pharma III-6 Antifungal Drugs 04.04.2020 (2)-10-35.pdf

Amphotericin B Mechanism of action: Amphotericin B binds to ergosterol in the plasma membranes of sensitive fungal cells. There, it forms pores (channels) that disrupt membrane function, allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in ce...

Amphotericin B Mechanism of action: Amphotericin B binds to ergosterol in the plasma membranes of sensitive fungal cells. There, it forms pores (channels) that disrupt membrane function, allowing electrolytes (particularly potassium) and small molecules to leak from the cell, resulting in cell death. Resistance: Fungal resistance, although infrequent, is associated with decreased ergosterol content of the fungal membrane. 10 Amphotericin B Pharmacokinetics: Amphotericin B has a low therapeutic index. Amphotericin B is administered by slow, intravenous (IV) infusion. Amphotericin B is insoluble in water and must be co-formulated with either sodium deoxycholate (conventional) or a variety of artificial lipids to form liposomes. The liposomal preparations have the primary advantage of reduced renal toxicity. However, due to high cost, liposomal preparations are reserved mainly as salvage therapy for patients who cannot tolerate conventional amphotericin B. 11 Amphotericin B Adverse effects 1. Fever and chills:  These occur most commonly 1 to 3 hours after starting the IV administration but usually subside with repeated administration of the drug.  Premedication with a corticosteroid or an antipyretic helps to prevent this problem. 2. Renal impairment:  Azotemia is exacerbated by other nephrotoxic drugs, such as aminoglycosides, and vancomycin, although adequate hydration can decrease its severity. 3. Hypotension:  A fall in blood pressure accompanied by hypokalemia may occur, requiring potassium supplementation. 4. Thrombophlebitis:  Adding heparin to the infusion can alleviate this problem. 12 Antimetabolite antifungals- 2. 5-Flucytosine (5-FC) 5-FC is a synthetic pyrimidine antimetabolite that is often used in combination with amphotericin B. This combination of drugs is administered for the treatment of systemic mycoses and for meningitis caused by:  Cryptococcus neoformans  Candida albicans. Antimetabolites are drugs that interfere with one or more enzymes or their reactions that are necessary for DNA synthesis. They affect DNA synthesis by acting as a substitute to the actual metabolites that would be used in the normal metabolism (for example antifolates interfere with the use of folic acid). 13 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 and 5-fluorodeoxyuridine 5′- monophosphate, which disrupt nucleic acid and protein synthesis.  Amphotericin B increases cell permeability, allowing more 5-FC to penetrate the cell and leading to synergistic effects. 14 Antifungal spectrum 5-FC is fungistatic. It is effective:  in combination with itraconazole for treating chromoblastomycosis (chronic skin and subcutaneous infections)  in combination with amphotericin B for treating candidiasis and cryptococcosis (potentially fatal fungal disease caused by Cryptococcus neoformans or Cryptococcus gattii).  for Candida urinary tract infections when fluconazole is not appropriate. 15 Resistance to (5-FC) Resistance can occur with repeated use of 5-FC. Resistance is due to: decreased levels of any of the enzymes in the conversion of 5-FC to 5-fluorouracil (5-FU) and beyond or from increased synthesis of cytosine can develop during therapy. Resistance is the primary reason that 5-FC is not used as a single antimycotic drug. The rate of emergence of resistant fungal cells is lower with a combination of 5-FC plus a second antifungal agent than it is with 5-FC alone. 16 Pharmacokinetics- (5-FC) 5-FC is well absorbed by the oral route. It distributes throughout the body water and penetrates well into the CSF. 5-FU is detectable in patients and is probably the result of metabolism of 5-FC by intestinal bacteria. Excretion of both the parent drug and its minimal metabolites is by glomerular filtration and, The dose must be adjusted in patients with compromised renal function. 17 Adverse effects- (5-FC) 5-FC causes bone marrow depression therefore, Caution must be exercised in patients undergoing radiation or chemotherapy with drugs that depress bone marrow. Reversible hepatic dysfunction may occur. Gastrointestinal disturbances (nausea, vomiting, and diarrhea) are common. severe enterocolitis may also occur. 18 3. Azole antifungals Azoles are synthetic compounds that can be classified as either: Imidazoles or Triazoles Classification is done according to the number of nitrogen atoms in the five-membered azole ring. 19 Azole antifungals Although these drugs have similar mechanisms of action and spectra of activity, their pharmacokinetics and therapeutic uses vary significantly. 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. 20 Mechanism of action  Azoles are predominantly fungistatic.  They inhibit C P450-14 α- demethylase (a cytochrome P450 [CYP450] enzyme), thereby blocking the demethylation of (14α-demethylase) 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. 