Ph- AntiMycobacterial Drugs Flashcards
What are the current first line drugs for TB?
What recently became accepted as first line?
What recently got “demoted” and why?
Current first line:
- rifampin
- Isoniazid
- pyrazinamide
- ethambutol
Demoted: streptomycin due to high level of resistance
Promoted: moxifloxacin - a fluoroquinolone
Sucessful treatment of TB requires several months of multi-drug therapy. This is because of what 3 reasons?
- mycobacteria have a mycolic acid cell wall that is very thick and can shield from drugs
- Efflux pumps - remove drug as soon as it enters cytoplasm
- mycobacteria get sequestered in host cells creating a third barrier for drug penetration
What is the only situation when one drug would be used for TB instead of the normal combination?
Prophylactic therapy - +PPD but no sign of disease, or living in the home of someone with active infection, etc.
All other situations require multiple drugs to avoid resistance
There can be ______ living organisms in a pulmonary lesion. The incidence of resistance is as high as one per _____ or _____. This means that resistance will likely occur with a single drug.
Incidences of resistance to multiples drugs are the ________ of resistances to single drugs, only one in _____ will be resistant to 2 drugs in combination.
10^9 organisms in a pulmonary lesion
The incidence of resistance is 1/10^6 or 1/10^7
Incidence of resistance to multiple drugs ins equal to the product of resistance to single drugs.
10^6 x 10^6 = 10^12
so drug resistance to 2 drug therapy only occurs in 1/10^12 cells
All initial isolates of TB should be tested for drug susceptibilities, but while you are waiting for results, what drug combination should be given?
Once the results are know, what drugs are typically given for the first 2 months of treatment?
What drugs are given for the following 4 months?
RIPE until results are know
RIP for first 2 months (Initial phase)
RI for next 4 months (continuation phase)
If there are circumstances of resistance or toxicity, what drugs should be used?
Second line drugs like: ethionamide PAS (para-aminosalicyclic acid) cycloserine amikacin kanamycin capreomycin
What technique is used in AFrica and the US to treat TB while minimizing the development of drug resistance?
DOT - directly-observed therapy where a health care worker goes to watch the people take their drugs to ensure compliance
What is the drug of choice for chemoprophylaxis for TB?
What 3 people are recommended to receive it?
Isoniazid is used for six months by:
- household contacts of TB patients
- recent convertors to + PPD
- old “inactive” TB to make sure it doesn’t reactivate
What is meant by MDR?
Resistant to both isoniazid and rifampin
What is meant by XDR?
Resistant to:
Isoniazid, rifampin, moxifloxicin (and other fluoroquinilones) and at least 1 injectible second line drug (aminoglycoside or capreomyin)
What are the 2 nicotinic acid analogs used for mycobacterial chemotherapy?
- isoniazid
2. pyrazinamide
_____________ is the most active anti-TB drug. Its use is confined to ________ and _________.
Isoniazid is the most active anti-TB drug and it is used for MTb and atypical mycobacteria
Describe the mechanism of action of isoniazid.
How is the prodrug activated?
What are the 2 actions of the active drug?
It is a prodrug that is activated to isonicotinoyl radical by mycobacterial catalase peroxidase katG.
Isonicotinyl radical can make :
- nicotinyl-NAD adduct which inhibits inhA and KasA (halting mycolic acid synthesis)
- nicotinyl-NADP adduct which inhibits DHFR (reducing folic acid synthesis)
Isoniazid is a prodrug converted to __________ but the mycobacterial ____________, ______.
isonicotinyl radical by katg, a catalase peroxidase
When isonicotinyl radical adducts with NAD, what are the two things that are inhibited?
- inhA- an enoyl acyl carrier protein reductase that catalyzes mycolic acid synthesis
- KasA- beta-ketoacyl protein synthase
When isonicotinyl radical adducts with NADP, what is inhibited?
DHFR
What is the mechanism of resistance bacteria develop against isoniazid?
Resistant strains tend to lack katG (the catalase-peroxidase enzyme necessary to convert isoniazid prodrug to the active drug isonicotinyl radical)
Describe the pharmacokinetics of isoniazid.
How well is it absorbed and distributed?
What are the 2 ways it is inactivated?
