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  1. 1. Antifungal drugs
  2. 2. <ul><li>Fungal Types /Growth Patterns </li></ul><ul><li>1. Yeasts </li></ul><ul><li>Unicellular fungi, solitaer round/ovale shape, ca. 5–8 μm </li></ul><ul><li>multiplication: budding , reproduce by budding </li></ul><ul><li>Moist mucoid or waxy colonies that resemble bacteria Eg: Candida spp., Cryptococcus neoformans </li></ul><ul><li>2. Molds (=Filamentous Fungi) </li></ul><ul><li>Multicellular filamentous, filament diameter 2-10 μm, “fluffy” colonies consisting of branching tubular structures called hyphae , Fungal colony: thallus </li></ul><ul><li>Collection of intertwined hyphae called mycelium </li></ul><ul><li>Vegetative hyphae act like roots, penetrating the supporting medium and absorbing nutrients </li></ul><ul><li>. Eg: Aspergillus , Penicillium Mucor </li></ul><ul><li>Dimorphic Fungi </li></ul><ul><li>Grow as molds at ambient environmental temperatures (e.g. 25° C) where they form </li></ul><ul><li>reproductive spore structures. </li></ul><ul><li>Spores are aerosolized and infectious, grow as yeasts at body temperature (37° C) in the host on inhalation </li></ul>
  3. 3. <ul><li>Fungal diseases </li></ul><ul><li>1. Allergy / asthma (spores) </li></ul><ul><li>2. Mycotoxicosis: e.g. aflatoxins, ochratoxins </li></ul><ul><li>3. Mycosis – infections caused by fungi </li></ul><ul><li>acute, subacute, chronic </li></ul><ul><li>local – general/systemic </li></ul><ul><li>Mycosis: Fungal infections (= mycosis) </li></ul><ul><li>spread generally from the environment to people (or animals) with limited </li></ul><ul><li>person-to-person spread. </li></ul><ul><li>Skin and lungs are prominent entry site for many fungi </li></ul><ul><li>Patients with impaired cell-mediated immunity (e.g. AIDS, organ transplant) at heightened risk for severe disease. </li></ul>
  4. 4. <ul><li>Classification/Types of fungal infections </li></ul><ul><li>1.Superficial : Outer skin layer - no immune response caused mostly by yeasts (Dandruff) </li></ul><ul><li>2. Cutaneous : Epidermal layers local, skin and other keratinized tissues - evoke immune response Tinea (Ringworm, Athlete’s foot, jock itch) caused by Dermatophytosis: : dermatophytes – Trichophyton, Epidermophyton Microsporum </li></ul><ul><li>3.Subcutaneous : Chronic inf.of subdermal tissues - surgical intervention as it may result in local granuloma formation and spread: via lymphatics Egs:Sporothrichosis( Sporothrixschenckii) ,Chromomycosis( Phialophora spp.), Chromoblastomycosis ( Fonsecaea spp.) , Maduromycosis/mycetoma (mixed) </li></ul><ul><li>4. Systemic : Mostly originating in the lung caused by virulent dimorphic exogen source fungi inhalation Eg: Histoplasmosis , Coccidioidomycosis, Blastomycosis . </li></ul><ul><li>5. Opportunistic : In immunocompromised host (AIDS; altered mucosal flora due to antibiotics): Eg: mostly Candidiasis and Aspergillus spp ., Penicillium and other molds- exogen or endogen source </li></ul>
  5. 5. <ul><li>Animal Fungi </li></ul><ul><li>Cell structure Eukaryotic Eukaryotic </li></ul><ul><li>DNA Diploid Haploid </li></ul><ul><li>Ribosomes 80S 80S </li></ul><ul><li>Cell wall No chitin ,mannans </li></ul><ul><li>glucans </li></ul><ul><li>Cell membrane cholesterol ergosterol </li></ul><ul><li>Microtubule affinity </li></ul><ul><li>for antifungal drug </li></ul><ul><li>(griseofulvin) No Yes </li></ul><ul><li>Cytosine deaminase No Yes </li></ul><ul><li>Squalene epoxidase No Yes </li></ul>
