Antifungal Drugs Infectious diseases caused by fungi are called mycoses, and they are often chronic in nature. Fungal infectious occur due to : 1- Abuse of broad spectrum antibiotics 2- Decrease in the patient immunity

They have rigid cell walls composed largely of a polymer of N-acetylglucosamine rather than peptidoglycan (a characteristic component of most bacterial cell walls). The fungal cell membrane contains ergosterol rather than the cholesterol found in mammalian membranes. These chemical characteristics are useful in targeting chemotherapeutic agents against fungal infections

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.

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

Classification of Antifungal Drugs 1- Antifungal Antibiotics : Griseofulvin Polyene macrolide : Amphotericin- B & Nystatin 2- Synthetic : Azoles : A) Imidazoles : Ketoconazole , Miconazole B) Triazoles : Fluconazole , Itraconazole

Synthetic Antifungal ( contin…) Flucytosine Squalene epoxidase inhibitors : e.g.Terbinafine & Naftifine.

Classification According to Route of Administration Systemic : Griseofulvin , Amphotericin- B , Ketoconazole , Fluconazole , Terbinafine. Topical In candidiasis : Imidazoles : Ketoconazole , Miconazole. Triazoles : Terconazole. Polyene macrolides : Nystatin , Amphotericin-B Gentian violet : Has antifungal & antibacterial.

In Dermatophytes : Squalene epoxidase inhibitors : Terbinafine & Naftifine. Tolnaftate. White field ointment : 11% Benzoic acid & 6% Salicylic acid . Castellani paint.

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 16 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 ).

Resistance to amphotericin B If ergosterol binding is impaired either by : Decreasing the membrane concentration of ergosterol. Or by modifying the sterol target molecule.

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.

2- Slower toxicity Most serious is renal toxicity (nearly in all patients ). 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. 3- 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.

Azoles They are classified into : Imidazole group Triazole group

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, H2 blockers , proton pump inhibitors & food . Cola drinks improve absorption in patients with achlorhydria. 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.

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

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

Contraindications & Drug interactions Contraindicated in : Prgnancy, lactation ,hepatic dysfunction Interact with enzyme inhibitors , enzyme inducers. H2 blockers & antacids decrease its absorption

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

Itraconazole Lacks endocrine side effects Has a broad spectrum activity Given orally & IV Food increases its absorption Metabolized in liver to active metabolite Highly lipid soluble ,well distributed to bone, sputum ,adipose tissues. Can not cross BBB

Itraconazole (cont.) Half-life 30-40 hours Used orally in dermatophytosis & vulvo-vaginal candidiasis. IV only in serious infections. Effective in AIDS-associated histoplasmosis Side effects : Nausea, vomiting, hypokalemia, hypertension, edema, inhibits the metabolism of many drugs as oral anticoagulants.

Fluconazole Water soluble Completely absorbed from GIT Excellent bioavailability after oral administration Bioavailability is not affected by food or gastric PH Concentrated 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 25-30 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

Voriconazole A broad spectrum antifungal agent Given orally or IV High oral bioavailability Penetrates tissues well including CSF Inhibit P450 Used for the treatment of invasive aspergillosis & serious infections. Reversible visual disturbances

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).

Phrmacokinetics 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

Caspofungin Inhibits the synthesis of fungal cell wall by inhibiting the synthesis of β(1,3)-D-glucan, leading to lysis & cell death. Given by IV route only Highly bound to plasma proteins Half-life 9-11 hours Slowly metabolized by hydrolysis & N-acetylation. Elimination is nearly equal between the urinary & fecal routes.

Clinical uses Effective in aspergillus & candida infections. Second line for those who have failed or cannot tolerate amphotericin B or itraconazole. Adverse effects : Nausea, vomiting Flushing (release of histamine from mast cells) Very expensive

Griseofulvin Fungistatic, has a narrow spectrum Given orally (Absorption increases with fatty meal ) Half-life 26 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.

TOLNAFTATE Effective in most cutaneous mycosis. Ineffective against Candida. Used in tinea pedis ( cure rate 80% ). Used as cream, gel, powder, topical solution. Applied twice daily.

NAFTIFINE Broad spectrum fungicidal . Available as cream or gel. Effective for treatment of tinea cruris.

TERBINAFINE Drug of choice for treating dermatophytes (onychomycoses). Better tolerated ,needs shorter duration of therapy. Inhibits fungal squalene epoxidase, decreases The synthesis of ergosterol .(Accumulation of squalene ,which is toxic to the organism causing death of fungal cell).

Fungicidal ,its activity is limited to candida albicans & dermatophytes. Effective for treatment of onychomycoses 6 weeks for finger nail infection & 12 weeks for toe nail infections . Well absorbed orally , bioavailability decreases due to first pass metabolism in liver.

Highly protein binding Accumulates in skin , nails, fat. Severely hepatotoxic, liver failure even death. Accumulate in breast milk , should not be given to nursing mother. GIT upset (diarrhea, dyspepsia, nausea ) Taste & visual disturbance.