ANTIFUNGAL DRUGSPrepared by:

Ahmad MoussaWalid Nabil Fouad

Microbiology Department

Medical Research Institute

Alexandria University

May 2010

An antifungal drug is a medication used to treat fungal infections such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and others. Such drugs are usually obtained by a doctor's prescription or purchased over-the-counter.

Antifungal drugs are of two kinds: systemic and topical.

Systemic antifungal drugs are medicines taken orally (by mouth) or by injection to treat infections caused by a fungus.

Topical antifungal drugs are medicines applied to the skin to treat skin infections caused by a dermatophyte.

Types of antifungals:

Topical antifungal drugs not only relieve the symptoms of fungal infection, such as itching, burning, and cracked skin, but they also eliminate the fungus. However, those that occur inside the body or that do not clear up after treatment with creams or ointments may need to be treated with systemic antifungal drugs.

Systemic antifungal drugs are used, for example, to treat a type of fungal infection called candidiasis also known as (thrush or yeast infection), which can occur in the throat, in the vagina, or in other parts of the body.

They may also be used to treat fungal infections, which can affect the lungs and other organs such as:

Histoplasmosis Blastomycosis Aspergillosis

Types of antifungals:

Antifungals work by exploiting differences between mammalian and fungal cells to kill the fungal organism without dangerous effects on the host.

Every component of the fungal cell wall and membrane can be targeted. For example:

Polyenes target ergosterol destroying the cell membrane’s integrity. Allylamines, imidazoles, and triazoles inhibit ergosterol synthesis. β-3-glucan synthase inhibitors (echinocandins) block the production

of the β-(1,3)-glucan protein damaging the cell wall. Drugs not available in the market such as Nikkomycin and Polyoxin

target chitin synthase. Mannoproteins are another potential target. Other antifungals such as flucytosine inhibit DNA/RNA synthesis and

griseofulvin inhibits fungal cell mitosis preventing cell proliferation and function.

How antifungals work?

How antifungals work?

Unlike bacteria, both fungi and humans are eukaryotes. Thus fungal and human cells are similar at the molecular level. This makes it more difficult to find or design drugs that target fungi without affecting human cells.

As a consequence, many antifungal drugs cause side-effects. Some of these side-effects can be life-threatening if the drugs are not used properly.

Apart from side-effects like liver-damage or affecting estrogen levels, many medicines can cause allergic reactions in people. For example, the azole group of drugs is known to have caused anaphylaxis.

Precautions in using antifungals:

A. Polyene antifungals:

Chemistry: A polyene is a molecule with multiple conjugated double bonds. A polyene antifungal is a macrocyclic polyene with a heavily hydroxylated region on the ring opposite the conjugated system. This makes polyene antifungals amphiphilic.

Mode of action: The polyene antimycotics bind with sterols in the fungal cell membrane, principally ergosterol. This causes the fungal cell's contents including monovalent ions (K+, Na+, H+, and Cl-) as well as small organic molecules to leak out of the cell, and thereby causing fungal cell death.

Classes of antifungals:

Polyene and toxicity to animal cells:

Animal cells contain cholesterol instead of ergosterol and so they are much less susceptible. However, at therapeutic doses, some amphotericin B may bind to animal membrane cholesterol, increasing the risk of human toxicity.

Amphotericin B is nephrotoxic when given intravenously. Amphotericin B molecules can form pores in the host membrane as well as the fungal membrane. This impairment in membrane barrier function can have lethal effects.

As a polyene's hydrophobic chain is shortened, its sterol binding activity is increased. Therefore, further reduction of the hydrophobic chain may result in it binding to cholesterol, making it toxic to animals.

Classes of antifungals:

Amphotericin-B:

Indications: One of the main intravenous uses of this drug is in treating various systemic fungal infections (e.g. in critically ill, comorbidly infected or immunocompromised patients), including cryptococcal meningitis.

Amphotericin B is also commonly used in tissue culture to prevent fungi from contaminating cell cultures.

Adverse effects: Intravenously administered Amphotericin B has also been associated with multiple organ damage in therapeutic doses.

Nephrotoxicity (kidney damage) is a frequently reported side-effect, and can be severe and/or irreversible.

Examples of polyene antifungals:

Although conventional amphotericin B (Fungizone) remains the standard therapy for many invasive or life-threatening mycoses, this polyene drug is associated with significant toxicity, including infusion-related events, such as chills, fever, headache, nausea and vomiting, and dose-limiting nephrotoxicity.

In addition, the clinical efficacy of amphotericin B in some settings (e.g., mold disease such as invasive aspergillosis in severely immuno-compromised patients) is sub-optimal.

Amphotericin-B:

Natamycin – 33 Carbons, binds well to ergosterolRimocidinFilipin – 35 Carbons, binds to cholesterol (toxic)NystatinCandicinHamycin

Other examples of polyene antifungals:

B. Azole antifungals:

Chemistry: An azole is a class of five-membered nitrogen heterocyclic ring compounds containing at least one other non-carbon atom of nitrogen, sulfur, or oxygen.

