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					Antifungal Drugs


 Rolf J. Craven, M.S., Ph.D.
     Office: 213 Combs
      Phone: 323-3832
E-mail: rolf.craven@uky.edu
          Learning objectives:
• Identify the most common pathogenic fungi and the
  diseases that they cause. Keyword:
  candidiasis/candidosis .
• Examine the general mechanisms of clinically
  utilized antifungal agents. Keywords: ergosterol,
  cytochrome P450, lanosterol demethylase, squalene
  epoxidase, thymidylate synthase, and permease.
• Understand the uses, mechanisms, pharmacokinetics,
  and side effects of the following drugs: fluconazole,
  clotrimazole, amphotericin, nystatin, flucytosine,
  terbinafine, and griseofulvin.
  Summary of fungal pathogens
• Superficial mycoses are among the most common
  infections in the world.
• In the U.S., 50% of women experience vulvuvaginal
  candidiasis/candidosis by the age of 25, with the
  majority of these infections being caused by Candida
  albicans.
• Risk factors for candidosis include corticosteroid
  therapy, broad-spectrum antibiotic, diabetes, and
  immunosuppression.
• Tight clothing and oral contraceptive use have also
  been associated with candidosis, and it is fairly
  common during pregnancy.
• Oral candidosis is often called thrush.
   Summary of fungal pathogens
• C. albicans is a normal
  component of the GI flora, present
  in 50-80% of the healthy human
  population, where they compete
  with harmful bacteria and are kept
  in check by the immune system.
• Candida are a dimorphous fungi,
  because they can live in a yeast
  state, in which they replicate by
  budding (Figure 1, “C” panel).
• Under the appropriate conditions,
  Candida can change into an
  invasive state (Figure 1, “D”
  panel) in which they grow
  filamentous processes.
  Summary of fungal pathogens

• Candidosis is usually treated topically with azole
  inhibitors of fungal ergosterol synthesis.
• Topical nystatin is an alternative treatment, with
  oral fluconazole as the next line of therapy.
• In extreme cases, intravaneous amphotericin with
  flucytosine may be considered. We will review all
  of these drugs in the lecture.
  Summary of fungal pathogens


Q: Bacteria and fungi infect some of the same
 areas of the body. How can you distinguish
 bacterial and fungal infections?
    Summary of fungal pathogens
• Although Candida albicans is the
  most common fungal pathogen, a
  number of other fungi are
  encountered clinically.
• In addition, fungi can colonize
  other areas of the body, with the
  common disorders being tinea
  pedis (“athletes’ foot”), tinea
  cruris (“jock itch”), tinea capitis
  (infections of the scalp), tinea
  barbae (infections of beards and
  moustaches), and onychomycosis
  (infection of the nails).
Q: Yeast are used to make beer. Does that mean
 that you can get a yeast infection from
 drinking beer? Should people taking
 corticosteroids by aerosol avoid beer?
  Summary of fungal pathogens
• Systemic infections are characteristic of
  HIV/AIDS patients, cancer patients, and other
  patients receiving immunosuppressive agents
  or broad-spectrum antibiotics.
• They are a major cause of death among cancer
  patients and transplant recipients.
• The fungi involved in systemic infections
  include Candida, Histoplasma, Aspergillus,
  and Cryptococcus species. We will review the
  drugs used to treat these infections.
          Learning objectives:
• Identify the most common pathogenic fungi and the
  diseases that they cause. Keyword:
  candidiasis/candidosis .
• Examine the general mechanisms of clinically
  utilized antifungal agents. Keywords: ergosterol,
  cytochrome P450, lanosterol demethylase, squalene
  epoxidase, thymidylate synthase, and permease.
• Understand the uses, mechanisms, pharmacokinetics,
  and side effects of the following drugs: fluconazole,
  clotrimazole, amphotericin, nystatin, flucytosine,
  terbinafine, and griseofulvin.
ANTIFUNGAL DRUGS
         SUMMARY of Antifungal
             Mechanisms:
• The majority of anti-fungal
  agents inhibit the
  biosynthesis or stability of
  ergosterol.
• This is the fungal version of
  cholesterol and is a major
  component of the fungal cell
  membrane.
• Ergosterol performs a
  variety of functions in the
  fungal cell, and the proteins
  that synthesize it are
  essential for viability.
Q: Ergosterol looks like cholesterol- can too
 much ergosterol clog your arteries?
SUMMARY of Antifungal Mechanisms:

• Most of the compounds that are described
  below affect ergosterol. Their mechanisms are
  as follows:
• (1) They bind to ergosterol and block its
  function.
• (2) They block ergosterol synthesis by
  inhibiting the enzyme lanosterol demethylase.
• (3) They block ergosterol synthesis by
  inhibiting the protein squalene synthase.
          Learning objectives:
• Identify the most common pathogenic fungi and the
  diseases that they cause. Keyword:
  candidiasis/candidosis .
• Examine the general mechanisms of clinically
  utilized antifungal agents. Keywords: ergosterol,
  cytochrome P450, lanosterol demethylase, squalene
  epoxidase, thymidylate synthase, and permease.
• Understand the uses, mechanisms, pharmacokinetics,
  and side effects of the following drugs: fluconazole,
  clotrimazole, amphotericin, nystatin, flucytosine,
  terbinafine, and griseofulvin.
  Azole drugs- inhibit ergosterol synthesis



