Antifungals

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MOA of azoles

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Azole antifungal drugs inhibit the enzyme lanosterol 14 α-demethylase; the enzyme necessary to convert lanosterol to ergosterol. Depletion of ergosterol in fungal membrane disrupts the structure and many functions of fungal membrane leading to inhibition of fungal growth.
inhibit cytochrome P 450 → impaired synthesis of ergosterol → impaired fungal cell membrane formation.

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MOA of polyenes

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bind to ergosterol in fungal cell membrane and disrupt membrane integrity.
causes: the cell's contents including monovalent ions (K+, Na+, H+, and Cl-), small organic molecules leak and this is regarded one of the primary ways cell dies

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MOA of Flucytosine

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anti-metabolite, inhibits RNA and DNA synthesis

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MOA of Echinocandins

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Echinocandins may be used for systemic fungal infections in immunocompromised patients, they inhibit the synthesis of glucan in the cell wall via the enzyme 1,3-β glucan synthase

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MOA of Griseofulvin

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anti-mitotic

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Triazols

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Metabolized more slowly. Less effect on human sterol synthesis:
Itraconazole Fluconazole
Voriconazole Posaconazole

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Imidazoles

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Mechanism of Action:
Inhibition of cytochrome P 450 → Impaired synthesis of ergosterol → Impaired fungal cell membrane formation
Clotrimazole Miconazole Ketoconazole

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Selective activity of imidazoles

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Selective Activity due to difference in membrane sterols:
Mammalian: Cholesterol
Fungal: Ergosterol

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Ketoconazole (Nizoral)

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No longer used commonly due to adverse effects: Anorexia, nausea and vomiting, Pruritus, rash, dizziness, photophobia. Reduced plasma testosterone → gynecomastia, decreased libido and erectile dysfunction in males, menstrual irregularities in females
Inhibition of adrenal steroidogenesis, decreased cortisol . Hepatic toxicity and necrosis
Teratogenic
Drug Interactions:
Strong inhibitor of CYP3A4 and other enzymes → increased serum concentrations of many other drugs. Absorption reduced by drugs that decrease gastric acidity (antacids, PPIs, H2-receptor blockers)

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Fluconazole (Diflucan)

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Active against:
Most Candida species
Coccidioides and Cryptococcus spp
Histoplasma capsulatum (at higher doses)
Not active against:
C. krusei (intrinsically resistant). Many strains of C. glabrata (increasingly resistant). Most molds. Lowest affinity for mammalian P450 enzymes. Good water solubility and CSF penetration

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SE of fluconazole

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Headache, GI distress, facial edema, rash, pruritus
Stevens-Johnson syndrome, anaphylaxis, hepatic toxicity, leukopenia, hypokalemia, QT prolongation, torsades de pointes reported. Teratogenic

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Drug interactions with fluconazole

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Strong inhibitor of CYP2C9 and 2C19. Moderate inhibitor of CYP3A4. May increase serum concentrations of drugs metabolized by these enzymes. Combination with other drugs known to prolong the QT interval, especially those metabolized by CYP2C9, CYP2C19 or CYP3A4

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Itraconazole

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Spectrum of activity broader than fluconazole
Active against:
Cryptococcus neoformans Aspergillus spp.
Blastomyces dermatitidis Coccidioides spp.
Paracoccidioides brasiliensis H. capsulatum
Sporothrix spp Dermatophytes
Most species of Candida
Not active against:
Scedosporium spp Fusarium spp
Scopulariopsis spp Zygomycetes

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SE of intraconazole

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GI distress- nausea, vomiting, rash
Stevens-Johnson syndrome, hepatic toxicity, edema, hypokalemia, hypertension, negative inotropic effects, congestive heart failure
Contraindicated in in patients with history of heart failure/ventricular dysfunction
Peripheral neuropathy, visual disturbances, hearing loss
Teratogenic

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Itraconazole

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Spectrum of activity broader than fluconazole
Active against:
Cryptococcus neoformans Aspergillus spp.
Blastomyces dermatitidis Coccidioides spp.
Paracoccidioides brasiliensis H. capsulatum
Sporothrix spp Dermatophytes
Most species of Candida
Not active against:
Scedosporium spp Fusarium spp
Scopulariopsis spp Zygomycetes

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Drug interactions with itraconazole

