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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)
slide7

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

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 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)

slide18

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.
slide23

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.
slide24

Why the drug does not act on human cells?

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

slide25

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.
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.
adverse effects2
Adverse Effects
  • Extremely well tolerated,
  • Minor GI side effects
  • Flushing
  • Elevated liver enzymes (caspofungin + cyclosporine).
  • Histamine release during IV infusion.
griseofulvin
Griseofulvin
  • Very insoluble, fungistatic
  • Derived from a species of penicillium.
  • Better absorption when given with fatty foods.
slide45

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.
slide49

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.

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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