  6. 6. <ul><li>Classification </li></ul><ul><li>I. Antibiotics a. Polyenes - Amphotericin B Nystatin Natamycin, Hamycin </li></ul><ul><li>b. Heterocyclic benzofurans- Griseofulvin, </li></ul><ul><li>II. Azoles </li></ul><ul><li>a. Imidazoles - Ketoconazole, Miconazole, Clotrimazole,Econazole , Tioconazole, Enilconazole </li></ul><ul><li>b. Triazoles - Fluconazole, Itraconazole,Voriconazole,Posaconazole, Ravuconazole </li></ul><ul><li>III. Antimetabolites - 5-Flucytosine </li></ul><ul><li>IV. Echinocandins - Caspofungin, ,Cilofungin, Micafungin, Anidulafungin </li></ul><ul><li>V. Allylamines - TerbinafineButenafine, Naftifine, Amorolfine ,) </li></ul><ul><li>VI. Others(Topical )- Ciclopirox olamine, haloprogin,tolnaftate,, undecylenicacid, ,quinidochlor, Thiabendazole, salicylic acid , benzoicacid, Sodiumthiosulphate, Copper sulphate , Dichlorophen, Monosulfiram, Sodium iodide, Lufenuron </li></ul>
  7. 8. Polyenes <ul><li>Selectively bind to ergosterol in fungal cell membrane, altering membrane fluidity and producing pores and osmotic cell death. Much less binding to cholesterol </li></ul><ul><li>alter selectively permeability to K+ (and Mg2+) => Fungicidal </li></ul><ul><li>Amphotericin B - Streptomyces nodosus, </li></ul><ul><li>– Given IV(poor oral absorption) and topical </li></ul><ul><li>– Active against most systemic fungi </li></ul><ul><li>Not well tolerated </li></ul><ul><li>Adverse effects : </li></ul><ul><li>Most toxic antibiotic antifungal </li></ul><ul><li>choice for systemic fungal infections in immunocompromised </li></ul><ul><li>Acute : Infusion-related Chills, fever, dyspnea, nausea, vomiting, bronchospasm, hypotension, convulsions . </li></ul><ul><li>Chronic - Nephrotoxicity, azotemia, impaired concentration, impaired urinary acidification, K & Mg wasting with hypokalemia and hypomagnesemiaNormochromic, normocytic anemia erythropoietin) </li></ul>
  8. 9. <ul><li>Nephrotoxicity - ameliorated or prevented by maintenance of intravascular volume, by avoiding diuretic drugs and saline-loading with 500–1000 mL of normal saline before infusion of amphotericin </li></ul><ul><li>Avoidance nephrotoxic agents: NSAIDS aminoglycosides, immunosuppressive agents- cyclosporine,tacrolimus </li></ul><ul><li>Nystatin - Only for topical application, ( Canidida, dermatophytes ) </li></ul><ul><li>Narrow spectrum, ineffective in dermatophytosis </li></ul>
  9. 10. <ul><li>Heterocyclic benzofurans : </li></ul><ul><li>Griseofulvin </li></ul><ul><li>Benzofuran cyclohexane antibiotic, </li></ul><ul><li>Produced by Penicillium griseofulvum </li></ul><ul><ul><li>Fungistatic antibiotic that inhibits fungal growth by binding to microtubules causing disruption of mitotic spindles , interfering with Cytoplasmic microtubules(mammalian microtubules less sensitive) and inhibiting the mitotic spindle formation </li></ul></ul><ul><ul><li>Oral administration (use declining due to better drugs - e.g. Triazoles </li></ul></ul><ul><ul><li>High fat meal enhances the oral absorption </li></ul></ul><ul><ul><li>Selectively deposited in the newly formed keratin of hair, nails, and skin and gradually moves from these deep layers to the site of infection in the superficial keratinized epithelium where keratinized cells mature and progressively desquamated. </li></ul></ul><ul><ul><li>For this reason the treatment is always a prolonged one </li></ul></ul><ul><ul><li>Actively growing fungus may be killed , but dormant cells are only inhibited </li></ul></ul>
