Antifungal agents - PDF

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					Anti fungal Agents
FUNGAL INFECTIONS

 • SYSTEMIC         • LOCAL
 • HISTOPLASMOSIS   • DERMATOPHYTO.
 • ASPERGILLOSIS    • SPOROTRICHIOSI.
 • CRYPTOCOCCOSIS   • ZYGOMYCOSIS
 • BLASTOMYCOSIS    • CHROMOMYCOSI.
 • MUCORMYCOSIS
 • CANDIDIASIS
AMPHOTERICIN B
• Therapy is limited by toxicity, drug-induced renal
  impairment.
• lipid-packaged drug binds to mammalian
  membrane less readily
• lipid vehicle serves as an amphotericin reservoir
• preferential binding allows for a reduction of
  toxicity
Amphotericin B
• some fungi contain lipases that liberate free
  amphotericin B
• poorly absorbed from the GIT
• Oral -effective only on fungi within the lumen of
  the tract and cannot be used for systemic
  disease.
Mechanism of Action
• It is selective in its fungicidal effect
• Ergosterol, a cell membrane sterol, is found in
  the cell membrane of fungi
• binds to ergosterol and alters the permeability of
  the cell by forming pores in the cell membrane
• amphipathic characteristic -lipophilic portions
  around the outside of the pore and the
  hydrophilic regions lining the inside.
• The pore allows the leakage of intracellular
  ions and macromolecules, eventually leading to
  cell death.
Antifungal Activity
• It has activity against the clinically significant yeasts,
  including
• Candida albicans
• Cryptococcus neoformans; the organisms causing
  endemic mycoses
• Histoplasma capsulatum
• Blastomyces dermatitidis
• Coccidioides immitis
• the pathogenic molds, such as Aspergillus fumigatus
Clinical Use
• useful agent for all life-threatening mycotic
  infections
• For treatment of systemic fungal disease,
  amphotericin B is given by slow I.V infusion
• Local or topical administration of amphotericin B
  is used
• Mycotic corneal ulcers and keratitis with topical
  drops and subconjunctival injection.
• Fungal arthritis with adjunctive local injection
  directly into the joint.
• Candiduria responds to bladder irrigation with
  amphotericin B, no significant systemic toxicity.
Adverse Effects
• The toxicity of amphotericin B can be divided
  into two broad categories:
• immediate reactions, related to the infusion of
  the drug, and
• occurring more slowly
INFUSION-RELATED TOXICITY
• fever, chills, muscle spasms, vomiting, headache,
  and hypotension.

• Premedication with antipyretics, antihistamines,
  meperidine, or corticosteroids could help
CUMULATIVE TOXICITY
• Renal damage -most significant toxic reaction.
• The degree of azotemia is variable
• The irreversible form of amphotericin
  nephrotoxicity
• Renal toxicity commonly manifests as renal
  tubular acidosis and severe potassium and
  magnesium wasting.
• Abnormalities of liver function due to reduced
  erythropoietin production by damaged renal
  tubular cells.
• After intrathecal therapy with amphotericin,
  seizures and arachnoiditis may develop
FLUCYTOSINE
• taken up by fungal cells via the enzyme cytosine
  permease.
• It is converted intracellularly first to 5-FU and
  then to FdUMP and fluorouridine triphosphate
  (FUTP), which inhibit DNA and RNA synthesis
• Synergy with amphotericin B has been observed
5-flucytosine permease 5-flucytosine
(outside)              (inside)
                                       Cytosine
                                          deaminase



     5dUMP&                      5-fluorouracil
     FUTP
     (inhibits
     thymidylate                   Phosphoribosyl
     synthase)                     transferase
     RNA                5-FUMP
• In vitro synergy with azole drugs has also been
  seen
• Resistance is mediated through altered
  metabolism of flucytosine
Clinical Use
• The spectrum of activity of flucytosine is
  restricted to
• C neoformans,
• candida species, and
• the dematiaceous molds that cause
  chromoblastomycosis.
Combination therapy
• Flucytosine is not used as a single agent
  combination therapy,
• with amphotericin B for cryptococcal meningitis
  or
• with itraconazole for chromoblastomycosis.
Adverse Effects
• metabolism to the toxic antineoplastic
  compound fluorouracil.
• Bone marrow toxicity with anemia, leukopenia,
  and thrombocytopenia
• derangement of liver enzymes occurring less
  frequently.
• A form of toxic enterocolitis can occur.
AZOLES
• Azoles are synthetic compounds that can be
  classified as either
• imidazoles or triazoles
• The imidazoles consist of ketoconazole,
  miconazole, and clotrimazole
• The triazoles include itraconazole, fluconazole,
  voriconazole, and posaconazole.
Mechanism of Action
• the reduction of ergosterol synthesis by
  inhibition of fungal cytochrome P450 enzymes
• Inhibit the synthesis of ergosterol by blocking
  demethylation (14-demethylase) of
  lanosterol - also inhibit cytochrome activity.

