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

Dr. Roshna S. AzizDepartment of Pharmacology

School of Medicine University of Sulaimani

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

ANTIFUNGAL DRUGS

Systemic & topicalSystemic & topical

some are fungistatic, some are fungistatic,

while others are fungicidalwhile others are fungicidal

SYSTEMIC ANTIFUNGAL

DRUGS FOR SYSTEMIC

INFECTIONS

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

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

o Local:

o Keratitis& corneal ulcers: drops, conjunctival

irrigation,

o Candiduria: bladder irrigation

o Fungal arthritis: local injection

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.

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.

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.

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

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

MECHANISM OF ACTION

CLINICAL USEBROAD SPECTRUM OF ACTIVITY –

Candida,

Cryptococcus,

Blastomyces,

Histoplasma,

Coccidiodes ,

Dermatophytes

ADVERSE EFFECTS

Relatively nontoxic.

Minor GI upset

Abnormalities in liver enzymes(inhibit cytochrome P450

enzymes)

Very rarely, clinical hepatitis

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

•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

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

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.

MECHANISM OF ACTION

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

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

ADVERSE EFFECTS

Allergic reaction

photosensitivity

Hepatitis

Teratogenesis

TERBINAFINE

Synthetic allylamine.

Orally Active.

Dermatophytoses, especially onychomycosis .

Keratophilic , fungicidal.

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 EFFECTS

Rare, mild, self-limiting

GI upset Rash

PruritisHeadache.

Topical antifungal therapy

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.

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

Thank you