Antiviral & Antifungal Drugs PDF

Module 7: Antiviral & Antifungal Drugs Lesson 7.2: Antifungal Drugs Introduction Fungi are the eukaryotic, saprophytic, parasitic microorganisms; can be - unicellular or multicellular Subdivided into groups: molds, mushrooms, yeasts Penic...

Module 7: Antiviral & Antifungal Drugs Lesson 7.2: Antifungal Drugs Introduction Fungi are the eukaryotic, saprophytic, parasitic microorganisms; can be - unicellular or multicellular Subdivided into groups: molds, mushrooms, yeasts Penicillium griseofulvum Griseofulvin: MOA From Penicillium griseofulvum Actively taken up by growing dermatophytes Binds to microtubules Inhibit spindle formation and mitosis Fungistatic (Microsporum spp. and Trichophyton spp.) Action is slow Infected cells shed and replaced with uninfected cells  Griseofulvin: Pharmacokinetics Absorption High oral absorption High- fat foods Preparation of micronized particles Fate: distributed to keratin precursor cells of the skin, hairs shafts and nails Metabolism: liver Demethylation Glucuronide conjugation Excretion: Urine Griseofulvin Administration and use: PO: dogs, cats and horses (for multifocal dermatophyte infections) Adverse effects Rare Idiosyncratic reaction in kittens: Leukopenia Anemia Azoles Have antibacterial, antifungal, antiprotozoal and anthelmintic activity Poorly water soluble except for fluconazole Divided into Imidazoles and Triazoles Clotrimazole Miconazole Econazole Ketoconazole Itraconazole Fluconazole Azoles: MOA Alter cell membrane permeability of susceptible yeasts and fungi Block synthesis of ergosterol Inhibit other enzyme systems- fatty acid synthesis (blocking of Cytochrome P450 enzymes) Fungistatic (Blastomyces, Coccidioides, Cryptococcus, and Histoplasma spp.) High doses cause inhibition of mammalian steroid synthesis Ketoconazole Imidazole antifungal for systemic use Mechanism of action Inhibits synthesis of ergosterol in fungal cytoplasmic membranes by blocking cytochrome P-450 enzymes Fungistatic Often given orally; topical preparations Ketoconazole Pharmacokinetics Well absorbed orally Widely distributed, esp. in tissues with high lipid content; except in CNS Metabolized in liver: microsomal enzymes Excreted in bile Patients with impaired renal function may have t ½ extended significantly Ketoconazole Therapeutic Uses Systemic mycoses and severe yeast infections: dogs, cats, horses and birds Hyperadrenocorticism (at high dosages): dogs and cats Adverse Effects Anorexia, vomiting and diarrhea Suppresion of adrenal or gonadal steroids (transient) Fluconazole Synthetic; only azole that is water soluble; fungistatic; excreted via kidney Cell membrane alteration-leakage of cellular contents; impaired uptake of purine and pyrimidine precursors Indications: Systemic mycoses: cryptococcal meningitis, blastomycosis and histoplasmosis Superficial candidiasis or dermatophytosis Fluconazole Contraindications: Hypersensitivity Hepatic diseases Renal impairment Not to be used in pregnant animals Miconazole Effective against fungal infections caused by Microsporum canis, Microsporum gypseum, and Trichophyton mentagraphytes Ophthalmic preparations available Will penetrate the intact corneal epithelium First choice agent for horse fungal keratitis (Aspergillus sp. and Fusarium sp.) Delivered by subconjunctival route Itraconazole For systemic mycoses Aspergillosis Cryptococcal meningitis Blastomycosis Histoplasmosis No effects on hormone synthesis Itraconazole Fewer side effects than ketoconazole in small animals but it can cause: Hepatic toxicity Anorexia Weight loss Vomiting Polyene macrolides From various strains of Actinomyces Amphotericin B Nystatin used in VM Pimaricin (natamycin) Poorly soluble in water  Amphotericin B Polyene macrolide Mechanism of action Binds to ergosterol of fungal membrane forming pores or channels which results in leakage of cellular contents Fungicidal or fungistatic fungicidal against most organisms causing systemic mycoses: Aspergillus, Blastomyces, Coccidioides, Cryptococcus, and Histoplasma spp. Amphotericin B: Pharmacokinetics Not absorbed in the GIT Distributed to most tissues except in the CNS, eye and bone Secreted unchanged in the urine Amphotericin B: Spectrum of activity For systemic mycoses of dog, cats, horses and birds Combined therapy with ketoconazole, fluconazole, itraconazole (reduce toxicity) Administered with flucytosine in treating CNS, bone and ocular infections Amphotericin B: Adverse effects Renal toxicity Renal vasoconstriction Decreased renal glomerular filtration Damage to tubular epithelium Renal function should be monitored weekly during therapy Nystatin Fungistatic or fungicidal From Streptomyces noursei Combined with other drugs: Neomycin, Thiostrepton, Triamcinolone acetonide For candidiasis infecting the skin, mucous membranes and intestinal tract of small animals and birds Adverse side effects: rare Natamycin Ophthalmic preparation: approved antifungal for eyes Poorly water soluble Will not penetrate the corneal epithelium For fungal dermatitis → Fusarium keratomycosis in horse Flucytosine Fluorinated pyrimidine Mechanism of action Fungicidal vs Cryptococcus, Candida & Aspergillus spp. Inhibits thymidylate synthetase Inhibit DNA and RNA synthesis in susceptible fungi Flucytosine Well absorbed orally Widely distributed, plus CNS Excreted unchanged in the urine Effective against Cryptococcus Candida Aspergilli Flucytosine: Therapeutic uses Combined with amphotericin B for the treatment of cryptococcosis (Esp. meningeal cryptococcosis) in dogs and cats For aspergillosis and candidiasis in psittacine birds Flucytosine Adverse side effects Low toxicity Mild gastrointestinal disturbances Bone marrow depression: Rare Terbinafine allylamine derivative MOA: inhibits the synthesis of ergosterol by blocking the enzyme squalene monooxygenase (squalene 2,3- epoxidase) → inhibits the conversion of squalene to sterols (ergosterol) and causes accumulation of squalene Fungicidal vs dermatophytes Fungistatic vs yeast Terbinafine Can be administered orally or topically → useful for treating dermatophytic infections in dogs and cats; useful for treating birds for systemic mycotic infections such as aspergillosis Pharmacokinetics. No information is available for animals; lipophilic Well tolerated by animals Other antifungals Chlorhexidine Iodine Tolnaftate Benzoic acid Salicylic acid Thiabendazole Reference Hsu, W.H. (2008). Handbook Of Veterinary Pharmacology. Wiley Blackwell. Plumbs, D.C. (2008). Plumb's Veterinary Drug Handbook. (6th ed.). Blackwell Publishing.