Anti-Fungal drugs

Pharmacology of different drugs used for the treatment of fungal infections

1. Anti-Fungal Drugs Dr. Sameh Ahmad Muhamad abdelghany Lecturer Of Clinical Pharmacology Mansura Faculty of medicine

2. Lecture objectives By the end of this lecture the students should be able; To give major groups and specific examples of the antifungal drugs. To describe the mechanisms of action antifungal drugs including their pharmacological effects. To outline clinical applications of the drugs in medicine . 2

3. Lecture outline 3 1 Introduction 2 Classification Of Antifungals 3 Azoles 4 Polyene Macrolides antifungals 5 Other antifungal drugs

4. INTRODUCTION

5. Introduction Pathogenic fungi of animals and humans are generally filamentous molds or intracellular yeasts. The fungal cell wall contains chitin and polysaccharides making it rigid, and acts as a barrier to drug penetration. The cell membrane contains ergosterol, which influences the efficacy and the risk of drug resistance. Most antifungal agents are fungistatic with infection-clearance largely dependent on host response. 5

6. FUNGI Fungi may be classified as Yeasts : Blastomyces , candida, histoplasma , coccidioides,cryptococcus . Moulds : Aspergillus spp. , Dermatophytes Clinically classified as : Superficial mycosis Deep (systemic) mycosis 7

7. FUNGI 8

8. Fungal Infection in Humans = Mycosis Major Types of Mycoses superficial cutaneous subcutaneous systemic opportunistic Symptoms vary from cosmetic to life threatening 9

9. Types of fungal infections 10 Mucocutaneous (superficial) infections: Dermatophytes: cause infection of skin, hair, and nails e.g. tinea capitis (scalp), tinea cruris (groin), tinea pedis (foot), onychomycosis (nails).

10. Types of fungal infections 11 Yeasts : cause infections of moist skin and mucous membranes e.g. Candida albicans causing oral, pharyngeal, vaginal, & bladder infections

11. Types of fungal infections 12 Systemic mycoses: are fungal infections affecting internal organs. It occurs in immunocompromized patients e.g. cryptococcosis , and aspergillosis (lung).

12. CLASSIFICATION OF ANTIFUNGALS

13. Classification of antifungal drugs Based on chemical structures : The classes include Polyene macrolides, Imidazoles , Fluorinated pyrimidines, Benzo-furans and Iodides Based on their sites of action : Either systemic or topical antifungal drugs. Miscellaneous classifications : Organic acids and their salts and other inorganic salts 14

14. Classification of antifungal drugs 15 Drugs for mucocutaneous infections : Systemic drugs Azoles : Fluconazole, Itraconazole , Voriconazole . Griseofulvin Terbinafine

15. Classification of antifungal drugs 16 Topical drugs Azoles : Ketoconazole, Miconazole , Clotrimazole , Tioconazole , etc. Nystatin Terbinafine . Other drugs : Tolnaftate , Ciclopirox, Naftifine , Whitfield ointment, Gentian violet, Castellani paint, Tincture iodine.

16. Classification of antifungal drugs 17 Drugs for Systemic infections : : Azoles : Fluconazole, Itraconazole , Voriconazole . Amphotericin-B Flucytosine Caspofungin

17. Classification based on mechanism of action 18 Fungal cell wall synthesis inhibition: Caspofungin . Bind to fungal cell membrane ergosterol : Amphotercin –B, Nystatin . Inhibition of ergosterol + lanosterol synthesis: Terbinafine , Naftifine , Butenafine . Inhibition of ergosterol synthesis: Azoles Inhibition of nucleic acid synthesis: 5– Flucytosine . Disruption of mitotic spindle and inhibition of fungal mitosis: Griseofulvin . Miscellaneous: Ciclopirox, Tolnaftate , Haloprogin , Undecylenic acid, Topical azoles

18. Classification based on structure 20 ANTIBIOTICS Polyene: Amphotericin, nystatin, hamycin Hetrocyclic benzofuran : griseofulvin ANTIMETABOLITE : Flucytosine AZOLES Imidazoles : Ketoconazole, clotrimazole , oxiconazole,miconazole , Triazoles : Fluconazole, itraconazole , voriconazole ,

19. Classification based on structure 21 ALLYLAMINES Terbinafine , butenafine ECHINOCANDINS Caspofungin , anidulafungin , micafungin OTHER TOPICAL AGENTS Tolnaftate , Undecyclinic acid, benzoic acid

20. I- Azoles 22 Chemistry Ketoconazole , Miconazole , Fluconazole, Itraconazole , Voriconazole

21. I- Azoles 23 Synthetic antifungals Broad spectrum Fungistatic or fungicidal depending on conc of drug Most commonly used Classified as imidazoles & triazoles

22. I- Azoles 24 Imidazoles : Two nitrogen in structure Topical : econazole , miconazole , clotrimazole Systemic : ketoconazole Newer : butaconazole , oxiconazole , sulconazole Triazoles : Three nitrogen in structure Fluconazole , itraconazole , voriconazole Terconazole : Topical for sup

23. Azoles 25 Pharmacokinetics Absorption of azoles from stomach is affected by food and gastric HCl . Fluconazole can reach the CSF with good concentrations. The other drugs cannot. Fluconazole is excreted in the urine mostly unchanged

24. Azoles 26 Mechanism of action Azoles inhibit fungal cytochrome P450 ( 14 α demthylase ) necessary for ergosterol synthesis, a major component of fungal cell membrane. This will alter membrane permeability and disrupt its function. are broad spectrum fungistatic against many dermatophytes and candida.

25. 27

26. Azoles 28 Therapeutic uses Superficial fungal infections : [ketoconazole – itraconazole – miconazole ] Dermatophytes infection of the skin (tinea), hair, and nails (onychomycosis): For skin infection: treatment continued for 2-4 weeks. For hair infection: treatment continued for 6-8 weeks. For nail infection: treatment continued for 3-6 months. Mucocautaneous candidiasis : oropharyngeal, vulvovaginal, etc.

27. Azoles 29 Systemic fungal infections : [ itraconazole – fluconazole – voriconazole ] Itraconazole (orally or IV) is the drug of choice for systemic blastomycosis . Fluconazole (orally or IV) is the drug of choice for systemic candidiasis, and cryptococcal meningitis (because it the only azole that can cross to CSF with good concentration ). Voriconazole is the drug of choice for inVasive aspergillosis of the lung.

28. Azoles 30 Adverse effects Hepatotoxicity and ↑ of serum transaminases. Azoles inhibit hepatic CYP450 enzymes (fluconazole is the least among them). Ketoconazole causes antianderogenic effects : gynecomastia and impotence due to ↓ gonadal steroid synthesis. V oriconazole causes transient V isual disturbances.

29. II- Amphotericin-B 31 Chemistry Obtained from Streptomyces Nodosus Amphoteric in nature

30. Amphotericin-B 32 Pharmacokinetics is polar compound that cannot be absorbed from the GIT or cross the CSF. Insoluble in water so colloidal suspension prepared with sodium deoxycholate (1:1 complex) 90 % bound to plasma proteins It should be administered IV or intrathecal. Half-life is 15 days. Dialysis is ineffective in case of toxicity.

31. Amphotericin-B 33 Pharmacokinetics(cont.) Because of significant toxicity, amphotericin B is available in liposomal form in which the drug is enclosed in lipid microspheres “liposomes”. These lipid microspheres bind preferentially to ergosterol in the fungal cell membrane with lower affinity to mammalian cell membranes.

32. Amphotericin-B 34 Mechanism of action Amphotericin B is polyene macrolide that binds to ergosterol of fungal cell membranes and forms “pores” that alter membrane stability and allow leakage of cellular contents.

33. Amphotericin-B 36 Therapeutic uses Amphotericin B has the broadest spectrum of activity. Treat severe Systemic fungal infections , including those caused by Candida albicans , Histoplasma capsulatum , Cryptococcus neoformans , Coccidioides immitis , Blastomyces dermatitidis and Aspergillus spp .

34. 37 Adverse effects I. Acute reaction: Chills , fever, headache, pain all over, nausea , vomiting, dyspnoea lasting 2-5 hrs because of release of IL & TNF II. Long term toxicity: Nephrotoxicity : Azotemia, Hypokalemia, acidosis, ↓ GFR anemia III. CNS toxicity : intrathecal administration , headache , vomiting, nerve palsies IV. Hepatotoxicity rarely

35. III- OTHER ANTIFUNGAL DRUGS 38 Flucytosine Prodrug, pyrimidine analog, antimetabolite Converted to 5-fluorouracil (5-FU) Human cells cant convert it to 5FU

36. 39 Flucytosine Mechanism of action Flucytosine is actively transported into fungal cells and is converted to the uracil form 5-fluorouracil (5-FU) which inhibits nucleic acid synthesis. Human cells lack the ability to convert large amounts of flucytosine into 5-FU.

37. Flucytosine 41 Uses Used in combination with other antifungal agents (because of rapid development of resistance) to treat Severe systemic fungal infections . Adverse effects Flucytosine is relatively nontoxic Depression of bone marrow at high doses Hair loss.

38. Griseofulvin 42 Pharmacokinetics: Oral administration, irregular absorption , increased by fatty food and microfine particles Gets conc in keratinized tissue Metabolized in liver, excreted in urine t1/2=24 hrs

39. Griseofulvin 43 Mechanism of action Griseofulvin binds to microtubules and prevents spindle formation and mitosis in fungi. It is fungistatic and requires long duration of therapy. The drug binds to keratin structures and accumulates in skin, hair, and nails.

40. Griseofulvin 45 Therapeutic uses used orally for long-term therapy of dermatophyte infections of the hair and nail. Adverse effects Hepatotoxicity (liver functions should be checked during therapy ) Hypersensitivity reactions (skin rash) CNS effects : confusion , fatigue, vertigo.

41. Nystain 46 Nystatin is polyene macrolide very similar in kinetics and mechanism to amphotericin B. It is too toxic for parenteral administration and is used only topically . It is active mainly against Candida, and is used topically for oralpharyngeal and vaginal candidiasis.

42. Caspofungin 47 It is large cyclic peptide that disrupts the fungal cell wall resulting in cell death. Used by i.v. route for therapy in Severe invasive aspergillosis Esophageal candidiasis who failed to respond to amphotericin B (second line drug).

43. Ciclopirox 49 Broad-spectrum antifungal effective against dermatophytes and yeasts. Mechanism is unclear. (Has high affinity for trivalent metal cations which inhibit essential co-factors in enzymes). Used topically for skin and nail infections.

44. Terbinafine 50 Act by inhibiting squalene epoxidase , thereby blocking the biosynthesis of ergosterol , an essential component of the fungal cell membrane. Accumulation of toxic amounts of squalene results in increased membrane permeability and death of the fungal cell . The drug of choice for treating dermatophyte onychomycoses better tolerated, requires a shorter duration of therapy , and is more effective than either itraconazole or griseofulvin

45. THANK Y OU! ANY QUESTIONS?