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32 Cards in this Set

  • Front
  • Back
Isoniazid Mechanism
- one of the best drugs for TB
– bacteriocidal
– inhibits synthesis of mycolic acids, which are in the mycobacterial cell walls
– it penetrates into phagocytic cells, so good for IC and EC
Isoniazid Pharmacokinetics
- given orally, well absorbed in GI though antacids can interfere
– well distributed, even to CNS
– mainly metabolized by acetylation in the liver via NATINH
– rate genetically controlled (asians are faster than whites)
– some is via kidney, unchanged
– T½ is 2 to 4 hrs, in rapid inactivators is 0.5 to 1.5 hrs
Isoniazid Toxicity
- usually safe and well-tolerated but
1) GI Sx
2) Neurotoxicity, usually w/ high blood levels – may get peripheral neuritis if pyridoxine deficiency
3) Hepatotoxicity, esp w/ rapid acetylators
4) Can reduce the metabolism of antiseizure phenytoin, ↑ blood level
Isoniazid Resistance
1) overproduction of the inhA gene product -> low level resistance to INH and cross-resistance to ethionamide
2) mutation or deletion of the katG gene, which encodes mycobacterial catalase -> high level resistance to INH and no cross-resistance to ethionamide
Rifampin Mechanism
bactericidal inhibitor of microbial, but not human, DNA-dependent RNA polymerase
Rifampin Pharmacokinetics
- well absorbed fromGI
– T½ 3 hours
– widely distributed, even to CNS
- Some active drug excreted in urine, but most deacetylated in liver and eliminated in the bile
Rifampin Toxicity
– usually safe and well-tolerated but
1) Hypersensitivity rxn’s
2) GI Sx
3) Hepatotoxicity
4) Autoimmune (thrombocytopenia, renal failure)
5) liver P450 induction (↑’s digitalis, BCPs, cyclosporine)
Rifampin resistance
Due to alterations of the RNA polymerase that prevent binding of rifampin
Ethambutol Mechanism
- active only against dividing cells
– inhibits synthesis of arabinogalactan, part of cell walls
Ethambutol Pharmacokinetics
– given orally, well absorbed
– largely excreted unchanged via kidney
– T½ 4 hours
– 10% converted to inactivate metabolites excreted in the urine
– 20% excreted in the feces
Ethambutol Toxicity
– usually safe and well-tolerated but
1) Retrobulbar neuritis (blurred vision, green color blindness, central scotoma) in high doses w/ renal failure
2) Peripheral neuritis (rare)
3) Nephrotoxicity (rare)
Pyrazinamide Mechanism
- unknown
– an analog of nicotinamide, so probably a cofactor in mycobacterial metabolism
Pyrazinamide Pharmacokinetics
– given orally, well absorbed
- largely excreted via GF in kidney
– T½ 4 hours
– 10% converted to inactivate metabolites excreted in the urine
Pyrazinamide Toxicity
- usually safe and well-tolerated but
1) Hepatotoxicity in 1-5%
2) Gout-like symptoms due to interference with urate excretion
3) Nausea, vomiting, drug fever
Combination Chemotherapy of Tuberculosis
- most widely used regimen is isoniazid, rifampin, and pyrazinamide for 2 months and then isoniazid and rifampin for 4 months
– isoniazid, rifampin, ethambutol, and pyrazinamide for 6 months also works
- Fluoroquinolones Ab’s for MDR TB
MAC treatment
- Isoniazid and pyrazinamide are ineffective
– clarithromycin or azithromycin + ethambutol for life
– prophylaxis with rifabutin for life should be seriously considered
Amphotericin B Mechanism
- a polyene antibiotic
– it binds cell membrates forming a complex with sterols, which leads to the formation of a transmembrane channel or pore
– this causes osmotic instability and cell death
– toxic to mamalian cells, so manufactured as a complex with the detergent deoxycholate
Amphotericin B Pharmokinetics
- slow IV infusion
– binds extensively to blood constituents and tissues
– penetrates CNS so cant use for crytococcal meningitis (use fluconazole)
– slowly excreted in the urine (5%/day) and unchanged
Amphotericin B Toxicity
- one of the most toxic agents
1) profoundly nephrotoxic
2) also cardiotoxic and neurotoxic
3) headache, fever, vomiting, chills, and hypotension
– a new liposomal formulation has reduced toxicity
Amphotericin B Theraputic uses
– for serious systemic fungal infections by Candida, Cryptococcus, Histoplasma, and other fungal pathogens
– usally only needed for pts already taking lots of drugs, so careful w/ interactions w/ other nephrotoxic agents (aminoglycosides, cisplatin, cyclosporine)
– often used w/ flucytosin
– little resistance
Flucytosine Mechansim
Fungal cells convert 5-FC to something that inhibits thymidylate synthetase for DNA synthesis
Flucytosine Pharmacokinetics
– given orally and distributes widely in tissues, even CNS
– excreted via kidney
Flucytosine Toxicity
– much less toxic than AMB, prolonged use can cause bone marrow depression, hair loss, GI toxicity, and hepatotoxicity
– careful in pts w/ bone marrow depletion
Flucytosine Therapeutic use
- generally used w/ AMB
– fungus often rapidly develop resistance as a single agent
– the combo is synergistic, esp in cryptococcal meningitis
Imidazoles and Triazoles Mechanism
– they inhibit ergosterol synthesis by blocking the P450-dependent C-14 a-demethylase, which is necessary for conversion of lanosterol to ergosterol
– actions on P450-dependent enzymes is toxic b/c they do synthesis of adrenal and gonadal steroids
– we can use these b/c they have a ↑ affinity for fungus
Imidazoles and Triazoles Pharmacokinetics
– give orally, but F can be given IV too
– for I and K, food enhances and antacids diminish uptake
– extensively protein bound, accumulate in tissues, but dont penetrate CSF or urine
– metaboized in liver and excreted via bile
– F is minimally bound, penetrates CSF, and is excreted via urine
Imidazoles and Triazoles Toxicity
1) GI Sx and mild hepatotoxicity are common
2) In about 1 in 15,000 have severe hepatotoxicity
3) exfoliative skin rashes
4) ↓ testosterone levels, altered libido, and gynecomastia (less so in triazoles)
Imidazoles and Triazoles Interactions
– isoniazid, phenytoin, and rifampin, ↑ metabolism of azoles by inducing P450 and ↓ blood levels
– azoles compete for P450 w/ cyclosporine, digoxin, warfarin, and some B-blockers, so ↑ levels
Imidazoles and Triazoles Therapeutic use
– good for systemic, MM, and topical dx
– best for endemic mycoses like blastomycosis, histoplasmosis, or coccidioidomysosis in normal patients
– F is an alternative to AMB + flucytosine in cryptococcal and coccidioidal meningitis
– azoles have a slower onset, so AMB for severe infections, esp. neutropenic patients
– azoles good for prophylaxis or maintenance since less toxic and oral