ANTIFUNGAL DRUGS
Fungal infections could be classified into:
A- Superficial fungal infections:
I- Dermatophytes: – Tinea: capitis (scalp), corporis (body), inguinum
(nails) and pedis (foot).
II- Candida:
a) Cutaneous, Vaginal, Oropharyngeal, Gastrointestinal Candidiasis.
b) Mucocutaneous candidiasis in severely immunodeficient patients and can
spread to deep tissues (disseminated candidiasis).
B- Deep fungal infections:
– Pneumonia, Gastro-enteritis, Endocarditis or Meningitis.
Classification of Antifungal drugs
I- Drugs for systemic fungal infections:
1. Amphotericin-B.
2. Flucytosine.
3. Azoles: – Ketoconazole, Fluconazole, Itraconazole.
II- Drugs for superficial infections:
A- Drugs given systematically:
1. Griseofulvin.(Dermatophytes)
2. Terbenafine. (Dermatophytes).
3. Azoles: – Ketoconazole, Fluconazole, Itraconazole (Dermatophytes and
Candida).
B- Drugs given topically:
1. Nystatin (Candida).
2. Gentian violet (Candida).
3. Whitefield ointment (Dermatophytes).
4. Azoles: – Ketoconazole, (Miconazole, Clotrimazole are too toxic for
systemic use).
5. Terbenafine.
Superficial fungal infections are treated first with topical agents.
Systemic therapy is used in:
1- Resistance to topical therapy, wide or inaccessible area.
2- Severe infection of the hair, skin and the nails. Decrease immunity of patient.
Amphotericin-B
Mechanism of action: – Binds to Ergosterol of fungal cell membrane leading to
formation of artificial pores resulting in leakage of important cell constituents leading to
fungal cell death.
Indications: – Most important Anti-fungal in deep infections especially:
1- Severe life threatening infections (Given I.V; not absorbed orally).
2- Fungal Meningitis (Intrathecal; does not reach CSF after I.V.I).
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Side effects and Toxicity:
· Fever, Rigor, Vomiting and Shock after I.V.I.
· Convulsions after intrathecal injection.
· Nephrotoxicity leading to decreased Erythropoietin resulting in anemia.
· Hypokalemia and Cardiac Arrhythmias.
Flucytosine
Cytotoxic drug: – Transformed in fungus to 5-fluro-uracil leading to inhibition of nucleic
acid synthesis.
Indications: – Given orally.
When given alone, resistance develops. Thus, it is usually combined with Amphotericin
in:
1- Cryptococcal meningitis.
2- Disseminated Candida.
Advantages of combination of Flucytosine and Amphotericin-B:
1) Decreases resistance to Flucytosine.
2) Decreases nephrotoxicity of Amphotericin because combination allows the use of
smaller doses of Amphotericin.
Adverse effects: – It is a cytotoxic drug.
· Bone marrow depression.
· Hepatotoxicity.
· Hair loss.
· Enterocolitis.
Azoles
Mechanism of action: – Inhibition of Ergosterol synthesis of cell membrane by inhibiting
cytochrome P450 isoenzyme responsible for conversion of Lanosterol to Ergosterol.
Members:
– Ketoconazole.
– Fluconazole.
– Itraconazole.
Ketoconazole
It is indicated in:
1- Deep fungal infections (Mild, non-meningeal); 2
nd
line to Amphotericin (can be
given orally).
2- Candida and Dermatophytes resistant to Griseofulvin (oral and topical).
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v Avoid combination of Ketoconazole with Antacids or Histamine-H2 blockers:
decreases gastric acidity resulting in decreased absorption of Ketoconazole.
Adverse effects of Ketoconazole:
– Nausea, vomiting, rash.
– Inhibition of Cytochrome P450 of human liver:
a) Hepatotoxicity.
b) Decreases steroid synthesis which depends on cytochrome P450:
· Decreased corticosteroid resulting in adrenal suppression (Used in Cushing
disease).
· Decreased testosterone leading to Gynaecomastia (Used in Prostate cancer).
· Decreases female sex hormones resulting in menstrual irregularities.
c) Decreased metabolism of drugs leading to drug interactions:
· Increases blood levels of Astemizole and Terfenadine leading to Arrhythmias.
· Increases blood level of oral Anticoagulants, Anti-epileptics and oral
Hypoglycemics leading to their toxicity.
Itraconazole and Fluconazole (oral)
They are more specific to fungal P450 than to human cytochrome P450 compared to
Ketoconazole.
Advantages of Fluconazole and Itraconazole over Ketoconazole:
1) Less toxic: Less hepatotoxicity, less adrenal suppression, less drug interactions.
2) More effective.
Advantages of Fluconazole over Ketoconazole and Itraconazole:
1) Absorption is better and does not depend on acidity of stomach, therefore
Antacids or H2 blockers could be taken safely with Fluconazole.
2) Reaches CSF, therefore, unlike Ketoconazole it could be given in fungal
meningitis.
3) Single dose, therefore increases patient compliance.
Griseofulvin
Mechanism:
· Interferes with microtubule function.
· Inhibition of nucleic acid synthesis.
Indications: – Dermatophyte infection (orally).
Adverse effects of Griseofulvin:
– Nausea, vomiting, headache and mental confusion.
– Hepatotoxicity, Enzyme inducer leading to decreased Warfarin level.
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Terbenafine
Mechanism: – Inhibition of Squalene epoxidase enzyme which is essential for Ergosterol
synthesis of cell membrane.
Advantages over Azoles:
1) Squalene epoxidase enzyme is not present in humans.
2) No inhibition of cytochrome P450 (no serious Adverse effects of Azoles).
Indications: – Dermatophytes of nails (oral and topical).
Side effects: – GIT and taste disturbances.
Nystatin
Mechanism: – Nystatin binds to Ergosterol of fungal cell membrane leading to formation
of artificial pores resulting in leakage of important cell constituents producing cell death.
Indications: – It acts locally. It is too toxic for systemic use.
1) GIT Candidiasis: – Oral (not absorbed).
2) Cutaneous Candidiasis: – Topical.
3) Vaginal Candidiasis: – Topical.