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Strong inhibitor of CYP3A4 → increased serum levels of other drugs metabolized by this system
Absorption reduced by drugs that decrease gastric acidity (antacids, PPIs, H2-receptor blockers)

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Voriconazole (Vfend)

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Spectrum of activity similar to itraconazole
Active against:
Most species of Candida Aspergillus spp
Blastomyces dermatitidis Coccidioides spp.
Cryptococcus neoformans H. capsulatum
Paracoccidioides brasiliensis Dermatophytes
Scedosporium spp Fusarium spp
Not active against:
Zygomycetes Sporothrix spp
Superior to Amphotericin for invasive aspergillosis

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SE of intraconazole

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GI distress- nausea, vomiting, rash
Stevens-Johnson syndrome, hepatic toxicity, edema, hypokalemia, hypertension, negative inotropic effects, congestive heart failure
Contraindicated in in patients with history of heart failure/ventricular dysfunction
Peripheral neuropathy, visual disturbances, hearing loss
Teratogenic

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SE of voriconazole

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Pharmacokinetics:
Serum concentrations vary- may require monitoring
Adverse effects:
Transient visual disturbances- blurred vision, photophobia and altered color or image perception
Rash, Stevens-Johnson syndrome, hepatic toxicity, confusion, hallucinations
Anaphylaxis
Teratogenic

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Drug interactions with itraconazole

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Strong inhibitor of CYP3A4 → increased serum levels of other drugs metabolized by this system
Absorption reduced by drugs that decrease gastric acidity (antacids, PPIs, H2-receptor blockers)

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Voriconazole (Vfend)

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Spectrum of activity similar to itraconazole
Active against:
Most species of Candida Aspergillus spp
Blastomyces dermatitidis Coccidioides spp.
Cryptococcus neoformans H. capsulatum
Paracoccidioides brasiliensis Dermatophytes
Scedosporium spp Fusarium spp
Not active against:
Zygomycetes Sporothrix spp
Superior to Amphotericin for invasive aspergillosis

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SE of voriconazole

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Pharmacokinetics:
Serum concentrations vary- may require monitoring
Adverse effects:
Transient visual disturbances- blurred vision, photophobia and altered color or image perception
Rash, Stevens-Johnson syndrome, hepatic toxicity, confusion, hallucinations
Anaphylaxis
Teratogenic

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Drug interactions with voriconazole

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Metabolized by and inhibits, CYP2C19, CYP2C9, and CYP3A4 → serum levels may be influenced by drugs that affect these enzymes and serum levels of other drugs metabolized by these enzymes may be increased

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Posaconazole (Noxafil)

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Spectrum of activity similar to itraconazole
Activity is twice that of itraconazole
Increased activity against Absidia spp
Randomized study in leukemia patients showed fewer invasive mycoses (including aspergillosis), lower mortality rates, when compared to patients treated with fluconazole or itraconazole
Oral administration, taken with meals

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SE of posaconazole

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Adverse effects: similar to fluconazole
Headache, GI distress, rash
Hepatic toxicity, QT prolongation
Arrythmias, anaphylaxis, angioedema (rare)
Teratogenic

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Drug interactions with posaconazole

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Metabolized by UDP glucuronidation
Substrate of P-glycoprotein (permeability glycoprotein)
Strong inhibitor of CYP3A4 → increased serum levels of other drugs metabolized by this system
Used with caution with other drugs known to prolong the QT interval; contraindicated with such drugs that are metabolized by CYP3A4
Absorption reduced by drugs that decrease gastric acidity (antacids, PPIs, H2-receptor blockers)

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Polyenes:Amphotericin B (Fungizone)

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From Streptomyces nodoses (soil bacterium)
Insoluble in water. Solubility increased by formation of complex with deoxycholate (bile salt)
Lipid Amphotericin B Products- less nephrotoxic:
Ampho B lipid complex (ABLC, Abelcet)- Ribbon-like sheets
Ampho B cholesteryl complex (ABCD, Amphotec)- Disk-shaped colloidal dispersion
Liposomal amphotericin B (Ambisome)- Unilamellar vesicle

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MOA of amphoterrible

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Mechanism of Action: binds to ergosterol in fungal cell membrane, disrupts membrane integrity

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Reasons for selective activity of amphoterrible

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Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible.
Mammalian: Cholesterol
Fungal: Ergosterol

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Clinical uses of amphoterrible

