Antifungal Agents (Pharmacology II - PHRM341) PDF

Pharmacology II PHRM341 Antifungal agents Dr. Aseel Rataan Faculty of Pharmacy Department of Clinical Pharmacy and Pharmacy Practice  Antifungal Agents: Fighting Fungal Infections  Fungal infections pose signif...

Pharmacology II PHRM341 Antifungal agents Dr. Aseel Rataan Faculty of Pharmacy Department of Clinical Pharmacy and Pharmacy Practice  Antifungal Agents: Fighting Fungal Infections  Fungal infections pose significant challenges, especially for immunocompromised patients.  Fungi are resist to conventional antimicrobials  Limited treatment options for systemic fungal diseases.  The primary weapons against systemic infections are amphotericin B, azoles (fluconazole, itraconazole, ketoconazole, voriconazole), and echinocandins.  They selectively target fungi by interacting with or inhibiting ergosterol synthesis, a sterol unique to fungal cell membranes. Mycoses :Infectious diseases caused by fungi , they are often chronic in nature. Candidiasis, dermatopytosis, aspergillosis, onchomycosis Some fungi are part of the normal flora (skin, mouth, intestines, and vagina). Fungi can be ingested orally or can be inhaled.  Major Types of Mycoses 1. Cutaneous: (superficial ) infections of the skin (ex. candidiasis, dermatophytosis). 2. Subcutaneous: fungi penetrate the skin. 3. Systemic : The most difficult to treat , and often life- threatening (systemic candiasis, meningitis, or in aspergillosis infection in lung )  Infection affects the mouth is called thrush or oral candidiasis (common in newborn infants and immunocompromised patients). Vaginal candidiasis, commonly called a “Yeast infection”, often affects :  Pregnant women  Women with DM  Women taking OCs and antibiotics  Incidence of fungal infections is increased in Individuals : On chronic immune suppression following organ transplant Infected with the (HIV) Drugs (Steroids, Chemotherapy, Antibiotic therapy, antineoplastic)  Pharmacology treatment :  Systemic anti-fungal  Topical anti-fungal  Systemic antifungals To treat systemic mycotic infections and some dermatomycoses Oral or parenteral drugs  Examples :  Polyenes: Amphotericin B  Azoles: fluconazole, ketoconazole, itraconazole.  Griseofulvin  Flucytosine  Caspofungin  Amphotericin B: The Polyene Powerhouse 1 Classification Amphotericin B is a polyene antibiotic related to nystatin. It is poorly absorbed orally and typically administered intravenously. 2 Distribution The drug distributes widely to tissues but does not penetrate the central nervous system (CNS) well. 3 Elimination Amphotericin B undergoes slow hepatic metabolism with a half-life of about 2 weeks. Small fraction is excreted in urine “dosage adjustment in extreme renal dysfunction since Amphotericin B is not dialyzable Mechanism of Action: Amphotericin B Membrane Disruption Amphotericin B's fungicidal action stems from its effects on fungal membrane permeability and transport properties. Amphipathic Nature As an amphipathic molecule, it has both hydrophilic and lipophilic regions, allowing it to interact with membranes. Ergosterol Binding The drug binds specifically to ergosterol, a sterol found in fungal cell membranes but not in human cells. Pore Formation This binding leads to the formation of artificial pores in the fungal cell membrane, disrupting its integrity. Resistance Uncommon (decreased level of or a structural change in membrane ergosterol)  Clinical Uses of Amphotericin B 1 Broad Spectrum Amphotericin B has the widest antifungal spectrum of any agent, making it crucial for treating systemic mycoses. 2 First-line Treatment It is often the drug of choice for initial induction regimens before transitioning to azole therapy. 3 Key Indications Amphotericin B is effective against infections caused by Aspergillus, Blastomyces, Candida albicans, Cryptococcus, Histoplasma, and Mucor. 4 Administration - Typically given by slow intravenous infusion, with intrathecal administration possible but risky for fungal meningitis. - Local administration for the treatment of mycotic corneal ulcers and keratitis.  Toxicity of Amphotericin B: Infusion-Related Effects Common Reactions Mitigation Strategies Intravenous infusion of These effects can be reduced by amphotericin B often causes using a slow infusion rate + fever, chills, muscle spasms, premedication with vomiting, and a shock-like drop in antihistamines, antipyretics, blood pressure. meperidine, or glucocorticoids. Dose-Limiting Toxicity of Amphotericin B 1 Renal Effects ↓ glomerular filtration rate and causes renal tubular acidosis with magnesium and potassium wasting 2 Anemia ↓ renal formation of erythropoietin 3 Nephrotoxicity and neurotoxicity Intrathecal administration may cause seizures and neurologic damage 4 Combination Therapy Using amphotericin B with flucytosine allows for dose reduction in some infections, potentially lowering toxicity Concomitant saline infusion may reduce renal damage and nephrotoxicity  Liposomal Formulations of Amphotericin B Reduced Nephrotoxicity Liposomal formulations of amphotericin B have shown decreased nephrotoxic effects compared to conventional forms. Mechanism This reduction in toxicity may be due to decreased binding of the drug to renal cells. Clinical Advantage The improved safety profile allows for potentially higher doses or longer treatment courses when necessary. Cost Consideration However, liposomal formulations are significantly more expensive than conventional amphotericin B. Flucytosine (5-Fluorocytosine) 1 Classification Flucytosine is a pyrimidine antimetabolite related to the anticancer drug 5-fluorouracil (5-FU). 