Pharmacology - Anti TB Flashcards
What are the agents used for tuberculosis?
RIPE
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol
+
Streptomycin
What is the mechanism of action of rifampicin?
Bactericidal drug that kills growing, metabolically active bacilli, and bacilli in the stationary phase
Blocks DNA-dependent RNA polymerase to prevent mRNA and protein synthesis, to result in cell death
How is rifampicin administered?
PO
What is rifampicin indicated for?
Treatment of active TB in combination w other anti-mycobacterials (RIPE + Streptomycin)
Treatment of latent TB
Treatment of leprosy (Mycobacterium leprae)
Is rifampicin able to penetrate the CSF?
Poor (10-20%)
Increases w meningitis
How is rifampicin excreted?
Hepatic metabolism, rapidly eliminated in bile (~65%)
Can rifampicin be used in renal impairment?
Yes. No dose adjustment required.
Can rifampicin be used in hepatic impairment?
Only if benefit > risk, monitor liver function closely
What are the adverse reactions associated with rifampicin?
- Cutaneous syndrome: flushing and/or pruitis, with or without rash, often with redness and watering of eyes
- Flu-like syndrome w intermittent Tx: fever, chills, malaise, headache, bone pain
- Respiratory syndrome: shortness of breath, rarely shock
- Rare, severe immune-mediated reactions eg thromobocytopenic purpura, haemolytic anemia, actue renal failure (discontinue, do not use anymore)
- Hepatitis - still less hepatotoxic than isoniazid or pyrazinamide
What are the DDIs with rifampicin?
Rifampicin induces hepatic microsomal enzymes, dec serum conc of oral contraceptives, warfarin, corticosteroids, methadone, protease inhibitors, cyclosporine
What is a side effect to counsel on for rifampicin?
Bodily fluids will turn orange
- sweat
- urine
- tears (will stain cotact lenses)
How can rifampicin resistance occur?
Mutations in gene coding for RNA polymerase beta chain
Can rifampicin be used in pregnancy?
Possible, but need to give vitamin K as precaution against postpartum hemorrhage (due to association w thrombocytopenia)
Can rifampicin be given to a breastfeeding mother?
Can use if benefit > risk, but need to monitor the infant for jaundice
What is the mechanism of action of isoniazid?
Prodrug activated by catalase peroxidase enzyme of M. tuberculosis - produces oxygen-derived free radicals that inhibit formation of mycolic acids of bacterial cell wall, cause DNA damage, so that bacteria subsequently die
How is isoniazid administered?
PO
(well absorbed on empty stomach, carbohydrates will decrease absorption)
What is isoniazid indicated for?
Treatment of active TB in combination with other antimycobacterials
Treatment of latent TB
Prophylaxis
Can isoniazid penetrate the CSF?
Yes, excellent
How is isonizaid excreted?
Hepatically metabolised by N-acetyltransferase
(Acetylation rate depends on genetics)
Renally excreted mainly inactive metabolites
Can isoniazid be used in hepatic dysfunction?
Possible but monitor v closely
Can isoniazid be used in renal impairment?
Yes, no dose adjustment required
What are the adverse reactions associated with isoniazid?
- Peripheral neuropathy: Pyridoxine should be given to prevent B6 deficiency for those at risk of neuropathy (10mg OD)
- isoniazid interferes competitively w pyridoxine metabolism by inhibiting formation of active form of vitamin B6, frequently resulting in peripheral neuropathy - Hepatitis: risk incs w age, female gender, alcohol use, concomitant use of other hepatotoxic agents. Reversible if stop early
- Rarely toxic psychosis, convulsions, haematologic reactions, lupus-like syndrome, hypersensitivity reactions
What are the DDIs with isoniazid?
Inhbits CYP450 - inc phenytoin and carbamazepine serum concentrations
How should isoniazid be taken?
Take on empty stomach
Should not be taken concomitantly w foods rich in tyramine and histamine eg certain types of fish (tuna), cheese and red wine - will result in side effects like flushing and headache by inhbiting monoamine oxidase and histamine
Separate from antacids by at least 2h (inc gastric pH delays absorption of isoniazid)
How can isoniazid resistance occur?
Common mechanisms of resistance include mutations to catalase-peroxidase enzyme and mutations of regulatory genes involved in mycolic acid synthesis
Can isoniazid be taken during pregnancy?
Yes but must take with pyridoxine
Can isoniazid be given to a breastfeeding mother?
Can but monitor infant for jaundice.
Both mother and baby should be taking pyridoxine at the same time.
What is the mechanism of action of pyrazinamide?
