Antifungal Drugs PDF

Antifungal Drugs  Overview Infectious diseases caused by fungi are called mycoses, and they are often chronic in nature. Mycotic infections may be superficial and involve only the skin (cutaneous mycoses extending into the epidermis), while oth...

Antifungal Drugs  Overview Infectious diseases caused by fungi are called mycoses, and they are often chronic in nature. Mycotic infections may be superficial and involve only the skin (cutaneous mycoses extending into the epidermis), while others may penetrate the skin, causing subcutaneous or systemic infections. The characteristics of fungi are so unique and diverse that they are classified in their own kingdom. Unlike bacteria, fungi are eukaryotic, with rigid cell walls composed largely of chitin rather than peptidoglycan (a characteristic component of most bacterial cell walls). In addition, the fungal cell membrane contains ergosterol rather than the cholesterol found in mammalian membranes. These structural characteristics are useful in targeting chemotherapeutic agents against fungal infections. Fungal infections are generally resistant to antibiotics, and, conversely, bacteria are resistant to antifungal agents. The incidence of fungal infections such as candidemia has been on the rise for the last few decades. This is attributed to an increased number of patients with chronic immune suppression due to organ transplantation, cancer chemotherapy, or infection with HIV. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOTIC INFECTIONS A. Amphotericin B Amphotericin B is a naturally occurring Polyene antifungal produced by Streptomyces nodosus. In spite of its toxic potential, amphotericin B remains the drug of choice for the treatment of several life-threatening mycoses. Amphotericin B is administered by slow, IV infusion. Amphotericin B is insoluble in water and must be coformulated with either sodium deoxycholate (conventional) or a variety of artificial lipids to form liposomes. The liposomal preparations have the advantage of reduced renal and infusion toxicity. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOTIC INFECTIONS B. Flucytosine Antimetabolite antifungal that is often used in combination with amphotericin B. Mechanism of action: 5-FC enters the fungal cell via a cytosine specific permease, an enzyme not found in mammalian cells. It is subsequently converted to a series of compounds, including 5-fluorouracil, which disrupt nucleic acid and protein synthesis. Note: Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell and leading to synergistic effects. Resistance: due to decreased levels of any of the enzymes in the conversion of 5-FC to 5-fluorouracil (5-FU) or from increased synthesis of cytosine can develop during therapy. This is the primary reason that 5-FC is not used as a single antimycotic drug. Adverse effects: reversible neutropenia, thrombocytopenia, and bone marrow depression. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOTIC INFECTIONS C. Azole antifungals Azole antifungals are made up of two different classes of drugs—imidazoles and triazoles. In general, imidazoles are given topically for cutaneous infections, whereas triazoles are given systemically for the treatment or prophylaxis of cutaneous and systemic fungal infections. The triazole antifungals include fluconazole, itraconazole, posaconazole, and voriconazole. Mechanism of action: They inhibit C-14 α-demethylase (CYP450] enzyme, thereby blocking the demethylation of lanosterol to ergosterol, the principal sterol of fungal membranes. The inhibition of ergosterol biosynthesis disrupts membrane structure and function, which, in turn, inhibits fungal cell growth. Resistance: mutations in the C-14 α-demethylase gene or efflux pumps that pump the azole out of the cell. Drug interactions: All azoles inhibit the hepatic CYP450 3A4 isoenzyme to varying degrees. Several azoles, including itraconazole and voriconazole, are metabolized by CYP450 3A4 and other CYP450 isoenzymes. Contraindications: Azoles are considered teratogenic. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOTIC INFECTIONS C. Azole antifungals Fluconazole was the first member of the triazole antifungal agents. It is the least active of all triazoles. It is commonly used as a single-dose oral treatment for vulvovaginal candidiasis. Fluconazol is available in oral or IV dosage formulations. Side effects: nausea, vomiting, headache, and skin rashes. Hepatotoxicity can also occur. Itraconazole has a broad antifungal spectrum compared to fluconazole. The oral capsule should be taken with food, and ideally an acidic beverage, to increase absorption. In contrast, the solution should be taken on an empty stomach, as food decreases the absorption. Adverse effects include nausea, vomiting, rash and headache. Hepatotoxicity can also occur. Itraconazole has a negative inotropic effect and should be avoided in patients with heart failure. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOTIC INFECTIONS C. Azole antifungals Posaconazole is structurally similar to itraconazole. It is available as an oral dosage formula, or IV formulation. Posaconazole has a low oral bioavailability and should be given with food. Unlike other azoles, posaconazole is not metabolized in the liver by CYP450 but is eliminated via glucuronidation. Adverse effects include gastrointestinal disturbances (nausea, vomiting, and diarrhea), headaches, and hepatotxicity. Drugs that affect the gastric pH (for example, PPI) may decrease the absorption of oral posaconazole Voriconazole, related to fluconazole, available in both IV and oral dosage forms. It has replaced amphotericin B as the drug of choice for invasive aspergillosis Adverse effects are similar to those of the other azoles; however, high trough concentrations are associated with visual and auditory hallucinations and an increased incidence of hepatotoxicity.  DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOTIC INFECTIONS C. Azole antifungals Fluconazole Itraconazole Voriconazole Posaconazole Spectrum of activity + ++ +++ ++++ Route(s) of administration Oral, IV Oral Oral, IV Oral, IV Drug levels affected No Yes No Yes By food or gastric PH Protein binding (%) 10 99 58 99 Primary route of Elimination Renal Hepatic Hepatic Hepatic CYP3A4 CYP2C19, 2C9, 3A4 Glucuronidation Cytochrome P450 enzymes Inhibited CYP3A4, 2C9, 2C19 CYP3A4, 2C9 CYP2C19, 2C9, 3A4 CYP3A4 CSF penetration Yes No Yes Yes Renal excretion of active drug (%) > 90