Antifungal drugs PHARMACOLOGY

Amphotericin b

 Important drug for treatment of systemic fungal infections

 Given IV
 Doesn’t enter CNS
 Dosage adjustment in renal dysfunctions
 Moa
 Effect on permeability and transport functions of fungal membrane
 They are amphipathic in nature
 Bind to the membrane ERGOSTEROL , and create artificial pores
 Resistance occurs via change in structure of ergosterol .
 Uses

 Treatment of systemic mycoses

 Used for initial regimen then after it azoles are given
Histoplasmosis
 Widest antifungal spectrum
blastomyces
 Drug of choice / co choice for Candida
 Given IV aspergilllus
 But in fungal meningitis intrathecal has been used cryptococcus
 Also used in treatment of mycotic corneal ulcers . Mucor and Rhizopus
 toxicity
 Fever
 Chills , muscle spasm , vomiting
 shock like fall in blood pressure
 Attenuation by slow infusion rate and by giving the anti histamines , anti pyretics
 And glucocorticoids

 Dec gfr
 Renal tubular acidosis
 Anemia from dec erythropoietin
 Nephrotoxic effects dose limiting
 Dosage reduction possible when used in combination to flucytosine.
 Seizures and neurologic damage
Flucytosine

 Pyrimidine antimetabolite related to anticancer drug 5 – florouracil

 Membrane permease drug accumulated in fungal cell  cytosine deaminase
convert it  5 flurouracil  inhibitor of thymidylate synthase
 Above mentioned enzymes present in fungus
 Mammalian cells have low level of these enzymes , so drug can prove toxic
 Resistance by dec act of fungal enzymes and when drug used alone
 Given in comb to amphotericn etc to delay resistance and improve antifungal
effects
uses

 Spectrum of its action is narrow

 Used in comb to amphotericin B / triazole
 Effective against
 Cryptococcus neoformans
 Systemic candida infections
 Chromoblastomycosis caused by molds.
 Mnemonic to remember spectrum is 785
Toxicity

 Reversible bone marrow depression

 Alopecia
 Liver dysfunction
Mechanism of action of azoles

 Azoles interfere with fungal cell membrane permeability by inhibiting synthesis

of ergosterols
 Lanosterol -- ergosterol and this is demethylation step
 Azoles inhibit this 14 alpha mediated demethylation by inhibiting cytp450
mediated reaction.
 Clinical uses ketoconazole

 Narrow antifungal spectrum

 Now rarely used for systemic mycoses
 But still used for chronic mucocutaneous candidiasis ( CMC ) and is also effective
against dermatophytes .
fluconazole

 Drug of choice in
 Esophageal and oropharyngeal candidiasis
 For most infections caused by coccidiodes
 Vaginal candidiasis
 For treatment and prophylaxis against Cryptococal meningitis
 Cryptoccus neoforms
 itraconazole

 Drug of choice for systemic infections caused by

 Blastomyces
 Sporothrix
 Subcutaneous chromoblastomycosis

 Alternative agent in
 Aspergillus
 Coccidiodes
 Cryptococcus
 Histoplasma
 Dermatophytosis
 In candida resistant to fluconazole
voriconazole

 Co drug of choice for treatment of invasive aspergillosis

 Candidiasis in case of resistance to fluconazole
Posaconazole

 Mainly opportunistic infections

 Candida
 Aspergillus
 Rhizopus
 Prophylaxis of fungal infections during cancer chemotherapy and in salvage
therapy

 Isavuconazole antifungal spectrum similar to Posaconazole

 Toxicity of azole drugs

 Vomiting
 Diarrhea
 Rash
 Hepatotoxicity
 Ketoconazole inhibitor of CYTP450 , interfering with the synthesis of the adrenal and gonadal
steroids leading to
 Gynecomastia
 Infertility
 Menstrual irregularities
 Voriconazole causes blurring of vision
 Posaconazole inhibitor of CYP 3A4 raising levels of cyclosporine.
 In general warfarin , estrogen , phenytoin , theophylline , digoxin level raised .
 Echinocandins
 Caspofungin
 Micafungin’
 Anidulafungin
 MOA
 It has a fungicidal function , inhibiting synthesis of Beta ( 1-3 ) glucan , an imp comp of cell wall
 USES
 Caspofungin and micafungin used for disseminated mucocutaneous candidiasis
 Caspofungin also used in treatment of mucormychosis by RHIZOPUS
 Anidulafungin used for oesophageal and invasive candidiasis
 TOXICITY
 Git distress , fever , rash , flushing
 Elevate blood level of ceratin drugs
 Griseofulvin
 It interfere with microtubule function of dermatophytes and also inhibits synthesis and
polymerization of the nucleic acids .
 It is fungistatic
 Uses
 Indicated for dermatophytosis of skin and hair
 Adverse effects
 Headache
 Mental confusion
 Git irritation
 Change in liver function
 Dec bioavailability of warfarin and interfere with anticoagulant functions of it
 Contraindicated in porphyria
Terbinafine imp U.Q

 Inhibits fungal enzyme squalene epoxidase

 Causes accumulation of toxic level of squalene
 Squalene inhibits ergosterol synthesis
 Available in both oral and topical forms
 Fungicidal
 Used for dermatophysis infections
 More effective in onchomycosis
 Git
 Rash taste disturbance
 Doesn’t inhibt cytp450
 Dermatophytosis treatment

 Fungal infections of nail are treated by oral griseofulvin and terbinafine drugs
 Fluconazole , ketoconazole and itraconazole also available in ( oral ) form for dermatophytosis
 Topically applied itraconazole persist in nail for several months , 1 week treatment followed by 3
weeks without drug
 Advantage of pulse dosing include lower incidence of adverse effects and cost saving
Topically applied antifungals

 Miconazole
 Clotrimazole , econazole
 Nystatin is an polyene antibiotic , that disrupts fungal membrane by binding to
ergosterol , for cutaneous candida infections
 Also used orally ( nystatin ) to eradicate git fungi in persons with impaired defense
mechanism .
 Terbinafine
 Tolnaftate
 Benzoic acid with salicylic acid
 Haloprogin
 Griseofulvin also applied topically .
Give azole drugs used topically ( u.q)

 Imidazoles e.g. miconazole, econazole, clotrimazole, luliconazole, efinaconazole, ketoconazole,

terconazole, butaconazole, tioconazole, oxiconazole, sertaconazole.
 Triazoles are available in oral as well as IV forms
Drugs used in candidal infections

 Triazoles
 Fluconazole
 Voriconazole
 Imidazoles
 Clotrimazole
 Ketoconazole
 Polyenes
 Nystatin
 Amphotericin B
 2nd line mein , flucytosine and echinocandins