Pyrazinamide is a prodrug activated by microbial pyrazinamidases to pyrazinoic acid
Pyrazinamide enters bacillus passively, converted to acid, reaches high conc in bacterial cytoplasm to dec intracellular pH to levels that inactivate critical pathways necessary for survival of bacteria
How is pyrazinamide administered?
PO
What are the indications for pyrazinamide?
Tx of active TB in combination with other anti-mycobacterials
How is pyrazinamide excreted?
Metabolites are renally eliminated - dose reducton requred for kidney failure pts due to accumulation
What are the adverse reactions associated with pyrazinamide?
- GI Sx: N/V
- Photosensitivity
- Hepatotoxicity - discontinue or even replace if it is due to pyrazinamide. Withheld or used cautiously in elderly, people who consume alcohol and underlying hepatic disease (monitor closely if must use)
- Hyperuricemia and arthralgia: pyrazinoic acid inhibits renal tubular secretion of uric acid, results in gout like Sx
- Exanthema (widespread rashes) and pruitus
What are the DDIs with pyrazinamide?
probenecid, rifampicin, isoniazid can potentiate toxic effects of pyrazinamide
Can pyrazinamide be used in pregnancy?
Deemed safe by WHO, but is pregnancy category C
Can pyrazinamide be used in breastfeeding?
Can, but monitor the infant for jaundice
What is the mechanism of action of ethambutol?
Inhibits arabinosyltransferase enzyme encoded by embB gene and interferes w polymerisation of arabinose into arabinogalactan (mycobacterial cell wall polysaccharide) - cell wall intergrity compromised, lipophilic antibiotics can better enter eg rifampicin, levofloxacin
How is ethambutol administered?
PO
What is ethambutol indicated for?
Tx of primary TB in combination w other anti-mycobacterials
Can ethambutol penetrate the CSF?
Can achieve therapeutic concentrations in cases of meningitis
Does not cross healthy meninges
How is ethambutol excreted?
25% metabolised by liver
25% excreted in faeces unchanged
50% excreted unchanged in urine
Can ethambutol be used in liver failure?
Yes, no dose adjustment required
Can ethambutol be used for kidney failure
Yes, dose reduction required
What are the adverse reactions associated with ethambutol?
- Visual toxicity: dec visual acuity, red-green color blindness, blurring, central scotoma - greater risk in kidney failure, elderly and Tx>2/12; toxicity is dose-dependent, recovery depends on withdrawal being early enough
- Hyperuricemia/gout: from reduced uric acid excretion by kidney
Any administration instructions for ethambutol?
Separate from antacids by at least 2h (inc gastric pH decs max serum conc)
How does ethambutol resistance arise?
Mutations in embB gene
Can ethambutol be administered in children?
Administer with caution (and avoid where possible) because their visual acuity is difficult to evaluate
Can ethambutol be used in pregnancy?
Deemed safe by WHO, but is cateogry C
Can ethambutol be given to breastfeeding mothers?
Yes
What is the mechanism of action of streptomycin?
Streptomycin is an aminoglycoside.
Blocks the formation of the ribosomal initiation complex, and causes misreading of codons in translation to inhibit translocation
Can streptomycin penetrate the CSF?
Poor, increases w meningitis
How is streptomycin excreted?
Excreted unchanged in urine
Which of the 4 standard first line anti-tuberculosis drugs are safe for use in patients with kidney failure?
Rifampicin and Isoniazid
Which enzyme is involved in the metabolism of isoniazid, and presents with wide variation in activity in the community due to genetic polymorphisms?
N-acetyl transferase (rapid acetylator vs slow acetylator phenotypes are found in the population due to the genetic polymorphism
Which of the first line anti-tuberculosis drugs is highly effective against the persistent bacilli
Pyrazinamide
Which of the 4 standard first line anti-tuberculosis drugs must be avoided or used with caution if the patient suffers from liver disease?
(RIP)
Rifampicin
Isoniazid
Pyrazinamide
Which of the 4 standard first line anti-tuberculosis drugs (R.I.P.E) is/are highly associated with causing gout like symptoms?
- Pyrazinamide (More common with pyrazinamide then ethambutol)
- Ethambutol
Which of the 4 standard first line anti-tuberculosis drugs must be avoided or used with caution if the patient suffers from kidney impairment?
- Pyrazinamide
- Ethambutol
Which of the 4 standard first line anti-tuberculosis drugs (R.I.P.E) is/are highly associated with causing visual toxicity?
Ethambutol
In which groups of individuals would physicians have a high index of suspicion for multi drug-resistant tuberculosis?
Individuals
- who were previously treated for TB,
- who have failed TB treatment,
- who are known contacts of patients with MDR-TB, or
- who come from countries with high prevalence of drug resistant tuberculosis
