ANTIFUNGAL DRUGS

 Prepared by:
Ahmad Moussa
 Walid Nabil Fouad


 Microbiology Department
 Medical Research Institute
 Alexandria University
 May 2010



Types of antifungals:
 An antifungal drug is a medication used to treat fungal
infections such as athlete's foot, ringworm, candidiasis
(thrush), serious systemic infections such as cryptococcal
meningitis, and others. Such drugs are usually obtained by a
doctor's prescription or purchased over-the-counter.


 Antifungal drugs are of two kinds: systemic

and topical.


 Systemic antifungal drugs are medicines taken orally

(by mouth) or by injection to treat infections caused by a
fungus.


 Topical antifungal drugs are medicines applied to the

skin to treat skin infections caused by a dermatophyte.



Types of antifungals:
 Topical antifungal drugs not only relieve the symptoms
of fungal infection, such as itching, burning, and cracked skin,
but they also eliminate the fungus. However, those that
occur inside the body or that do not clear up after treatment
with creams or ointments may need to be treated with
systemic antifungal drugs.


 Systemic antifungal drugs are used, for example, to treat

a type of fungal infection called candidiasis also known as
(thrush or yeast infection), which can occur in the throat, in
the vagina, or in other parts of the body.


 They may also be used to treat fungal infections, which

can affect the lungs and other organs such as:


 Histoplasmosis
 Blastomycosis
 Aspergillosis
How antifungals work?
 Antifungals work by exploiting differences between
mammalian and fungal cells to kill the fungal organism
without dangerous effects on the host.


 Every component of the fungal cell wall and

membrane can be targeted. For example:


 Polyenes target ergosterol destroying the cell

membrane’s integrity.
 Allylamines, imidazoles, and triazoles inhibit
ergosterol synthesis.
 β-3-glucan synthase inhibitors (echinocandins) block
the production of the β-(1,3)-glucan protein
damaging the cell wall.
 Drugs not available in the market such as Nikkomycin
and Polyoxin target chitin synthase.
Mannoproteins are another potential target.
 Other antifungals such as flucytosine inhibit DNA/RNA
How antifungals work?



Precautions in using
antifungals:
 Unlike bacteria, both fungi and humans are eukaryotes.
Thus fungal and human cells are similar at the molecular
level. This makes it more difficult to find or design
drugs that target fungi without affecting human cells.


 As a consequence, many antifungal drugs cause side-

effects. Some of these side-effects can be life-threatening if
the drugs are not used properly.


 Apart from side-effects like liver-damage or affecting

estrogen levels, many medicines can cause allergic
reactions in people. For example, the azole group of drugs is
known to have caused anaphylaxis.



Classes of antifungals:
 A. Polyene antifungals:



Chemistry: A polyene is a molecule with
multiple conjugated double bonds. A polyene antifungal
is a macrocyclic polyene with a heavily hydroxylated region
on the ring opposite the conjugated system. This makes
polyene antifungals amphiphilic.



Mode of action: The polyene antimycotics bind
with sterols in the fungal cell membrane,
principally ergosterol. This causes the fungal cell's contents
including monovalent ions (K+, Na+, H+, and Cl-) as well as
small organic molecules to leak out of the cell, and thereby
causing fungal cell death.

Classes of antifungals:
 Polyene and toxicity to animal cells:


 Animal cells contain cholesterol instead of ergosterol

and so they are much less susceptible. However, at
therapeutic doses, some amphotericin B may bind to animal
membrane cholesterol, increasing the risk of human toxicity.


 Amphotericin B is nephrotoxic when
given intravenously. Amphotericin B molecules can form
pores in the host membrane as well as the fungal membrane.
This impairment in membrane barrier function can have lethal
effects.


 As a polyene's hydrophobic chain is shortened, its sterol

binding activity is increased. Therefore, further reduction of
the hydrophobic chain may result in it binding to cholesterol,
making it toxic to animals.
Examples of polyene
antifungals:
 Amphotericin-B:


 Indications: One of the main intravenous uses of this

drug is in treating various systemic fungal infections (e.g.
in critically ill, comorbidly infected or immunocompromised
patients), including cryptococcal meningitis.


 Amphotericin B is also commonly used in tissue culture

to prevent fungi from contaminating cell cultures.



Adverse effects: Intravenously administered
Amphotericin B has also been associated with multiple
organ damage in therapeutic doses.


 Nephrotoxicity (kidney damage) is a frequently

reported side-effect, and can be severe and/or irreversible.

Amphotericin-B:


 Although conventional
amphotericin B (Fungizone)
remains the standard therapy
for many invasive or life-
threatening mycoses, this
polyene drug is associated
with significant toxicity,
including infusion-related
events, such as chills, fever,
headache, nausea and
vomiting, and dose-limiting
nephrotoxicity.


 In addition, the clinical

efficacy of amphotericin B in
some settings (e.g., mold
disease such as invasive
aspergillosis in severely
immuno-compromised
patients) is sub-optimal.
Other examples of polyene
antifungals:


 Natamycin – 33 Carbons, binds well to ergosterol

 Rimocidin
 Filipin – 35 Carbons, binds to cholesterol (toxic)
 Nystatin
 Candicin
 Hamycin



Classes of antifungals:
 B. Azole antifungals:



Chemistry: An azole is a class of five-membered
nitrogen heterocyclic ring compounds containing at least
one other non-carbon atom of nitrogen, sulfur, or oxygen.