• Description: The azoles
  are named for ring
  structures within the
  drug.
Azole drugs are heavily marketed
Azole drugs- inhibit ergosterol synthesis
• Mechanism: This class
  of drugs acts by
  inhibiting the enzyme
  lanosterol
  demethylase, a key
  step in ergosterol
  synthesis.
Azole drugs- inhibit ergosterol synthesis

Side effects: Lanosterol demethylase is a
  cytochrome P450 protein. It is closely related
  to human lanosterol demethylase and other
  P450 proteins. As a result, azole drugs inhibit
  human P450 proteins in the liver and alter the
  metabolism of other drugs.
   Resistance to antifungal drugs
• Resistance: Resistance has gradually emerged
  with prolonged use and generally involves
  mutations or changes in expression of the
  target protein, lanosterol demethylase.
• Remember: some people who are taking these
  drugs have chronic conditions and might take
  the drugs for a long time.
Azole drugs- inhibit ergosterol synthesis

• All members of this class of antifungals are
  potential teratogens.


Why would azole compounds be teratogens? Do they act
on DNA directly?
                 Fluconazole
a) Uses: Fluconazole is the drug of choice for
  candidosis and both cryptococcal and coccidioidal
  meningitis.
b) Dosage: Fluconazole is effective orally and is also
  given i.v. Fluconazole is minimally metabolized and
  can cross the blood-brain barrier.
c) Side effects: Fluconazole can cause nausea, vomiting
  or rash. There are significant drug interactions
  between fluconazole and warfarin, cyclosporine,
  phenytoin, lovastatin, oral hypoglycemics, and
  protease inhibitors.
   Fluconazole drug interactions

Why would drug interactions between
 fluconazole and protease inhibitors be
 important? Why would interactions with
 cyclosporine be important?
                    Clotrimazole
a) Uses: Clotrimazole can be used for a number of fungal
   infections, including oropharyngeal candidosis. It can also be
   used cutaneously and intravaginally.
b) Application: Clotrimazole can be administered as a 10 mg oral
   troche (Mycelex). Its effects are purely topical. Other forms
   of clotrimazole are a cream (Lotrimin, Mycelex) and a vaginal
   tablet (Gynelotrimin, Mycelex-G). Remember
   Clotrimazole=Lotrimin. Why they did not call it clotrimin, I
   do not know.
c) Side effects: About 5% of patients taking the oral troche
   experience some gastric irritation. Other topical uses can
   cause local irritation.
    Other azole drugs of interest:
•   Itraconazole (Sporanox, a widely used
    antifungal agent similar to fluconazole)
•   Miconazole (widely used for topical
    infections)
•   Econazole (Spectazole)
•   Butoconazole (Femstat)
•   Tioconazole (Vagistat, sometimes used in
    combination with miconazole)
•   Oxiconazole (Oxistat)
Terbinafine, a non-azole inhibitor of sterol
   synthesis (also naftifine, butenafine)

Mechanism: Terbinafine
   inhibits an enzyme
   called squalene
   epoxidase. This
   enzyme functions in
   the same ergosterol
   biosynthetic pathway
   as the azole drugs
   (described above).
  Terbinafine, a non-azole inhibitor of sterol
     synthesis (also naftifine, butenafine)


Administration: Terbinafine
    concentrates in skin and
    especially at nail beds,
    making it quite useful for
    fungal infection of nails.

Q: Do the organisms targeted
    by terbinafine have pointy
    ears, tails, a single tooth,
    and legs?
  Terbinafine, a non-azole inhibitor of sterol
     synthesis (also naftifine, butenafine)



Side effects: Minimal toxicity after topical use,
   but can cause allergic reactions when given
   orally.
ANTIFUNGAL DRUGS
         ANTIFUNGAL DRUGS
• Polyene drugs: Amphotericin B- punctures cell membranes
• a) Mechanism: Amphotericin is a rigid, rod-shaped molecule
  that kills cells by disrupting the cell membrane, causing
  leakage of electrolytes and small molecules. Amphotericin
  bind to ergosterol, the major membrane lipid in fungal cells.
• b) Uses: Amphotericin B is effective against a broad spectrum
  of fungi. Resistance is uncommon, but may occur if ergosterol
  synthesis is altered or decreased.
• c) Side effects: Fever and chills often accompany i.v. injection
  and allergic reactions may occur. Principal, dose-limiting
  toxicity is renal dysfunction. Amphotericin can also cause
  hypotension, hypokalemia, reversible normocytic anemia, and
  thrombophlebitis.
       ANTIFUNGAL DRUGS
• Polyene drugs: Nystatin (synthesized by NY state
  laboratory)
• a) Uses: Nystatin is similar to amphotericin B except
  that it is used only for topical treatment or oral
  candidosis
• b) Administration: There is minimal absorption
  orally, but can be used for oral candidosis. It has an
  extremely bitter taste which limits its use.
• c) Side effects: There are minimal side-effects when
  used topically, but highly toxic after parenteral
  administration
      ANTIFUNGAL DRUGS

