Antimycobacterial drugs Flashcards
(33 cards)
Description of Isoniazid
Most important first-line agent for TX of tuberculosis; structurally related to pyridoxine
Can be used prophylactically as single agent for skin test converters or if contacting patients with active disease
Mechanism of Action of Isoniazid
Enters bacilli as a prodrug, activated to an isonicotinoyl radical by KatG, a mycobacterial heme-containing catalase-peroxidase enzyme; the isonicotinoyl radical reacts with NAD and NADP to produce a dozen adducts
An isonicotinoyl-NAD adduct inhibits enoyl acyl carrier protein reductase (InhA) and β-ketoacyl acyl carrier protein synthase (KasA), decreasing the synthesis of mycolic acid and leading to cell death
An isonicotinoyl-NADP adduct inhibits DHFR to reduce nucleic acid synthesis
Pharmacokinetics of Isoniazid
Usually administered PO; food decreases absorption so best taken on an empty stomach; widely distributed into all body fluids and tissues
Dosing is fairly long-term, e.g., 300 mg QD for 6-12 months
Metabolized mainly by acetylation (genetically variable); ca. 75% of drug and metabolites are excreted in the urine (rapid vs. slow acetylators need different doses).
Adverse reactions and counterindications of isoniazid
Elevated LFTs (10-20%), hepatitis (1%, DC if symptoms of hepatitis occur)
Peripheral neuropathy via pyridoxine depletion (2%; occurs more frequently at high doses and in malnourished patients, diabetics, and alcoholics): twitching, paresthesias
Hepatitis; monitor LFTs; avoid alcohol and acetaminophen
Administer vitamin B6 to avoid neuropathy
Description of Rifampin
One of a group of rifamycin-class antibiotics
First-line anti-TB agent; available alone or in combination with INH
Broad-spectrum antibiotic, active in most gram-positive and many gram-negative bacteria and mycobacteria; a DOC for leprosy, DOC for prophylaxis of H. influenzae meningitis and meningococcal disease
Mechanism of Action of rifampin
Bactericidal; binds to bacterial b subunit of RNA polymerase thereby inhibiting RNA synthesis with consequent decreased protein synthesis
Resistance arises from point mutations in rpoB gene coding for b subunit of RNA polymeras
Pharmacokinetics of rifampin
Administered PO and IV; best taken on an empty stomach
Usual dose for TB is 600 mg PO QD for 6-9 months; for meningitis and meningococcal prophylaxis, dosing is for 2-4 days; in leprosy TX, dosing is 600 mg Q month
Rifampin and its metabolite are primarily excreted (60%) in feces via biliary elimination; and up to 30% is excreted in urine
Adverse reactions and counterindications of rifampin
GI: NVD, cramps, hepatitis
Strong inducer of most hepatic CYPs → many drug interactions, ↓ bioavailability over time
Flu-like hypersensitivity reaction (50%): fever, chills, headache, fatigue
Harmless reddish-orange or reddish-brown discoloration of bodily fluids
Hepatic disease: hepatitis, jaundice; alcoholism; monitor LFTs (No frank hepatoxicity like isoniazid)
In HIV+ PX receiving protease inhibitors or nonnucleoside reverse transcriptase inhibitors, replace rifampin with rifabutin
Description of Ethambutol
First-line anti-TB agent, used in combination with INH, pyrazinamide, rifampin
Mechanism of action of ethambutol
Complex mechanism of action: blocks arabinosyl transferase III involved in cell wall biosynthesis; appears to inhibit RNA synthesis, resulting in impaired protein synthesis; may interfere with mycolic acid biosynthesis
Ethambutol is only effective against bacilli that are actively dividing (bacteriostatic)
Pharmacokinetics of ethambutol
Administered PO, usually 15 mg/kg QD for 6-9 months
Well-absorbed, widely distributed
Metabolism via sequential oxidation of alcohols resulting in dicarboxylic acid metabolite
Parent drug and its metabolites are excreted primarily in the urine (50-65%), with 20-25% excreted unchanged in the feces
Adverse reactions and precautions against ethambutol
The most common adverse effect is a dose-dependent (but rare at standard doses), usually reversible, optic neuritis resulting in decreased visual acuity and red-green color blindness
