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.

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

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

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

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)

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

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

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

Systemic antifungal drugs for systemic infections

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.

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

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

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

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.

Amphotericin B Amphotericin B

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.

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)

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

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

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.

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

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

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

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.

Azoles

Azoles Imidazoles Ketoconazole Miconazole Clotrimazole Triazoles Itraconazole Fluconazole Voriconazole Posaconazole

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

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

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

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.

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

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

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.

Caspofungin Micafungin Echinocandins Caspofungin Micafungin Anidulafungin  

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

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.

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.

Systemic antifungal drugs for Mucocutaneous infections

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.

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

Allergic reaction photosensitivity Hepatitis Teratogenesis Adverse effects Allergic reaction photosensitivity Hepatitis Teratogenesis

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

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

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.

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

Topical antifungal therapy

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.

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.

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

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