Lec 6 - Antifungal Drugs PDF

**Lec 6 - Antifungal Drugs** Classification - Superficial infections -- on surf of skin - Cutaneous infections -- Dermatophytes, Ringworm infec, All Tinea spc, Candida spc - Sub-cutaneous infections - Deep mycosal infections or Systemic mycosal infections - Fungi are Eukaryotes -...

**Lec 6 - Antifungal Drugs** Classification - Superficial infections -- on surf of skin - Cutaneous infections -- Dermatophytes, Ringworm infec, All Tinea spc, Candida spc - Sub-cutaneous infections - Deep mycosal infections or Systemic mycosal infections - Fungi are Eukaryotes -- thus antifungal drugs are more toxic than anti-bact - Fungi have rigid cell walls containing chitin + polysacc & cell memb composed of ergosterol instead of chol in humans Sites of Antifungal Activity - Memb func -- Amphotericin B - Ergosterol Syn -- Fluconazole, Itraconazole, Voriconazole, Naftifine, Terbinafine - Nucleic acid syn -- 5-Fluorocytosine - Cell wall syn -- Caspofungin - Alter cell memb permeability -- Azoles, Polyenes, Terbinafine - Disrupt microtubule func -- Griseofulvin Classifications based on mech of action - Fungal cell wall syn inhib (Echinocandins) -- Caspofungin - Bind to fungal cell memb ergosterol (Polyenes) -- Amphotercin-B, Nystatin - Inhib of ergosterol + Lanosterol syn -- Terbinafine, Naftifine, Butenafine - Inhib of ergosterol syn -- Azoles - Inhib of nucleic acid syn -- 5-Fluorocytosine - Disruption of mitotic spindle & inhib of fungal mitosis -- Griseofulvin - Miscellaneous -- Ciclopirox, Tolnaftate, Haloprogin, Undecylenic acid, Topical azoles Classification based on Struc - Antibiotics - Polyene -- Amphotericin, Nystatin, Hamycin - Hetrocyclic -- Benzofuran, Griseofulvin - Antimetabolite -- Flucytosine - Azoles - Imidazoles -- Ketoconazole, Clotrimazole, Oxiconazole, Miconazole - Triazoles -- Fluconazole, Itraconazole, Voriconazole - Allylamines -- Terbinafine, Butenafine - Echinocandins -- Caspofungin, Anidulafungin, Micafungin - Other topical agents -- Tolnaftate, Undecyclinic acid, Benzoic acid - Topical drugs - Azoles - Ketoconazole, Miconazole, Clotrimazole, Tioconazole - Nystatin - Terbinafine - Other drugs -- Tolnaftate, Ciclopirox, Naftifine, Whitfield ointment, Gentian violet, Castellani paint, Tincture iodine - Drugs for systemic infec - Azoles -- Fluconazole, Itraconazole, Voriconazole - Amphotericin-B - Flucytosine - Caspofungin Amphotericin A & B - Prod by Streptomyces nodosus - Polyene macrolide - Nearly insol in water & thus prep as colloidal suspension of Ampho B & Sodium desoxycholate - IV - Ampho A -- not in clinical use - Ampho B -- only available antifungal drug for systemic use - Binds to Ergosterol to create pores (Ampho B pores) in fungi cell memb -- Alters permeability -- Allows leakage of intracell ions & macromol -- leads to death of fungus -- Fungicidal - Pharmacokinetics - Poorly absorb from GI, so oral Ampho B is only used for fungi within lumen of tract not for systemic - IV, Topical - Widely distributed, but only 2-3% reaches CSF - Met in liver slowly excreted in urine - T1/2 = 15 days - Hepatic dis, Renal dis & Dialysis has little effect on drug conc -- thus no dose adjustment needed - Spectrum -- Broad -- Fungicidal at high conc; Static at low conc - Aspergillus, Blastomyces dermatitidis, Candida albicans, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Mucor spp - Leishmania - Administration - Systemic mycosis - IV - Intestinal monoliasis -- Gastrointestinal candidiasis - Vaginitis -- Topical - Otomycosis -- Drops - Intrathecal -- for fungal meningitis - Uses - In all life-threatening mycotic infec - Treatment of invasive aspergillosis - Rapidly progressive Blastomycosis & Coccidiomycosis - Cryptococcus neoformans - Mucormycosis - Disseminated rapidly progressing Histoplasmosis - Reserve drugs for resistant kala azar - Adverse effects - Acute rxn - Chills, fever, pain all over, nausea, dyspnoea - Lasts 2-5 hrs -- release of IL & TNF - Treated -- Hydrocortisone - Long-term toxicity - Nephrotoxicity -- Azotemia, Hypokalemia, Acidosis, â GFR - Anemia - CNS toxicity - Hepatotoxicity -- Rarely - Mech of resistance - When ergosterol binding is impaired by - â memb conc of ergosterol - Modifying sterol target mol to reduce its affinity for drug Nystatin - Polyene macrolide - Sim kinetics to Ampho B - Too toxic for parenteral administration & is used ONLY TOPICALLY - Active mainly against -- Candida -- Topically used for oropharyngeal & vaginal candiasis Flucytosine - Prodrug - Struc resembles -- Pyrimidine bases -- essential building blocks of DNA & RNA - Antimetabolite -- interferes with met of essen nutrients needed by fungus - Mech - Flucytosine is actively transported into fungal cells - Once inside the fungal cell, flucytosine is converted into 5-FU. - 5-FU interferes with the synthesis of nucleic acids (DNA and RNA) in the fungus - Disrupting its growth - Selectivity - Human cells have a limited ability to convert flucytosine into 5-FU. This selective toxicity makes flucytosine less toxic to humans compared to fungi - Adverse effects - Bone marrow toxicity - Alopecia, Skin rash, Itching - Hepatitis -- Rarely - Used in combo with other antifungals -- to treat severe systemic fungal infec - Ampho B + Flucytosine = **Synergism** - Advantages - Entry of 5 FC - â toxicity - Rapid culture conversion - â duration of therapy - â resistance Azole Antifungals agents - Represent a class of synthetic antifungal agents that possess unique mech of action - 1^st^ members of class were highly substituted imidazoles -- clotrimazole, miconazole - Broad spectrum - With these drugs, one can achieve selectivity for the infecting fungus over the host - Depending on the azole drug used -- can treat infec from simple to life-threatening infec - 2 groups - Imidazole grp -- 2 nitrogen in azole ring - Clotrimazole, Econazole, Miconazole, Ketoconazole, Oxiconazole - Triazole grp -- 3 nitrogen in azole ring - Itraconazole, Fluconazole, Posaconazole, Voriconazole - Mech - Bind to fungal cytochrome P450 dep 14-α demethylase enzyme -- responsible for demethylation of -- Lanosterol - Thus, Ergosterol syn is impaired -- leading to leaky fungal cell memb - Pharmacokinetics - Absorp of azoles from stomach is affected by -- Food & Gastric HCl - Fluconazole -- can reach CSF with good conc. Others can't - Fluconazole excreted in urine -- mostly unchanged - Ketoconazole -- only imidazole which is systemic; Other 3 are Topical Only - Triazoles -- used systemically -- largerly replacing ketoconazole - Therapeutic Uses - Superficial fungal infec -- Keto, Itra, Mico - Dermatophytes infec of skin (Tinea), hair, nails (onychomycosis) - Mucocutaneous candidiasis -- Oropharyngeal, Vulvovaginal - Systemic fungal infec -- Keto, Fluco, Vorico - Itra -- Oral or IV -- DOC for systemic Blastomycosis - Fluco -- Oral or IV -- DOC for systemic Candidiasis & Cryptococcal meningitis (since only azole which enters CSF) - Vorico -- DOC for invasive -- Aspergillosis of lung - Adverse effects - Hepatotoxicity & serum transaminase - Inhib hepatic CypP450 enzymes -- fluco least inhib - **Keto** -- causes **antianderogenic** effects -- Gynecomastia & Impotence due â gonadal steroid synthesis - Vorico -- causes transient Visual disturbances Ketoconazole (Imi) - 1^st^ orally effective broad spec antifungal - Effective against -- Dermatophytosis, Deep mycosis, Candidiasis - Spectrum - Yeasts & Moulds - Poor absorp limits its role for severe infec -- gen used in mucosal infec only (Dematophytosis) - Pharmacokinetics - Effective Orally -- Acidic environment favors absorp - High prot binding - Readily distributed -- Not to BBB - Met in liver -- excreted in bile - T1/2 = 8-10 hrs - Adverse effects - Nausea, Vomiting, Anorexia - Headache, Parethesia - â steroid, testosterone & estrogen syn - Causing -- Gynaecomastia, Oligospermia, Loss of libido & impotence in males - of liver enzymes - Hypersensitivity rxn -- skin, rashes, itching - Drug interactions - Potent of CytP450 3A4 - Rifampin & Phenytoin - â keto lvls - Keto cyclosporin, warfarin, astemizole, corticosteroid & theophylline - Antacids, Omeprazole, H2 blockers - gastric pH will â keto blood lvls - Keto + Ampho B = **Contraindicated** - Uses - Keto conc in stratum corneum -- outmost layer of skin -- effective against Dermatophytosis - Monilial Vaginitis - Systemic mycosis -- blastomycosis, histoplasmosis, coccidioidomycosis -- less effective than Ampho B & has slower response - â efficacy in immunocompromised & meningitis - Lower toxicity than Ampho B, but higher than triazole - High doses -- Cushing's syndrome - Topical infec -- T. pedis, Cruris, Corporis, Versicolor Fluconazole (Tri) - Water sol - Completely absorb & better tolerated - Wider range activity than Keto - Good activity against -- C. albicans & Cryptococcus neoformans - Non-albicans Candida spc more likely to exhibit 1˚ resistance - C. krusei -- Always resistant - C. glabrata -- Mid resistant - C. parapsilosis, C. tropicalis, C. kefyr -- Sometimes resistant - Resistance - 1˚ resistance - severely ill or immunocompromised patients - Selection of resistant species or subpopulations - Replacement with more resistant strain - 2˚ resistance - seen in patients with AIDS who experienced recurrent orophayrngeal candidiasis and received long-term fluconazole therapy - Genetic mut - Upreg of efflux pumps - Kinetics - IV & Oral - T1/2 = 24 hrs - Excreted unchanged through urine Itraconazole (Tri) - Newer orally active triazole - Varied absorp - Broader spectrum than KTZ & FCZ -- includes moulds & aspergillus - Fungistatic action but very effective in immunocompromised patients - Steroid horm syn inhib is absent & no serious hepatotoxicity - Met by Cyt (Liver) - Many srug interactions -- due to inhib of cytP450 Voriconazole - 2^nd^ gen Triazole - High oral bioavailability & low prot binding -- thus well absorb from GI when taken orally & spreads through blood -- good distribution - Good CSF penetration - Doesn't req gastric acidity for absorp - T1/2 = 6 hrs - Uses - DOC -- Invasive aspergillosis - Most useful for esophageal candidiasis - 1^st^ line -- Moulds -- Fusarium - Useful in resistant candida infec - Adv effects - Transient visual changes -- blurred vision, altered clr perception & photophobia - Rashes, hepatic enzymes, prolonged QT Posaconazole - Newest triazole - Struc sim to ITZ - Acts against -- Candida spc, Aspergillus, Cryptococcus neoformans, Zygomycetes & other filamentous fungi - Indication - Used as salvage therapy in immunocomp -- who haven't