Antifungal Drugs

Lectures (7, 8)
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Antifungal Drugs
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 Unlike bacteria, fungi are eukaryotes which have rigid cell walls

composed of chitin (a polymer of N-acetylglucosamine) rather than peptidoglycan.

The fungal cell membrane contains ergosterol rather than the

cholesterol found in mammalian membranes.

Antifungal drugs are agents used to treat infections

caused by fungi.
Infectious diseases caused by fungi are called mycoses,

which may be superficial mycoses (dermatophytes), mucous membranes mycoses and systemic mycoses.

1. Amphotericin B

It is a fungicidal drug and effective against a wide range of

fungi including Candida, Histoplasma, Cryptococcus, aspergillus and Blastomyces.

It is often used intravenously and sometimes orally for

systemic fungal infections.

Mechanism of action It binds to ergosterol in the plasma membrane of fungal cells forming pores (channels). These pores increases the fungal cell membrane permeability and the loss of intracellular constituents, resulting in cell death.
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amphotericin B mechanism of action

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Uses

1. Amphotericin B is most commonly used to treat serious fungal infections in immunocompromised patients as AIDS patients.
2. Oral amphotericin B is used to treat oral thrush (oral candidiasis).

3. Intravenous amphotericin B is used to treat cryptococcal meningitis.

Adverse effects Amphotericin B has a low therapeutic index and it has many adverse effects as: a. Fever and chills, so premedication with an antipyretic prevents this problem. b. Nephrotoxicity: infusion of normal saline before and after amphotericin B use can reduce this problem. (Note: it must not be used with other nephrotoxic drugs as aminoglycosides and methicillin. c. Hypotension due to hypokalemia, so potassium supplementation is required. d. Anemia, thrombocytopenia and leukopenia are less common.
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2. Ketoconazole
Ketoconazole is an antifungal drug used orally and topically. It is active against many fungi, including Histoplasma,

Blastomyces, Candida, but not aspergillus species.

Mechanism of action It is a fungistatic drug that inhibits C-14 -demethylase enzyme, thereby blocking the demethylation of lanosterol to ergosterol (the principal sterol of fungal membranes).
This inhibition disrupts membrane structure and function,

which, in turn, inhibits fungal cell growth.

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Ketoconazole mechanism of action

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Uses

It is used the treatment of cutaneous and mucous

membrane mycoses.
Topical ketoconazole is used to treat tinea infections. It is also used topically in treatment of seborrheic

dermatitis and dandruff.

Penetration into BBB is slight, so ketoconazole is

ineffective in the treatment of fungal meningitis.

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 Ketoconazole can be used in the treatment of non-fungal

conditions as prostate cancer and Cushing's syndrome because it has antiandrogen and antiglucocorticoid effects by inhibiting the activity of several enzymes necessary for the conversion of cholesterol to steroid hormones such as testosterone and cortisol.
Adverse effects Nausea, anorexia and vomiting. Endocrine effects, such as gynecomastia, decreased libido, impotence and menstrual irregularity, which result from the blocking of androgen and glucocorticoids synthesis. Hepatitis occurs rarely

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3. Fluconazole
It inhibits the synthesis of fungal membrane ergosterol

in the same manner as ketoconazole.

It is administered orally or intravenously. It is better than ketoconazole because of its lack of the

endocrine side effects of ketoconazole.

It has an excellent penetrability into BBB, so it is effective

in the treatment of fungal meningitis.

It is very effective against candidiasis, where single

dose only is used in treatment of esophageal and vaginal candidiasis.

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 Nausea, vomiting, abdominal pain, diarrhea and skin rash

are the main side effects of fluconazole.

Alopecia can occurs with prolonged high-dose therapy.

Notes: (Ketoconazole and amphotericin B) and (fluconazole and amphotericin B) should not be used together.
Ketoconazole, fluconazole and amphotericin B are

teratogenic drugs, so they must not be used in pregnancy.

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4. Terbinafine It is a fungicidal drug and available as orally and topically.

It inhibits squalene epoxidase enzyme which converts

squalene to lanosterol. This inhibits the synthesis of ergosterol.

It active mainly against the fungi that cause the majority of

cutaneous infections (Trichophyton, Microsporum, and Epidermophyton).

These fungi cause different tinea infections as tinea pedis

(infection of the feet), Tinea capitis (infection of the scalp), tinea corporis (infection of the arms and legs), and tinea unguium (infection of the nails).
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 Terbinafine is the drug of choice for treating tinea

infections.
Diarrhea, dyspepsia, nausea, headache, rash, hepatotoxicity

and neutropenia are its side effects.

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5. Griseofulvin It is an oral fungistatic agent used in the long-term treatment of dermatophyte infections (4 to 6 weeks, 6 to 12 months).
It inhibits fungal growth by binding to the microtubules

responsible for mitotic spindle formation, leading to inhibition of mitosis division.

Griseofulvin is used orally only for dermatophyte

infections.
Dizziness, fatigue, headache, nausea, itching and loss of

taste sensation are its side effects.

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6. Nystatin It is a fungicidal drug and its mechanism of action is identical to that of amphotericin B (increasing the permeability of the fungal cell membrane).
It is used topically only due to its very poor absorption from

GIT and its toxic effects for systemic use.

Its use is limited to the superficial and mucous membrane

infections caused by Candida as oral candidiasis, esophageal candidiasis and vaginal candidiasis.
Nystatin adverse effects are rare because of its very poor

absorption, but nausea and vomiting can occur.

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