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Broad-spectrum fungicidal
Drug of choice for most life-threatening fungal infections
Aspergillus, cryptococcus, histoplasmosis, invasive candidiasis, blastomycosis, mucor, neutropenic fever
Initial therapeutic agent, treatment continued with less toxic antifungal
nephrotoxic when given IV

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Pharmokinetics of amphoterrible

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No oral bioavailability
Metabolism not understood-
Hepatic or renal impairment does not affect levels
Extensive tissue binding →
Long T1/2 (~15 days)\
Concentrates in liver & spleen

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SE of amphoterrrible lipid formulations

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Adverse Effects:
Infusion reactions least severe with liposomal amphotericin B
Nephrotoxicity less common and less severe than with amphotericin B deoxycholate
Hepatotoxicity (rare)

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Flucytosine (Ancoban)

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Converted in fungal cytosol to 5- fluorouracil
5-fluorouracil inhibits DNA and RNA synthesis. Selective Activity based on:
Cellular uptake by specific fungal enzyme, cytosine permease. Conversion to 5- fluorouracil by another specific fungal enzyme, cytosine deaminase
Active against:
Cryptococcus neoformans
Candida spp
Chromoblastomycosis

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Clinical uses of flucytosine

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Used in combination with amphotericin B for cryptococcal meningitis or systemic candidiasis
Resistance develops rapidly

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PK and SE of flucytosine

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Good oral bioavailability- administered orally. Volume of distribution equals total body water. Penetrates the blood brain barrier. Renal excretion
Adverse effects: Dose-related bone marrow toxicity

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Name the Echinocandins

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Caspofungin (Cancidas)
Anidulafungin (Eraxis®)
Micafungin (Mycamine®)

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MOE of echinocandins

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Inhibition of synthesis of B (1,3)-D-glucan (fungal cell wall component) → cell wall becomes permeable
Selective Activity based on:
Absence of cell wall in mammalian cells
Active against: Most species of Candida Aspergillus spp

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PK of echinocandins

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No oral bioavailability
T1/2 ~ 10 hours after IV infusion. Extensively bound to albumin. Hepatic metabolizm, does not involve cytochrome P450 enzymes. No clinically significant drug interactions. No dose adjustment required in renal dysfunction

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SE of echinocandins

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Generally well tolerated
Occasional rash, fever, nausea, vomiting, headache, hypokalemia and mild hepatic toxicity
Stevens-Johnson syndrome, exfoliative dermatitis, anaphylaxis - rare
Teratogenic

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Griseofulvin (Fulvicin, Grifulvin V)

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For mucocutaneous infections-
Fungal skin, nail, hair infections. Mechanism of Action: Antimitotic- interacts with polymerized microtubules leading to disruption of the mitotic spindle
Activity: Fungistatic for various species of the dermatophytes Microsporum, Epidermophyton, and Trichophyton

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PK of Griseofulvin

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Blood levels quite variable
Best absorption when taken with a fatty meal
T1/2 = 24 hours
Keratophilic- binds to keratin, protects skin and nails from further infection

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SE and drug interactions with griseofulvin

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Adverse Effects:
Generally well tolerated- incidence of adverse effects is very low, Headache, nausea, vomiting, Teratogenic
Drug Interactions:
Induces hepatic cytochrome P450 isoforms

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MOA of Terbinafine (Lamisil)

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For mucocutaneous infections
Mechanism of Action:
Inhibits squaline epoxidase →
Blocks ergosterol synthesis →
Impaired fungal cell membrane synthesis
Fungicidal
Selective Activity due to 1000 to 10,000 times higher binding affinity for the fungal enzyme

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Pharmacokinetics of terbinafine

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Well absorbed but significant first pass metabolism to inactive metabolites
Highly lipophilic
Accumulates in skin and nails
T1/2 = 200 to 400 hours at steady state
Keratophilic

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SE and drug interactions with terbinafine

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Well tolerated- incidence of adverse effects is very low
Nausea, diarrhea, headache, rash, Hepatotoxicity, neutropenia, Stevens-Johnson syndrome (rare), Teratogenic
Drug Interactions: none significant. Does not affect cytochrome P450 isoforms

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Name topical antifungals

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Azoles:
Clotrimazole (Lotrimin, Mycelex)
Ketoconazole
Miconazole (Monostat, Micatin)
Polyenes:
Amphotericin B
Nystatin (Mycostatin)
Allylamines
Terbinafine (Lamisil)
Naftifine (Naftin)