Antifungal Drugs Class

Antifungal Drugs : 

Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong Antifungal Drugs

Introduction - Also called antimycotic drugs : 

Introduction - Also called antimycotic drugs Used to treat two types of fungal infection: Superficial fungal infections - skin or mucous membrane Systemic fungal infections - lungs or central nervous system Fungi causing mycosis live as commensally or are present in the environment. Earlier superficial infections were uncommon and systemic rather rare. Recently there is increase in local as well as systemic fungal infections. Reason for this is opportunistic infections

Opportunistic infections : 

Opportunistic infections Immuno-suppression due to - Cancer chemotherapy - AIDS Corticosteroid overuse Indiscriminate use of broad spectrum antibiotics

Fungal infections : 

Fungal infections Superficial Skin Hair Nails Mucous membrane Deep Tissues (muscle & connective tissue) Organs Images of some superficial skin infections

Types of fungal infections - Mycoses : 

Types of fungal infections - Mycoses Superficial mycoses Affect the skin, hair and nails – ringworm/tinea or onychomycosis Subcutaneous mycoses (tropical) Affect the muscle and connective tissue immediately below the skin Systemic (invasive) mycoses Involve the internal organs Allergic mycoses Affect lungs or sinuses Patients may have chronic asthma, cystic fibrosis or sinusitis There is some overlap between these groups

MOST COMMON FUNGAL PATHOGENS : 

MOST COMMON FUNGAL PATHOGENS Dermatophytes – Microsporum, Epidermophyton and Trichophyton Candida – C. albicans, C. glabrata, C. tropicalis Aspergillus Cryptococcus Rhizopus

Causative fungi : 

Causative fungi Superficial infections by Dermatophytes (ring worms): athlete`s foot or tinea pedis, jock itch or tinea cruris, tinea capitis etc. Candida: oral thrush, vaginitis and diaper candidiasis etc. Deep infections are Candidiasis: Chronic mucocutaneous candidiasis, systemic candidiasis etc. Aspergillosis: broncho-pulmonary aspergillosis Coccidiomycosis: pulmonary and disseminated (complications – pneumonia) Histoplasmosis: H. capsulatum (common in HIV)

What are the targets for antifungal therapy? : 

What are the targets for antifungal therapy? Cell membrane Fungi use principally ergosterol instead of cholesterol Cell Wall Unlike mammalian cells, fungi have a cell wall DNA Synthesis Some compounds may be selectively activated by fungi, arresting DNA synthesis.

Cell Membrane Active Antifungal : 

Cell Membrane Active Antifungal Cell membrane 1. Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical) 2. Azole antifungals Imidazoles: Topical: Clotrimazole, econazole, miconazole Systemic: Ketoconazole Triazoles: Fluconazole, itraconazole and voriconazole

Polyene antibiotics-Amphotericin B : 

Polyene antibiotics-Amphotericin B Fermentation product of Streptomyces nodusus High affinity for ergosterol present in fungal cell membrane Hydrophilic polyhydroxyl chain along one side and a lipophilic polyene hydrocarbon chain on the other Binds sterols in fungal cell membrane – high affinity for ergosterol present in fungal cell membrane affinity is less for host cell membrane although closely resembles Creates transmembrane channel and electrolyte leakage. Active against most fungi except Aspergillus terreus, Scedosporium spp. Bacteria lack sterols so insensitive to polyenes

Antifungal spectrum : 

Antifungal spectrum Most Toxic antifungal Fungicide at high and static at low conc. Effective against Candida albicans Histoplasma capsulatum Cryptococcus

Pharmacokinetics : 

Pharmacokinetics Insoluble in water Unstable at 37degree Poorly absorbed from GIT Cannot cross BBB Highly bound to plasma proteins Takes 2 months for complete clearance of drug Given as I/V infusion For fungal meningitis given intrathecally Has immuno-stimulant action also Given in immuno-compromised patients for fungal infections

Uses : 

Uses Broad spectrum antifungal Useful for 1. Candida that causes oral vaginal cutaneous candidiasis 2. Cryptococcus 3. Histoplasma 4. Aspergillosis 5. Also effective for Leishmaniasis(Reserve drug for resistant cases of Kala Azar)

