Antifungal Drugs PDF

Antifungal Drugs Fungal infectious occur due to : 1- use of broad spectrum antibiotics 2- Decrease in the patient immunity  Types of fungal infections 1. Superficial : Affect skin – mucous membrane. e.g. Tinea versicolor Dermatophytes : Fungi that affect keratin layer of skin, hair, nail....

Antifungal Drugs Fungal infectious occur due to : 1- use of broad spectrum antibiotics 2- Decrease in the patient immunity  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 systemic drugs (oral or parenteral) for systemic infections oral systemic drugs for mucocutaneous infections, and topical drugs for mucocutaneous infections. SYSTEMIC ANTIFUNGAL DRUGS FOR SYSTEMIC INFECTIONS 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 ). Resistance to amphotericin B If ergosterol binding is impaired either by : Decreasing the membrane concentration of ergosterol. Or by modyfing 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. 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  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 through kidney Half-life 3-6 hours  Clinical uses The spectrum of activity of flucytosine is restricted to C neoformans, some Candida sp, and the dematiaceous molds that cause chromoblastomycosis. with amphotericin B for cryptococcal meningitis or with itraconazole for chromoblastomycosis.  Adverse Effects Nausea, vomiting , diarrhea, severe enterocolitis Reversible neutropenia, thrombocytopenia, bone marrow depression Alopecia Elevation in hepatic enzymes (some adverse effects related to 5-Fu formed by intestinal organisms from5-FC) narrow therapeutic window  Azoles A group of synthetic fungistatic agents with a broad spectrum of activity.  Azoles Azoles are synthetic compounds that can be classified as: 1. Imidazole group: ketoconazole,clotrimazole, miconazole,… 2. Triazole group: fluconazole, itraconazole,…… They are fungistatic agents.  Mechanism of Action 1-Inhibit the fungal cytochrome P450 enzymes, (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. Clinical Uses, Adverse Effects, & Drug Interactions The spectrum of action of azole medications is broad, including: many species of Candida, C neoformans, the endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), the dermatophytes, and, in the case of itraconazole, posaconazole, isavuconazole, and voriconazole, even Aspergillus infections. They are also useful in the treatment of intrinsically amphotericin-resistant organisms such as P boydii.  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 & 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 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 Itraconazole Voriconazole Fluconazole Posaconazole isavuconazole They are : Selective Resistant to degradation Causing less endocrine disturbance  Itraconazole Lacks endocrine side effects Has a broad spectrum activity Given orally & IV Drug absorption from capsules is increased by food and by low gastric pH. Metabolized in liver to active metabolite Highly lipid soluble ,well distributed to bone, sputum, adipose tissues. Can not cross BBB An important drug interaction is reduced bioavailability of itraconazole when taken with rifamycins (rifampin, rifabutin, rifapentine)  Itraconazole (cont.) Half-life 30-40 hours Used orally in dermatophytosis Itraconazole is the azole of choice for treatment of disease due to the dimorphic fungi Histoplasma, Blastomyces, and Sporothrix. IV only in serious infections. Side effects : Nausea, vomiting, hypokalemia, hypertension, edema, inhibits the metabolism of many drugs as oral anticoagulants. Rifamycines decrease itraconazole bioavailiblity  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 azole 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 Clinical uses Candidiasis ( is effective in all forms of mucocutaneous candidiasis) Cryptococcus meningitis Coccidioidal disease, Not effective in aspergillosis Side effects  Voriconazole A broad spectrum antifungal agent Given orally or IV High oral bioavailability Penetrates tissues well including CSF Metabolism is predominantly hepatic Inhibit CYP450 dose reduction of a number of medications is required when voriconazole is started. These include: cyclosporine, tacrolimus, and HMG-CoA reductase inhibitors. Used for the treatment of invasive aspergillosis & serious infections. Side effects: Reversible visual disturbances (Iv) rash and elevated hepatic enzymes Photosensitivity dermatitis Photosensitivity dermatitis is commonly observed in patients, and skin cancers have been reported in patients receiving chronic oral therapy. Rare toxicities include fluorosis (painful bone inflammation associated with elevated blood fluoride levels).  