responded to other treatments - Prophylaxis for Neutropenia & HSCT (hematopoietic stem cell therapy) - Availabe as Cherry-flavored liq suspension & 100mg tab -- Oral - IV available - **Better absorp with Fatty food & low stomach pH** Topical Azoles - Clotrimazole, Miconazole - Uses - Vulvovaginal candidiasis - Oral thrush - Dermatophytic infec -- tinea corporis, tinea pedis, tinea cruris - Absorp is negligible - Adv effects are rare - Topical & Shampoo forms of KTZ for -- seborrheic dermatitis & pityriasis versicolor - Inhib syn of Ergosterol by demethylation of Lanosterol with 14 α demethylase Topical Allylamines - Terbinafine & Naftifine - Both effective for treatment of -- Tinea cruris & tinea corporis - Terbinafine conc in skin -- espec at nail beds -- making it useful for fungal infec of nails - Adv effects - Taste disturbances - Nausea, Vomiting, Diarrhea - Rarely hepatic dysfunc - Topical -- Erythema, Itching, Dryness, Urticaria & rashes - Terbinafine - Act by inhib Squalene epoxidase -- thus blocking syn of Lanosterol & further Ergosterol - Accum of squalene - memb permeability & death of fungal cell - Fungicidal - DOC -- Dermatophyte onychomycoses - Better tolerated, Req shorter duration of therapy & more effective that ITZ or Griseofulvin - Orally & Topically -- effective drug against - candida & dermatophytes - Kinetics - Well absorb orally 75% - Highly keratophilic & lipophilic - High prot bound -- thus poor BBB permeability - T1/2 = 15 days - Negligible effect on CytP450 Echinocandins - Newer antifungals - Inhib fungal cell wall syn - During fermentation process -- some metabolites were found to inhib Candida sp -- were named Echinocandins - Have potent activity against Aspergillus & most Candida sp -- espec those resistant azoles - Have minimal activity against others - CASPOFUNGIN, MICAFUNGIN & ANIDULAFUNGIN -- semisynthetic echinocandin derivatives - Mech - Inhib syn of β-1,3 -- D -- glucan --\> via noncompetitive inhib of enzyme - 1,3-β glucan synthase -\> resulting in inhib of cell wall -\> leading to lysis & death - Thus, are called -- Penicillin of antifungals - Kinetics - Due to larger mol weight -- they have poor oral bioavailability -- thus give IV - Also limits penetration into CSF, Urine & Eyes - In plasm -- echinocandins have high affinity to serum prot - Don't have 1˚ interactions with CytP450 or P-glycoprot pumps - Exhibit fungicidal activity against -- Candida spc (also triazole resistant ones) - Exhibit fungistatic activity against -- Aspergillus spc - Caspofungin is orally not absorbed and hence infused slowly - Therapeutic uses - Treatment of invasive Aspergillus infection - Adv effects - Thrombophlebitis - Abnorm liver func - Sensation of warmth, flushing - Headache & rashes - Drug interactions - Combo of Caspofungin with Cyclosporine -- AVOIDED -- due to risk of Hepatotoxicity - Enzyme inducers clearance of Caspofungin while Caspofungin clearance of Tacrolimus Griseofulvin - Mech - Binds to microtub & prevents spindle form & mitosis in fungi - Fungistatic & req long duration therapy - Drug binds to -- Keratin struc & accum in skin, hair & nails - Kinetics - Oral -- irreg absorp - by fatty food & microfine particles - Gets conc in keratinized tis - Met in liver -- excret by kidneys - T1/2 = 24 hrs - Uses - For long-term therapy of dermatophyte infecof hair & nail - Adv effects - Hepatotoxicity -- liver func should be checked during therapy - Hypersensitivity rxn -- skin rash - CNS effects -- confusion, fatigue, vertigo