Mode of action: Azole antifungal drugs inhibit the
fungal cytochrome P-450 3-A dependent enzyme 14-alpha
demethylase (lanosterol 14 α-demethylase); the enzyme
necessary to convert lanosterol to ergosterol (an important
component of the fungal plasma membrane). Inhibition of this
critical enzyme in the ergosterol synthesis pathway leads to
the depletion of ergosterol in fungal membrane and
disrupts the structure and many functions of fungal
membrane, thereby leading to inhibition of fungal growth.

Azole antifungals:

Adverse effects: Azole antifungals can also inhibit
many mammalian cytochrome P450-dependent
enzymes involved in hormone synthesis or drug metabolism.
Therefore, azole antifungals are particularly susceptible to
clinically-significant drug interactions with other
medications metabolized through the P450 pathway.



Subclasses of Azole group:

I. Imidazole:


 Imidazole is an organic compound with the formula

C3H4N2.
 The substituted imidazole derivatives are valuable in
treatment of many systemic fungal infections. The
imidzaoles include:


 Clotrimazole
 Ketoconazole
 Econazole
 Bifonazole
 Butoconazole
 Fenticonazole
 Isoconazole
 Oxiconazole
 Sertaconazole
 Sulconazole
 Tioconazole
 Miconazole

Example of imidazole
antifungal:
 Clotrimazole:


 This is a broad spectrum antifungal developed in 1967.

It was one of the first azoles to be developed. Formulations
are now generic in a number of countries.


 It is effective against Candida albicans and

dermatophytes.


 Its action is fungistatic or fungicidal, depending upon

the concentration used. This azole drug is available in a
variety of dosage forms.


 It is marketed as Lotrimin or Lotrimin AF (and Canesten

in the UK).



Subclasses of Azole group:

II. Triazoles:


 Triazole refers to either one of a pair of isomeric

chemical compounds with molecular formula
C2H3N3, having a five-membered ring of two carbon
atoms and three nitrogen atoms.
 The triazoles are newer, less toxic and more effective.
 The triazole antifungal drugs include:


 Fluconazole
 Itraconazole
 Isavuconazole
 Ravuconazole
 Posaconazole
 Voriconazole
 Terconazole

Examples of triazole
antifungals:
 Fluconazole:
 A broad spectrum antifungal, first approved in Europe
in 1988 and then in America in 1990. It was the first single
dose treatment approved for vaginal candidiasis.
Fluconazole is an effective agent in the treatment and
prophylaxis of candidal infection.


 Itraconazole:


A synthetic triazole analogue with a wide spectrum of

antifungal activity. It was first synthesized in 1980, and
approved in Europe in 1987. It was approved by the FDA in
1992 for systemic mycoses, and then for onychomycoses
in 1995, and for use by pulse therapy in 1997. In 2000,
itraconazole was also approved to treat blastomycosis,
histoplasmosis, and aspergellosis in patients intolerant of
amphotericin B.
Classes of antifungals:
 C. Allylamine drugs:


 Allylamines inhibit squalene epoxidase, another

enzyme required for ergosterol synthesis. These include:
 Amorolfine
 Naftifine – marketed as "Naftin" in North America
 Butenafine – marketed as Lotrimin Ultra
 Terbinafine – Marketed as "Lamisil" in North America,
Australia, the UK, Germany and the Netherlands. It is
one of the first antifungals of the allylamine class,
discovered in 1974. It was approved for systemic use
in the UK in 1991, and for topical use in the USA in
1992. Terbinafine is an antifungal effective
against Dermatophytes, Aspergillus sp.,
and Candida and Pityrosporum yeasts.

Classes of antifungals:
 D. Echinocandins:


 Echinocandins inhibit the synthesis of glucan in

the cell wall, probably via the enzyme 1,3-β glucan
synthase. Inhibition of this enzyme results in depletion of
glucan polymers in the fungal cell, resulting in an abnormally
weak cell wall unable to withstand osmotic stress. Examples
include:


 Anidulafungin
 Caspofungin
 Micafungin


 These drugs are administered parenterally only, NOT

orally. They may be used for systemic fungal infections in
immunocompromised patients.

Classes of antifungals:
 E. Antimetabolites antifungals:


 DNA and protein synthesis have historically been difficult

targets for the development of selectively-toxic antifungal
therapy, as fungal and mammalian cells share remarkable
homology in DNA replication and RNA translation. However,
advances in molecular biology and functional genomics are
beginning to highlight important differences between
mammalian and fungal cells that could be exploited for the
development of new antifungal therapies. For the time being,
only one class of agents in clinical use targets DNA/RNA
synthesis.  


 Flucytosine: Flucytosine was originally developed

in the 1950's as a potential antineoplastic agent. Although
ineffective against tumors it was later found to have
antifungal activity.

Flucytosine:
 Flucytosine is transported into susceptible fungal cells by a
specific enzyme cytosine permease and converted in the
cytoplasm by cytosine deaminase to 5-fluorouracil (5-FU)- a
pyrimidine anti-metabolite used as chemotherapy for many types
of colorectal cancer.


 5-FU is phosphorylated and incorporated into RNA where

it causes miscoding and halts protein synthesis. Additionally,
phosphorylated 5-FU is converted to its deoxynucleoside, which
inhibits DNA synthesis by blocking the functions of a key enzyme
in DNA replication- thymidylate synthetase.

Flucytosine can be converted to 5-FU by bacteria residing in the

gastrointestinal tract. Not surprisingly, the most common
adverse effects seen with flucytosine are similar to 5-FU
chemotherapy (diarrhea, nausea and vomiting, bone marrow
suppression) but at reduced intensity.