What is the half life?
It is well absorbed and distributed.
It is inactivated by acetylation, but there are 2 types:
- fast- half life 1 hour
- slow- half life 3 hours
In US it is a 50/50 for fast/slow acetylators
In the US there are fast and slow acetylators. This is determined by a dominant genetic trait.
Who is likely to accumulate toxic concentrations of isoniazid? Why?
Slow acetylators that have renal function impairment are likely to get toxic concentrations of isoniazid
What are the 2 main side effects of isoniazid?
Who is each likely to occur in and why?
- peripheral neuropathy- high doses, slow acetylators caused by a pyridoxine deficiency (B6). INH is a pyridoxine homolog that competes for cofactor. Avoid toxicity by giving pyroxidine cofactor
- Hepatic toxicity- multilobar necrosis with increasing age (patients >50)
You are worried that your patient on isoniazid is developing a peripheral neuropathy.
What is the likely deficiency and how can you treat them without taking them off the TB drug?
They are deficient in pyridoxine (B6) and can be treated by administering pyridoxine
What is the mechanism of action of rifampin?
It inhibits prokaryotic DNA-directed RNA polymerase
It is efficient against G+ and G- bacteria
What is the mechanism of bacterial resistance to rifampin?
It is caused by a mutation in the polymerase rpoB gene in TB
What is the first thing you want to warn patients of when they are about to take rifampin?
It turns all secretions orange- urine, feces, tears, sputum, sweat
How is rifampin eliminated from the body?
It is eliminated in bile and deacytelated
What are the adverse effects of rifampin?
What is a similar drug with fewer drug-drug interactions that be used for patients taking many drugs?
- hepatotoxic
- inducer of p450s so lots of drug-drug interactions
ex. steroids are more rapidly metabolized so women on BC can become pregnant
If your patient is on a lot of drugs, give them rifabutin instead
What is the mechanism of action of pyrazinamide?
It gets activated to pyrazinoic acid by nicotinamidase (pytazinamidase pncA)
Pyrazinoic acid (POA) inhibits small ribosomal subunit RspA by binding to it. When this happens:
- growing mycobacterial cells cannot synthesize proteins
- semi-dormant/starving cells cannot perform TRANS-TRANSLATION
Pyrazinamide is a prodrug converted by __________ to become _________ .
nicotinamidase (pncA) to become pyrazinoic acid
What does active pyrazinoic acid inhibit?
What are the 2 results?
It inhibits RspA which :
- stops growing cells from doing normal translation
- stops starving cells from doing trans translation to recover and recycle
What is trans-translation?
In cells not able to grow well, ribosomes stall on mRNA and the mRNA degrade.
The ribosome then binds tmRNA (tRNA and mRNA function to allow ribosomes to terminate translation by providing a stop codon and releasing the ribosome, freeing it to be able to translate a different protein.
What is the mechanism of bacterial resistance to pyrazinamide?
a mutation in pncA gene
What are the adverse effects of pyrazinamide?
- hepatic damage
2. inhibits uric acid secretion so can cause gout
What is the mechanism of action of ethambutol?
It inhibits arabinosyl transferase III which catalyzes the first step in the biosynthesis of arabinogalactans (a part of the mycobacterial cell wall)
What is the mechanism of bacterial resistance to ethambutol?
embB gene (encoding the arabinosyl transferase enzyme) is mutated
What are the adverse effects of ethambutol?
optic neuritis- visual acuity and color differentiation are affected
What kind of drug is moxifloxacin?
What is it approved to treat?
What is the mechanism of action?
It is a fluoroquinolone that inhibits topo II enzymes in bacteria.
It treats G+ and G-
Who is likely to get infected by MAC? What are the drugs given for treatment (and sometimes prophylaxis?)
People with HIV and CD4 below 50 are likely to get MAC.
They are treated with new macrolides like clarithromycin and azithromycin
Rifabutin, quinolones, and amikacin are helpful too.
What is the other name for leprosy?
What is the causative agent?
What is first line treatment? How long is it given?
What if the organism is resistant?
It is Hansen’s disease caused by M. leprae
1. Dapsone & rifampin
Given 4 year - life
Dapsone resistant–> give rifampin & clofazimine