• Imidazoles exhibit a lesser degree of selectivity
  than the triazoles
                   Acetyl CoA

                   Squalene             Allylamine
Squalene
monooxygenase                           drugs
                   Squalene-2,3 oxide

                   Lanosterol
14- -demethylase                        Azoles
                         (ergosterol)
Resistance
• Resistance to azoles occurs via multiple
  mechanisms.
• altered demethylase
• Increased production of 14-α-sterol
  demethylase
• increasing use of these agents for prophylaxis
  and therapy –lead to resistance
Clinical Use
• The spectrum including many
• candida species
• C neoformans
• the endemic mycoses (blastomycosis,
  coccidioidomycosis, histoplasmosis)
• dermatophytes
• itraconazole and voriconazole, even aspergillus
  infections.
• amphotericin-resistant organisms such as P
  boydii.
Adverse Effects
• relatively nontoxic.
• minor gastrointestinal upset
• abnormalities in liver enzymes
• very rarely, clinical hepatitis.
Drug Interactions
• All azole drugs affect the mammalian
  cytochrome P450 system of enzymes to some
  extent
KETOCONAZOLE
• Ketoconazole was the first oral azole introduced
  into clinical use.
• greater propensity to inhibit mammalian than for
  fungal P450
• As a result, systemic ketoconazole has fallen out
  of clinical use in the USA
Ketoconazole
• Inhibits hepatic cytochrome P450 isozymes and
  increase plasma levels of other drugs, including
  anticoagulants,
• cyclosporine,
• oral hypoglycemics, and
• phenytoin.
• life-threatening cardiotoxicity when cisapride is
  used concomitantly with ketoconazole.
• Inhibition of cytochrome P450 isoforms by
  ketoconazole interferes with the synthesis of
  adrenal and gonadal steroids and may lead
• gynecomastia
• menstrual irregularities, and
• infertility.
ITRACONAZOLE
• available in oral and intravenous formulations
• Drug absorption is increased by food and by low
  gastric pH.
• interacts with hepatic microsomal enzymes



• drug interaction -reduced bioavailability of
  itraconazole when taken with rifamycins
  (rifampin, rifabutin, rifapentine).
• does not affect mammalian steroid synthesis
• itraconazole displays potent antifungal activity,
  effectiveness reduced by bioavailability.
Newer formulations

• oral liquid and an I.V preparation, have utilized
  cyclodextran as a carrier molecule
• enhance solubility and bioavailability.
• penetrates poorly into the CSF
• Itraconazole is the azole of choice for treatment
  of disease due to the dimorphic fungi
  histoplasma, Blastomyces and sporothrix
• Itraconazole has activity against Aspergillus sp,
  but replaced by voriconazole as choice for
  aspergillosis.



• Itraconazole is used extensively in the treatment
  of dermatophytoses and onychomycosis
FLUCONAZOLE
• Unlike ketoconazole and itraconazole, its oral
  bioavailability is high.
• fluconazole has the least effect of all the azoles
  on hepatic microsomal enzymes.
• few hepatic enzyme interactions and
FLUCONAZOLE
• better gastrointestinal tolerance
• fluconazole has widest therapeutic index of the
  azoles

• the azole of choice in the treatment and
  secondary prophylaxis of cryptococcal meningitis
• I.V fluconazole - candidemia
Fluconazole
• commonly used for the treatment of
  mucocutaneous candidiasis
• Coccidioidal disease, and in particular for
  meningitis
• high doses of fluconazole / intrathecal
  amphotericin B. (only if not responding)
• Fluconazole displays no activity against
  aspergillus
• Prophylactic - reduce fungal disease in bone
  marrow transplant recipients and AIDS patients,
• but the emergence of fluconazole-resistance
  seen
Voriconazole
• I.V and oral formulations.
• Metabolism is predominantly hepatic.
• clinically relevant inhibitor of mammalian
  CYP3A4.
• dose reduction required when voriconazole is
  started, including cyclosporine, tacrolimus, and
  HMG-CoA reductase inhibitors.
• toxicities include rash and elevated hepatic
  enzymes.
• Visual disturbances
• include blurring and changes in color vision or
  brightness.
• Photosensitivity dermatitis is commonly
  observed in patients receiving chronic oral
  therapy.
• excellent activity against Candida sp (including
  fluconazole-resistant species such as C krusei)
• Voriconazole is less toxic than amphotericin B
  and is the treatment of choice for invasive
  aspergillosis.
Posaconazole
• Posaconazole is the newest triazole to be
  licensed in the USA.
• It is available only in a liquid oral formulation
• Absorption is improved when taken with meals
  high in fat.
Posaconazole
• Rapidly distributed to the tissues, resulting in
  high tissue levels

