Anti-fungal agents

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Anti-fungal agents

• Fungal infections to a large extent are
  iatrogenic in nature.
• Fungal infections are associated with the use of
  broad spectrum antibiotic, indwelling catheters,
  AIDS.
• Poor penetration of the drug because fungus
  infects poorly vascularized.

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Anti-fungal agents

• Eukaryotic nature of fungus resembling human
  cell makes it difficult treat.
• Fungus cell wall contains ergosterol whereas
  mammalian cell contains cholesterol.

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Anti-fungal agents

• Amphotericin B
• It is obtained from streptomyces nodosus.
• It has double bonds on one side lipid soluble.
  It has OH on other - water soluble
• They have amino and carboxyl group.

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Anti-fungal agents

• Amphotericin B
• Mechanism of action
• It has affinity for ergosterol present in the
  cell membrane and forms a micropore thus disrupt
  the membrane function and cell death.

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Anti-fungal agents

• Amphotericin B
• It is active against wide range Aspergillosis,
  Candida albicans, Cryptococcus neoformans,
  Coccidioides immitis, Histoplasma, Mucormycosis
• It is active against Naegleria fowleri and
  Leishmaniasis

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Anti-fungal agents

• Amphotericin B Pharmacokinetics
• It is not absorbed orally
• Half life is 15 days
• Metabolized in liver and excreted in urine and
  bile
• Relatively safe in pregnancy.

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Anti-fungal agents

• Amphotericin B
• It can be given intravenously and intrathecally
• New formulations have reduced nephrotoxicity
  
• ABCD amphotericin B colloidal dispersion
• ABLC -- amphotericin B lipid complex

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ABCD amphotericin B colloidal dispersion

• is a lipid formulation of amphotericin B.
• the major goal of developing ABCD has been to
  attain a compound with
• lower toxicity
• at least similar efficacy compared to the parent
  compound, amphotericin B deoxycholate.
• ABCD is composed of amphotericin B complexed with
  cholesteryl sulfate.

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ABLC -- amphotericin B lipid complex

• ABLC is composed of amphotericin B complexed with
  dymyristoyl phosphatidylcholine and dimyristoyl
  phosphatidylglycerol..

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Anti-fungal agents

• Amphotericin B Adverse reactions
• INFUSION-RELATED TOXICITY Acute reactions
  (immediate reactions) related to the infusion of
  the drug Fever and chills, muscle spasms,
  vomiting, headache, and hypotension
• CUMULATIVE TOXICITY Long term - Nephrotoxicity,
  anemia, CNS toxicity

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Anti-fungal agents

• Amphotericin is used in
• Aspergillosis
• Coccidioidomycosis
• Cryptococcosis
• Candidiasis
• Histoplasmosis
• Mucormycosis

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Flucytosine is a fluorinated pyrimidine

• 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.

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Anti-fungal agents

• Flucytosine Fungi static
• blockade of fungal DNA synthesis
• Selectivity occurs because mammalian cells do not
  accumulate and do not deaminate flucytosine
• Well absorbed orally and penetrates into CSF.

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Anti-fungal agents

• Flucytosine Antifungal spectrum
• Cryptococcus neoformans Candida
  albicans Chromoblastomycosis

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Anti-fungal agents

• Flucytosine Adverse effects
• Reversible bone marrow depression (
  leukopenia, thrombocytopenia)
• Liver dysfunction
• Enterocolitis - rare

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Anti-fungal agents

• Flucytosine Therapeutic uses
• Candida infections ( in combination with
  amphotericin B)
• Cryptococcal meningitis ( in combination with
  amphotericin B)
• Chromoblastomycocis ( in combination with
  Itraconazole )

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Anti-fungal agents

• Azoles mainly fungistatic in nature
• Ketoconazole, Fluconazole, Itraconazole,
  Voriconazole
• Clotrimazole, Econazole, Miconazole

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Anti-fungal agents

• Ketoconazole
• First orally effective broad spectrum azole
  anti-fungal agent.
• Mechanism of action
• It inhibits C -14 demethylase
  thus blocking the demethylation of lanosterol to
  ergosterol sterol of fungal membrane.

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Anti-fungal agents

• Ketoconazole
• Gastric acidity promotes absorption.
• Hepatic metabolism is extensive and metabolites
  are excreted mainly in bile.
• CNS penetration is poor.

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Anti-fungal agents

• Ketoconazole Replaced by Itraconazole
• Anti-fungal spectrum
• Candidia, Coccidioides, Blastomyces, Histoplasma.
• Active against dermatophytes also

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Anti-fungal agents

• Ketoconazole adverse effects
• Nausea and vomiting.
• Hepatitis.
• Hair loss, gynaecomastia, loss of libido,
  Oligospermia -- decrease androgen production.
• Menstrual irregularities in women due to
  decreased estradiol synthesis.

