Anti fungal drugs Pharma 2nd mbbs
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Antifungal Drugs
Pharmacology - 2nd MBBS | Based on Lippincott Illustrated Reviews: Pharmacology & Goodman & Gilman
Overview
Fungi are eukaryotic organisms with rigid cell walls made of chitin (not peptidoglycan like bacteria). Their cell membranes contain ergosterol instead of cholesterol. These two differences from mammalian cells are the primary targets for antifungal drugs.
Mycoses are classified as:
- Superficial/Cutaneous - involve skin, hair, nails
- Subcutaneous - involve deeper tissues
- Systemic (invasive) - life-threatening; common in immunocompromised patients
Classification of Antifungal Drugs
| Class | Drugs | Target |
|---|---|---|
| Polyenes | Amphotericin B, Nystatin | Ergosterol (bind & disrupt membrane) |
| Azoles - Imidazoles | Ketoconazole, Clotrimazole, Miconazole | Ergosterol synthesis (CYP450 inhibition) |
| Azoles - Triazoles | Fluconazole, Itraconazole, Voriconazole, Posaconazole | Ergosterol synthesis |
| Echinocandins | Caspofungin, Micafungin, Anidulafungin | β-D-glucan synthesis (cell wall) |
| Allylamines | Terbinafine, Naftifine | Squalene epoxidase (ergosterol synthesis) |
| Antimetabolite | Flucytosine (5-FC) | Nucleic acid/protein synthesis |
| Others | Griseofulvin | Microtubule disruption |
1. POLYENES
Amphotericin B
Mechanism: Binds to ergosterol in the fungal cell membrane → forms transmembrane pores/channels → leakage of K⁺, Mg²⁺, and other intracellular contents → cell death. It is fungicidal.
Spectrum: Broad-spectrum:
- Candida, Aspergillus, Cryptococcus neoformans
- Histoplasma, Blastomyces, Coccidioides
- Mucor (Zygomycetes)
Uses:
- Drug of choice for most life-threatening systemic fungal infections
- Cryptococcal meningitis (combined with flucytosine)
- Invasive aspergillosis (second line to voriconazole)
- Empiric therapy in febrile neutropenia
Route: IV only (poorly absorbed orally). Liposomal formulations (AmBisome) reduce toxicity.
Adverse Effects (Major - must know):
| Toxicity | Details |
|---|---|
| Nephrotoxicity | Most common dose-limiting toxicity; renal tubular acidosis, azotemia |
| Infusion-related | Fever, chills, rigors, hypotension, nausea (during IV infusion) - "shake and bake" |
| Hypokalemia/Hypomagnesemia | Due to renal tubular damage |
| Anemia | Normochromic normocytic (reduced erythropoietin) |
| Thrombophlebitis | At infusion site |
- Premedication with acetaminophen, diphenhydramine, and hydrocortisone reduces infusion reactions
- Liposomal AmB has reduced nephrotoxicity
Nystatin
- Same mechanism as Amphotericin B (polyene)
- Too toxic for systemic use - used only topically/orally for local infections
- Used for oral candidiasis (thrush) - "swish and swallow"
- Used for vulvovaginal candidiasis, skin/mucosal candidiasis
- Not absorbed from GI tract
2. AZOLES
Mechanism (All Azoles): Inhibit fungal CYP450-dependent enzyme (14α-demethylase) → blocks conversion of lanosterol → ergosterol → depletion of ergosterol → membrane disruption. Generally fungistatic.
Key Drug Interactions: Azoles inhibit CYP3A4 (and other CYP enzymes) → increase levels of warfarin, cyclosporine, phenytoin, statins, etc.
Imidazoles (Mainly Topical)
| Drug | Key Uses |
|---|---|
| Ketoconazole | First oral azole; now mainly topical (seborrheic dermatitis, dandruff shampoo); systemic use abandoned due to hepatotoxicity |
| Clotrimazole | Topical - vaginal candidiasis, dermatophytoses, oral thrush (troches) |
| Miconazole | Topical - skin/vaginal fungal infections |
Triazoles (Systemic)
Fluconazole
- Most widely used systemic azole
- Excellent oral bioavailability (~90%) - "oral equals IV"
- Penetrates CSF well - drug of choice for cryptococcal meningitis maintenance and coccidioidal meningitis
- Active against most Candida spp. and Cryptococcus
- NOT effective against Aspergillus or Mucor
- Uses: Oropharyngeal candidiasis, esophageal candidiasis, vulvovaginal candidiasis (single 150 mg oral dose), UTI due to Candida
- Adverse effects: Generally well tolerated; hepatotoxicity (rare); QT prolongation; teratogenic
Itraconazole
- Broader spectrum than fluconazole
- Drug of choice for histoplasmosis, blastomycosis, sporotrichosis, paracoccidioidomycosis
- Also used for onychomycosis
- Poor CSF penetration
- Multiple formulations (capsule, solution, IV); absorption requires acid - give with food/Coca-Cola
- Significant drug interactions (strong CYP3A4 inhibitor); negative inotrope - avoid in heart failure
Voriconazole
- Broadest spectrum triazole
- Drug of choice for Aspergillosis (invasive aspergillosis)
- Active against Candida, Cryptococcus, Fusarium
- Adverse effects: Visual disturbances (photopsia - flashes, blurred vision - unique to voriconazole), hepatotoxicity, photosensitivity/skin rash, hallucinations, QT prolongation
Posaconazole
- Active against Mucor (unlike other azoles) - drug of choice for mucormycosis prophylaxis
- Prophylaxis in neutropenic patients and stem cell transplant recipients
- Metabolized by liver; no renal dose adjustment needed
3. ECHINOCANDINS
Mechanism: Inhibit β-(1,3)-D-glucan synthase → prevent synthesis of β-D-glucan (essential component of fungal cell wall) → cell lysis. Fungicidal against Candida, fungistatic against Aspergillus.