  10. 11. <ul><ul><li>Metabolism </li></ul></ul><ul><li>in liver, may be affected by microsomal enzyme inducers(rifampin) coadministration </li></ul><ul><ul><li>Interaction: </li></ul></ul><ul><ul><li>It is a hepatic enzyme (CYP 450) inducer, may increase the metabolism of other co-administered drugs resulting in their diminished therapeutic effect </li></ul></ul><ul><ul><li>Indications: </li></ul></ul><ul><li>popular effective drug against ringworm- Mainly effective against dermatophytes - requires several weeks of therapy. </li></ul><ul><li>Fungal Infections of skin, hair, nails </li></ul><ul><li>Side effects : Nausea, mild CNS effects(dizziness,) hepato- and renal toxicity, photosensitivity, and GI disturbances in humans. </li></ul><ul><ul><ul><li>GI disturbances- nausea, vomition in dog and cats(more susceptible). </li></ul></ul></ul><ul><ul><ul><li>Ideosyncracy in cats </li></ul></ul></ul><ul><ul><ul><li>Decreased WBC and RBC count, anaemia </li></ul></ul></ul><ul><ul><ul><li>Teratogenic- induce congenital brain, skeletal malformations, contraindicated in pregnant animals, particularly in cats </li></ul></ul></ul><ul><ul><ul><li>Impaired liver function </li></ul></ul></ul>
  11. 12. <ul><li>Antimetabolites </li></ul><ul><li>5’-Flucytosine </li></ul><ul><li>Activated by deamination within the fungal cells to 5-fluorouracil </li></ul><ul><li>5-fluorouracil inhibits thymidylate synthetase </li></ul><ul><li>Also inhibits fungal protein synthesis by replacing uracil with 5-FU in fungal RNA </li></ul><ul><li>Resistance common (used in combination with other antifungals like AmB in cryptococcal meningitis) </li></ul><ul><li>Broad range (only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcal meningitis) </li></ul><ul><li>orally well absorbed </li></ul><ul><li>Selective toxicity to fungal cells (no deaminase in mammalian cells) </li></ul><ul><li>Bone marrow toxicity – pancytopenia –reversible </li></ul>
  12. 13. <ul><li>Azoles </li></ul><ul><li>inhibit the synthesis of ergosterol (block demethylation of lanosterol by inhibiting fungal CYP3A 14-demethylase) </li></ul><ul><li>Fungistatic , active against systemic fungi and dermatophytes: </li></ul><ul><li>fungicidal at higher concentration </li></ul><ul><li>Resistance due to altered 14-demethylase </li></ul><ul><li>Limitations : </li></ul><ul><li>1. Interactions: The frequency of their interactions with coadministered drugs, which results in adverse clinical consequences . One type of azole-drug interaction may lead to decreased plasma concentration of the azole, related to either decreased absorption or increased metabolism of the azole. </li></ul><ul><li>The other type of azole-drug interaction may lead to an unexpected toxicity of the coadministered drug, relating to the ability of the azoles to </li></ul><ul><li>increase plasma concentrations of other drugs by altering hepatic metabolism via the cytochrome P-450 system. </li></ul>
  13. 14. <ul><li>Increased plasma concentration of co administered drug </li></ul><ul><li>Cyclosporine Nephrotoxicity </li></ul><ul><li>Tacrolimus Nephrotoxicity </li></ul><ul><li>Phenytoin Phenytoin toxicity </li></ul><ul><li>Sulfonylureas Hypoglycemia </li></ul><ul><li>Increased metabolism of azoles </li></ul><ul><li>Isoniazid </li></ul><ul><li>Rifampin, </li></ul><ul><li>Phenytoin, </li></ul><ul><li>Carbamazepine </li></ul><ul><li>Phenobarbital </li></ul><ul><li>2. Resistance : </li></ul><ul><li>The emergence of resistance of fungal organisms, especially Candida species, to fluconazole.. </li></ul><ul><li>Injudicious use </li></ul>
