Pharmacology - Antifungal Drugs

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Drugs that alter cell membrane permeability

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- Polyenes
- Azoles
- Allylamines and Benzylamines

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Drugs that block nucleic acid synthesis

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- Flucytosine

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Drugs that disrupt microtubule function

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Griseofulvin

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Drugs that disrupt the fungal cell wall

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Echinocandins

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Systemic drugs for subcutaneous and systemic mycoses

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- Amphotericin B
- Flucytosine
- Azoles
- Echinocandins

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Amphotericin B

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- Polyeme antibiotic
- FIRST CHOICE for SYSTEMIC MYCOSES
- MOA: polyenes bind to ergosterol in fungal cell memb to form pores --> electrolytes and small molecules leak from cell --> cell death

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Amphotericin B - PK

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- highly insoluble: formulated as deoxycholate colloidal suspension
- poorly absorbed from GIT -- must be given IV
- penetration into CSF low
- Intrathecal therapy may be necessary for meningeal disease

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Amphotericin B - Uses

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- most important for SYSTEMIC MYCOSES
- DOC for most systemic infections caused by Aspergillus, Candida albicans, Cryptococcus, Histoplasma, and Mucor

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Amphotericin B - Toxicity

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- Infusion-related: universal; fever, chills, muscle spasms, vomiting, headache, hypotension; attenuated by slowing infusion rate or decreasing daily dose; premedication w/ antihistamines, glucocorticoids, antipyretics, or meperidine helpful
- Slower toxicity: renal impairment in nearly all pts; anemia due to reduced EPO prod by damaged tubular cells; Intrathecal admin can cause seizures and serious neurological damage

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Amphotericin B - Lipid Formulations

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- developed to reduce nephrotoxicity
- packaged in lipid carriers to reduce exposure to nephron
- nephrotoxicity less common and less severe w/ lipid formulations**

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Flucytosine

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- pyrimidine antimetabolite
- used only in COMBINATION with amphotericin for tx of systemic mycoses and meningitis caused by Cryptococcus neoformans and Candida

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Flucytosine - MOA

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- taken by fungal cells via the enzyme cytosine permease and converted to 5-FU and then to 5-FdUMP
- 5-FdUMP inhibits thimidylate synthetase, thus blocking synthesis of dTMP
- 5-FUTP also formed, which inhibits protein synthesis
- mammalian cells UNABLE to convert parent drug to active metabolite
- Flucytosine + amphotericin B = syngeristic

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Flucytosine - Uses

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- clinical use limited to combination therapy
- w/ amphotericin B or w/ itraconazole

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Flucytosine - AE

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- result from metabolism (by intestinal flora) to 5-fluorouracil
- bone marrow toxicity most common

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Azoles

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- classified as imidazoles or triazoles
- imidazoles = Ketoconazole, Miconazole, Clotrimazole
- triazoles = Itraconazole, Fluconazole, Voriconazole, Posaconazole

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Azoles - MOA

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- fungal CYP450 enzyme 14-alpha-sterol demethylase catalyzes conversion of lanosterol to ergosterol
- azoles INHIBIT the enzyme --> reduced ergosterol synthesis
- this disrupts membrane fxn and increases permeability
- azole drugs have higher affinity for fungal than for human P450 enzymes
- imidazoles less specific than triazoles

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Azoles - AE

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- relatively NONTOXIC
- most common AE = minor GI upset

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Ketoconazole

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- an imidazole that inhibits mammalian CYP450 enzymes
- can decrease plasma testosterone levels --> gynecomastia, dec libido, loss of potency in men and menstrual irregularity in women
- is also a strong inhibitor of CYP3A4 --> can potentiate toxicities of other drugs like warfarin and cyclosporine
- best absorbed at low gastric pH: antacids, H2 blockers, and PPI's interfere
- poor penetration in CSF

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Ketoconazole - Uses

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- rarely used for systemic mycoses
- used for superficial mycoses

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Fluconazole

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- triazole that has good CSF penetration and high oral bioavailability
- available in oral and IV formulations
- moderate inhibitor of CYP3A4
- strong inhibitor of CYP2C9: can increase plasma levels of phenytoin, zidovudine, and warfarin