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Anti-fungal agents

• Ketoconazole adverse effects
• Disulfiram like reaction with alcohol.
• It inhibits gonadal and steroid synthesis.
• It inhibits cyto P450 dangerous interaction
  with astemizole, terfenadine and cisapride
  resulting in ventricular fibrillation.

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Anti-fungal agents

• Fluconazole Not active against dermatophytes
• It has good activity against Cryptococcus,
  Coccodioides, Candidiasis.
• Oral absorption is very good not dependent on
  gastric acidity
• Fungicidal concentration in CNS, saliva and nails.

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Anti-fungal agents

• Fluconazole adverse effects
• Nausea, skin rash
• Hepatitis
• It does not inhibit androgen synthesis
• Inhibit cyto P 450 metabolizing drugs
• Not recommended for pregnant women.

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Anti-fungal agents

• Fluconazole Uses
• Candidiasis Disseminated.
• Cryptococcal meningitis.
• Coccidioidomycosis.

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Anti-fungal agents

• Itraconazole
• Broad spectrum than fluconazole includes
  Aspergillus, Blastomyces, Histoplamosis, Tinea,
  Sporotrichosis.
• Inhibits cyto P450 like ketoconazole
• CNS penetration is poor
• Impotence is common

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Anti-fungal agents

• Voriconazole
• Broad spectrum includes aspergillosis.
• Orally well absorbed
• Good tissue distribution including CNS
• Visual disturbance is the limitation.

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Anti-fungal agents

• Clotrimazole
• Effective for topical treatment of tinea
  infections
• oral, vaginal and cutaneous candidiasis respond
  to it
• Miconazole
• effective for tinea, pityriasis Versicolor,
  candidiasis

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Anti-fungal agents

• Griseofulvin
• It is obtained from penicillium griseofulvum
• It is active against Dermatophytes
  Epidermatophyton, Trichophyton and Microsporum

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Anti-fungal agents

• Griseofulvin Mechanism of action
• It gets deposited in the keratin forming cells of
  the skin, hair and nails especially
  concentrated and retained in the tinea infected
  cells disruption of mitotic spindles - thus
  interferes with mitosis.
• Newly formed keratin is not invaded by the fungus

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Anti-fungal agents

• Griseofulvin Pharmacokinetics
• Absorption from the GIT is irregular better
  with ultramicrofine granules
• Better absorption with high fat meals
• It is an inducer of liver enzymes

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Anti-fungal agents

• Griseofulvin
• It is used only for the Dermatophytes
• Body skin -------- 3 weeks
  Palm and Soles -------- 4 6 weeks
  Finger nails -------- 4 6 months
  Toe nails -------- 8 12 months

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Anti-fungal agents

• Griseofulvin
• Headache is the common complaint
• Peripheral neuritis and Leucopenia
• Potentiates the intoxicating effects of alcohol.

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Anti-fungal agents

• Terbinafine Fungicidal
• Active against dermatophytes and candidiasis
• Short course of therapy and relapse is poor
• It acts as a non competitive inhibitor of
  squalene epoxidase in the ergosterol synthesis

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Anti-fungal agents

• Terbinafine Fungicidal
• Oral absorption 40 .
• It is lipophilic, concentrated in skin and nail.

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Anti-fungal agents

• Terbinafine adverse effects
• Taste and visual disturbances
• Hepatic dysfunction, hematological disorder
• No inhibition of cyto P450

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Anti-fungal agents

• Terbinafine Uses
• Topical and Oral
• Tinea - Onchomycosis - nails
• Pityriasis Versicolor
• Candidiasis

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Anti-fungal agents

• NYSTATIN
• It is very toxic when given systemically and used
  only for local anti-fungal effect
• It is not absorbed orally
• Used only for oral candidiasis - locally

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Anti-fungal agents

• Caspofungin
• It is the first approved of Echinocandins
• It interferes with the synthesis of fungal cell
  wall by inhibiting the synthesis of beta ( 1,3 )
  D glucan, leading to cell lysis.
• Specific for aspergillus and Candida.
• Excreted by urine and feces
• Available for intravenous use only.

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Anti-fungal agents

• Other topical anti-fungal agents
• Tolnaftate effective drug for dermatophytes and
  tinea versicolor
• Ciclopirox used for tinea infections,
  pityriasis versicolor and candidiasis
• Benzoic acid anti-fungal agents and
  anti-bacterial property .
• Salicylic acid acts as keratolytic action

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