ADRs : 

ADRs Acute reactions - occurs with each infusion Chills, Nausea, Vomiting, Pain, Fever, Aches, Dyspnoea So corticosteroids are administered along with the drug Thrombophlebitis Bone marrow depression - Reversible anemia On intrathecal injection – Headache, Vomiting, Nerve paralysis Renal toxicity leading to – Azotemia, Decreased GFR, Acidosis, Hypokalemia, Inability to conc. urine

Newer Amphotericin B : 

Newer Amphotericin B They are developed to overcome 1. Side effects 2. To improve tolerability 3. To get the drug at site of action 4. To reduce the toxicity i.e.. Less nephrotoxic and minimal anemia Formulations are: 1. Amphotericin B lipid complex 2. Amphotericin B colloidal dispersion 3. Liposomal Amphotericin B (Only drawback of these formulations is less efficacy)

Drug Interactions of Amphotericin B : 

Drug Interactions of Amphotericin B With Flucytocin-synergistic action Rifampicin and Minocyclin – Both potentiate Amphotericin B Vancomycin and Aminoglycoside – Both increase risk of nephrotoxicity Preparation and doses: 50 – 100 mg four times a day orally 3% ear drops Systemic: 50 mg vial (one vial diluted in 500 ml of 5% glucose and initially 1 mg test dose followed by infusion for 4 – 8 Hrs)

Nystatin : 

Nystatin Similar to Amphotericin B but more toxic than Amphotericin B Used only for superficial candidiasis of Skin, Mouth, Vagina, Intestine As ointment ,oral tablets & suppositories Available as tablets and ointments (1 to 5 lacs U) – also vaginal tablets Orally not absorbed but can be used in monilial diarrhoea

Other Polyenes : 

Other Polyenes Hamycin: Water soluble Absorption from GIT not reliable Not used for systemic fungal infections Used topically for Aspergillus, Candida, Monilial, Trichomonas vaginalis infections Natamycin: Broad spectrum Used topically for – Keratitis, Monilial infections, Trichomonas vaginalis

Imidazoles and Triazoles : 

Imidazoles and Triazoles Azole antifungals Imidazoles: Topical: Clotrimazole, econazole, miconazole Systemic: Ketoconazole Triazoles: Fluconazole, itraconazole and voriconazole Remember that among imidazoles, only ketocanazole is systemic, other 3 are topical only While, Triazoles are used systemically and largely replacing ketoconazole

Azole Structures : 

Azole Structures Fluconazole Ketoconazole

Azoles – Common Mechanism : 

Azoles – Common Mechanism In fungi, the cytochrome P450-enzyme lanosterol 14-alpha demethylase is responsible for the conversion of lanosterol to ergosterol Azoles bind to lanosterol 14α-demethylase inhibiting the production of ergosterol Some cross-reactivity is seen with mammalian cytochrome p450 enzymes leading to Drug Interactions Impairment of steroidneogenesis (ketoconazole, itraconazole)

Effect of azoles on C. albicans : 

Effect of azoles on C. albicans Before exposure After exposure Decreased budding from the parent cells

Individual Agents : 

Individual Agents Ketoconazole: Spectrum: yeasts and moulds - poor absorption limits its role for severe infections, generally used in mucosal infections only (dematophytosis) Pharmacokinetics Variable oral absorption, dependent on pH (often given with cola or fruit juice) T1/2 = 7-10 hours Protein binding > 99% Hepatic, bile and kidney elimination

Ketoconazole – contd. : 

Ketoconazole – contd. Adverse effects N&V, worse with higher doses (800 mg/day) Hepatoxicity (2-8%), increase in transaminases, hepatitis Dose related inhibition of CYP P450 responsible for testosterone synthesis Gynecomastia, oligosperma, decreased libido Dose-related inhibition of CYP P450 responsible for adrenal cortisol synthesis

Ketoconazole – contd. : 

