?
Rifampin because it is metabolized by CYP3A4.
What are the principal adverse effects of Bedaquiline?
Increased liver enzymes
What is the MoA and Resistance for Bedaquiline?
MoA: unique: inhibits ATP synthesis in mycobacterial so it does not have enough energy to survive.
Resistance: atpE of ATP synthase
Bedaquiline has a Box Warning. Why?
Can cause deadly QT prolongation.
Patients should get regular EKGs.
What is the MoA of streptomycin?
Targets 30S ribosomal unit to inhibit protein synthesis
Under what circumstances to you prescribe streptomycin for TB and why?
Severe active TB
It cannot enter the cells re latent TB
It is ototoxic and hepatotoxic and C/I re pregnancy
What TB drug is okay re pregnancy?
Bedaquiline.
What is the MoA of flouroquinolones like levofloxacin?
Inhibit DNA synthesis and supercoiling by targeting topoisomerase.
What drugs regimen is used to treat M. avium complex (MAC)?
A macrolide (clarithromycin or azithromycin)
+
Ethambutol
+
A rifamycin (rifabutin or rifampin)
What drug regiment is used to treat M. leprae?
(aka Leprosy or Hansen’s Disease)
Rifampin
+
Dapsone (anti-folate)
+
Clofazimine
What is the primary risk factor for isoniazid- associated hepatitis?
Old age
Why do you give B6 when taking isoniazid?
It causes isoniazid induced depletion of B6/pyridoxine
What is the mechanism of the drug drug interaction between protease inhibitors and rifampin?
Rifampin induces CYP 3A4 enzyme making PIs less effective
What affect does ethnic background have on the use of isoniazid?
Whites and blacks tend to be slow acetylators leading to drug toxicity.
