Anti-TB Pharm Flashcards
most active TB drugs
isoniazid
rifampin
benefit of adding pyrazinamide to the 9 month regimen of isoniazid + rifampin
allows duration of therapy to be reduced to 6 months without a drop in efficacy
benefit of adding ethambutol (or streptomycin) to 9 month regimen of isoniazid and rifampin
provides additional coverage in case TB strain is resistant to isoniazid or rifampin
MOA of isoniazid
inhibits mycolic acid synthesis
resistance to isoniazid
- overexpression of inhA
- mutation or deletion in katG gene
- promotor mutations resulting in overexpression of ahpC
- mutations in kasA
adverse effects isoniazid
- isoniazid-induced hepatitis
- peripheral neuropathy
MOA of rifampin
- inhibits RNA synthesis by binding to the beta subunit of bacterial DNA-dependent RNA polymerase
- bactericidal
- good at penetration and can kill intracellular organisms and those sequestered in abscesses and lung cavities
how does rifampin increase metabolism of other drugs
it induces CYP450 isoforms
resistance to rifampin
- point mutations in rpoB (gene for beta subunit of RNA polymerase)
- cross resistance to other rifampin derivatives
why must rifampin be administered with another anti-TB med
to prevent emergence of drug resistance
adverse effects rifampin
- harmless orange color to urine, sweat, tears
- occasionally: rashes, thrombocytopenia, nephritis
MOA of ethambutol
inhibition of mycobacterial arabinosyl transferases
resistance to ethambutol
mutation resulting in overexpression of emb gene products or within the embB structural gene (overwhelms ethambutol)
adverse effects ethambutol
retrobulbar nephritis
- loss of visual acuity and red-green color blindness
MOA of pyrazinamide
converted to pyrazinoic acid by mycobacterial pyrazinamidase which then disrupts the mycobacterial cell wall metabolism and transport functions
resistance to pyrazinamide
- impaired uptake of pyrazinamide
- mutations in pncA that impair conversion of pyrazinamide to its active form
adverse effects pyrazinamide
- hepatotoxicity, nausea, vomiting, drug fever, photosensitivity, hyperuricemia
MOA streptomycin
aminoglycoside antibiotic (blocks protein synthesis)
adverse effects streptomycin
- ototoxic and nephrotoxic
- vertigo and hearing loss
MOA ethionamide
blocks synthesis of mycolic acids similarly to isoniazid
resistance ethionamide
(same as isoniazid)
- overexpression of inhA
- mutation or deletion in katG gene
- promotor mutations resulting in overexpression of ahpC
- mutations in kasA
adverse effects ethionamide
gastric irritation and neurologic sx
MOA capreomycin
peptide protein synthesis inhibitor
adverse effects capreomycin
nephrotoxic and ototoxic
- tinnitus, deafness, vestibular disturbances
MOA cycloserine
structural analog of D-alanine and incorporates into peptidoglycan pentapeptide which inhibits cell wall synthesis
adverse effects cycloserine
peripheral neuropathy and CNS dysfunction (depression and psychoses)
- HA, tremors, convulsions
MOA aminosalicylic avid
folate synthesis inhibitor active exclusively against M. tuberculosis
adverse effects aminosalicylic acid
- GI (peptic ulceration, hemorrhage)
- hypersensitivity reactions
MOA kanamycin/amikacin
aminoglycoside antibiotics (inhibits protein synthesis)
when to use amikacin
tx for TB suspected to be caused by streptomycin-resistant or multi-drug resistant strains
adverse effects kanamycin/amikacin
ototoxic and nephrotoxic
- vertigo and hearing loss
MOA of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin
fluoroquinolone antibiotics (inhibit topoisomerase II and IV)
resistance to ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin
point mutations in DNA gyrase
adverse effects to ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin (fluoroquinolone drugs)
- GI: abd discomfort, nausea, vomiting, C. diff
- CNS: HA, dizziness
- achiles tendon rupture
- QT prolongation and torsades de poinets
MOA linezolid
oxazolidinone antibiotic (inhibits protein synthesis)
resistance to linezolid
point mutations at oxazolidinone binding site or methyltransferases altering oxazolidinone binding to the ribosome
adverse effects oxazolidinone drug class (linezolid)
- myelosuppression
- mitochondrial toxicity
- drug-drug interactions
MOA rifabutin
- bacterial RNA polymerase inhibitor
resistance to rifabutin
point mutations in rpoB (beta subunit for RNA polymerase)
adverse effects rifabutin
hepatotoxicity and rash
- also leukopenia, thombotypenia, optic neuritis
MOA rifapentine
bacterial RNA polymerase inhibitor
resistance to rifapentine
point mutations in rpoB (beta subunit for RNA polymerase)
adverse effects rifapentine
hepatotoxicity and rash
MOA bedaquiline
inhibits ATP synthase in mycobacteria
resistance bedaquiline
upregulation of multi-substrate efflux pump
adverse effects bedaquiline
- nausea, arthralgia, HA
- hepatotoxicity and cardiac toxicity
- QT prolongation