  14. 15. <ul><li>a.Imidazoles </li></ul><ul><li>Impair synthesis of ergosterol; inhibit sterol 14 α-demethylase (of cyt. P450). Acumulation of precursors which inhibit growth. </li></ul><ul><li>Mammalian cells can incorporate already formed cholesterol; fungi have to synthesize </li></ul><ul><li>Adverse effects due to inhibition of mammalian steroid synthesis </li></ul><ul><li>Drug interactions due to inhibition of cyt. P450 enzymes . </li></ul><ul><li>Clotrimazole : topical – Candidiasis, tinea </li></ul><ul><li>Ketoconazole </li></ul><ul><li>First oral -azole , older, and more toxic (mostly replaced by fluconazole and itraconazole) </li></ul><ul><li>Absorption variable (better in acidic medium, antacids interfer) </li></ul><ul><li>Poor concentration in CSF </li></ul><ul><li>Metabolized by Cyt. P450 enzymes </li></ul>
  15. 16. <ul><li>Adverse effects of ketoconazole: </li></ul><ul><li>Nausea, anorexia, vomiting, dizziness , itching, increased liver enzyme values. </li></ul><ul><li>Cats are more susceptible - anorexia, vomiting, diarrhoea, fever. hepatitis </li></ul><ul><li>Pruritus, alopecia, reversible lightening of hair, and cataract (long term) are the most common adverse effects in dogs </li></ul><ul><li>Endocrine: menstrual abnormalities, gynaecomastia, azoospermia, decreased libido and potency. Thus Contraindicated in breeding animals </li></ul><ul><li>Emryotoxic and teratogenic- avoided in pregnancy </li></ul><ul><li>Hypertension and fluid retention </li></ul><ul><li>Hepatitis (rare-fatal) </li></ul><ul><li>Drug Interactions (inhibition of cyt. P450) </li></ul><ul><li>Therapeutic Use : coccidiomycosis, histoplasmosis if not severely ill or immunocompromized. Oral, esophageal, mucocutaneous candidiasis </li></ul>
  16. 17. <ul><li>b.Triazoles </li></ul><ul><li>Newer, less toxic, more effective </li></ul><ul><li>Fluconazole: – Used i.v. and p.o. </li></ul><ul><li>possesses the most desirable pharmacologic properties, including high bioavailability, high water solubility, low degree of protein binding, wide volume of distribution into body tissues and fluids, including cerebrospinal fluid, and urine, and long half-life In addition, </li></ul><ul><li>fluconazole and itraconazole are better tolerated and more effective than ketoconazole. </li></ul><ul><li>Completely absorbed and better tolerated </li></ul><ul><li>Renal excretion, 90% excreted unchanged </li></ul><ul><li>Less endocrine effects </li></ul><ul><li>Penetrates well into CSF </li></ul><ul><li>Cryptococcal, coccidial meningitis. Candidiasis. </li></ul><ul><li>Drug Interactions </li></ul>
  17. 18. <ul><li>Itraconazole </li></ul><ul><li>Used i.v. and p.o. (p.o.- poor absorption) </li></ul><ul><li>Varied absorption. Metabolized by cyt P450 </li></ul><ul><li>– Absorption increased by acids (Orange juice, Coke) </li></ul><ul><li>– Absorption decreased by antacids </li></ul><ul><li>– Does not reach CSF </li></ul><ul><li>– Highly lipophilic => fatty tissue accumulation </li></ul><ul><li>Very broad spectrum </li></ul><ul><li>Has less endocrine effects but occur at high doses </li></ul><ul><li>Less hepatic adverse effect </li></ul><ul><li>Indicated mainly in Histoplasmosis and blastomycosis </li></ul><ul><li>Many drug interactions (due to inhibition of cyt P4503A4) </li></ul>
