1. Recommended text books
Basic and Clinical pharmacology, 10th or 11th edition, B.G.Katzung, LANGE medical book.
Lippincott´s ilustrated reviews: Pharmacology 3rd edition, R.A.Harvey, Champe P.C., R.D. Howland, M.J. Mycek, Lippincott-Raven,.
Pharmacology, 6th edition, H.P.Rang, M.M. Dále, J.M. Ritter, Churchill Livingstone, 2007.

2. Department of Pharmacology University of Sulaimani
Antifungal Agents
Dr. Roshna S. Aziz
Department of Pharmacology
School of Medicine
University of Sulaimani

4. surgery AIDS Wide-spectrum antibiotics
Increase risk
Wide-spectrum antibiotics
surgery
Immunosuppressant agents & chemotherapy
AIDS

5. Fungal infections = mycoses
Opportunistic or primary
Systemic or local
Slow onset
Long duration of therapy
Difficult to diagnose & eradicate
Symptoms vary from cosmetic to life threatening

6. Antifungal drugs
Work by exploiting differences between mammalian and fungal cells to kill the fungal organism without dangerous effects on the host.
Both fungi and humans are eukaryots.
Difficult to find or design drugs that target fungi without affecting human cells. (side effects)

7. Fungal cell membranes have a unique sterol, ergosterol, which replaces cholesterol found in mammalian cell membranes

9. Systemic & topical some are fungistatic, while others are fungicidal
Antifungal drugs
Systemic & topical some are fungistatic, while others are fungicidal

10. systemic /systemic Amphotericin B. Azoles Flucytosine Echinocandins
Systemic /mucocutaneous
Griseofulvin
Terbinafine
Topical /mucocutaneous
Nystatine
Topical Azoles
Topical Allylamines

11. Systemic antifungal drugs for systemic infections

12. AMPHOTERICIN B Produced by Streptomyses nodosum
Broad-spectrum polyene macrolide antibiotic is the most potent antifungal agent for systemic mycosis, in clinical use since 1960
Fungicidal drug at higher concentrations & static at lower levels.
Produced by Streptomyses nodosum
CSF conc.= 2-3 % of blood conc.
Highest concentrations in liver, spleen, bone marrow with less in kidneys and lungs.

13. Cell death Alters permeability & transport
Mechanism of Action
Binds to fungal cell membrane (Ergosterol)
Forms pores
Alters permeability & transport
Cell death

14. MECHANISM OF ACTION
High affinity for fungal ergosterol, forms “micropore” in fungal cell membrane through which ions, amino acids, & other water soluble substances move out.
Markedly increases cell permeability.
Cholestrol, present in host cell membranes, closely resembles fungal ergosterol & thus explains the high toxicity of AMB in humans

16. Clinical use
Treatment of nearly all life threatening mycotic infections.
For systemic disease: slow IV
Local:
Keratitis& corneal ulcers: drops, conjunctival irrigation,
Candiduria: bladder irrigation
Fungal arthritis: local injection

17. Anemia (↓erythropoietin)
Side effects
Infusion related
Fever & chills,
Dyspnea,
Nausea &vomiting,
Hypotension,
Convulsions
Cumulative toxicity
Nephrotoxicity
K & Mg wasting
Anemia (↓erythropoietin)
To reduce the severity of the infusion-related reactions, pretreatment with an antipyretic (acetaminophen), antihistamines, and antiemetics may be given.

18. Amphotericin B
Amphotericin B

19. Liposomal Amphotericin B
New lipid formulations
Amphotericin B is incorporated into lipid formulations to reduce toxicity & enhance efficacy. This allows higher dose to be used without increasing the toxicity.
Much more expensive than ordinary AMB.

20. KEY POINTS
AMB is not absorbed enterally; hence can be given orally for intestinal candidiasis.
Drug concentration achieved in infected skin is very low, & hence ineffective against superficial fungal infections.
Penetration in brain & CSF is poor (but extremely effective in fungal meningitis when combined with 5-FC)

21. FLUCYTOSINE (5-FC)
Pyrimidine antimetabolite, narrow-spectrum fungistatic
Water soluble
Oral only,
Poor protein binding
CSF conc. ≈ 75% serum conc.

22. Cytosine permease enzyme Inhibits thymidylate synthase
5-FC (outside)
5-FC (inside)
Inhibits thymidylate synthase
5-FU (inside)
Inhibits DNA & RNA synthesis

23. Flucytosine is taken up by fungal cells via the enzyme cytosine permease.
It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA synthesis, respectively.

24. Why the drug does not act on human cells?
Human cells are unable to convert the parent drug to its active metabolites.

25. Clinical use at present is confined to combination therapy, either with:
Amphotericin B for cryptococcal meningitis , or
Itraconazole for chromoblastomycosis

26. Adverse Effects
Bone marrow toxicity with anemia, leukopenia, thrombocytopenia, (Mammalian bone marrow cell have the capacity to convert 5-FC to 5-FU)
GI disturbances
Mild & reversible liver dysfunction

27. KEY POINTS
Since this is a narrow-spectrum fungistatic, it is mainly used as an adjuvant drug & not used as a sole therapy.
CSF penetration is excellent, hence it is combined with AMB in fungal meningitis.