Mode of action: Azole antifungal drugs inhibit the fungal cytochrome P-450 3-A dependent enzyme 14-alpha demethylase (lanosterol 14 α-demethylase); the enzyme necessary to convert lanosterol to ergosterol (an important component of the fungal plasma membrane). Inhibition of this critical enzyme in the ergosterol synthesis pathway leads to the depletion of ergosterol in fungal membrane and disrupts the structure and many functions of fungal membrane, thereby leading to inhibition of fungal growth.

Classes of antifungals:

Adverse effects: Azole antifungals can also inhibit many mammalian cytochrome P450-dependent enzymes involved in hormone synthesis or drug metabolism. Therefore, azole antifungals are particularly susceptible to clinically-significant drug interactions with other medications metabolized through the P450 pathway.

Azole antifungals:

I. Imidazole: Imidazole is an organic compound with the formula C3H4N2. The substituted imidazole derivatives are valuable in treatment of many

systemic fungal infections. The imidzaoles include:

• Clotrimazole• Ketoconazole• Econazole• Bifonazole• Butoconazole• Fenticonazole• Isoconazole• Oxiconazole• Sertaconazole• Sulconazole• Tioconazole• Miconazole

Subclasses of Azole group:

Clotrimazole:

This is a broad spectrum antifungal developed in 1967. It was one of the first azoles to be developed. Formulations are now generic in a number of countries.

It is effective against Candida albicans and dermatophytes.

Its action is fungistatic or fungicidal, depending upon the concentration used. This azole drug is available in a variety of dosage forms.

It is marketed as Lotrimin or Lotrimin AF (and Canesten in the UK).

Example of imidazole antifungal:

II. Triazoles: Triazole refers to either one of a pair of isomeric chemical compounds

with molecular formula C2H3N3, having a five-membered ring of two carbon atoms and three nitrogen atoms.

The triazoles are newer, less toxic and more effective. The triazole antifungal drugs include:

Fluconazole Itraconazole Isavuconazole Ravuconazole Posaconazole Voriconazole Terconazole

Subclasses of Azole group:

Fluconazole: A broad spectrum antifungal, first approved in Europe in 1988 and then in America in 1990. It was the first single dose treatment approved for vaginal candidiasis. Fluconazole is an effective agent in the treatment and prophylaxis of candidal infection.

Itraconazole:A synthetic triazole analogue with a wide spectrum of antifungal activity. It was first synthesized in 1980, and approved in Europe in 1987. It was approved by the FDA in 1992 for systemic mycoses, and then for onychomycoses in 1995, and for use by pulse therapy in 1997. In 2000, itraconazole was also approved to treat blastomycosis, histoplasmosis, and aspergellosis in patients intolerant of amphotericin B.

Examples of triazole antifungals:

C. Allylamine drugs:

Allylamines inhibit squalene epoxidase, another enzyme required for ergosterol synthesis. These include: Amorolfine Naftifine – marketed as "Naftin" in North America Butenafine – marketed as Lotrimin Ultra Terbinafine – Marketed as "Lamisil" in North America, Australia, the

UK, Germany and the Netherlands. It is one of the first antifungals of the allylamine class, discovered in 1974. It was approved for systemic use in the UK in 1991, and for topical use in the USA in 1992. Terbinafine is an antifungal effective against Dermatophytes, Aspergillus sp., and Candida and Pityrosporum yeasts.

Classes of antifungals:

D. Echinocandins:

Echinocandins inhibit the synthesis of glucan in the cell wall, probably via the enzyme 1,3-β glucan synthase. Inhibition of this enzyme results in depletion of glucan polymers in the fungal cell, resulting in an abnormally weak cell wall unable to withstand osmotic stress. Examples include:

Anidulafungin Caspofungin Micafungin

These drugs are administered parenterally only, NOT orally. They may be used for systemic fungal infections in immunocompromised patients.

Classes of antifungals:

E. Antimetabolites antifungals:DNA and protein synthesis have historically been difficult targets for the development of selectively-toxic antifungal therapy, as fungal and mammalian cells share remarkable homology in DNA replication and RNA translation. However, advances in molecular biology and functional genomics are beginning to highlight important differences between mammalian and fungal cells that could be exploited for the development of new antifungal therapies. For the time being, only one class of agents in clinical use targets DNA/RNA synthesis.

Flucytosine: Flucytosine was originally developed in the 1950's as a potential antineoplastic agent. Although ineffective against tumors it was later found to have antifungal activity.

Classes of antifungals:

Flucytosine is transported into susceptible fungal cells by a specific enzyme cytosine permease and converted in the cytoplasm by cytosine deaminase to 5-fluorouracil (5-FU)- a pyrimidine anti-metabolite used as chemotherapy for many types of colorectal cancer.

5-FU is phosphorylated and incorporated into RNA where it causes miscoding and halts protein synthesis. Additionally, phosphorylated 5-FU is converted to its deoxynucleoside, which inhibits DNA synthesis by blocking the functions of a key enzyme in DNA replication- thymidylate synthetase.

Flucytosine can be converted to 5-FU by bacteria residing in the gastrointestinal tract. Not surprisingly, the most common adverse effects seen with flucytosine are similar to 5-FU chemotherapy (diarrhea, nausea and vomiting, bone marrow suppression) but at reduced intensity.

Flucytosine: