Antifungal Drugs

Antifungal Drugs Rolf J. Craven, M.S., Ph.D. Office: 213 Combs Phone: 323-3832 E-mail: rolf.craven@uky.edu Downloaded from www.pharmacy123.blogfa.com

Learning objectives: • Identify the most common pathogenic fungi and the diseases that they cause. Keyword: candidiasis/candidosis. • Examine the general mechanisms of clinically utilized antifungal agents. Keywords: ergosterol, cytochrome P450, lanosterol demethylase, squalene epoxidase, thymidylate synthase, and permease. • Understand the uses, mechanisms, pharmacokinetics, and side effects of the following drugs: fluconazole,clotrimazole,amphotericin, nystatin, flucytosine, terbinafine, and griseofulvin. Downloaded from www.pharmacy123.blogfa.com

Summary of fungal pathogens • Superficial mycoses are among the most common infections in the world. • In the U.S., 50% of women experience vulvuvaginal candidiasis/candidosis by the age of 25, with the majority of these infections being caused by Candida albicans. • Risk factors for candidosis include corticosteroid therapy, broad-spectrum antibiotic, diabetes, and immunosuppression. • Tight clothing and oral contraceptive use have also been associated with candidosis, and it is fairly common during pregnancy. • Oral candidosis is often called thrush. Downloaded from www.pharmacy123.blogfa.com

Summary of fungal pathogens • C. albicans is a normal component of the GI flora, present in 50-80% of the healthy human population, where they compete with harmful bacteria and are kept in check by the immune system. • Candida are a dimorphous fungi, because they can live in a yeast state, in which they replicate by budding (Figure 1, “C” panel). • Under the appropriate conditions, Candida can change into an invasive state (Figure 1, “D” panel) in which they grow filamentous processes. Downloaded from www.pharmacy123.blogfa.com

Summary of fungal pathogens • Candidosis is usually treated topically with azole inhibitors of fungal ergosterol synthesis. • Topical nystatin is an alternative treatment, with oral fluconazole as the next line of therapy. • In extreme cases, intravaneous amphotericin with flucytosine may be considered. We will review all of these drugs in the lecture. Downloaded from www.pharmacy123.blogfa.com

Summary of fungal pathogens Q: Bacteria and fungi infect some of the same areas of the body. How can you distinguish bacterial and fungal infections? Downloaded from www.pharmacy123.blogfa.com

Summary of fungal pathogens • Although Candida albicans is the most common fungal pathogen, a number of other fungi are encountered clinically. • In addition, fungi can colonize other areas of the body, with the common disorders being tinea pedis (“athletes’ foot”), tinea cruris (“jock itch”), tinea capitis (infections of the scalp), tinea barbae (infections of beards and moustaches), and onychomycosis (infection of the nails). Downloaded from www.pharmacy123.blogfa.com

Q: Yeast are used to make beer. Does that mean that you can get a yeast infection from drinking beer? Should people taking corticosteroids by aerosol avoid beer? Downloaded from www.pharmacy123.blogfa.com

Summary of fungal pathogens • Systemic infections are characteristic of HIV/AIDS patients, cancer patients, and other patients receiving immunosuppressive agents or broad-spectrum antibiotics. • They are a major cause of death among cancer patients and transplant recipients. • The fungi involved in systemic infections include Candida, Histoplasma,Aspergillus, and Cryptococcus species. We will review the drugs used to treat these infections. Downloaded from www.pharmacy123.blogfa.com

azole drugs and terbinafine disrupt ergosterol synthesis griseofulvin disrupts the mitotic spindle nucleus amphotericin and nystatin form pores in the cell membrane flucytosine blocks DNA synthesis ANTIFUNGAL DRUGS Downloaded from www.pharmacy123.blogfa.com

SUMMARY of Antifungal Mechanisms: • The majority of anti-fungal agents inhibit the biosynthesis or stability of ergosterol. • This is the fungal version of cholesterol and is a major component of the fungal cell membrane. • Ergosterol performs a variety of functions in the fungal cell, and the proteins that synthesize it are essential for viability. Downloaded from www.pharmacy123.blogfa.com

Q: Ergosterol looks like cholesterol- can too much ergosterol clog your arteries? Downloaded from www.pharmacy123.blogfa.com

SUMMARY of Antifungal Mechanisms: • Most of the compounds that are described below affect ergosterol. Their mechanisms are as follows: • (1) They bind to ergosterol and block its function. • (2) They block ergosterol synthesis by inhibiting the enzyme lanosterol demethylase. • (3) They block ergosterol synthesis by inhibiting the protein squalene synthase. Downloaded from www.pharmacy123.blogfa.com

Azole drugs- inhibit ergosterol synthesis • Description: The azoles are named for ring structures within the drug. Downloaded from www.pharmacy123.blogfa.com

Azole drugs are heavily marketed Downloaded from www.pharmacy123.blogfa.com

Azole drugs- inhibit ergosterol synthesis • Mechanism: This class of drugs acts by inhibiting the enzyme lanosterol demethylase, a key step in ergosterol synthesis. Downloaded from www.pharmacy123.blogfa.com

Azole drugs- inhibit ergosterol synthesis Side effects: Lanosterol demethylase is a cytochrome P450 protein. It is closely related to human lanosterol demethylase and other P450 proteins. As a result, azole drugs inhibit human P450 proteins in the liver and alter the metabolism of other drugs. Downloaded from www.pharmacy123.blogfa.com

Resistance to antifungal drugs • Resistance: Resistance has gradually emerged with prolonged use and generally involves mutations or changes in expression of the target protein, lanosterol demethylase. • Remember: some people who are taking these drugs have chronic conditions and might take the drugs for a long time. Downloaded from www.pharmacy123.blogfa.com

Azole drugs- inhibit ergosterol synthesis • All members of this class of antifungals are potential teratogens. Why would azole compounds be teratogens? Do they act on DNA directly? Downloaded from www.pharmacy123.blogfa.com

Fluconazole a) Uses: Fluconazole is the drug of choice for candidosis and both cryptococcal and coccidioidal meningitis. b) Dosage: Fluconazole is effective orally and is also given i.v. Fluconazole is minimally metabolized and cancross the blood-brain barrier. c) Side effects: Fluconazole can cause nausea, vomiting or rash. There are significant drug interactions between fluconazole and warfarin, cyclosporine, phenytoin, lovastatin, oral hypoglycemics, and protease inhibitors. Downloaded from www.pharmacy123.blogfa.com

Fluconazole drug interactions Why would drug interactions between fluconazole and protease inhibitors be important? Why would interactions with cyclosporine be important? Downloaded from www.pharmacy123.blogfa.com

Clotrimazole a) Uses: Clotrimazole can be used for a number of fungal infections, including oropharyngeal candidosis. It can also be used cutaneously and intravaginally. b) Application: Clotrimazole can be administered as a 10 mg oral troche (Mycelex). Its effects are purely topical. Other forms of clotrimazole are a cream (Lotrimin, Mycelex) and a vaginal tablet (Gynelotrimin, Mycelex-G). Remember Clotrimazole=Lotrimin. Why they did not call it clotrimin, I do not know. c) Side effects: About 5% of patients taking the oral troche experience some gastric irritation. Other topical uses can cause local irritation. Downloaded from www.pharmacy123.blogfa.com

Other azole drugs of interest: • Itraconazole (Sporanox, a widely used antifungal agent similar to fluconazole) • Miconazole(widely used for topical infections) • Econazole (Spectazole) • Butoconazole (Femstat) • Tioconazole (Vagistat, sometimes used in combination with miconazole) • Oxiconazole (Oxistat) Downloaded from www.pharmacy123.blogfa.com

Terbinafine, a non-azole inhibitor of sterol synthesis (also naftifine, butenafine) Mechanism: Terbinafine inhibits an enzyme called squalene epoxidase. This enzyme functions in the same ergosterol biosynthetic pathway as the azole drugs (described above). Downloaded from www.pharmacy123.blogfa.com

Terbinafine, a non-azole inhibitor of sterol synthesis (also naftifine, butenafine) Administration: Terbinafine concentrates in skin and especially at nail beds, making it quite useful for fungal infection of nails. Q: Do the organisms targeted by terbinafine have pointy ears, tails, a single tooth, and legs? Downloaded from www.pharmacy123.blogfa.com

Terbinafine, a non-azole inhibitor of sterol synthesis (also naftifine, butenafine) Side effects: Minimal toxicity after topical use, but can cause allergic reactions when given orally. Downloaded from www.pharmacy123.blogfa.com

ANTIFUNGAL DRUGS • Polyene drugs: Amphotericin B- punctures cell membranes • a) Mechanism: Amphotericin is a rigid, rod-shaped molecule that kills cells by disrupting the cell membrane, causing leakage of electrolytes and small molecules. Amphotericin bind to ergosterol, the major membrane lipid in fungal cells. • b) Uses: Amphotericin B is effective against a broad spectrum of fungi. Resistance is uncommon, but may occur if ergosterol synthesis is altered or decreased. • c) Side effects: Fever and chills often accompany i.v. injection and allergic reactions may occur. Principal, dose-limiting toxicity is renal dysfunction. Amphotericin can also cause hypotension, hypokalemia, reversible normocytic anemia, and thrombophlebitis. Downloaded from www.pharmacy123.blogfa.com

ANTIFUNGAL DRUGS • Polyene drugs: Nystatin (synthesized by NY state laboratory) • a) Uses: Nystatin is similar to amphotericin B except that it is used only for topical treatment or oral candidosis • b) Administration: There is minimal absorption orally, but can be used for oral candidosis. It has an extremely bitter taste which limits its use. • c) Side effects: There are minimal side-effects when used topically, but highly toxic after parenteral administration Downloaded from www.pharmacy123.blogfa.com

ANTIFUNGAL DRUGS Amphotericin B and nystatin seem similar to penicillin in disrupting cell walls of microorganisms. How are they different? Downloaded from www.pharmacy123.blogfa.com

Flucytosine- blocks DNA and protein synthesis Mechanism: An antimetabolite of pyrimidine, flucytosine (Ancobon) selectively enters fungal cells via a cytosine-specific permease, where it is converted to active metabolites (5-fluorouracil and 5-FdUMP) that disrupt DNA and protein synthesis. Mammalian cells do not convert flucytosine to fluorouracil! Downloaded from www.pharmacy123.blogfa.com

Flucytosine- blocks DNA and protein synthesis Resistance arises through decreased uptake of the drug or decreased cytosine deaminase activity. Q: Why does resistance to flucytosine arise more quickly than resistance to azole drugs? 5-FC permease 5-FU Downloaded from www.pharmacy123.blogfa.com

Flucytosine- blocks DNA and protein synthesis Administration: Flucytosine is well absorbed orally and penetrates into CNS. Flucytosine acts synergistically with amphotericin B and is always used in combination with amphotericin B to slow development of resistance to flucytosine’s antifungal effects. Side effects: Flucytosine may depress the function of the bone marrow, resulting in leucopenia and thrombocytopenia. Flucytosine also causes nausea, vomiting or diarrhea, perhaps because of the release of 5-FU by the gastrointestinal flora. Downloaded from www.pharmacy123.blogfa.com

What are some drugs that have a similar action to flucytosine but act on mammalian cells? What are they used for? Downloaded from www.pharmacy123.blogfa.com

Griseofulvin 1. Mechanism: Griseofulvin binds to polymerized microtubules, disrupting the mitotic spindle and blocking replication in mitosis. While this resembles other drugs acting on mammalian cells, griseofulvin is quite specific to fungi. 2. Administration: Administered orally, it concentrates in skin at sites of newly synthesized keratin-containing tissues (ineffective topically). Extensively metabolized, it also induces cytochrome P450 enzymes leading to possible drug interactions. 3. Side effects: These are rare and include allergic reactions, headache, nausea, and possible liver toxicity. Downloaded from www.pharmacy123.blogfa.com

Other drugs have a similar mechanism of action to griseofulvin, but they act on mammalian cells. How would these drugs be used? Downloaded from www.pharmacy123.blogfa.com

Clinical example: • Q1. L.T. is a 40-year-old man who has whitish marks on his tongue and buccal mucosa that can be removed by scraping, leaving a reddish mark. L.T. has experienced a severe chest infection and marked weight loss in the last six months. What is his diagnosis and course of therapy? Downloaded from www.pharmacy123.blogfa.com

Clinical example: • Q1. L.T. is a 40-year-old man who has whitish marks on his tongue and buccal mucosa that can be removed by scraping, leaving a reddish mark. L.T. has experienced a severe chest infection and marked weight loss in the last six months. What is his diagnosis and course of therapy? • L.T. appears to have oral candidosis. Because of the chest infection and weight loss, L.T. should be tested for H.I.V. L.T. is prescribed clotrimazole, which is superior to nystatin (which has a bitter taste). OTC drugs are as effective as prescription brands, and prescription drugs offer no additional benefit. However, if there are questions about L.T.’s ability to stick to the regimen, a single dose of fluconazole is effective. Downloaded from www.pharmacy123.blogfa.com

Clinical example: • Q2. L.T. returns soon and says that the medication prescribed (oral fluconazole) made him feel dizzy. Upon further questioning, he reveals that he has been taking diazepam. Why would the anti-fungal drug cause this side effect? Downloaded from www.pharmacy123.blogfa.com

Clinical example: • Q2. L.T. returns soon and says that the medication prescribed (oral fluconazole) made him feel dizzy. Upon further questioning, he reveals that he has been taking diazepam. Why would the anti-fungal drug cause this side effect? • Fluconazole inhibits the cytochrome P450 pathway, which metabolizes a variety of drugs. When the pathway is inhibited, drug metabolism is decreased and the drugs accumulate in the bloodstream, amplifying normal side effects. Downloaded from www.pharmacy123.blogfa.com

Clinical example: • Q3. After a brief period of effectiveness, L.T.’s infection returns and is unresponsive to therapy. What are the most likely reasons for this? What are the next options? Are terbinafine or griseofulvin good choices? Downloaded from www.pharmacy123.blogfa.com

Clinical example: • Q3. After a brief period of effectiveness, L.T.’s infection returns and is unresponsive to therapy. What are the most likely reasons for this? What are the next options? Are terbinafine or grisofulvin good choices? • Azole compounds work by inhibiting the synthesis of ergosterol by the enzyme lanosterol demethylase (also called Cyp51). Mutations in this enzyme can cause resistance to azole compounds like fluconazole. Nystatin is a reasonable second choice, although the infection may be systemic at this point. Terbinafine or griseofulvin would not be good alternative therapies because they are not effective for candidosis. L.T. may be shifted to a regimen of 5-flucytosine and amphotericin for further treatment. Downloaded from www.pharmacy123.blogfa.com

Antifungal Drugs