Anti fungal drugs Pharma 2nd mbbs

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Antifungal Drugs - 2nd MBBS Pharmacology

Source: Lippincott Illustrated Reviews: Pharmacology

Why Antifungals Are Different

Fungi are eukaryotes - their cell biology resembles human cells, leaving fewer unique targets compared to bacteria. Key exploitable differences:

Fungal Feature	Drug Target
Ergosterol in cell membrane (not cholesterol)	Amphotericin B, Azoles, Allylamines
β-D-glucan in cell wall (no human equivalent)	Echinocandins
Chitin-rich rigid cell wall	(future targets)

Classification of Antifungal Drugs

ANTIFUNGALS
│
├── POLYENES            → Amphotericin B, Nystatin
├── AZOLES
│   ├── Imidazoles      → Ketoconazole, Clotrimazole, Miconazole (mostly topical)
│   └── Triazoles       → Fluconazole, Itraconazole, Voriconazole, Posaconazole
├── ECHINOCANDINS       → Caspofungin, Micafungin, Anidulafungin
├── PYRIMIDINE ANALOG   → Flucytosine (5-FC)
├── ALLYLAMINES         → Terbinafine, Naftifine
└── OTHERS              → Griseofulvin, Ciclopirox, Tavaborole

1. POLYENES

Amphotericin B (Amp B)

Mechanism: Binds to ergosterol in the fungal cell membrane → forms pores/channels → leakage of K⁺, Mg²⁺, and other intracellular contents → cell death. It is fungicidal.

Spectrum: Broadest spectrum antifungal. Active against:

Candida spp.
Aspergillus
Cryptococcus neoformans
Histoplasma, Blastomyces, Coccidioides
Mucormycosis (Mucor, Rhizopus)

Administration: IV only (poorly absorbed orally). Also given intrathecally for fungal meningitis in some cases.

Formulations:

Conventional (deoxycholate) - more nephrotoxic
Lipid formulations (liposomal, lipid complex, colloidal dispersion) - same efficacy, less nephrotoxicity; used in patients with renal impairment

Adverse Effects (MAJOR - high-yield):

Nephrotoxicity - most important; causes renal tubular acidosis, ↓K⁺, ↓Mg²⁺. Monitor creatinine, electrolytes
Infusion-related reactions - fever, chills, rigors, headache, nausea during IV infusion. Premedicate with acetaminophen + diphenhydramine ± meperidine (for rigors)
Anemia - normochromic, normocytic (↓ erythropoietin)
Electrolyte disturbances - hypokalemia, hypomagnesemia (supplement K⁺ and Mg²⁺)
Phlebitis at IV site

Clinical Uses:

Drug of choice for severe, life-threatening systemic fungal infections
Cryptococcal meningitis (often combined with flucytosine)
Mucormycosis (drug of choice)
Empiric therapy in febrile neutropenic patients

Nystatin

Mechanism: Same as Amphotericin B - binds ergosterol, forms pores.

Key point: Too toxic for systemic use. Used topically only.

Uses:

Oral candidiasis ("thrush") - oral rinse/swallow ("swish and swallow")
Cutaneous and mucocutaneous candidiasis
Vaginal candidiasis (vaginal tablets)

Mnemonic: "Nystatin stays local - NYSTATin for local use"

2. AZOLES

Common Mechanism: Inhibit fungal CYP450 enzyme (14-α-demethylase) → blocks conversion of lanosterol → ergosterol → depletion of ergosterol → disrupted membrane function. Generally fungistatic (except at high concentrations).

Drug Interactions (high-yield): Azoles inhibit CYP3A4 (and other CYPs) → elevated levels of:

Warfarin (↑ bleeding risk)
Cyclosporine, tacrolimus (↑ nephrotoxicity)
Statins (↑ rhabdomyolysis risk)
Oral hypoglycemics
Benzodiazepines
Phenytoin levels altered

Certain drugs reduce azole levels (enzyme inducers): rifampin, phenytoin, carbamazepine.

