Antifungal Drugs Fungal infectious occur due to : 1- Abuse of broad spectrum antibiotics 2- Decrease in the patient immunity e.g DM, corticosteroid therapy, immunosuppressive therapy.

Types of fungal infections 1. Superficial : Affect skin – mucous membrane.e.g. Tinea versicolor Dermatophytes : Fungi that affect keratin layer of skin, hair, nail.e.g.tinea pedis,ring worm infection Candidiasis : Yeast-like, oral thrush, vulvo-vaginitis, nail infections.

Tinea Pedis

Ringworm of scalp, Tinea capitis

2- Deep infections Affect internal organs as : lung,heart, brain leading to pneumonia, endocarditis, meningitis.

Classification of Antifungal Drugs 1- Antifungal Antibiotics : Griseofulvin Polyene antibiotic: Amphotericin- B Nystatin Natamycin Rimocidin Filipin Pimaricin

Synthetic Antifungal ( contin…) Flucytosine Allylamines: Squalene epoxidase inhibitors : e.g.Terbinafine & Naftifine. Azoles : A) Imidazoles : Ketoconazole, Miconazole B) Triazoles : Fluconazole, Itraconazole Echinocandin:Caspofungin,Micafungin

Drug Classification A) Drugs that disrupt fungal cell membrane A) Drugs that disrupt fungal cell membrane i) Polyenes i) Polyenes Amphotericin Amphotericin Nystatin Nystatin Natamycin Natamycin ii) Azoles ii) Azoles A) Imidazole A) Imidazole B) Triazole B) Triazole iii) Allylamines iii) AllylaminesTerbinafine Naftifine Naftifine vi) vi) Echinocandins caspofungin,

B)Drugs that inhibits mitosis Griseofulvin C)Drugs that inhibits DNA synthesis flucytosine flucytosine d) Miscellaneous Tolnaftate Whitefield's ointment

Amphotericin B Amphotericin A & B are antifungal antibiotics. Amphotericin A is not used clinically. It is a natural polyene macrolide (polyene = many double bonds ) (macrolide = containing a large lactone ring )

Pharmacokinetics Poorly absorbed orally, is effective for fungal infection of gastrointestinal tract. For systemic infections given as slow I.V.I. Highly bound to plasma protein. Poorly crossing BBB. Metabolized in liver Excreted slowly in urine over a period of several days. Half-life 15 days.

Mechanism of action It is a selective fungicidal drug. Disrupt fungal cell membrane by binding to ergosterol, so alters the permeability of the cell membrane leading to leakage of intracellular ions & macromolecules ( cell death ).

The Fungal Cell Wall Atlas of fungal Infections, Richard Diamond Ed Introduction to Medical Mycology. Merck and Co. 2001

Adverse Effects 1- Immediate reactions ( Infusion –related toxicity ). Fever, muscle spasm, vomiting,headache, hypotension. Can be avoided by : A. Slowing the infusion B. Decreasing the daily dose C. Premedication with antipyretics, antihistamincs or corticosteroids. D. A test dose. A test dose of 1 mg per 20 mL 5% dextrose in water infused over 30 minutes should be given

2- Slower toxicity Most serious is renal toxicity (nearly in all patients ). Nephrotoxicity—Dose-dependent decrease in GFR because of vasoconstrictive effect on afferent renal arterioles Hypokalemia Hypomagnesaemia Impaired liver functions Thrombocytopenia Anemia

Clinical uses Has a broad spectrum of activity & fungicidal action. The drug of choice for life-threatening mycotic infections. For induction regimen for serious fungal infection. Also, for chronic therapy & preventive therapy of relapse. In cancer patients with neutropenia who remain febrile on broad –spectrum antibiotics.

Routes of Administration 1- Slow I.V.I. For systemic fungal disease. 2- Intrathecal for fungal C.N.S. infections. Topical drops & direct subconjunctival injection for Mycotic corneal ulcers & keratitis. 3- Local injection into the joint in fungal arthritis. 4- Bladder irrigation in Candiduria.

Liposomal preparations of amphotericin B Amphotericin B is packaged in a lipid- associated delivery system to reduce binding to human cell membrane, so reducing : A. Nephrotoxicity B. Infusion toxicity Also, more effective More expensive

Nystatin It is a polyene macrolide,similar in structure & mechanism to amphotericin B. Too toxic for systemic use. Used only topically. It is available as creams, ointment, suppositories & other preparations. Not significantly absorbed from skin, mucous membrane, GIT.

