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Antifungal Drugs - 2nd MBBS Pharmacology

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I. OVERVIEW

• Superficial/Cutaneous (e.g., tinea, ringworm, candidiasis of skin)
• Subcutaneous (e.g., sporotrichosis)
• Systemic/Deep (e.g., cryptococcosis, aspergillosis, histoplasmosis)

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II. CLASSIFICATION OF ANTIFUNGAL DRUGS

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III. DRUGS FOR SYSTEMIC MYCOSES

A. Amphotericin B (Polyene)

• Binds to ergosterol in the fungal cell membrane
• Forms pores/channels in the membrane
• Causes leakage of electrolytes (especially K⁺) and small molecules → cell death
• Selectivity: binds ergosterol >> cholesterol (mammalian membrane)

• Also used in leishmaniasis (protozoal infection)

• Given by slow IV infusion (insoluble in water; formulated with sodium deoxycholate or as liposomal preparation)
• Extensively protein bound; distributed throughout body
• Poor CSF penetration (even with inflammation)
• Excreted slowly in urine

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B. Flucytosine (5-Fluorocytosine)

1. Enters fungal cells via cytosine permease
2. Converted intracellularly to 5-fluorouracil (5-FU) by cytosine deaminase
3. 5-FU → inhibits thymidylate synthase → disrupts DNA synthesis
4. Also incorporated into RNA → disrupts protein synthesis

• Never used alone - rapid resistance develops
• Combined with Amphotericin B for cryptococcal meningitis
• Combined with fluconazole for cryptococcal meningitis in HIV patients

• Bone marrow suppression - reversible neutropenia, thrombocytopenia (pancytopenia)
• Nausea, vomiting, diarrhea
• Hepatotoxicity (elevated liver enzymes)
• Monitor CBC regularly

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C. Azoles

• Inhibit fungal CYP450 enzyme (lanosterol 14-α-demethylase)
• This blocks conversion of lanosterol → ergosterol
• Depleted ergosterol → increased membrane permeability → fungistatic

1. Ketoconazole (Imidazole)

• Systemic imidazole, but largely replaced by triazoles due to toxicity
• Inhibits mammalian steroid synthesis at high doses → gynecomastia, decreased libido, menstrual irregularities
• Oral; poor CNS penetration
• Hepatotoxicity (can be severe)
• Now used mainly topically (shampoo for seborrheic dermatitis)

2. Fluconazole (Triazole)

• Good oral bioavailability; excellent CSF penetration (unlike most azoles)
• Drug of choice: Oropharyngeal/esophageal candidiasis, urinary tract candidiasis, cryptococcal meningitis (maintenance/consolidation)
• Prophylaxis in immunocompromised patients
• Does NOT cover Aspergillus - this is important!
• Dose adjustment needed in renal impairment
• Generally well tolerated; nausea, headache, rash

3. Itraconazole (Triazole)

• Broad spectrum including Aspergillus, Blastomyces, Histoplasma, Sporothrix
• Poor CNS penetration
• Requires acidic environment for absorption (give with food/cola; avoid antacids/PPIs)
• Negative inotrope - contraindicated in heart failure
• Hepatotoxicity; peripheral neuropathy

4. Voriconazole (Triazole)

• Drug of choice for invasive Aspergillosis (superior to amphotericin B in trials)
• Also covers Fusarium, Scedosporium, Candida
• Metabolized by CYP2C19 (genetic polymorphism affects levels)
• Unique ADR: Visual disturbances (photopsia - blurred/altered vision, photophobia) - usually transient
• Hepatotoxicity; phototoxicity (skin rash with sun exposure); hallucinations

5. Posaconazole (Triazole)

• Broadest spectrum triazole; covers Mucor (unlike other azoles)
• Used for salvage therapy and prophylaxis in high-risk patients (neutropenic)
• Metabolized by liver; no renal dose adjustment needed

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D. Echinocandins

• Inhibit synthesis of β(1,3)-D-glucan (a major component of fungal cell wall)
• No β-glucan in mammalian cells → highly selective, well tolerated

• NOT effective against Cryptococcus (minimal cell wall glucan)

• IV only (no oral formulation)
• Metabolized hepatically
• Minimal drug interactions compared to azoles

• Invasive candidiasis, candidemia (first-line in many guidelines)
• Aspergillosis (second-line/salvage)
• Esophageal candidiasis (refractory)

• Generally well tolerated
• Mild: nausea, flushing, histamine-like infusion reactions
• Hepatotoxicity (mild elevation of liver enzymes)
• Caspofungin: dose reduction in hepatic impairment

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IV. DRUGS FOR CUTANEOUS MYCOSES

A. Nystatin (Polyene)

• Too toxic for systemic use
• Used topically for cutaneous/mucosal candidiasis (oral thrush, diaper rash, vaginal candidiasis)
• Mechanism: same as amphotericin B (binds ergosterol, forms pores)
• Not absorbed from GI tract → oral nystatin used for GI candidiasis/oropharyngeal thrush (acts locally)

B. Topical Azoles (Imidazoles)

• Clotrimazole, Miconazole, Econazole, Oxiconazole - for tinea infections, cutaneous candidiasis, vulvovaginal candidiasis
• Clotrimazole troches for oral candidiasis

C. Terbinafine (Allylamine)

• Inhibits squalene epoxidase → accumulation of toxic squalene → fungicidal
• Drug of choice for onychomycosis (nail infections)
• Oral terbinafine for systemic use; topical for tinea pedis/cruris/corporis
• Metabolized by CYP450; inhibits CYP2D6
• Contraindicated in hepatic dysfunction and moderate-severe renal impairment
• ADR: GI upset, taste disturbances, hepatotoxicity

D. Griseofulvin

• Produced by Penicillium griseofulvum
• Mechanism: Binds to polymerized microtubules → disrupts fungal mitosis (inhibits mitosis at metaphase); deposits in keratin-containing tissues
• Spectrum: Dermatophytes only (Trichophyton, Microsporum, Epidermophyton) - no yeast activity
• Uses: Tinea capitis (scalp ringworm - drug of choice in children), tinea corporis, tinea pedis when severe
• Requires long duration of treatment (months for nail infections)
• Induces CYP450 → decreases efficacy of warfarin, OCPs
• ADR: Headache, GI disturbances, photosensitivity, hepatotoxicity, teratogenic
• Contraindicated in pregnancy, liver disease, porphyria
• Absorption enhanced by fatty meals

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V. SUMMARY TABLE: KEY EXAM POINTS

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VI. MECHANISMS AT A GLANCE

Fungal Cell Wall:
  └── β(1,3)-D-glucan  ← Echinocandins block synthesis

Fungal Cell Membrane:
  Lanosterol → [14-α-demethylase] → Ergosterol  ← Azoles BLOCK this step
                                                 ← Terbinafine blocks squalene → ergosterol
  Ergosterol + Amphotericin B/Nystatin → PORES → K⁺ leakage → cell death

Fungal Nucleus:
  └── DNA/RNA synthesis  ← Flucytosine (via 5-FU)

Fungal Mitosis:
  └── Microtubules  ← Griseofulvin disrupts

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VII. IMPORTANT CLINICAL PEARLS (MCQ HIGH-YIELD)

1. DOC for invasive Aspergillosis = Voriconazole
2. DOC for Cryptococcal meningitis (induction) = Amphotericin B + Flucytosine; (maintenance) = Fluconazole
3. DOC for Candidal meningitis = Amphotericin B
4. DOC for Onychomycosis = Oral Terbinafine
5. DOC for Tinea capitis = Griseofulvin (children)
6. Drug covering Mucor = Posaconazole, Amphotericin B (azoles typically don't cover Mucor except posaconazole)
7. Fluconazole does NOT cover Aspergillus - remember!
8. Echinocandins do NOT cover Cryptococcus
9. Flucytosine never given alone (rapid resistance)
10. Liposomal AmB = less nephrotoxic, used when renal impairment is present
11. Griseofulvin = induces CYP → reduces OCP efficacy (pregnancy risk!)
12. Itraconazole needs acidic pH for absorption; contraindicated in CHF
13. Voriconazole = unique visual side effects (photopsia)
14. Amphotericin B = also used in Leishmaniasis
15. Azoles in pregnancy = generally avoided (teratogenic, especially fluconazole at high doses)

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