Flashcards in 03 Pharmacology/PK/Therapeutic Use of Antifungal Agents Cupo Deck (122)
What are the general characteristics of Amphotericin B?
Broad spectrum, fungicidal, rare resistance. Polyene antibiotic. Binds ergosterol in fungal cell membrane. Creates transmembrane channel and electrolyte leakage
What is Amphotericin B NOT active against?
Candida lusitaniae, Aspergillus terreus, Scedosporium spp.
What is the PK of Amphotericin B (Fungizone) like?
Low BA, IV only. 24-48 hr initial t1/2 w/ terminal t1/2 15 days. High protein binding (90%)
What is the distribution of Amphotericin B (Fungizone) like?
High in kidney, liver, spleen. Very good in lung, heart, skeletal muscle. POOR: Brain, Bone, CSF, Eye
What is the dosage of Amphotericin B (deoxycholate) like?
Dose range: 0.25-1mg/kg/day. Treatment duration: total dose ~1-2 grams. Dosages are not altered with renal or hepatic dysfunction
What is the Tolerability to Amphotericin B like?
Infusion-related: fever, chills, N/V, HA, myalgias, arthralgias, rigors. Anemia, rare thrombocytopenia. Phlebitis. Maculopapular rash. Hepatotoxicity (rare)
What are the current recommendations for testing Amphotericin B tolerability?
Start with ~30% target dose on day 1, infuse slowly for first 15 min, monitor for ADRs. Rapidly escalate to full dose w/in 24 hrs
What is renal insufficiency like for Amphotericin B?
Decrease in renal blood flow leads to decreased GFR, increased BUN. Distal tubular ischemia - wasting of potassium, sodium, and magnesium. Enhanced in patients who are volume depleted or who are on concomitant nephrotoxic agents
How can renal insufficiency be reduced with Amphotericin B?
Sodium loading - administer 500-1000 ml NS prior to administration of AMB
What are the drug interactions associated with AMB?
Avoid concomitant use with nephrotoxic agents (aminoglycosides, foscarnet, cyclosporine, tacrolimus)
What is the dosing of Abelcet like?
5mg/kg/day (can push it to 10mg/kg/day at times)
What is the dosing of Amphotec like?
What is the dosing of Ambisome like?
3-5mg/kg/day (can push it to 10mg/kg/day, mainly 3mg/kg/day used)
What is a general summary for the Non-Conventional Amphotericin B formulations?
All have different phospholipid:molar ratios. Cleared by RES; highest distribution to liver and spleen w/ less to kidneys. All have propensity for infusion-related effects ABCD (Amphotec) >> ABLC (Abelcet) >> L-AMB (AmBisome)
What are the subclasses of Azole Antifungals?
Imidazole. Triazoles. 2nd gen Triazole
What drug falls under Imidazole (type of Azole)?
What drugs fall under Triazoles (type of Azole)?
Itraconazole (Sporanox). Fluconazole (Diflucan)
What drug falls under 2nd Generation Triazole (type of Azole)?
What is the MOA of Azoles?
Bind to CYP P450 enzyme lanosterol 14-a demethylase. Inhibits formation of ergosterol. Sterol biosynthesis is halted
What are the pharmacodynamics of Azoles?
Concentration-dependent fungistatic agents (dosage escalation may be necessary when faced with more resistant fungal species). Goal of dosing is to maintain AUC: MIC > 50 (i.e. maintain concentrations 1-2x MIC for the entire dosing interval)
What is the spectrum of coverage from Ketoconazole?
Candida spp., B. dermatidis, C. immitis, H. capsulatum
What is the PK of Ketoconazole?
BA 75%. T1/2 8 hrs. Highly protein bound 99%. Extensive metabolism (O-dealkylation, oxidation). Biliary and renal elimination
What is the tolerability of Ketoconazole like?
Gastrointestinal (N/V, dose-dependent). Hepatotoxicity (<10%), increased LFTs, hepatitis. Gynecomastia, oligosperima, decreased libido. Adrenal insufficiency
What is a unique ADR associated with Ketoconazole and why does it occur?
Gynecomastia, Oligospermia, decreased libido, and adrenal insufficiency all occur d/t Ketoconazole inhibiting testosterone and cortisol synthesis
What are the drug interactions with Ketoconazole?
CYP 3A4 mediated (potent inhibitor). Increases cyclosporine, tacrolimus, sirolimus, WARFARIN levels. Decreased ketoconazole levels when taken with Rifampin, phenytoin. Altered absorption w/ increased gastric pH (antacids, PPIs, H2-antagonists, sucralfate)
What is the dosing of Ketoconazole like?
Serious infections: 800mg PO QD. Other: 200-400mg PO QD
What is the spectrum of activity from Fluconazole?
Candida albicans, Cryptococcus neoformans, Candida parapsilosis
What does Fluconazole NOT very active against?
C. krusei, +/- C. glabrata (S-DD), Aspergillus spp.
What is the PK of Fluconazole like?
Available as both IV and PO. BA > 90%. T1/2 ~24h. Low protein binding. Low metabolism. High elimination unchanged through kidney