Clinical uses Prevent or treat superficial candidiasis of mouth, esophagus, intestinal tract. Vaginal candidiasis Can be used in combination with antibacterial agents & corticosteroids.

Azoles A group of synthetic fungistatic agents with a broad spectrum of activity. They have antibacterial, antiprotozoal anthelminthic & antifungal activity.

Mechanism of Action 1-Inhibit the fungal cytochrome P450 enzyme, (α-demethylase) which is responsible for converting lanosterol to ergosterol ( the main sterol in fungal cell membrane ). 2- Inhibition of mitochondrial cytochrome oxidase leading to accumulation of peroxides that cause autodigestion of the fungus. 3- Imidazoles may alter RNA& DNA metabolism.

Imidazoles Ketoconazole Miconazole Clotrimazole They lack selectivity,they inhibit human gonadal and steroid synthesis leading to decrease testosterone & cortisol production. Also, inhibit human P-450 hepatic enzyme.

Ketoconazole Well absorbed orally. Bioavailability is decreased with antacids, H 2 blockers, proton pump inhibitors & food. Half-life increases with the dose, it is (7-8 hrs).

Ketoconazole (cont.) Inactivated in liver & excreted in bile (feces ) & urine. Does not cross BBB. It should not be given with Anphotericin-B

Clinical uses Used topically or systematic (oral route only ) to treat : 1- Oral & vaginal candidiasis. 2- Dermatophytosis. 3- Systemic mycoses & mucocutaneous candidiasis.

Adverse Effects Nausea, vomiting,anorexia Hepatotoxic Inhibits human P 450 enzymes Inhibits adrenal & gonadal steroids leading to : Menstrual irregularities Loss of libido Impotence Gy naecomastia in males

Triazoles Fluconazole Itraconazole Voriconazole They are : Selective Resistant to degradation Causing less endocrine disturbance

Fluconazole Water soluble Completely absorbed from GIT Excellent bioavailability after oral administration Bioavailability is not affected by food or gastric PH Conc. in plasma is same by oral or IV route Has the least effect on hepatic microsomal enzymes

Fluconazole (cont.) Drug interactions are less common Penetrates well BBB so, it is the drug of choice of cryptococcal meningitis Safely given in patients receiving bone marrow transplants (reducing fungal infections) Excreted mainly through kidney Half-life hours Resistance is not a problem

Clinical uses Candidiasis ( is effective in all forms of mucocutaneous candidiasis) Cryptococcus meningitis Histoplasmosis, blastomycosis,, ring worm. Not effective in aspergillosis

Side effects Nausea, vomiting, headache, skin rash, diarrhea, abdominal pain, reversible alopecia. Hepatic failure may lead to death Highly teratogenic ( as other azoles) Inhibit P450 cytochrome No endocrine side effects

Flucytosine Synthetic pyrimidine antimetabolite (cytotoxic drug ) often given in combination with amphotericin B & itraconazole. Systemic fungistatic

Mechanism of action Converted within the fungal cell to 5- fluorouracil( Not in human cell ), that inhibits thymidylate synthetase enzyme that inhibits DNA synthesis. ( Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell, they are synergistic).

Pharmacokinetics Rapidly & well absorbed orally Widely distributed including CSF. Mainly excreted unchanged through kidney Half-life 3-6 hours

Clinical uses Severe deep fungal infections as in meningitis Generally given with amphotericin B For cryptococcal meningitis in AIDS patients

Adverse Effects Nausea, vomiting, diarrhea, severe enterocolitis Reversible neutropenia, thrombocytopenia, bone marrow depression Alopecia Elevation in hepatic enzymes

Griseofulvin Fungistatic, has a narrow spectrum Given orally (Absorption increases with fatty meal ) Half-life 24 hours Taken selectively by newly formed skin & concentrated in the keratin. Induces cytochrome P450 enzymes Should be given for 2-6weeks for skin & hair infections to allow replacement of infected keratin by the resistant structure

Griseofulvin(cont.) Inhibits fungal mitosis by interfering with microtubule function Used to treat dermatophyte infections ( ring worm of skin, hair, nails ). Highly effective in athlete, s foot. Ineffective topically. Not effective in subcutaneous or deep mycosis. Adverse effects ; Peripheral neuritis, mental confusion, fatigue, vertigo,GIT upset,enzyme inducer, blurred vision. Increases alcohol intoxication. Decreased effectiveness of cyclosporine ( ↓40%), estrogens, warfarin