A. Imidazoles (mostly topical)

Drug	Key Use
Ketoconazole	Systemic (but largely replaced); also inhibits adrenal/gonadal steroid synthesis → used in Cushing's; topical for tinea, seborrheic dermatitis
Clotrimazole	Topical - oral thrush, vaginal candidiasis, tinea
Miconazole	Topical - vaginal candidiasis, tinea; also OTC
Econazole, Oxiconazole, Sulconazole	Topical dermatophyte infections

Ketoconazole Special Points:

Inhibits adrenal steroid synthesis → gynecomastia, decreased libido, menstrual irregularities
Hepatotoxic (black box warning)
No longer first-line systemically; largely replaced by triazoles
Inhibits testosterone synthesis → used in prostate cancer (off-label)

B. Triazoles (systemic - important group)

Fluconazole

Water soluble, excellent oral bioavailability (~90%)
Penetrates CSF well (>70% of plasma levels) - useful for cryptococcal meningitis
Excreted renally (dose-adjust in renal failure)
Narrow spectrum: mainly Candida and Cryptococcus; NOT active vs. Aspergillus
Drug of choice: Candida infections, cryptococcal meningitis (maintenance), vulvovaginal candidiasis (single dose 150 mg)
Generally well tolerated; nausea, headache

Itraconazole

Broad spectrum including Aspergillus and dimorphic fungi (Histoplasma, Blastomyces, Sporotrichosis)
Poor CNS penetration
Requires acidic environment for absorption (take with food/cola; avoid antacids)
Hepatotoxic; monitor LFTs
Negative inotrope - avoid in heart failure
Available as capsules, solution, IV

Voriconazole

Drug of choice for invasive aspergillosis (superior to amphotericin B in clinical trials)
Active vs. Candida, Fusarium, Cryptococcus, molds
Good oral bioavailability; CNS penetration good
Adverse effects: Visual disturbances (photopsia, color changes - "flashes"), hepatotoxicity, skin rash, photosensitivity, hallucinations
Extensive CYP interactions

Posaconazole

Broadest-spectrum azole; active against Mucor/Zygomycetes
Used as prophylaxis in immunocompromised (neutropenic) patients
Also used for refractory aspergillosis, candidiasis

Isavuconazole

Newer triazole; active against Aspergillus and Mucor
Better tolerability than voriconazole (no visual side effects)

3. ECHINOCANDINS

Drugs: Caspofungin, Micafungin, Anidulafungin

Mechanism: Inhibit β-(1,3)-D-glucan synthase → block synthesis of β-D-glucan (major component of fungal cell wall) → cell wall weakens → osmotic lysis. Fungicidal against Candida.

Key Features:

IV only (not orally absorbed)
Active against Candida and Aspergillus
NOT active against Cryptococcus (lacks significant glucan in wall)
Minimal drug interactions compared to azoles
Generally well tolerated

Adverse Effects: Mild - infusion reactions, GI upset, elevated LFTs (mild)

Clinical Uses:

Invasive candidiasis (especially in ICU, biofilm-forming Candida)
Candida esophagitis
Aspergillosis (second-line)
Caspofungin: approved for empiric antifungal therapy in febrile neutropenic patients

4. FLUCYTOSINE (5-Fluorocytosine, 5-FC)

Mechanism: Enters fungal cells via cytosine permease → converted to 5-fluorouracil (5-FU) by cytosine deaminase → disrupts RNA synthesis AND inhibits thymidylate synthase → disrupts DNA synthesis.

Key Points:

Used almost exclusively in combination with Amphotericin B for cryptococcal meningitis (synergistic)
Good oral bioavailability; penetrates CSF
Excreted renally - dose-adjust in renal failure
Resistance develops rapidly if used alone

Adverse Effects:

Bone marrow suppression - reversible neutropenia, thrombocytopenia (monitor CBC)
GI toxicity (nausea, vomiting, diarrhea)
Hepatotoxicity

5. ALLYLAMINES

Terbinafine

Mechanism: Inhibits squalene epoxidase → blocks ergosterol synthesis → squalene accumulates (toxic to fungi) → fungicidal.

Key Features:

Oral and topical formulations
Excellent for onychomycosis (nail fungal infections) - drug of choice (oral, 6 weeks for fingernail, 12 weeks for toenail)
Active against dermatophytes (Trichophyton, Microsporum, Epidermophyton)
NOT active against Candida or systemic fungi
Hepatotoxic (rare); monitor LFTs

6. GRISEOFULVIN

Mechanism: Binds to tubulin → disrupts mitotic spindle → inhibits fungal cell division (fungistatic). Also binds to keratin - concentrates in keratin-containing tissues (skin, nails, hair).

