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Fungal infections are termed mycoses Can be divided into: Superficial mycoses
Affect the skin, hair and nails
Allergic mycoses
Affect lungs or sinuses Patients may have chronic asthma, cystic fibrosis or sinusitis
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Introduction
Fungal infections are usually more difficult to treat than
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Mechanism of Action
Amphotericin B and other polyene macrolide antibiotics bind to
Form pores or channels that increase the permeability of the membrane Leakage of a variety of small molecules.
It avidly with lipids (ergosterol) along the double bond-rich side Associates with water molecules along the hydroxyl-rich side
The lipophilic portions surround the outside of the pore and the hydrophilic regions line the inside.
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membrane component cholesterol, but this interaction does account for most adverse toxic effects associated with this drug.
The predominant sterol of bacteria, like in human cells, is
Oral amphotericn B effective only on fungi with in the GIT tract and not be used for treatment of systemic infection .
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Three lipid-associated formulations have been used: 1) Liposomal : drug is encapsulated in phospholipid-containing liposomes 2) Colloidal dispersion: drug is packaged into small lipid disks containing cholesterol sulphate 3) Lipid complex: drug is complexed with phospholipids to produce ribbon-like structures
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Ribbon-like particles Carrier lipids: DMPC, DMPG Particle size (m): 1.6-11
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Disk-like particles Carrier lipids: Cholesteryl sulfate Particle size (m): 0.120.14
Unilaminar liposome Carrier lipids: HSPC, DSPG, cholesterol Particle size (m) : 0.08
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DMPC-Dimyristoyl phospitidylcholine HSPC-Hydrogenated soy phosphatidylcholine DMPG- Dimyristoyl phospitidylcglycerol DSPG-Distearoyl phosphitidylcholine
Antifungal Activity
Has the broadest spectrum of antifungal and is fungicidal action
including;
Sporotrichum schenkii and Cryptococcus neoforman, Histoplasma capsulatum, Blastomycosis Coccidioides immitis,
Aspergillus fumigatus.
Candida albicans respond to higher concentrations
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Therapeutic use
The use of amphotericin B has diminished due to reduced
Once a clinical response has been elicited maintenance therapy is continued with an azole.
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meningitis,
Once infection is controlled, fluconazole in a daily oral dose is superior to and more convenient than weekly intravenous amphotericin B in the prevention of clinical relapses.
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invasive aspergillosis.
Adverse Effects
Infusion-Related Adverse Effects
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Which can lead to destruction of renal tubular cells and disruption of the tubular basement membrane.
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Keeping patients well hydrated may reduce nephrotoxicity; Saline infusions prior to amphotericin B dosing have been
advocated, and
Concomitant diuretic therapy should be avoided.
Prolonging the infusion rate may decrease toxicity infuse
over 4-6 hrs for first dose and if tolerated reduce infusion to over 2 hrs.
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It is used in caution in patients with renal dysfunction, electrolyte imbalances, and in combination with antineoplastic
threatening.
When given with the corticosteroids, severe hypokalemia may
occur.
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Flucytosine
Flucytosine (5-fluorocytosine) is a fluorinated pyrimidine
5-FUMP is then;
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are common.
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Adverse Effects
Fluorouracil is responsible for the ADRs of flucytosine. Bone marrow toxicity with anemia, leukopenia, and
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The Azoles
Are broad spectrum antifungal Concentration-independent fungistatic agents Drugs include
Triazoles :
Imidazoles:
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Mechanism of Action
All azoles exert antifungal activity by binding to cytochrome
ergosterol.
Impair the biosynthesis of ergosterol for the cytoplasmic membrane. Result in damaged, leaky cell membranes.
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Resistance
The primary mechanism of resistance in C. albicans is
accumulation of mutations in ERG11, the gene coding for the 14-a-sterol demethylase.
Increased production of 14-a-sterol demethylase and Increased azole efflux are other potential cause
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Ergosterol biosynthetic
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Fluconazole
Fluconazole is very effective and commonly used in the treatment
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It has a plasma t of 31hrs and given once daily It penetrates readily into the CSF Almost 80% of the drug is eliminated in urine unchanged
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Adverse Effects
Fluconazole is well tolerated. Nausea, vomiting, abdominal pain, diarrhea, and skin rash
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Drugs interaction
Fluconazole is an inhibitor of CYP3A4 and CYP2C9.
cyclosporine, phenytoin, sulfonylureas (glipizide, tolbutamide, others), tacrolimus, theophylline, telithromycin, and warfarin.
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Fluconazole
Spectrum vs. Candida and
Itraconazole
Similar Candida coverage as fluconazole, + Aspergillus
Voriconazole
Broad, includes most Candida spp.,
Aspergillus
Clearance
Serum half life (hr) CSF penetration CYP 3A4 inhibition Adverse effects
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Renal (80%)
24 Excellent Weak N&V, hepatic
Hepatic 3A4
24-30 Poor Strong N&V, diarrhea (solution), hepatic, CHF
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Ketoconazole
Systemic use of ketoconazole has diminished;
It has been replaced by itraconazole for the treatment of all mycoses except when the lower cost of ketoconazole
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while retaining most of ketoconazole's pharmacological properties and expanding the antifungal spectrum.
IN large doses, Ketoconazole inhibit several biosynthetic steps in the synthesis of adrenal and gonadal steroids. Thus reduce the plasma conc. Of cortisol and testosterone
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concentrations (2-4hrs) :
1) disintegration/dissolution rate (favoured by acidic pH?) 2) Gastric emptying rate 3) Intestinal metabolism (CYP 3A4 in intestinal wall) 4) Rate of absorption from the intestine 5) First Pass effect (metabolism in liver) 6) Clearance rate. Food delays absorption, but does not decrease peak serum concentrations significantly.
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ketoconazole
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testosterone synthesis
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Griseofulvin
Griseofulvin is fungistatic in vitro for various species of the
dermatophytes.
It is not effective against candida albicans. Is mild cytotoxic and damage the microtubular protien, thus
synthesized keratin in the stratum corneum of the skin, hair, and nails, stopping the progression of dermatophyte infection
.
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Indications
6months while infection of the toenail is treated for 6-12 months. Since chronic fungal infections tend to cause
Adverse effect
Headache, skin rashes and urticaria, dry mouth, an altered
Drug interaction
Griseofulvin increases warfarin metabolism, and Griseofulvin metabolism is increased by phenobarbital. Griseofulvin has been largely replaced by newer antifungal
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Topical Antifungal
Nystatin
Nystatin is a polyene macrolide much like amphotericin B.
It has similar mechanism of action with amphotericin B. Nystatin is active against most candida species.
infections.
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topically.
Produce nephrotoxicity
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Topical Azoles
Often used in vulvovaginal candidiasis and oral thrush.
Several other azoles are available for topical use. Clotrimazole Fungicidal concentrations remain in the vagina for as long as 3
mg.
On the skin, applications are made twice a day
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For the vagina, the standard regimens are one 100-mg tablet
once a day at bedtime for 7 days, one 200-mg tablet daily for 3 days, one 500-mg tablet inserted only once, or 5 g of cream once a day for 3 days (2% cream) or 7 days (1% cream).
Clotrimazole has been reported to cure dermatophyte
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