Drugs: Caspofungin, Micafungin, Anidulafungin
Key Features:
- Active against Candida (including azole-resistant strains) and Aspergillus
- NOT active against Cryptococcus or Mucor (these organisms lack β-glucan)
- IV administration only (poor oral bioavailability)
- Generally well tolerated - minimal toxicity
- Caspofungin: first-line for invasive candidiasis; alternative for invasive aspergillosis
- Rarely cause histamine-mediated infusion reactions
4. ALLYLAMINES
Terbinafine
- Mechanism: Inhibits squalene epoxidase → accumulation of squalene (toxic to fungi) → depletion of ergosterol
- Drug of choice for onychomycosis (nail fungal infection) - oral
- Also active against dermatophytes (tinea infections)
- Topical forms for tinea pedis, corporis, cruris
- Adverse effects: GI upset, hepatotoxicity (rare); inhibits CYP2D6
- Contraindicated in hepatic dysfunction and moderate-severe renal impairment
Naftifine
- Topical allylamine for dermatophyte infections
5. FLUCYTOSINE (5-Fluorocytosine, 5-FC)
Mechanism: Prodrug - converted by fungal cytosine deaminase to 5-fluorouracil (5-FU) → incorporated into fungal RNA → disrupts RNA/protein synthesis; also converted to 5-FdUMP → inhibits thymidylate synthase → blocks DNA synthesis.
Spectrum: Candida, Cryptococcus
Key Use: Only used in combination with Amphotericin B for cryptococcal meningitis (synergistic effect; prevents resistance)
Adverse Effects:
- Bone marrow suppression - reversible neutropenia, thrombocytopenia (must monitor CBC)
- GI upset, hepatotoxicity
- Resistance develops rapidly if used alone
6. GRISEOFULVIN
Mechanism: Deposits in keratin precursor cells of skin, hair, nails → disrupts fungal microtubule assembly (binds tubulin) → inhibits mitosis → fungistatic
Spectrum: Only dermatophytes (Trichophyton, Microsporum, Epidermophyton) - does NOT work against Candida
Uses: Tinea capitis (especially in children - drug of choice), tinea unguium
Adverse effects: Headache (very common), GI upset, photosensitivity, hepatotoxicity, teratogenic (contraindicated in pregnancy), induces CYP450 (reduces warfarin, OCP efficacy)
Route: Oral; better absorbed with fatty meal
Drugs of Choice - Quick Reference
| Infection | Drug of Choice |
|---|---|
| Invasive Aspergillosis | Voriconazole |
| Cryptococcal meningitis (induction) | Amphotericin B + Flucytosine |
| Cryptococcal meningitis (maintenance) | Fluconazole |
| Invasive Candidiasis | Echinocandin (Caspofungin) |
| Vulvovaginal Candidiasis | Single-dose oral Fluconazole |
| Histoplasmosis/Blastomycosis | Itraconazole |
| Mucormycosis | Amphotericin B ± Posaconazole |
| Onychomycosis | Oral Terbinafine |
| Tinea capitis (children) | Griseofulvin |
| Oral thrush | Nystatin (swish & swallow) or Fluconazole |
| Life-threatening systemic mycosis | Amphotericin B |
Mechanism Summary at a Glance
CELL WALL:
Echinocandins → inhibit β-glucan synthase
CELL MEMBRANE:
Polyenes (AmB, Nystatin) → bind ergosterol → pores
Azoles → inhibit ergosterol synthesis (CYP450/14α-demethylase)
Allylamines → inhibit squalene epoxidase (upstream of ergosterol)
NUCLEUS/DNA:
Flucytosine → disrupts RNA/protein synthesis, DNA synthesis
Griseofulvin → disrupts microtubule formation (mitosis)
High-Yield Adverse Effects for MCQs
| Drug | Key Adverse Effect |
|---|---|
| Amphotericin B | Nephrotoxicity, infusion reactions, hypokalemia |
| Flucytosine | Bone marrow suppression (neutropenia, thrombocytopenia) |
| Voriconazole | Visual disturbances (photopsia), hallucinations |
| Ketoconazole | Hepatotoxicity, gynecomastia (inhibits testosterone synthesis) |
| Griseofulvin | Headache, photosensitivity, teratogenic, CYP inducer |
| Terbinafine | Hepatotoxicity; inhibits CYP2D6 |
| Itraconazole | Negative inotropy (avoid in heart failure) |
Sources: Lippincott Illustrated Reviews: Pharmacology, Chapter 33; Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 61
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