Antifungal Drugs

Fluconazole: What are the major advantages of fluconazole over ketoconazole?

Fluconazole can enter the CSF in high concentrations and is not dependent on acidic pH for absorption.

What are the pharmacokinetics of flucytosine?

Flucytosine distributes well throughout the tissues, including the CSF. It is excreted intact in the urine.

When is it used?

Flucytosine is used predominantly in conjunction with amphotericin B, except for the treatment of subcutaneous chromomycoses, in which case flucytosine can be used alone.

Does amphotericin B bind to cholesterol?

No. Only ergosterol is affected by this drug.

What is its importance?

It is the drug of choice for treating systemic mycotic infections.

What are the therapeutic uses of fluconazole?

* Coccidioidal meningitis: drug of choice * Disseminated histoplasmosis * Oral and esophageal candidiasis * Prevention of relapse of cryptococcal meningitis in AIDS patients whose infection has been controlled by amphotericin B

What are ketoconazole's major toxicities?

* Gynecomastia and decreased libido due to inhibition of testosterone and cortisol synthesis * GI distress: nausea, vomiting * Hepatic dysfunction * Allergies

What are the toxicities of this drug?

* Hematologic: reversible bone marrow depression leading to neutropenia and thrombocytopenia * Elevated hepatic enzymes * Gastrointestinal disturbances: nausea, vomiting, enterocolitis

What are the adverse signs to watch for during administration?

* Renal impairment: 80% of patients exhibit decreased glomerular filtration rate and changes in renal tubular function. * Hypotension * Fever, chills * Hypochromic normocytic anemia * Neurologic effects

Itraconazole: What is itraconazole's therapeutic use?

* Subcutaneous chromomycosis (blastomycosis): drug of choice * Histoplasmosis * Cutaneous sporotrichosis * Candida infections * Tinea

State this drug's adverse effects.

- Headache - Hepatotoxicity - GI irritation

What toxicities are associated with ketoconazole?

- Nausea and vomiting - Headache - Skin rash

Systemic and Subcutaneous Mycoses: Name five drugs used for systemic and subcutaneous mycoses.

1. Amphotericin B (Fungizone) 2. Flucytosine (Ancobon) 3. Ketoconazole (Nizoral) 4. Fluconazole (Diflucan) 5. Itraconazole (Sporanox)

Superficial mycoses: Identify five major drugs used to treat superficial mycotic infections.

1. Griseofulvin (Fulvicin) 2. Nystatin (Mycostatin) 3. Miconazole (Monistat) 4. Clotrimazole (Canesten cream) 5. Econazole (Spectazole)

Flucytosine: What type of drug is flucytosine?

A synthetic pyrimidine antimetabolite. It is related in structure to an anticancer drug called 5-fluorouracil.

Amphotericin B: What is the classification of this drug?

Amphotericin B is a polyene antibiotic.

What is this drug's antifungal spectrum?

Amphotericin B is effective against: - Candida - Histoplasma Capsulatum - Cryptococcus neoformans - Blastomyces dermatitidis - Aspergillus - Coccidioides immitis

What are its pharmacokinetics?

Amphotericin B is poorly absorbed from the gastrointestinal tract. Bile is the major route of excretion. A small part of the drug, however, is eliminated in the urine.

What is a mycosis?

An infectious disease caused by a fungus. The infections can be systemic or superficial in nature.

How does this drug work?

Fungal cells contain ergosterol, a sterol specific to fungal cell membranes. Amphotericin B binds to ergosterol and forms pores or channels within the membrane. This allows electrolytes to leak from the cell, which results in cell death.

Antifungal Drugs: What is the structure of a fungus?

Fungi are eukaryotic organisms with rigid cell walls that contain chitin as well as polysaccharides.

What are the adverse effects of itraconazole?

GI distress, hypertriglyceridemia and hypokalemia.

Griseofulvin: What is its mode of action?

Griseofulvin enters susceptible fungal cells and inhibits microtubule function. With long-term therapy (weeks to months), this drug accumulates in the newly synthesized stratum corneum, making these cells undesirable for fungal growth.

What are the pharmacokinetics of this drug?

Griseofulvin is absorbed well orally, especially with a high-fat diet, and distributed to the keratin-containing stratum corneum. It is eliminated through the bile.

How does Ketoconazole work?

It blocks cytochrome P-450-mediated lanosterol demethylation to ergosterol.

How does flucytosine work?

It enters fungal cells through a cytosine-speific permease and is first converted to 5-FU. Subsequently, it is converted to 5-fluorodeoxyuridine monophosphate (5-FdUMP). This acid inhibits thymidylate synthetase, which is an essential enzyme in the production of DNA. Mammalian cells do not convert flucytosine to 5-FU.

What is the antifungal spectrum of this drug?

It is effective only against dermatophytes, including Trichophyton, Microsporum, and Epidermophyton.

What is its spectrum?

It is most useful against Histoplasma but can be used against Candida, Cryptococcus, Blastomyces and dermatophytes.

What are its pharmacokinetics?

Ketoconazole depends on gastric acidity to be dissolved and absorbed; drugs such as cimetidine and antacids impair its absorption. Ketoconazole is metabolized in the liver and excreted through the bile.

Ketoconazole: Into what category does this drug fit?

Ketoconazole is an azole, along with fluconazole, itraconazole, miconazole, clotrimazole, and econazole. They all have the same mechanism of action but different therapeutic indications. Their development provided a way to treat systemic infections orally.

State contraindications to the use of this drug.

Never use ketoconazole and amphotericin B together- they antagonize each other's actions.

Does amphotericin B eneter the CNS?

No

Is its antifungal spectrum broad or narrow?

Narrow; it only affects the following: - Candida - Cryptococcus neoformans - Aspergillus - Agents causing chromomycosis

Nystatin: What is the structure of this drug?

Nystatin is a polyene similar in structure to amphotericin B, with the same mechanism of action.

How is flucytosine usually administered?

Orally

How is this drug administered?

Orally only

What are the indications for use?

Superficial infections of the skin and mucous membranes.

What are the pharmacologic properties of these drugs?

They are very similar to ketoconazole in mechanism of action, spectrum and distribution.

What is the route of administration?

Topical

Miconazole, Clotrimazole, and Econazole: What is the route of administration for these drugs?

Topical. They are highly toxic if used systemically.

What is nystatin's therapeutic use?

Treatment of local Candida infections

What is the route of administration?

Usually intravenous; however, for fungal meningitis intrathecal administration is required.