21 Resistance to azoles Resistance to azole antifungals is becoming a significant clinical problem. Mechanisms of resistance include: mutations in the C-14 α-demethylase gene that lead to decreased azole binding. efflux pumps that pump the azole out of the cell. Reduced affinity to azoles Reduced azole entry Enzyme overproduction 22 Drug interactions of Azoles  All azoles inhibit the hepatic CYP450 3A4 isoenzyme to varying degrees.  Patients on concomitant medications that are substrates for this isoenzyme may have increased concentrations and risk for toxicity. 23 24 Contraindications of Azoles  Azoles are considered teratogenic, and they should be avoided in pregnancy 25 Triazoles Main triazole are Fluconazole Itraconazole Posaconazole Voriconazole 26  Fluconazole  Fluconazole is the least active of all triazoles, with most of its spectrum limited to yeasts and some dimorphic fungi. It is available in oral or IV formulations.  It is highly active against Cryptococcus neoformans and certain species of Candida including C. albicans.  Fluconazole is effective against mucocutaneous and vulvovaginal candidiasis. and is used for the treatment of candidemia. It is also used for prophylaxis against invasive fungal infections in recipients of bone marrow transplants.  Majority of the drug is excreted unchanged via the urine, and doses must be reduced in patients with renal dysfunction.  Hepatotoxicity can also occur, and the drug should be used with caution in patients with liver dysfunction The most common adverse effects with fluconazole are nausea, vomiting, headache, and skin rashes. 27  Itraconazole  Itraconazole has a broad antifungal spectrum compared to fluconazole. It is available in capsule and oral solution forms  Itraconazole is the drug of choice for the treatment of blastomycosis, sporotrichosis, paracoccidioidomycosis, and histoplasmosis (dimorphic fungi).  It is rarely used for treatment of infections due to Candida and Aspergillus species because of the availability of newer and more effective agents.  Itraconazole is extensively metabolized by the liver, and the drug and inactive metabolites are excreted in the feces and urine.  Hepatotoxicity can also occur, especially when given with other drugs that affect the liver. 28 Posaconazole  Posaconazole, a synthetic triazole, is a broad-spectrum antifungal agent structurally similar to itraconazole.  Posaconazole is commonly used for the treatment and prophylaxis of invasive Candida and Aspergillus infections in severely immunocompromised patients.  Unlike other azoles, posaconazole is not metabolized in the liver by CYP450 but is eliminated via glucuronidation.  Like other azoles, posaconazole can cause an elevation in serum hepatic transaminases.  The most common adverse effects include gastrointestinal disturbances (nausea, vomiting, and diarrhea) and headaches. 29 Voriconazole  Voriconazole, a broad-spectrum antifungal agent that is available in both IV and oral dosage forms.  Voriconazole has replaced amphotericin B as the drug of choice for invasive aspergillosis.  It is also approved for treatment of invasive candidiasis, as well as serious infections caused by other fungal species. 30  Voriconazole  Elimination is primarily by metabolism through the CYP450 enzymes.  Voriconazole is not only a substrate but also an inhibitor of CYP2C19, 2C9, and 3A4 isoenzymes. Inhibitors and inducers of these enzymes may impact levels of voriconazole, leading to toxicity or clinical failure, respectively.  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. 31 32 4- Echinocandins  Echinocandins interfere with the synthesis of the fungal cell wall by inhibiting the synthesis of β(1,3)-d-glucan, leading to lysis and cell death. Caspofungin, micafungin, and anidulafungin are available as IV form for once daily administration. 33 Caspofungin, micafungin and anidulafungin Caspofungin, micafungin and anidulafungin are first-line options for patients with invasive candidiasis, including candidemia, and a second-line option for invasive aspergillosis in patients who have failed or cannot tolerate amphotericin B or an azole. The dose of caspofungin does not need to be adjusted in renal impairment, but adjustment is warranted with moderate hepatic dysfunction. Anidulafungin can be administered in severe hepatic dysfunction, but micafungin has not been studied in this condition 34 Caspofungin, micafungin and anidulafungin Concomitant administration of caspofungin with certain CYP450 enzyme inducers (for example, rifampin) may require an increase in the daily dose. Micafungin and anidulafungin are not substrates for CYP450 enzymes and do not have any associated drug interactions. Caspofungin should not be co-administered with cyclosporine due to a high incidence of elevated hepatic transaminases with concurrent use. All three agents are well tolerated, with the most common adverse effects being fever, rash, nausea, phlebitis at the infusion site and a histamine-like reaction (flushing) when infused too rapidly. 35