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ANTI FUNGAL DRUGS(I)

By Gary Shaw,2014-09-04 04:47
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ANTI FUNGAL DRUGS(I)ANTI

ANTI FUNGAL DRUGS(I)

; LEARNING OBJECTIVE

    ; At the end of lecture students should be bale to know,

    ; Classification of antifungal drugs,

    ; Drugs for cutanoeus mucosis, ; ketoconazole.,

    ; Antifungal spectrum,

    ; Classification of drugs according to their clinical use

    ; Drugs for subcutaneous and systemic mycoses ; 1)Amphotericin-B

    ; 2)Flucytosine

    ; 3)Azoles

    ; a)Ketoconazole

    ; b)Fluconazole

    ; c)Itraconazole

    ; Classification of drugs according to their clinical use

    ; Drugs for subcutaneous and systemic mycoses ; 4)Echinocandins

    ; a)Caspofungin

    ; b)Micafungin

; Drugs for Cutaneous Mycoses

    ; Terbinafine

    ; Griseofulvin

    ; Nystatin

; AMPHOTERICIN B

    ; Naturally occuring polyene macrolide antibiotic.

    ; Drug of choice for the treatment of life threatening systemic

    mycosis.

    ; Mechanism of Action

    ; Several amphotericin B molecules bind to ergosterol in the

    plasma membranes of sensitive fungal cells. there they form

    pores( channels) which disrupt membrane function , allowing

    electrolytes particularly potassium and small molecules to

    leak from the cells resulting in cell death.

    ; PHARMCOKINETICS

    ; It is administered by slow intravenous infusion. It is insoluble

    in water, require the addition of sodium deoxycholate which

    produces a soluble colloidal dispersion.

    ; Intra-thecal route is chosen for meningitis.

    ; Liposomal preparations have the advantage of reduce renal

    and infusion toxicity.

; ADVERSE EFFECTS

    ; Amphotericin has a low therapeutic index.

    ; Total daily dose should not exceed 1.5 mg per Kg. ; Test dose is usually administered .

    ; OTHER ADVERSE EFFECTS

    ; Fever and chills repeated administration of the drug cause

    these effects to subside. Premeditation with corticosteroid

    and an anti pyretic helps to prevent them.

    ; ANTIFUNGAL SPECTRUM

    ; It can be fungicidal or fungistatic depending on the organism

    and the concentration of the drug.

    ; Spectrum includes candida albicans, histoplasma

    capsulatum , cryptococcus.neoformins.

    ; It is also used in leishmaniasis.

    ; Resistance to the drug may be due to decreased ergosterol

    content of the fungal membrane.

    ; Flucytosine.(5 FC)

    ; It is a synthetic pyrimidine.

; MECHANISM OF ACTION

    ; 5 FC enters fungal cells via a cytosine specific permease,

    converted to 5 fluro deoxyuridine 5 mono phosphate (5-

    FdUMP).

    ; It inhibits thymidylate synthase, depriving the organism of

    thimidylic acid an essential DNA component.

    ; Then 5-FdUMP is converted into 5-Fd UTP and incorporated

    into fungal RNA.

    ; Thus disrupting nucleic acid and protein synthesis.

; PHARMACOKINETICS

    ; Well absorbed by oral route

    ; Distributed in the body water and penetrates well into the

    CSF.

    ; Metabolized by intestinal flora to 5- FU.

    ; Both that parent drug and it metabolites are excreted in

    urine.

; ADVERSE EFFECTS

    ; Heamopoietic tissue Reversible neutropenia ,

    thrombocytopenia and occasional bone marrow depression. ; Reversible hepatic dysfunction with elevation of serum

    transaminases and alkaline phosphatase may occur. ; GIT disturbance such as nausea vomiting and diarrhea are

    common even severe enterocolitis may occur.

; ANTI FUNGAL SPECTRUM

    ; 5 FC is fungistatic

    ; It is used in combination with amphotericin B for the

    treatment of systemic mycosis and meningitis caused by

    cryptococcus neoformins and candida albicans. ; RESISTANCE TO THE DURG

    ; Due to decreased level of the enzymes in the conversion of

    5- FC to 5-FU, this occurs more when 5-FC is used alone . ; KETOCONAZOLE

    ; It was the first orally active Azole used for the treament of

    systemic mycosis.

    ; M.O.A of azoles they are predominantly fungistatic. ; They inhibit C-14 alpha demethylase, blocking the

    demethylation of Lanosterol to ergosterol.

    ; This disrupts membrane structure and function and there by

    inhibits fungal cell growth.

    ; Pharmacokinetics

    ; Ketoconazol is orally administered it requires gastric acid for

    dissolution and is absorbed through the gastric mucosa. ; Antacids H2 histamine blockers and proton pump inhibitors

    impair absorption. Acidifying agents such as cola drinks can

    improve absorption in patients with achlorhydria ; Extensively bound to plasma proteins. The drug does not

    enter the CSF.

    ; Extensive metabolism occurs in the liver and the excretion is

    primarily through the bile.

    ; The level of parent drug in urine is very low

; ADVERSE EFFECTS

; Allergies

    ; Gastrointestinal disturbance dose dependent like nausea

    anorexia and vomiting

    ; Endocrine effects such as gynecomastia decreased libido

    impotence and menstrual irregularities results from the

    blockade of androgens and adrenal steroid synthesis by

    ketoconazole

    ; Transient increase in serum transaminases, frank hepatitis

    occurs rarely but requires immediate cessation of treatment.

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