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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 ,.

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Recommended text books

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.


Antifungal agents

AntifungalAgents

Dr. Roshna S. Aziz

Department of Pharmacology

School of Medicine

University of Sulaimani


Fungal infections mycoses

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

Antifungal drugs

  • Work by exploiting differencesbetween 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)


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


Antifungal drugs1

Antifungal drugs

Systemic & topicalsome are fungistatic, while others are fungicidal


Systemic antifungal drugs for systemic infections

Systemic antifungal drugs for systemic infections


Amphotericin b

AMPHOTERICIN B

  • 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.


Mechanism of action

Mechanism of Action


Mechanism of action1

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

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


Side effects

Side effects

To reduce the severity of the infusion-related reactions, pretreatment with an antipyretic (acetaminophen), antihistamines, and antiemetics may be given.

  • Infusion related

    Fever & chills,

    Dyspnea,

    Nausea &vomiting,

    Hypotension,

    Convulsions

  • Cumulative toxicity

    Nephrotoxicity

    K & Mg wasting

    Anemia (↓erythropoietin)


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Amphotericin B

Amphotericin B


Liposomal 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

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

FLUCYTOSINE (5-FC)

  • Pyrimidine antimetabolite, narrow-spectrum fungistatic

  • Water soluble

  • Oral only,

  • Poor protein binding

  • CSF conc. ≈ 75% serum conc.


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  • 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.


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Why the drug does not act on human cells?

Human cells are unable to convert the parent drug to its active metabolites.


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Clinical use at present is confined to combination therapy, either with:

  • Amphotericin B for cryptococcal meningitis , or

  • Itraconazole for chromoblastomycosis


Adverse effects

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 points1

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


Mechanism of action2

Mechanism of Action


Clinical use1

Clinical Use

BROAD SPECTRUM OF ACTIVITY –

Candida,

Cryptococcus,

Blastomyces,

Histoplasma,

Coccidiodes ,

Dermatophytes


Adverse effects1

Adverse Effects

Relatively nontoxic.

MinorGI upset

Abnormalities in liver enzymes

(inhibit cytochrome P450 enzymes)

Very rarely, clinical hepatitis


Ketoconazole

Ketoconazole

  • (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.


Itraconazole

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

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


Posaconazole

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.


Echinocandins

Echinocandins

Caspofungin

Micafungin

Anidulafungin


Echinocandins1

Echinocandins

  • The newest class of antifungal .

  • Active against candida and aspergillus, but not c neoformans or the agents of zygomycosis and mucormycosis.


Mechanism of action3

Mechanism of Action


Adverse effects2

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

Systemic antifungal drugs for Mucocutaneous infections


Griseofulvin

Griseofulvin

  • Very insoluble, fungistatic

  • Derived from a species of penicillium.

  • Better absorption when given with fatty foods.


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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


Adverse effects3

Adverse effects

  • Allergic reaction

  • photosensitivity

  • Hepatitis

  • Teratogenesis


Terbinafine

Terbinafine

  • Synthetic allylamine.

  • Orally Active.

  • Dermatophytoses, especially onychomycosis .

  • Keratophilic , fungicidal.


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  • 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.


Adverse effects4

Adverse effects

Rare, mild, self-limiting

GI upset

Rash

Pruritis

Headache.


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Topical antifungal therapy


Nystatin

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

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.


Topical allylamines

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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Thank you


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