Ketoconazole – contd. Drug Interaction: Potent inhibitor of cytochrome P450 3A4 Rifampin and phenytoin decrease ketoconazole levels Ketoconazole increases cyclosporin, warfarin, astemizole, corticosteroid, and theophylline levels Many of these drug interactions are severe Drugs that increase gastric pH will decrease blood levels of ketoconazole Antacids, omeprazole, H2 blockers Doses: Serious infections 800 mg/day PO Other: 200-400 mg/day PO

Fluconazole : 

Fluconazole Water soluble having wider range of activity than Ketoconazole Good activity against C. albicans and Cryptococcus neoformans Non-albicans Candida species more likely to exhibit primary resistance Always resistant Sometimes resistant C. krusei > C. glabrata > C. parapsilosis C. tropicalis C. kefyr

Resistance : 

Resistance Primary resistance (seen in severely ill or immunocompromised patients) Selection of resistant species or subpopulations Replacement with more resistant strain Secondary resistance (seen in patients with AIDS who experienced recurrent orophayrngeal candidiasis and received long-term fluconazole therapy) Genetic mutation Upregulation of efflux pumps

Mechanisms of antifungal resistance : 

Mechanisms of antifungal resistance Target enzyme modification Ergosterol biosynthetic pathway Efflux pumps Drug import

Fluconazole - Kinetics : 

Fluconazole - Kinetics Available as both IV and PO Bioavailibility > 90% Pharmacokinetics t 1/2 = ~24 hours Protein binding < 12% Vd 0.85 L/kg (widely distributed) >90% excreted unchanged through the kidney Dosing Mucosal candidiasis 100-200 mg/day (150 mg tablet vulvovaginal candidiasis) Systemic fungal infections 400-800 mg q24h > 800 mg q24h in unstable patient, S-DD isolate, or if non-albicans spp. (except C. krusei) Maintenance for cryptococcal meningitis 400 mg q24h

Fluconazole - ADRs : 

Fluconazole - ADRs N&V, rash: More likely with high doses and in AIDS patients Asymptomatic increase in LFTs (7%) Drug interactions: May increase phenytoin, cyclosporin, rifabutin, warfarin, and zidovudine concentrations Rifampin reduced fluconazole levels to half (even though FLU is not a major substrate)

Itraconazole : 

Itraconazole Some Features: Newer orally active triazole Broader spectrun than KTZ and FCZ – includes moulds like aspergillus Fungistatic action but very effective in immunocompromizrd patients Steroid hormone synthesis inhibition is absent and no serious hepatotoxicity

Local azoles : 

Local azoles Very popular local azoles are – Clotrimazole, Econazole and Miconazole (For Tinea, Ring worm, Athlete’s foot, otomycosis, oral, cutaneous & vaginal candidiasis) Mechanism of action is same as that of Ketoconazole i.e. ergosterol inhibition by inhibiting CYP450 Clotrimazole is favoured in vaginitis because of long lasting residual effect and once daily dosing Miconazole causes frequently vaginal irritation & pelvic cramp. Available s lotion, cream, powder, vaginal tablet etc.

Heterocyclic Nitrofurans - Griseofulvin : 

Heterocyclic Nitrofurans - Griseofulvin Used for superficial fungal infections by dermatophytes Derived from Penicillium griseofulvum but no antibacterial activity Effective against most dermatophytes, but not against candida causing deep mycosis Dermatophytes actively concentrate it – accounts for selective toxicity against them Taken up by newly formed keratin

Griseofulvin - MOA : 

Griseofulvin - MOA Interferes with mitosis – results in multinucleated and stunted hyphae (In most fungi, hyphae are the main mode of vegetative growth, and are collectively called a mycelium yeasts are unicellular fungi that do not grow as hyphae) Abnormal metaphase configurations leading to failure of daughter nuclei to fall apart (Colchicine and vinca alkloids also mitotic inhibitors but they cause arrest of mitosis) Disorientation of polymerized microtubules

Griseofulvin – contd. : 

Griseofulvin – contd. Pharmacokinetics: Given orally and fats improve absorption Absorption depends on the particle size Duration of treatment depends upon tissue turn over 1. 3-6 wks for skin & hair 2. 3-6 months for nails Treatment should continue till whole infected tissue is shed off. Doses: Used orally only for dermatophytosis (125 to 250 mg 4 times daily, but depends on site of infection

Griseofulvin - ADRs : 