28. Azoles

29. Azoles Imidazoles Ketoconazole Miconazole Clotrimazole Triazoles
Itraconazole
Fluconazole
Voriconazole
Posaconazole

30. Inhibition of fungal cytochrome P450 enzymes
Mechanism of Action
Inhibition of fungal cytochrome P450 enzymes
Reduction of ergosterol synthesis

32. Candida, Cryptococcus, Blastomyces, Histoplasma, Coccidiodes ,
Clinical Use
BROAD SPECTRUM OF ACTIVITY –
Candida,
Cryptococcus,
Blastomyces,
Histoplasma,
Coccidiodes ,
Dermatophytes

33. Abnormalities in liver enzymes (inhibit cytochrome P450 enzymes)
Adverse Effects
Relatively nontoxic.
Minor GI upset
Abnormalities in liver enzymes
(inhibit cytochrome P450 enzymes)
Very rarely, clinical hepatitis

34. Ketoconazole The first oral azole introduced into clinical use.
(older, more toxic, replaced by itraconazole, but less costly)
The first oral azole introduced into clinical use.
It is less selective for fungal P450 than are the newer azoles.
Absorption variable (better in acidic medium)
Penetration in brain & CSF is poor
In high doses inhibits adrenocortical steroids and testosterone synthesis, resulting in gynecomastia in some males.

35. Much more selective than ketoconazole
Itraconazole
Broad-spectrum antifungal with fungistatic action
MOA: Inhibits fungal ergosterol synthesis like other azoles
Drug absorption is increased by food and by low gastric ph.
Penetration of drug in brain & CSF is poor.
Much more selective than ketoconazole

36. Fluconazole Broad-spectrum Fungicidal drug;
It is also somewhat effective against some Gram-positive & anaerobic bacteria
Of the orally administered fluconazole 94% is absorbed;
Penetration in brain & CSF is good, hence used for cryptococcal meningitis

37. It is the broadest spectrum member of the azole family.
Posaconazole
The newest triazole
It is the broadest spectrum member of the azole family.
It is the only azole with significant activity against the agents of zygomycosis and mucormycosis.

38. Caspofungin Micafungin
Echinocandins
Caspofungin
Micafungin
Anidulafungin  

39. Echinocandins The newest class of antifungal .
Active against candida and aspergillus, but not c neoformans or the agents of zygomycosis and mucormycosis.

40. Disruption of the fungal cell wall and cell death.
Mechanism of Action
Inhibit the synthesis of B glucan in the fungal cell wall
Disruption of the fungal cell wall and cell death.

41. Histamine release during IV infusion.
Adverse Effects
Extremely well tolerated,
Minor GI side effects
Flushing
Elevated liver enzymes (caspofungin + cyclosporine).
Histamine release during IV infusion.

43. Systemic antifungal drugs for Mucocutaneous infections

44. Very insoluble, fungistatic Derived from a species of penicillium.
Griseofulvin
Very insoluble, fungistatic
Derived from a species of penicillium.
Better absorption when given with fatty foods.

45. It is deposited in newly forming skin where it binds to keratin, protecting the skin from new infection.
Interferes with spindle formation in dividing cells and therefore with mitosis

46. Allergic reaction photosensitivity Hepatitis Teratogenesis
Adverse effects
Allergic reaction
photosensitivity
Hepatitis
Teratogenesis

47. Terbinafine Synthetic allylamine. Orally Active.
Dermatophytoses, especially onychomycosis .
Keratophilic , fungicidal.

48. Inhibiting the fungal enzyme squalene epoxidase
It interferes with ergosterol biosynthesis by:
Inhibiting the fungal enzyme squalene epoxidase
Accumulation of the sterol squalene,

49. Like the azole drugs, it interferes with ergosterol biosynthesis, but rather than interacting with the P450 system, terbinafine inhibits the fungal enzyme squalene epoxidase. This leads to the accumulation of the sterol squalene, which is toxic to the organism.

50. Rare, mild, self-limiting GI upset Rash Pruritis Headache.
Adverse effects
Rare, mild, self-limiting GI upset Rash Pruritis Headache.

51. Topical antifungal therapy

52. Only used topically: creams, ointments, suppositories, and other
Nystatin
Only used topically: creams, ointments, suppositories, and other
Acts as amphotericin B
It is not absorbed , unpleasant taste.
Local candidal infections, oropharyngeal thrush, vaginal candidiasis.
adverse effects are rare.

53. Topical Azoles Clotrimazole , Miconazole;
Vulvovaginal candidiasis, oral thrush , dermatophytic infections, including tinea corporis, tinea pedis, and tinea cruris.
Absorption is negligible, and adverse effects are rare.
Topical and shampoo forms of ketoconazole for seborrheic dermatitis and pityriasis versicolor.

54. Terbinafine and Naftifine
Topical Allylamines
Terbinafine and Naftifine
Both are effective for treatment of tinea cruris and tinea corporis.
MOA: Inhibits the squalene epoxidase, leading to accumulation of intrcellular squalene & deficient ergosterol synthesis with subseqent fungal cell death.
Terbinafine concentrates in skin and especially at nail beds, making it quite useful for fungal infection of nails

57. Thank you