Antifungal Chemotherapy Flashcards Preview

Infection & Immunity Block > Antifungal Chemotherapy > Flashcards

Flashcards in Antifungal Chemotherapy Deck (18):

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

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 >> 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)


Terbinafine (LAMISIL)

Classified chemically as an allylamine
Inhibits fungal squalene epoxidase (fungicidal due to accumulation of toxic amounts of squalene)
Used orally or topically in the treatment of dermatophytoses (ringworm & especially useful for onychomycosis)
More effective than itraconazole for onychomycosis (given systemically)


Terbinafine Adverse Effects

Adverse effects include a low incidence of G.I. distress, headache, & rash; rarely, hepatotoxicity may occur (avoid in patients with hepatic failure);

Cytochrome P450 drug interactions (e.g. it may inhibit metabolism of tricyclic antidepressants & rifampin increases its metabolism); 2D6 inhibitor – inhibits metabolism of tricyclic antidepressants and rifampin

Contraindicated in pregnancy


Echinocandins, Amphotericin B, Griseofulvin, Azoles, and Terbinafine Mechanisms of Action

Echinocandins: inhibit beta glucan synthase (disrupt cell wall)

Amphotericin B: polyene that forms artificial pores by binding to ergosterol

Azoles: blocks lanosterol to ergosterol (inhibits ergosterol synthesis)

Griseofulvin: disrupts microtubules and blocks mitosis

Terbinafine: blocks squalene to lanosterol (inhibits lanosterol synthesis)