Optic neuritis
Monitor visual function; avoid ethambutol in young children in whom visual assessment is not reliable
Adjust dosage with renal impairment: if CrCL 10-50 mL/min: extend dosing interval to every 24-36 hr; if CrCL
Description of pyrazinamide
First-line anti-TB agent, used in combination with INH, ethambutol, rifampin
Mechanism of action of pyrazinamide
Requires metabolic activation (hydrolysis) to pyrazinoic acid by M. tuberculosis pyrazinamidase enzyme
Exact MOA unknown but three proposed mechanisms are 1) inhibition of eukaryotic-like fatty acid synthetase I of M. tuberculosis, 2) reduction of intracellular pH 3) disruption of membrane transport
Bacteriostatic at low concentrations and bactericidal at high concentrations
Pharmacokinetics of ethambutol
Administered PO, 15-30 mg/kg QD, usually for 2 months if bacilli are not resistant
Well-absorbed, widely distributed, peak plasma concentration achieved within 2 hours
Pyrazinamide and its metabolites (liver) are excreted in the urine (70%), mainly via glomerular filtration
Adverse reactions and precautions against pyrazinamide
Hepatotoxicity is the most serious adverse reaction of pyrazinamide, manifesting as hepatitis, jaundice, elevated LFTs, but hepatotoxicity is uncommon (1-5%) with current regimens
Hyperuricemia; interferes with uric acid excretion
Skin: rash, photosensitivity
Arthralgia (40-70%)
Hepatic disease: hepatitis, jaundice, alcoholism; monitor LFTs
Interferes with urine ketone determination (Ketostix®, etc.)
Gout
Second line therapies for TB include:
Ethionamide (blocks mycolic acid synthesis like isoniazid)
para-Aminosalycilic acid (mimics PABA, inhibits dihydropteroate synthase to decr purine synthesis)
Cycloserine (d-ala analog to inhibit alanine racemase to decr cell wall synthesis)
Capreomycin (cyclic peptide protein synthesis inhibitor)
Aminoglycoside antibiotics (bind 30S ribosome subunits)
Fluoroquinolone antibiotics (inhibits topoisomerases)
Description of aminoglycosides
Primary agents: amikacin, gentamicin, kanamycin, neomycin, tobramycin, streptomycin; all are amino sugars
Active mainly vs. aerobic, gram-negative bacilli including Escherichia coli, Klebsiella sp., Enterobacter sp., Proteus sp., Pseudomonas sp
Mechanism of action of aminoglycosides
Bactericidal: inhibit protein synthesis; bind to 30S ribosomal subunit
Resistance via inactivating enzymes, increased expression of efflux pumps, mutations in 30S subunit components 16S mRNA and ribosomal protein S12
Pharmacokinetics of aminoglycosides
Polar compounds; not well-absorbed orally, so usually given parenterally or used topically
Major elimination route is via glomerular filtration; excretion is directly proportional to creatinine clearance and adjustments must be made in patients with renal insufficiency
Plasma drug levels often monitored to make dosing adjustments
Toxicity of aminoglycosides
Ototoxicity, nephrotoxicity, NMJ blockade (curare-like), allergic skin rxn or contact dermatitis, pregnancy category D.
Description of Moxifloxacin
Broad spectrum fluoroquinolone antibacterial agent for oral and intravenous administration
Used as adjunctive second-line tuberculosis therapy in relapse, treatment failure, or M. tuberculosis resistant to isoniazid, rifampin, or when first-line drugs cannot be tolerated
Mechanism of action of moxifloxacin
Interferes with bacterial DNA function by stabilizing topoisomerase II- and topoisomerase IV-DNA cleavage complexes, inhibiting DNA duplication, transcription, repair, and recombination
Resistance (1.8 x 10–9 to
Pharmacokinetics of moxifloxacin
Formulated as 400 mg tablets and in NS for IV infusion, given as 400 mg QD for 12-18 months if rifampin-resistant strain is involved; 18-24 months if isoniazid- and rifampin-resistant strains are involved, 24 months if strain is resistant to isoniazid, rifampin, ethambutol, and/or pyrazinamide
F = 0.9, widely distributed; peak plasma concentration achieved within 3-4 hr, t1/2 ca. 12 hr
Metabolized (ca. 50%) via glucuronide (urine) and sulfate (feces) conjugation, no CYP involvement; remainder is excreted as unchanged drug