• drug interactions with increased levels of
  CYP3A4 substrates such as tacrolimus and
  cyclosporine have been documented.
Posaconazole
• activity against most species of candida and
  aspergillus.
• It is the only azole with activity against the
  agents of zygomycosis and mucormycosis.
• prophylaxis of fungal infections
ECHINOCANDINS
• Caspofungin, micafungin, and anidulafungin are
  the only licensed agents in this category of
  antifungals

• These agents are active against candida and
  aspergillus
Pharmacokinetics
• Echinocandins are available only in I.V
  formulations.
• Caspofungin is administered as a single loading
  dose
• Dosage adjustments are required in hepatic
  insufficiency.
MOA
• Echinocandins act at the level of the fungal cell
  wall by inhibiting the synthesis of (1–3) -glucan
• This results in disruption of the fungal cell wall
  and cell death.
Adverse Effects
• minor gastrointestinal side effects
• Elevated liver enzymes -in several patients
  receiving caspofungin in combination with
  cyclosporine
• Micafungin has been shown to increase levels of
  nifedipine, cyclosporine, and sirolimus.
• Anidulafungin no drug interactions, but
  histamine release may occur during intravenous
  infusion.
Clinical Use
• Caspofungin is currently licensed for
  disseminated and mucocutaneous candida
  infections,
• empiric antifungal therapy during febrile
  neutropenia
• Micafungin is licensed for mucocutaneous
  candidiasis, candidemia, and prophylaxis of
  candida infections

• Anidulafungin is approved for use in esophageal
  candidiasis and invasive candidiasis, including
  candidemia.
SYSTEMIC ANTIFUNGAL DRUGS FOR
MUCOCUTANEOUS INFECTIONS
• Griseofulvin fungistatic drug derived from a
  species of penicillium.
• systemic treatment of dermatophytosis
• Absorption is improved when it is given with
  fatty foods.
Griseofulvin
• it is deposited in
  newly forming skin -
  it binds to keratin
• Nail infections may
  require therapy for
  months
Adverse effects

• include an allergic syndrome -serum sickness,
  hepatitis, and drug interactions with warfarin
  and phenobarbital.
Terbinafine
• used in the treatment of dermatophytoses,
  especially onychomycosis
• terbinafine is a keratophilic medication it is
  fungicidal.
• it interferes with ergosterol biosynthesis, inhibits
  the fungal enzyme squalene epoxidase
• This leads to the accumulation of the sterol
  squalene, which is toxic to the organism.
                   Acetyl CoA

                   Squalene             Allylamine
Squalene
monooxygenase                           drugs
                   Squalene-2,3 oxide

                   Lanosterol
14- -demethylase

                         (ergosterol)
Adverse effects
• gastrointestinal upset and headache.
• no significant drug interactions
TOPICAL ANTIFUNGAL
THERAPY
• Nystatin is a polyene macrolide only used
  topically.
• nystatin has little toxicity, - oral use is often
  limited by the unpleasant taste.
• Nystatin is active against most Candida sp and is
  most commonly used for suppression of local
  candidal infections
TOPICAL AZOLES
• The two azoles most commonly used topically
  are clotrimazole and miconazole
• used for vulvovaginal candidiasis.
• Oral clotrimazole troches are available for
  treatment of oral thrush.
• useful for dermatophytic infections, including
  tinea corporis, tinea pedis, and tinea cruris.
• useful in the treatment of seborrheic dermatitis
  and pityriasis versicolor.
Topical Allylamines
• Terbinafine and naftifine are allylamines
  available as topical creams
• Both are effective for treatment of tinea cruris
  and tinea corporis.
• These are prescription drugs in the USA.

				
DOCUMENT INFO
Description: Pharmacology of Drugs used in Infectious Diseases