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Fluconazole - Uses

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- DOC in esophageal, oropharyngeal, and vulvovaginal candidiasis
- DOC for most infections due to Coccidioides
- DOC for initial and secondary prophylaxis against cryptococcal meningitis
- INEFFECTIVE against Aspergillus or other filamentous fungi
- PENETRATES CSF
- Renal excretion (rest hepatic)

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Itraconazole

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- metabolized by CYP3A4
- Strong inhibitor of CYP3A4 --> can cause fatal arrhythmias when given w/ cisapride or quinidine
- poor bioavailability
- poorly penetrates CSF
- absorption reduced by antacids, H2 blockers, and PPIs

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Itraconazole - Uses

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- preferred azole for mycoses due to dimorphic fungi BLASTOMYCES, SPOROTHRIX, and HISTOPLASMA
- effective against aspergillus, but has been replaced by voriconazole for this indication
- used extensively for DERMATOPHYTOSES and ONYCHOMYCOSIS
- NOT active against FUSARIUM

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Voriconazole

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- more effective against Aspergillus and some Candida
- unlike itraconazole, ACTIVE AGAINST FUSARIUM
- not active against Zygomycetes
- approved for tx of INVASIVE ASPERGILLOSIS (replaces amphotericin B as DOC for this)

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Voriconazole - AE

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- transient visual disturbances
- metabolized and inhibits CYP2C19, CYP2C9, CYP3A4 --> sig number of drug interactions due to its metabolism may limit use

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Posaconazole

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- activity against ZYGOMYCETES such as MUCOR
- inhibits CYP3A4

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Echinocandins

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- large cyclic peptides linked to long-chain fatty acid
- Caspofungin, micafungin, and anidulafungin
- active against candida and aspergillus but NOT cryptococcus neoformans
- only available IV

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Echinocandins - MOA

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- inhibit synthesis of Beta(1-3)-D-glucans in the fungal cell wall --> disruption of fungal cell wall --> cell death

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Drugs for Superficial Mycoses: Systemic Drugs

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- Griseofulvin
- Terbinafine
- Ketoconazole
- Fluconazole
- Itraconazole

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Griseofulvin

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- Only use = tx of DERMATOPHYTOSIS
- absorption improved when given w/ fatty foods
- MOA = DISRUPTS MITOTIC SPINDLE AND INHIBITS MITOSIS

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Griseofulvin - Uses

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- Severe dermatophytoses of the skin, hair, and nails
- replaced by newer antifungal drugs like itraconazole and terbinafine
- induces liver P450 enzymes, thus increasing the metabolism of a number of drugs, including warfarin

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Terbinafine

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- Allylamine, available orally
- MOA: inhibits squalene epoxidase which prevents synthesis of ergosterol
- causes acc of toxic levels of squalene in the fungal cell
- AE: GI upset, rash, headache, taste disturbances
- DOESNT AFFECT P450 system--> NO DRUG INTERACTIONS

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Azoles

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Ketoconazole, fluconazole, and itraconazole commonly used orally in tx of dermatophytoses

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Drugs for Superficial Mycoses: Topical Drugs

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- Nystatin
- Amphotericin B
- Clotrimazole
- Miconazole
- Ketoconazole
- Terbinafine

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Nystatin

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- similar to amphotericin B w/ similar MOA
- too toxic for IV admin
- used ONLY for CANDIDIASIS
- cutaneous/vaginal/oral admin
- not absorbed in GIT, skin, or vagina --> little toxicity

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Amphotericin B

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- topical amphotericin B used for cutaneous candidiasis

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Topical Azoles

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- CLOTRIMAZOLE and MICONAZOLE most common
- both available OTC

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Terbinafine

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- available as topical creams for TINEA CRURIS and TINEA CORPORIS

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Pneumocystis Jiroveci Pneumonia

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- organism is a fungus but doesnt respond to antifungals
- common cause of pneumonia in IC
- therapy: DOC = CO-TRIMOXAZOLE (trimethoprim + sulfamethoxazole)
- also the DOC for prevention of P. jiroveci infection in IC

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Pneumocystis Jiroveci Pneumonia - Alternative Therapy

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- Clindamycin + Primaquine
- Dapsone + trimethprim
- Atovaquone
- Pentamidine

Pts w/ moderate to severe disease should also be given Prednisone