Griseofulvin - ADRs Safe with mild side effects 1. GIT upsets 2. CNS symptoms 3. Hepatotoxicity 4. Leucopenia 5. Photosensitivity 6. Allergy etc. Microsomal enzyme inducer Causes decrease in activity of anticoagulants Cause intolerance to alcohol Phenobarbitone reduces its oral absorption so failure of therapy

Flucytosin : 

Flucytosin Fluorinated pyrimidine related to flurouracil Restricted spectrum of activity. Acquired Resistance due to > result of monotherapy Due to: 1) Decreased uptake (permease activity) 2) Altered 5-FC metabolism (cytosine deaminase or UMP pyrophosphorylase activity) Kinetics: Orally absorbed Widely distributed even in CSF Exc. in urine. Converted in fungal cell to 5-FU which is antimetabolite. Mammalian cells remain unaffected except few bone marrow cells

Flucytosin : 

Flucytosin Monotherapy : Never Candidiasis Cryptococcosis ?Aspergillosis } In combination with amphotericin B or fluconazole. Doses: Vaginal candidiasis: 200 mg OD for 3 days Dermatophytosis; 100-200 mg OD for 7-15 days Onychomycosis: 200 mg per day for 3 months ADRs: 1.Mild BM depression 2. Loss of hair 3. Dose should be decreased in the presence of renal impairment

Terbinafine : 

Terbinafine Belongs to a newer allylamine class of antifungals Given both orally & locally Lipophillic so widely distributed Fungicidal in contrast to azoles (fungistatic) Acts by non-competitive inhibition of “squalene epoxidase” (early step enzyme in ergosterol synthesis (Image in Slide No. 22) – accumulation of squalene in fungal cells – cidal effect Used for dermatophytes & candida Dose is 250mg OD for 2-6 wks Locally 1% ointment.

Terbinafine – contd. : 

Terbinafine – contd. ADRs With oral GIT upset Hepatic dysfunction Rash Taste disturbance No interaction with CYP450 Preparations and doses: 1% cream 125/250 mg tablets etc. Tinea pedis: 250 mg OD for 2-6 weeks Onychmycosis: 3-12 months (alternative to fluconazole) On local application - dryness, Erythema, Rash, itching etc.

Expected Questions : 

Expected Questions Classify antifungals. Write MOA, ADRs and Uses of Amphotericin B Classify azoles. Write briefly on MOA and Uses of azoles Write briefly on MOA and mechanism of resistance of azoles MCQs: Amphotericin B is: fungistatic, fungicidal etc. choices Azoles: inhibits ergosterol, inhibits nucleic acid, inhibits microtubule etc. Ketoconazole may cause: cortisol deficiency, testosterone deficiency etc. Griseofulvin causes: destruction of fungal microtubule, inhibits fungal cell membrane etc. Griseofuvin is best administered: with fatty diet, in empty stomach etc. Short Notes: Fluconazole, Griseofulvin, Ketoconazole, Clotrimazole, Terbinafine

Thank you : 

Thank you

Slide 45: 

A fungus (pronounced /ˈfʌŋɡəs/; pl. fungi)) is a member of a large group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms These organisms are classified as a kingdom, Fungi (pronounced /ˈfʌndʒaɪ/ or /ˈfʌŋɡaɪ/), that is separate from plants, animals and bacteria. One major difference is that fungal cells have cell walls that contain chitin, unlike the cell walls of plants, which contain cellulose. he yeast species Saccharomyces cerevisiae has been used in baking and fermenting alcoholic beverages for thousands of years.[5] It is also extremely important as a model organism in modern cell biology research, and is one of the most thoroughly researched eukaryotic microorganisms. Researchers have used it to gather information about the biology of the eukaryotic cell and ultimately human biology.[6] Other species of yeast, such as Candida albicans, are opportunistic pathogens and can cause infections in humans. Yeasts have recently been used to generate electricity in microbial fuel cells,[7] and produce ethanol for the biofuel industry.

Slide 46: 

The Fungal Cell Wall Atlas of fungal Infections, Richard Diamond Ed. 1999 Introduction to Medical Mycology. Merck and Co. 2001