Amphotericin B and nystatin seem similar to
 penicillin in disrupting cell walls of
 microorganisms. How are they different?
ANTIFUNGAL DRUGS
      Flucytosine- blocks DNA and
            protein synthesis
Mechanism: An antimetabolite
  of pyrimidine, flucytosine
  (Ancobon) selectively enters
  fungal cells via a cytosine-
  specific permease, where it
  is converted to active
  metabolites (5-fluorouracil
  and 5-FdUMP) that disrupt
  DNA and protein synthesis.
  Mammalian cells do not
  convert flucytosine to
  fluorouracil!
     Flucytosine- blocks DNA and
           protein synthesis
Resistance arises
  through decreased
  uptake of the drug or
  decreased cytosine
  deaminase activity.

Q: Why does resistance to
  flucytosine arise more
  quickly than resistance
  to azole drugs?
      Flucytosine- blocks DNA and
            protein synthesis

Administration: Flucytosine is well absorbed orally and
   penetrates into CNS. Flucytosine acts synergistically with
   amphotericin B and is always used in combination with
   amphotericin B to slow development of resistance to
   flucytosine’s antifungal effects.
Side effects: Flucytosine may depress the function of the bone
   marrow, resulting in leucopenia and thrombocytopenia.
   Flucytosine also causes nausea, vomiting or diarrhea, perhaps
   because of the release of 5-FU by the gastrointestinal flora.
What are some drugs that have a similar action
 to flucytosine but act on mammalian cells?
 What are they used for?
ANTIFUNGAL DRUGS
                     Griseofulvin
1. Mechanism: Griseofulvin binds to polymerized microtubules,
   disrupting the mitotic spindle and blocking replication in
   mitosis. While this resembles other drugs acting on
   mammalian cells, griseofulvin is quite specific to fungi.
2. Administration: Administered orally, it concentrates in skin at
   sites of newly synthesized keratin-containing tissues
   (ineffective topically). Extensively metabolized, it also
   induces cytochrome P450 enzymes leading to possible drug
   interactions.
3. Side effects: These are rare and include allergic reactions,
   headache, nausea, and possible liver toxicity.
Other drugs have a similar mechanism of action
 to griseofulvin, but they act on mammalian
 cells. How would these drugs be used?
            Clinical example:
• Q1. L.T. is a 40-year-old man who has whitish marks
  on his tongue and buccal mucosa that can be
  removed by scraping, leaving a reddish mark. L.T.
  has experienced a severe chest infection and marked
  weight loss in the last six months. What is his
  diagnosis and course of therapy?
              Clinical example:
•   Q1. L.T. is a 40-year-old man who has whitish marks on his
    tongue and buccal mucosa that can be removed by scraping,
    leaving a reddish mark. L.T. has experienced a severe chest
    infection and marked weight loss in the last six months.
    What is his diagnosis and course of therapy?
•   L.T. appears to have oral candidosis. Because of
    the chest infection and weight loss, L.T. should be
    tested for H.I.V. L.T. is prescribed clotrimazole,
    which is superior to nystatin (which has a bitter
    taste). OTC drugs are as effective as prescription
    brands, and prescription drugs offer no additional
    benefit. However, if there are questions about
    L.T.’s ability to stick to the regimen, a single dose
    of fluconazole is effective.
           Clinical example:
• Q2. L.T. returns soon and says that the
  medication prescribed (oral fluconazole) made
  him feel dizzy. Upon further questioning, he
  reveals that he has been taking diazepam.
  Why would the anti-fungal drug cause this side
  effect?
             Clinical example:
• Q2. L.T. returns soon and says that the medication
  prescribed (oral fluconazole) made him feel dizzy.
  Upon further questioning, he reveals that he has been
  taking diazepam. Why would the anti-fungal drug
  cause this side effect?
• Fluconazole inhibits the cytochrome P450 pathway,
  which metabolizes a variety of drugs. When the
  pathway is inhibited, drug metabolism is decreased
  and the drugs accumulate in the bloodstream,
  amplifying normal side effects.
            Clinical example:
• Q3. After a brief period of effectiveness, L.T.’s
  infection returns and is unresponsive to
  therapy. What are the most likely reasons for
  this? What are the next options? Are
  terbinafine or griseofulvin good choices?
               Clinical example:
• Q3. After a brief period of effectiveness, L.T.’s infection
  returns and is unresponsive to therapy. What are the most
  likely reasons for this? What are the next options? Are
  terbinafine or grisofulvin good choices?
• Azole compounds work by inhibiting the synthesis of
  ergosterol by the enzyme lanosterol demethylase (also called
  Cyp51). Mutations in this enzyme can cause resistance to
  azole compounds like fluconazole. Nystatin is a reasonable
  second choice, although the infection may be systemic at this
  point. Terbinafine or griseofulvin would not be good
  alternative therapies because they are not effective for
  candidosis. L.T. may be shifted to a regimen of 5-flucytosine
  and amphotericin for further treatment.

				
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posted:2/20/2010
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