2 Administration It is effective when given orally and distributes widely to most body tissues, including the CNS. 3 Elimination The drug is eliminated intact in the urine, with dosage adjustment necessary in renal dysfunction. Mechanism of Action: Flucytosine Cellular Uptake Flucytosine is accumulated in fungal cells through the action of a membrane permease. Conversion Inside the cell, it is converted by cytosine deaminase to 5-fluorouracil (5-FU). Inhibition 5-FU inhibits thymidylate synthase, disrupting fungal DNA synthesis. Selectivity Mammalian cells have low levels of the necessary permease and deaminase, providing selective toxicity to fungi. Clinical Uses and Resistance of Flucytosine Narrow Spectrum Key Indications Resistance Concerns Flucytosine has a limited It is used with amphotericin B or Rapid when used alone “due to antifungal spectrum, primarily triazoles for Cryptococcus decreased activity of fungal used in combination therapy. neoformans infections, some permeases or deaminases” systemic candidal infections, and chromoblastomycosis caused by Combination therapy helps molds. prevent resistance and may provide synergistic effects.  Toxicity of Flucytosine Bone Marrow Suppression (reversible) Hair Loss (Alopecia) Monitoring Liver dysfunction Regular blood tests are necessary to monitor for these potential toxicities during treatment.  Azole Antifungal Agents 1 Classes 2 Administration Azoles include imidazoles (ketoconazole) and Most triazoles are available in both oral and intravenous triazoles (fluconazole, itraconazole, posaconazole, formulations. Oral bioavailability varies, with fluconazole, voriconazole). posaconazole, and voriconazole being more reliably absorbed. 3 Distribution 4 Metabolism Azoles distribute to most body tissues, but CNS Most azoles undergo hepatic metabolism, with penetration is generally low, except for fluconazole fluconazole being the exception, eliminated largely (accumulates in the CSF). unchanged by the kidneys. Inducers of drug metabolizing enzymes (eg, rifampin) decrease the bioavailability of itraconazole Mechanism of Action: Azole Antifungals Target Azoles interfere with fungal cell membrane permeability by inhibiting ergosterol synthesis. Specific Inhibition They act at the step of 14α-demethylation of lanosterol, catalyzed by a fungal cytochrome P450 isozyme. Resistance Concerns With increasing use, especially for long-term prophylaxis, resistance is emerging, possibly due to changes in target enzyme sensitivity.  Clinical Uses of Ketoconazole Limited Use Formulation Ketoconazole has a narrow antifungal spectrum The drug is not available in parenteral form, limiting its and more adverse effects than other azoles, leading applications. to rare use in systemic mycoses. Current Applications Dermatophyte Treatment Ketoconazole continues to be used for chronic It remains effective against dermatophytes in certain mucocutaneous candidiasis. situations.  Clinical Uses of Fluconazole 1 Candidiasis Fluconazole is a drug of choice for esophageal and oropharyngeal candidiasis. A single oral dose usually eradicates vaginal candidiasis. 2 Coccidioidomycosis It is effective against most infections caused by Coccidioides. 3 Cryptococcal Meningitis Fluconazole is the drug of choice for treatment and secondary prophylaxis against cryptococcal meningitis. 4 Candidemia The drug is equivalent to amphotericin B in treating candidemia.  Clinical Uses of Itraconazole First-line Treatment Alternative Agent Resistant Strains Itraconazole is the drug of choice It serves as an alternative in In esophageal candidiasis, for systemic infections caused by treating infections caused by itraconazole is active against Blastomyces and Sporothrix, as Aspergillus, Coccidioides, some strains resistant to well as subcutaneous Cryptococcus, and Histoplasma. fluconazole. chromoblastomycosis. It's also widely used for dermatophytoses, especially onychomycosis.  Clinical Uses of Voriconazole 1 Broad Spectrum Voriconazole has an even wider spectrum of fungal activity than itraconazole. 2 Aspergillosis It is a co-drug of choice for treatment of invasive aspergillosis, with some studies reporting greater efficacy than amphotericin B. 3 Candidemia Voriconazole serves as an alternative drug in candidemia, with activity against some fluconazole-resistant organisms. 4 AIDS Patients In AIDS patients, it has been used to treat candidal esophagitis and stomatitis.  Clinical Uses of Posaconazole Broadest Spectrum Posaconazole has the broadest spectrum of activity among triazoles. Candida and Aspergillus It is effective against most species of Candida and Aspergillus. Unique Activity Posaconazole is the only azole with activity against Rhizopus, one of the agents of mucormycosis. Prophylaxis It is used for prophylaxis of fungal infections during cancer chemotherapy Salvage therapy in invasive aspergillosis  Toxicity of Azole Antifungals Drug Common Side Effects Specific Concerns Ketoconazole GI upset, rash, Endocrine dysfunction hepatotoxicity (gynecomastia, menstrual irregularities, and infertility), drug interactions Fluconazole GI upset, rash Least effect on drug metabolism Itraconazole GI upset, rash Drug interactions Voriconazole Visual disturbances, rash Pregnancy risk (Class D) Posaconazole GI upset CYP3A4 inhibition (↑ level of tachrolimus and cyclosporine)  Echinocandins: A Novel Class of Antifungals 1 Introduction Caspofungin was the first echinocandin introduced, followed by anidulafungin and micafungin. 2 Administration Echinocandins are used intravenously and distribute widely to tissues. 3 Metabolism They are eliminated largely via hepatic metabolism. 4 Half-life Caspofungin has a half-life of 9-12 hours, micafungin slightly longer (11- 21 hours), and anidulafungin 24-48 hours. Mechanism of Action: Echinocandins Unique Target Echinocandins have a unique fungicidal action, distinct from other antifungal classes. Cell Wall Synthesis They inhibit the synthesis of β(1-3)glucan, a critical component of fungal cell walls. Selectivity This mechanism provides selective toxicity to fungi, as human cells lack cell walls.  Clinical Uses of Echinocandins Caspofungin Anidulafungin Micafungin Used for disseminated and Indicated for esophageal and Approved for prophylaxis of mucocutaneous Candida invasive candidiasis. Candida infections in patients infections in patients who fail to undergoing hematopoietic stem respond to amphotericin B. Also cell transplantation. used in the treatment of mucormycosis.  Toxicity of Echinocandins 1 Infusion-related Effects Caspofungin can cause headache, gastrointestinal distress, fever, rash, and flushing due to histamine release. 2 Micafungin Concerns Micafungin also causes histamine release and elevates blood levels of immunosuppressant drugs like cyclosporine and sirolimus. 3 Liver Function Combined use of echinocandins with cyclosporine may elevate liver transaminases. 4 Monitoring Regular liver function tests and drug level monitoring are important during echinocandin therapy. Griseofulvin: An Oral Antifungal for Dermatophytoses 1 Absorption Oral absorption of griseofulvin depends on the physical state of the drug. Ultra-micro-size formulations with finer particles are more effectively absorbed (high-fat foods is required) 2 Distribution The drug is distributed to the stratum corneum, where it binds to keratin. 3 Elimination Biliary excretion is responsible for griseofulvin's elimination from the body.  Mechanism of Action: Griseofulvin Microtubule Nucleic Acid Fungal Uptake Fungistatic Agent Interference Synthesis Sensitive Inhibit the synthesis dermatophytes take up and polymerization of the drug by an energy- nucleic acids dependent mechanism.  Clinical Uses and Toxicity of Griseofulvin Indications Administration Adverse Effects Griseofulvin is indicated for The drug is not active topically Side effects include headaches, dermatophytoses of the skin and and must be given orally. mental confusion, gastrointestinal hair, but has been largely irritation, photosensitivity, and replaced by terbinafine and changes in liver function. It should azoles. Drug interaction not be used in patients with Decrease anticoagulant effect porphyria. of warfarin Disulfiram-like reactions with ethanol  Terbinafine (Fungicidal agent) Mechanism Terbinafine inhibits fungal squalene epoxidase, causing accumulation of toxic levels of squalene and interfering with ergosterol synthesis. Action Unlike griseofulvin, terbinafine is fungicidal. Formulations Available in both oral and topical forms. Efficacy Particularly effective in onychomycosis, accumulating in keratin like griseofulvin but with greater potency.  Toxicity and Interactions of Terbinafine 1 Common Side Effects GI upsets, rash, headache, and taste disturbances 2 Liver Function Rare cases of liver toxicity have been reported, necessitating monitoring of liver function during treatment. 3 Drug Interactions Unlike many azoles, terbinafine does not inhibit cytochrome P450 enzymes, resulting in fewer drug interactions. 4 Long-term Effects The drug's persistence in nails allows for shorter treatment courses, potentially reducing the risk of adverse effects. Azoles for superficial fungal infections Pulse or intermittent dosing with itraconazole is as effective in onychomycoses as continuous dosing because the drug persists in the nails for several months Treatment for 1 wk is followed by 3 wk without drug Advantages of pulse dosing : - ↓ adverse effects and major cost savings Topical forms of various azoles are also available for use in dermatophytoses  Topical Antifungal Agents Nystatin Azole Compounds Other Formulations A polyene antibiotic used topically Miconazole, clotrimazole, and Antifungal shampoos, powders, for Candida infections. It disrupts other azoles are widely used and sprays are available for fungal membranes by binding to topically for superficial fungal various superficial fungal ergosterol but is too toxic for infections. infections. systemic use.