Recommended text books

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Recommended text books

• ?Basic and Clinical pharmacology, 10th or 11th
  edition, B.G.Katzung, LANGE medical book.
• ?Lippincotts 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.

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Antifungal Agents

• Dr. Roshna S. Aziz
• Department of Pharmacology
• School of Medicine
• University of Sulaimani

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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

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Antifungal drugs

• Work by exploiting differences between 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)

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• Fungal cell membranes have a unique sterol,
  ergosterol, which replaces cholesterol found in
  mammalian cell membranes

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Antifungal drugs

• Systemic topicalsome are fungistatic,
  while others are fungicidal

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Systemic antifungal drugs for systemic
infections
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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.

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Mechanism of Action
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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

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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

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Side effects

• Infusion related
• Fever chills,
• Dyspnea,
• Nausea vomiting,
• Hypotension,
• Convulsions

• Cumulative toxicity
• Nephrotoxicity
• K Mg wasting
• Anemia (?erythropoietin)

• To reduce the severity of the infusion-related
  reactions, pretreatment with an antipyretic
  (acetaminophen), antihistamines, and antiemetics
  may be given.

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Amphotericin B
Amphotericin B
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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.

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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)

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FLUCYTOSINE (5-FC)

• Pyrimidine antimetabolite, narrow-spectrum
  fungistatic
• Water soluble
• Oral only,
• Poor protein binding
• CSF conc. 75 serum conc.

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• 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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• Why the drug does not act on human cells?

Human cells are unable to convert the parent drug
to its active metabolites.
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• Clinical use at present is confined to
  combination therapy, either with
• Amphotericin B for cryptococcal meningitis , or
• Itraconazole for chromoblastomycosis

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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

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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.

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Azoles
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Mechanism of Action
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Clinical Use
BROAD SPECTRUM OF ACTIVITY Candida,
Cryptococcus, Blastomyces, Histoplasma,
Coccidiodes , Dermatophytes
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Adverse Effects
Relatively nontoxic. Minor GI upset
Abnormalities in liver enzymes (inhibit
cytochrome P450 enzymes) Very rarely,
clinical hepatitis
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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.

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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

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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

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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.

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Echinocandins
Caspofungin Micafungin Anidulafungin  
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Echinocandins

• The newest class of antifungal .
• Active against candida and aspergillus, but not c
  neoformans or the agents of zygomycosis and
  mucormycosis.

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Mechanism of Action
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Adverse Effects

• Extremely well tolerated,
• Minor GI side effects
• Flushing
• Elevated liver enzymes (caspofungin
  cyclosporine).
• Histamine release during IV infusion.

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Systemic antifungal drugs for Mucocutaneous
infections
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Griseofulvin

• Very insoluble, fungistatic
• Derived from a species of penicillium.
• Better absorption when given with fatty foods.

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• 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

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Adverse effects

• Allergic reaction
• photosensitivity
• Hepatitis
• Teratogenesis

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Terbinafine

• Synthetic allylamine.
• Orally Active.
• Dermatophytoses, especially onychomycosis .
• Keratophilic , fungicidal.

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• 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.

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Adverse effects

• Rare, mild, self-limiting
• GI upset
• Rash
• Pruritis
• Headache.

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Topical antifungal therapy
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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.

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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.

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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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• Thank you