Key Features:

Active against dermatophytes only (tinea capitis, tinea corporis, tinea pedis, tinea unguium)
Drug of choice for tinea capitis (scalp ringworm) in children
Oral only; take with fatty meal (↑ absorption)
Long treatment duration needed (weeks to months for nails)
Induces CYP enzymes → reduces levels of warfarin, oral contraceptives
Adverse: headache, GI upset, photosensitivity, disulfiram-like reaction with alcohol

Quick Comparison Table (High-Yield)

Drug	MOA	Route	Key Use	Key Toxicity
Amphotericin B	Binds ergosterol → pores	IV	Broad systemic/mucormycosis	Nephrotoxicity, infusion reactions
Nystatin	Binds ergosterol → pores	Topical/oral	Oral/vaginal candidiasis	Too toxic for systemic use
Fluconazole	Inhibits 14-α-demethylase	PO/IV	Candida, Cryptococcus meningitis	CYP drug interactions
Itraconazole	Inhibits 14-α-demethylase	PO/IV	Aspergillus, dimorphic fungi	Hepatotoxicity, negative inotrope
Voriconazole	Inhibits 14-α-demethylase	PO/IV	Aspergillosis (DOC)	Visual disturbances, hepatotoxicity
Ketoconazole	Inhibits 14-α-demethylase	PO/topical	Superficial mycoses; Cushing's	Hepatotoxicity, ↓ steroid synthesis
Caspofungin	Inhibits β-glucan synthase	IV	Candida, Aspergillus	Mild infusion reactions
Flucytosine	↓ DNA/RNA synthesis	PO	Combo for Cryptococcus meningitis	Bone marrow suppression
Terbinafine	Inhibits squalene epoxidase	PO/topical	Onychomycosis, dermatophytes	Hepatotoxicity (rare)
Griseofulvin	Disrupts mitotic spindle (tubulin)	PO	Tinea capitis (DOC in children)	CYP induction, photosensitivity

Drug of Choice Summary (Very High-Yield for Exams)

Condition	Drug of Choice
Cryptococcal meningitis (induction)	Amphotericin B + Flucytosine
Cryptococcal meningitis (maintenance)	Fluconazole
Invasive Aspergillosis	Voriconazole
Mucormycosis	Amphotericin B (+ Posaconazole)
Invasive Candidiasis (ICU/severe)	Echinocandin (Caspofungin)
Candida esophagitis	Fluconazole (or Caspofungin if refractory)
Vulvovaginal Candidiasis	Fluconazole single dose (150 mg oral)
Oral Candidiasis (thrush)	Nystatin or Fluconazole
Tinea Capitis (scalp ringworm, children)	Griseofulvin
Onychomycosis (nail fungal infection)	Terbinafine (oral)
Histoplasmosis/Blastomycosis (mild)	Itraconazole
Histoplasmosis/Blastomycosis (severe)	Amphotericin B

Key Mnemonics

"F-CAKI" = Fluconazole for Candida, Azoles block 14-alpha-demethylase, Ketoconazole kills steroids, Itraconazole for Invasive mold
"AmphoTERRIBLE" = Amphotericin B has terrible side effects (nephrotoxicity, infusion reactions)
Echinocandins = "CANDA-ins" = They primarily target Candida (and Aspergillus)
Flucytosine + Ampho B = SYNERGY for Crypto
Griseo = Keratin lover = concentrates in keratin (skin, hair, nails)

Special Points for 2nd MBBS Exams

Ergosterol is the key target (not present in mammalian membranes)
Amphotericin B - broadest spectrum, most nephrotoxic, forms pores in membrane
Azoles - fungistatic, inhibit CYP enzymes (important drug interactions!)
Echinocandins - target cell wall (unique, not membrane); IV only; safest profile
Voriconazole - DOC for Aspergillus; causes visual disturbances
Fluconazole - best CSF penetration among azoles; good for Cryptococcus
Flucytosine - never used alone (rapid resistance); always combined
Griseofulvin - tinea capitis in children; CYP inducer
Terbinafine - onychomycosis; works by squalene epoxidase inhibition
Ketoconazole - inhibits steroid synthesis (used in Cushing's); hepatotoxic

Source: Lippincott Illustrated Reviews: Pharmacology, Chapter 33 - Antifungal Drugs

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