Antifungal Chemotherapy Flashcards Preview

Infection & Immunity Block > Antifungal Chemotherapy > Flashcards

Flashcards in Antifungal Chemotherapy Deck (18):
1

Antifungal Agents: Polyene, Azole, and Others

Polyene antifungal agents: Amphotericin B

Azole antifungal agents: Itraconazole, fluconazole, etc.

Other antifungal agents (non-azole): Terbinafine

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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

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Amphotericin B: Examples

Examples: Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, & Histoplasma capsulatum

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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)

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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

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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)

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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

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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

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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)

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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)

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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)

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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

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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)

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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

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Other Azoles

Examples of other azoles commonly used topically for cutaneous fungal infections (too toxic for systemic use)
Miconazole (MICATIN)
Clotrimazole (LOTRIMIN)

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Terbinafine (LAMISIL)

Non-Azole
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)

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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

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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)