Antifungal Chemotherapy Flashcards
Antifungal Agents: Polyene, Azole, and Others
Polyene antifungal agents: Amphotericin B
Azole antifungal agents: Itraconazole, fluconazole, etc.
Other antifungal agents (non-azole): Terbinafine
Amphotericin B
Polyene antifungal agent
Lipid loving portion and water loving portion = amphiteric
Drug of choice for most rapidly progressive, life-threatening (severe) systemic fungal infections (deep mycoses) such as severe pneumonia, fungal meningitis, or fungal sepsis
Amphotericin B often used as initial induction treatment followed by a switch to a less toxic oral agent
Amphotericin B: Examples
Examples: Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, & Histoplasma capsulatum
Amphotericin B Mechanism of Action
Mechanism of action:
Binds to ergosterol in fungal cell membrane
Alters cell permeability by forming pores in the cell membrane
Pores allow leakage of important intracellular ions & macromolecules resulting in cell death (fungicidal)
Amphotericin B Pharmacokinetics
Pharmacokinetics Poorly absorbed from GI tract (given IV) Mostly metabolized in liver Metabolites & some unchanged drug excreted in urine Only low concentrations achieved in CSF
Amphotericin B Adverse Effects
Anemia (reversible)
Infusion-related toxicity - fever, chills, muscle spasms, nausea, vomiting, headache & hypotension
CNS toxicity after injection directly into CSF (e.g., headache, seizures, impaired vision)
Amphotericin B Nephrotoxicity
Nephrotoxicity - occurs in 80% patients
Causes electrolyte disturbances (e.g., potassium & magnesium wasting) and decreased creatinine clearance
Two stages of nephrotoxicity:
Stage 1 is a reversible form where amphotericin B decreases glomerular & renal tubular blood flow by constriction of afferent arterioles (i.e. the pre-renal form);
Stage 2 is an irreversible form due to renal tubular injury (associated with high doses & prolonged treatment)
Lipid formulations (liposomal, etc.) of amphotericin B have been introduced to reduce nephrotoxicity; these preparations are less toxic but much more expensive
Azole Antifungals
Drugs include ketoconazole, itraconazole, fluconazole, voriconazole, & posaconazole (oral only)
Most are available for both oral & IV administration (ketoconazole now employed topically)
Imidazole: greater toxicity where X = C; Ketoconazole
Triazole: X= N, broader spectrum, lesser toxicity
Fluconazole, itraconazole, voriconazole
Azole Antifungals Mechanism of Action
Mechanism of action
Decrease synthesis of ergosterol by inhibiting a fungal cytochrome P450 enzyme (14-alpha-demethylase); exhibit greater affinity for fungal versus human cytochrome P450 enzymes
Ergosterol depletion disrupts fungal cell membrane structure and function (increases permeability & alters activity of various membrane-bound enzymes)
Inhibit growth of fungi (fungistatic)
Azole Antifungal Drug Pharmacokinetics
Ketoconazole, itraconazole, voriconazole & posaconazole undergo extensive hepatic metabolism; fluconazole undergoes mostly renal excretion
Fluconazole is best at penetrating into the CSF (voriconazole & posaconazole also cross); ketoconazole & itraconazole do not exhibit good CSF penetration
Cytochrome P450-related drug interactions are common with most azole antifungal drugs (less for fluconazole)
Azole Antifungal Clinical Use
Azole antifungals are very broad spectrum agents
Includes candida species, Cryptococcus neoformans, blastomycosis, coccidioidomycosis, histoplasmosis, dermatophytes & others
Used in preference to the more toxic amphotericin B if the fungal infection is not life-threatening (otherwise, amphotericin B is used for emergency treatment to ‘save a life & then a switch is made over to an oral agent when possible)
Azole Preferred Uses
Some azoles have preferred uses for specific fungal infections (examples):
Voriconazole for invasive aspergillosis
Fluconazole for coccidioidal meningitis
Fluconazole for cryptococcal meningitis (initial treatment & maintenance therapy)
Itraconazole for blastomycosis, histoplasmosis & sporotrichosis
Posaconazole for invasive mucormycosis
Azole Adverse Reactions
Local reactions to topical application include: stinging, pruritis, erythema, & local irritation
Adverse effects related to systemic administration:
Nausea, vomiting, & anorexia
Hepatotoxicity (rare, but can be serious)
Inhibition of steroid hormone synthesis (ketoconazole)
Visual disturbances (voriconazole) including blurring, altered color vision & photophobia
Negative inotropic effect & possible heart failure (itraconazole)
Teratogenic (azole antifungals should be avoided in pregnancy)
Azole and cP450
Cytochrome P450-related (CYP3A4, 2C19 & 2C9) drug interactions (less for fluconazole); for example, azoles decrease liver metabolism of warfarin, statins & other drugs; on the other hand, rifampin increases metabolism of azole antifungals
Propensity to exhibit inhibition of host cell Cytochrome P450 enzymes (leading to inhibition of endogenous steroid hormone synthesis & inhibition of hepatic microsomal enzyme metabolism, i.e. drug interactions):
Ketoconazole»_space; itraconazole, voriconazole & posaconazole > fluconazole
Other Azoles
Examples of other azoles commonly used topically for cutaneous fungal infections (too toxic for systemic use)
Miconazole (MICATIN)
Clotrimazole (LOTRIMIN)