  18. 19. <ul><li>Second generation triazoles </li></ul><ul><li>Voriconazole </li></ul><ul><li>Structurally related to fluconazole </li></ul><ul><li>High Vd and excellent tissue penetration </li></ul><ul><li>Visual disturbance(reversible, dose related ) is the adverse effect in humans </li></ul><ul><li>Used for severe systemic infections and emerging fungi (very broad pectrum) </li></ul><ul><li>Mainly indicated for invasive asoergillosis and serious infections caused by Fusarium spp,Scedosporium spp etc. </li></ul><ul><li>Posaconazole </li></ul><ul><li>– Very broad spectrum , good oral bioavailability and longer half life(15hrs) </li></ul><ul><li>- structurally similar to itraconazole </li></ul><ul><li>- Active against zygomycetes </li></ul><ul><li>Ravuconazole- Derivative of fluconazole, expanded spectrum against yeast and filamentous fungi </li></ul>
  19. 20. <ul><li>Echinocandins </li></ul><ul><li>Lipopeptide antifungals </li></ul><ul><li>Inhibit synthesis of glucan in the fungal cell wall ( block 1,3-beta glucan synthase) resulting in formation of defective cell walls </li></ul><ul><li>Newest antifungals, limited oral bioavailability , only IV formulations </li></ul><ul><li>Well tolerated, No dose adaptation needed in renal insufficiency </li></ul><ul><li>Fewer drug interactions, as the metabolism is independent of cyp450 system </li></ul><ul><li>Major indication is against Candida and invasive Aspergillus unresponsive to other drugs. </li></ul>
  20. 21. <ul><li>Allylamines </li></ul><ul><li>Inhibit fungal sterol synthesis (ergosterol) by inhibiting squalene epoxidase. </li></ul><ul><li>This effect causes fungal death, due to increased membrane permeability mediated by the accumulation of high concentration of squalene, rather than by ergosterol deficiency. </li></ul>
  21. 22. <ul><li>Terbinafine </li></ul><ul><li>Synthetic antifungal (mostly topical; p.o. for tinea unguium) </li></ul><ul><li>Lipophilic: accumulates in fat, skin and nails </li></ul><ul><li>Short course of therapy </li></ul><ul><li>Low relapse ratio </li></ul><ul><li>Microsomal CYP 450 enzyme inhibitor, dose to be reduced on co administration </li></ul><ul><li>Synergestic activity with azoles (invitro) , antagonistic with amphotericin B . </li></ul><ul><li>Well tolerated, limited adverse GI effects </li></ul><ul><li>– Mostly first line drugs for most dermatophytes (tinea, onychomycosis, ringworm) </li></ul><ul><li>Butenafine </li></ul><ul><li>anti-inflammatory activity </li></ul><ul><li>Superior antifungal activity over Terbinafine </li></ul>
  22. 23. <ul><li>Iodides </li></ul><ul><li>Sodium iodide (20mg/kg- cats; 40mg/kg –dogs, oral bid, for 4 weeks; OR 10% NaI 1g/ 15kg in cattle, IV ) </li></ul><ul><li>the action thought to result from enhancement of the immune response by spurring the halide peroxide killing system of phagocytic cells. </li></ul><ul><li>Due to signs of iodism and prolonged tissue residues entering the human food chain, their use is discouraged Lufenuron </li></ul><ul><li>is oral insecticide for flea control in dogs and cats </li></ul><ul><li>interferes with chitin synthesis and the deposition of chitin in the cuticle of insects. Chitin is also an important component of the outer cellwall of fungi </li></ul><ul><li>The therapeutic utility of this agent as antifungal is also under consideration </li></ul><ul><li>Others -Ciclopirox olamine, haloprogin,tolnaftate,, undecylenicacid,quinidochlor, Thiabendazole, salicylic acid, benzoicacid, Sodiumthiosulphate, Copper sulphate, Dichlorophen, Monosulfiram, </li></ul>