Anti-Tuberculosis Flashcards
Is Mycobacterium Tuberculosis aerobic or anaerobic?
Aerobic, rod shaped, acid-fast bacilli
According to MOH guidelines, what tests must be done prior to TB tx initiation?
- Liver enzymes
- Visual acuity
According to MOH guidelines, what must be monitored at each visit?
- Weight, drug dosages adjusted accordingly
- Risk factors for drug-induced hepatitis
How long is the standard TB tx?
6 months
- 2 months intensive phase: daily RIPE
- 4 months continuation phase: daily/3x per week RI
*Restart therapy if non-compliance for 2 weeks
What are common adverse effects among all first line anti-TB drugs?
- Cutaneous reactions (pruritus, rash) - be alert for SJS, DRESS, TEN
RIP only:
2. GI symptoms: anorexia, nausea, abdominal discomfort
3. Hepatitis (*monitor infant for jaundice if breastfeeding)
Which of the 4 drugs in RIPE require dose adjustment in renal and hepatic impairment?
Renal impairment: PE
Hepatic impairment: RIP
Which drugs (RIPE) are batericidal?
Bactericidal: RIP
Bacteriostatic: E
Pyrazinamide is only indicated for ____ TB
Active
Which drugs (RIPE) have good CSF penetration?
*All are given oral
Good CSF penetration: IP
Poor CSF penetration: RE
Rifampicin is indicated for Tuberculosis caused by Mycobacterium Tuberculosis and _____ caused by __________
Leprosy caused by Mycobacterium leprae
Rifampicin inhibits gene transcription by blocking which enzyme?
DNA-dependent RNA polymerase
=> thus, prevent synthesis of mRNA and proteins, cause cell death
How is Rifampicin eliminated?
Hepatic metabolism, rapidly excreted in bile
Which of the 4 RIPE drugs can be used in pregnancy?
All are Cat C but weight risk and benefit
Mothers and neonates born to mothers under treatment with Rifampicin should be given _____ to prevent _________
Vitamin K
Prevent postpartum hemorrhage
*Because Rifampicin can cause thrombocytopenia
Rifampicin is a CYP450 ______, while Isoniazid is a CYP450 ______
Rifampicin: CYP450 inducer
Isoniazid: CYP450 inhibitor
What are Rifampicin Adverse effects?
- GI
- Cutaneous
- Hepatitis
- Flu-like syndrome (fever, chills, malaise)
- Orange discoloration of body fluids (e.g., sweat, urine, tears)
- (RARE) respiratory syndrome - SOB
- (RARE) thrombocytopenia, hemolytic anemia, acute renal failure *if these occur, stop and never give again as they are severe immune mediated reactions
Which of the 4 RIPE can be used for prophylaxis?
Isoniazid
Isoniazid is a prodrug activated by ________ enzyme.
This causes production of ___________ that can inhibit formation of _______ and causes _________.
Catalase-peroxidase enzyme
Activation of isoniazid produces oxygen-derived free radicals
Inhibit formation of mycolic acid of the bacterial cell wall and causes DNA damage
Isoniazid resistance can be due to
1. Mutation of catalase peroxidase enzyme
2. Mutation of ______
Mutation of the regulatory genes involved in mycolic acid synthesis
Isoniazid undergoes metabolism in the liver through __________
Acetylation by N-acetyltransferase
*Inactive metabolites are excreted by kidneys
Explain why Isoniazid can cause hepatotoxicity
Two metabolic pathways of isoniazid
- NAT2 pathway => acetylhydrazine
- Amidase pathway => hydrazine (hepatotoxic metabolite)
Pregnant women receiving Isoniazid should receive ________ because Isoniazid ___________________
Pyridoxine (Vit B6) supplementation 10mg daily
Isoniazid interferes competitively with pyridoxine metabolism
Isoniazid metabolites can also react with pyridoxine to deactivate it
What is the role of pyridoxine?
Pyridoxine metabolised in the liver to active Vit B6, pyridoxal phosphate
Pyridoxal phosphate is involved in metabolic processes + CNS function
Hence, Vit B6 deficiency causes risk of peripheral neuropathy
Explain the food-drug and drug-drug interactions of Isoniazid
Food-drug:
- Carbohydrates decrease absorption
- Avoid tyramine and histamine rich food as Isoniazid as MAO and histaminase inhibitory activity => flushing headache, serotonin syndrome
DDI:
- Antacids (incr pH) decrease absorption (*E as well)
- Isoniazid is a CYP450 inhibitor
Isoniazid has similar structure to ______, but no cross-resistance of Mycobacterium Tuberculosis
Pyrazinamide
Pyrazinamide is most effective in eliminating _______
Pyrazinamide also has potent sterilizing effect
Persisters (these persistent bacilli can cause relapse)
Pyrazinamide is a prodrug converted by pyrazinamidase to _______ which acts by ___________
Pyrazinoic acid, accumulation of pyrazinoic acid decreases intracellular pH to levels that inactivate critical pathways for survival
Pyrazinamide metabolites are eliminated by _______
When is dose adj required?
Kidneys
Therefore can accumulate in kidney impairment require dose adj
Also require dose adj in liver failure since it is a hepatotoxic drug (usually avoid in these pt)
Which of the 4 drugs RIPE cause photosensitivity?
Pyrazinamide
Which of the 4 RIPE drugs cause hyperuricemia and gout-like symptoms (arthralgia)?
Pyrazinamide and Ethambutol
P: inhibit tubular secretion of uric acid
E: reduce renal excretion of uric acid
Ethambutol inhibits the arabinosyltransferase enzyme encoded by the embB gene.
This enzyme is involved in ________
The polymerization of arabinose to arabinogalactan, a principal polysaccharide on the mycobacterial cell wall
Therefore Ethambutol interferes with this, affecting the intergrity of mycobacterial cell wall, causing entry of lipophilic antibiotics
How is ethambutol eliminated?
25% metabolized in liver
24% excreted unchanged in feces
50% excreted unchanged in urine
There is higher risk of visual toxicity caused by Ethambutol in patients who:
- have kidney failure
- elderly
- prolonged treatment >2months
- taking higher dose of the drug
Can Ethambutol be used in breastfeeding?
Yes, compatible
(RIP => must monitor for baby jaundice)
Ethambutol serum conc. may be reduced by concomitant _____
Antacids - increase in pH
Which drug may be used to replace Ethambutol as 1st line anti-TB?
Streptomycin (IM) - aminoglycoside
High index of suspicion of drug resistant TB in patients who:
- Previously treated for TB
- Failed TB treatment
- Known contacts of pt with drug resistant TB
- Visited country with high prevalence of drug resistant TB
What drugs are second line for MDR-TB?
Respiratory quinolones (Levo and Moxifloxacin)
How is cure for TB demonstrated?
Negative sputum spear or culture in the last month of treatment (6th month) and on at least one previous occasion (usually in the 5th month)
*Tx failure:
- Positive sputum at or after 5 months
- Nonconversion of sputum cultures after 2 months (means likely risk of relapse)
**Recall usually after 2 months or RIPE majority should have been eliminated