POSACONAZOLE It is available in a liquid oral formulation and is used at a dosage of 800 mg/d, divided into two or three doses. An intravenous form of posaconazole and a sustained-acting tablet form with higher bioavailability are available. Absorption is improved when taken with meals high in fat rapidly distributed to the tissues Posaconazole is the broadest spectrum member of the azole family Drug interactions with increased levels of CYP3A4 substrates such as tacrolimus and cyclosporine have been documented.  It is the first azole with significant activity against the agents of mucormycosis. It is currently licensed for salvage therapy in invasive aspergillosis, prophylaxis of fungal infections during induction chemotherapy for leukemia, allogeneic bone marrow transplant patients with graft- versus host disease.  rare side effect of posaconazole is hyperaldosteronism, which can cause hypertension and hypokalemia. ISAVUCONAZOLE (ISAVUCONAZONIUM SULFATE) It is available as highly bioavailable oral capsules and an intravenous formulation Food does not significantly impact the oral absorption of isavuconazonium sulfate. Measurement of isavuconazole levels has not been demonstrated to be of benefit. Coadministration with strong 3A4 inhibitors (eg, ritonavir) or inducers (eg, rifampin) is not recommended  Isavuconazole has an antifungal spectrum similar to that of posaconazole. It is currently licensed for the treatment of invasive aspergillosis and invasive mucormycosis. Data from published clinical trials are limited. Preliminary evidence indicates that it is better tolerated than voriconazole  ECHINOCANDINS  Caspofungin  Micafungin  Anidulafungin These agents are active against Candida and Aspergillus, but not C neoformans or the agents of zygomycosis and mucormycosis.  Echinocandines 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, 11-15 and 24-48 hours Slowly metabolized by hydrolysis & N-acetylation. Elimination is nearly equal between the urinary & fecal routes.  Clinical uses Caspofungine Effective in candida infections. empiric antifungal therapy during febrile neutropenia Second line in invasive aspergillosis for those who have failed or cannot tolerate amphotericin B Micafungin Mucocutaneous candidiasis, candidemia, prophylaxis of candidal infections in bone marrow transplant patients. Anidulafungin esophageal candidiasis invasive candidiasis include candidemia Adverse effects of echinocandines Nausea, vomiting Flushing ( release of histamine from mast cells) Very expensive Caspofungin in combination with cyclosporine should be avoided Micafungin has been shown to increase levels of nifedipine, cyclosporine, and sirolimus. Histamine release may occur during intravenous infusion of anidulafungin ORAL SYSTEMIC ANTIFUNGAL DRUGS FOR MUCOCUTANEOUS INFECTIONS 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.  TERBINAFINE Terbinafine is a synthetic allylamine. available in an oral formulation and is used at a dosage of 250 mg/d. Drug of choice for treating dermatophytoses (onychomycosis). 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). Gastrointestinal upset and headache  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. ITRACONAZOLE Effective for treatment of onychomycoses. Should not be given in patients with ventricular dysfunction. Evaluation of hepatic function is recommended. TOPICAL ANTIFUNGAL THERAPY Topical Antifungal Agents Used in superficial fungal infections , such as : Dermatophytosis ( ring worm), candidiasis, fungal keratitis. They are not effective in mycoses of the nails & hair or subcutaneous mycoses. The preferred formulation for cutaneous application is cream or solution.  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. oral use is often limited by the unpleasant taste Clinical uses Prevent or treat superficial candidiasis of mouth, esophagus, intestinal tract. Vaginal candidiasis intertriginous candidal infections Can be used in combination with antibacterial agents & corticosteroids. Azoles for topical use In the form of vaginal creams, suppositories, tablets for vaginal candidiasis given once daily. CLOTRIMAZOLE and MICONAZOL Absorption is less than 0.5% from intact skin, 3-10% from vagina (its activity remains for 3 days ). Used in dermatophytes , cutaneous candidiasis & vulvovaginal candidiasis. Causes : Erythema, edema, , urticaria & mild vaginal burning sensation. KETOCONAZOL TOPICAL CREAM Topical and shampoo forms of ketoconazole are also available treatment of seborrheic dermatitis and pityriasis versicolor.  TOPICAL ALLYLAMINES Terbinafine Naftifine Both are effective for treatment of tinea cruris and tinea corporis. 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.