Antifungal drugs
Anti fungals are the medicines that are used to treat fungal infections.
Fungal infections: Fungi are plant-like organisms that feed by breaking down living tissue.
Fungi cause infections in humans are known as dermatophytes. Dermatophytes are particularly attracted to a type of tissue called keratin, which is a waterproof, tough tissue found in many parts of the body such as in the:
· nails
· hair
· skin’s outer surface
Fungal infections:
Invasive fungal infections: These are a less common but more serious type of fungal infection, that occur in one of the organs or deep inside the body’s tissue, such as in the:
Brain – Fungal meningitis, in which a fungus causes an infection of the protective membranes that surround the brain and spinal cord.
Lungs –Aspergillosis, which is a lung infection caused by a fungal mould called aspergillus
Mechanism of antifungal drugs: Antifungal medicines work by either:
· killing the fungal cells –By affecting a substance in the cell wall, causing the contents of the cell to leak out and the cell to die
· preventing the fungal cells from growing and reproducing
Types of antifungal medicines: Depending on specific fungal infection, antifungal drugs are used in several ways. The main types of antifungal drugs include:
· Topical anti fungals: applied to the skin, hair or nails
· Oral anti fungals: swallowed in capsule, pill form or liquid
· Intravenous anti fungals: injected into a bloodstream.
Classification of antifungal drugs:
Drugs for systemic fungal infections:-
Polyene antibiotics
-Amphotericin B
Pyrimidine antimetabolites
-Flucytosine
Antifungal azoles
-Ketoconazole
-Fluconazole
-Itraconazole
Echinocandins
Caspofungin, micafungin, and anidulafungin
Drugs for superficial fungal infections
Systemic drugs
-Griseofulvin
-Iodide
Topical drugs
-Nystatin
-Haloprogin
-Tolnaftate
-Azoles: miconazole, econazole, clotrimazole
Pharmacology of amphotericin B: Amphotericin B is a polyene antibiotic
Mechanism of action:
Ø Binding to ergosterol present in the membranes of fungal cells
Ø Formation of “pores” in the membrane
Ø Leaking of small molecules (mainly K+) from the cells
Ø The ultimate effect may be fungicidal or fungistatic depending on the organism and on drug concentration.
Adverse effects: Headache, nausea, arthralgias, vomiting fever and chills, Malaise, weight loss, Nephrotoxicity.
Therapeutic uses: Deep candidiasis, Disseminated and meningeal coccidioidomycosis, disseminated histoplasmosis, Invasive aspergillosis, Mucormycosis.
Pharmacology of flucytosine: Flucytosine is a fluorinated pyrimidine
Mechanism of action
-The drug is accumulated in fungal cells by the action of a membrane permease and is converted by a cytosine deaminase to 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluorouridylic acid which can be
a) Incorporated into the RNA, this leads to a misreading of the fungal genetic code
b) Further metabolized to 5-deoxyfluorouridylic acid, a potent inhibitor of thymidylate synthase, this leads to a blockade of fungal DNA synthesis
The ultimate effect may be fungicidal or fungistatic depending on the organism and on drug concentration.
Action of flucytosine in fungi: 5-Flucytosine is transported into the fungal cell, where it is deaminated to 5-fluorouracil (5-FU). The 5-FU is then converted to 5-fluorouracil-ribose monophosphate (5-FUMP) and then is either converted to 5-FUTP and incorporated into RNA or converted by ribonucleotide reductase to 5-FdUMP, which is a potent inhibitor of thymidylate synthase.
Antifungal spectrum and resistance: Antifungal spectrum includes Cryptococcus neoformans, Candida albicans, Aspergillus fumigatus, and several soil fungi which cause chromomycosis. Resistance may arise rapidly during therapy and is an important cause of therapeutic failure when the drug is used alone.
Pharmacokinetics and administration
-F (oral): > 80%
-Distribution in all body tissues, including CNS and the eye.
