Pharmacology of Antifungal Agents

Antifungal and Antiparasitic Drugs

• These drugs treat infections caused by fungi and parasites.

• Images show different types of fungal infections.

• Common fungal diseases: ringworm, athlete's foot, jock itch, ringworm of the scalp, onychomycosis, vaginal candidiasis, oral thrush.

  • Ringworm ('tinea corporis'): Affects body skin, caused by Trichophyton, Microsporum, & Epidermophyton.
  • Athlete's foot ('tinea pedis'): Affects the feet, often between toes.
  • Jock itch ('tinea cruris'): Affects armpits, groin, & thighs.
  • Ringworm of the scalp ('tinea capitis'): Affects scalp hair follicles, mostly in children.
  • Onychomycosis ('tinea unguium'): Fungal infection of the nails, affecting fingernails and toenails.
  • Vaginal candidiasis: Vaginal yeast infection caused by Candida albicans.
  • Oral thrush: Candida albicans infection in the mouth, throat, and esophagus.

• Fungal diseases that affect people with compromised immune systems: aspergillosis, candidiasis, cryptococcosis, invasive candidiasis, pneumocystis pneumonia (PCP).

  • Aspergillosis: Caused by molds Aspergillus flavus and Aspergillus fumigatus.
  • Candidiasis: Serious infection if grows uncontrollably or enters deep into the body.
  • Cryptococcosis: Cryptococcus neoformans infection of the brain causing meningitis.
  • Invasive candidiasis: Serious infections affecting blood, brain, eyes, bones, and other body parts (mostly in hospitalized patients).
  • PCP: Serious infection caused by Pneumocystis jirovecii (renamed Pneumocystis carinii).

Common Antifungal Drugs

• Examples of common antifungal drugs are shown.
• Different classes of drugs are shown.

Polyenes

• Polyenes are drugs obtained from Streptomyces species.
• Example drugs: amphotericin B, natamycin, nystatin.
• Polyenes bind to ergosterol in the fungal cell membrane, disrupting it and causing leakage of intracellular ions.

Echinocandins

• Echinocandins are lipopeptide molecules that block the synthesis of β-glucan.
• β-glucans are carbohydrate polymers crucial to fungal cell walls, akin to bacterial peptidoglycans.
• Example drugs: caspofungin, anidulafungin, micafungin.
• Effective against invasive candidiasis and some strains resistant to fluconazole.

Amphotericin B

• Primary antifungal for most pathogenic Candida species.
• Not water-soluble, administered intravenously.
• Optimal dose: 0.5–1.0 mg/kg/day once daily.
• Dose may be increased if no substantial toxicity.
• Immature blood-brain barrier (BBB) in neonates has higher amphotericin B concentrations in cerebrospinal fluid (CSF) compared to adults.
• Toxicities include bone marrow suppression, anemia, thrombocytopenia, renal failure, hypokalemia, abnormal hepatic enzymes, and decreased urine output.

Flucytosine (5-FC)

• Also known as Ancobon.
• Oral and intravenous administration.
• Weak antifungal properties and rapid resistance development.
• Commonly used in combination with other antifungals.
• Distributed in breast milk, so use during pregnancy requires careful consideration.
• Well-absorbed from the gastrointestinal tract (GIT).

Terbinafine

• Also called Lamisil.
• Treats fungal nail infections and skin infections (ringworm, jock itch, athlete's foot).
• Effective in cream/ointment form, but less so for deep nail infections.
• Oral granules and tablets are used for scalp infections and onychomycosis (nail fungus).
• Long elimination half-life (200–400 hours).
• Highly lipophilic, accumulating in hair, skin, nails, and fatty tissues.
• Inhibits the enzyme squalene epoxidase, preventing ergosterol synthesis, which damages the fungal cell walls.

Griseofulvin

• Orally administered for treating ringworm infections, particularly when topical treatments fail.
• Binds to keratin, making it resistant to fungal infection.
• Interferes with fungal cell division by inhibiting microtubule function.
• Absorption is increased with a fatty meal.

Invasive Fungal Infections (IFIs)

• Significantly risky among immunocompromised patients.
• Risk factors include neutropenia, hematological malignancies, bone marrow transplant, prolonged corticosteroid use, prolonged hospitalization, chemotherapy, HIV infection, malnutrition, severe burns, and solid organ transplantation.
• Often requires combination therapy (complementary agents with diverse mechanisms).

Azoles

• Structurally related group of antifungals (e.g. fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole).
• Commonly used to treat systemic mycoses and IFIs.
• Inhibits lanosterol synthesis to ergosterol in the fungal cell (inhibition of cytochrome P450).

Malaria

• Caused by Plasmodium species and transmitted by Anopheles mosquitos.
• Symptoms include fever, chills, flu-like symptoms, headache, vomiting, diarrhea, jaundice, cough, and discharge from eyes.
• Cycles (F-R-C) are repeated every 1-3 days.
• Types of malaria species and complications: P. falciparum (cerebral malaria, black water fever, pregnancy malaria); P. vivax, P. malariae, P. ovale, and P. knowlesi.

Antimalarial Drugs

• Drugs used to prevent and treat malaria.
• Examples are quinine, chloroquine, artemisinin derivatives (artemether, artesunate), suramin, metronidazole.

Other Protozoa and Helminthic Infections

• Non-malarial protozoa infections often treated with suramin, metronidazole, or ivermectin.
• Helminthic (worm) infections often treated with ivermectin, albendazole, pyrantel pamoate, or other drugs.

Topical Antifungal Drugs (TAfDs)

• Drugs applied directly to the skin, nails, or scalp to treat fungal skin conditions.
• Includes clotrimazole, miconazole, terbinafine, ketoconazole as examples.