-Volume of distribution: » 42 L
-Renal excretion: » 99%
-Half-life: » 4 hours (in renal failure, half-life may be as long as 200 hours)
-Administration: oral, IV
Adverse effects:- Headache, dizziness, confusion, Anorexia, nausea and vomiting, diarrhoea, Skin rashes, Severe ulcerative enterocolitis (rare), Reversible bone marrow depression (8-13%)(leucopoenia, thrombocytopenia), Alopecia, peripheral neuritis (rare), Liver dysfunction (5-10%).
Therapeutic uses: cryptococcal meningitides, Deep Candida infections, Chromomycosis.
Contraindication: Pregnancy (5-fluorouracil is teratogenic)
Pharmacology of azoles:
Imidazole derivatives: ketoconazole, miconazole, econazole, clotrimazole
Triazole derivatives: itraconazole, fluconazole.
Mechanism of action: Inhibition of sterol 14-alpha-demethylase, a cytochrome P450-dependent enzyme (relative selectivity occurs because the affinity for mammalian P450 isozymes is less than that for the fungal isozyme) blockade of the synthesis of ergosterol in fungal cell membranes. The ultimate effect may be fungicidal or fungistatic depending on the organism and on drug concentration.
Antifungal spectrum and resistance: Histoplasma capsulatus, Coccidioides immitis, Paracoccidioidoides braziliensi, Aspergillus fumigatus Blastomyces dermatitidis, Cryptococcus neoformans Candida albicans, Sporothrix schenckii Dermatophytes.
Resistance can occur but is rare. Cross-resistance between azoles is a common finding.
Other effects: It inhibits the synthesis of androgens and of corticosteroids, potentiates the effects of several drugs including Phenytoin, cyclosporine, terfenadine, astemizole, tolbutamide and warfarin.
Pharmacokinetics and administration:
Adverse effects: Gynecomastia, decreased libido, impotence, menstrual irregularities, anorexia, nausea and vomiting, hypokalemia.
Therapeutic uses: Blastomycosis, chronic pulmonary histoplasmosis, Cutaneous and deep candidiasis, meningeal coccidioidomycosis, Para coccidioidomycosis.
Contraindications: Systemic azoles are contraindicated in pregnancy.
Pharmacology of griseofulvin: It is a benzofuran derivative, practically insoluble in water.
Mechanism of action: An active transport accumulates the drug in sensitive fungal cells where griseofulvin causes disruption of the mitotic spindle by interacting with polymerized microtubules. The ultimate effect is fungi static.
Antifungal spectrum and resistance: Antifungal spectrum includes only Dermatophytes (Microsporum, Epidermophyto, and Trichophyton). The drug is ineffective against other fungi producing superficial lesions (like Candida and Malassezia) and those producing deep mycoses. Resistance is uncommon. It seems to be due to a decrease of the energy- dependent transport mechanism.
Echinocandins: Newest class of antifungal agent, inhibiting the synthesis of (1–3)-glucan
Eg: Anidulafungin, Caspofungin, Micafungin
Pharmacokinetics and administration:
Adverse effects: Headache, diarrhoea, nausea and vomiting, allergic reactions, xerostomia, hepatotoxicity.
Therapeutic uses: Mycotic disease of the skin, hair and nails.
Topical antifungal drugs:
Nystatin: A polyene antibiotic useful only for local candidiasis.
Administration: Cutaneous, vaginal, oral.
Haloprogin: The drug is fungicidal to various species of dermatophytes and Candida.
Tolnaftate: The drug is effective against most dermatophytes and Malassezia but not against Candida. In tinea pedis the cure rate is » 80%
Antifungal azoles: Azoles are reported to cure dermatophyte infections in 60-100% of cases. The cure rate of mucocutaneous candidiasis is > 80% and that of tinea vesicular > 90%.
Administration: cutaneous, vaginal.
Cutaneous application rarely causes edema, erythema, vescication, desquamation and urticaria.
Vaginal application may cause mild burning sensation and abdominal pain.
fungicide, fungistatic, ring worm
