Antifungal Drugs

Dr. K. Sreedhara R. Pai

Professor
Department of Pharmacology
MCOPS, MAHE,
MANIPAL-576 104
ksr.pai@manipal.edu
 Types of fungal infections - Mycoses
 Superficial mycoses
 Affect the skin, hair and nails
 Subcutaneous mycoses (tropical)
 Affect the muscle and connective tissue immediately
below the skin
 Systemic (invasive) mycoses
 Involve the internal organs
 Primary vs. opportunistic


Allergic mycoses
 Affect lungs or sinuses
 Patients may have chronic asthma, cystic fibrosis or
sinusitis

There is some overlap between these groups

Fungal infections (Mycoses)

 Three groups of fungi

 Multinucleate filamentous forms -
Moulds
 Round/ovoid single cells- Yeasts
 Dimorphic fungi- characteristics of
both
 Moulds
 Trichophyton – Foot infections
 Yeast
 Cryptococcus – Meningitis
 Dimorphic
 Candida – Thrush
Fungal infections (Superficial)

 Dermatomycosis
 Tinea pedis (athlete’s foot)
 Tinea corporis (skin ringworm)

 Tinea cruris (dhobie itch)

 Tinea capitis ((fungal infection on the scalp)

 Tinea unguium

 Candidiasis – skin, mouth, vagina

s
Fungal infections (Systemic)

 Cryptococcosis (meningitis- brain or nervous system)

 Aspergillosis (infection of the lungs)
 Histoplasmosis (infection of the lungs)
 Coccidiomycosis (infection of the lungs)
 Blastomycosis (affects the skin)
 Mucormycosis (a disease of the ear and throat)
 Disseminated sporotrichosis (infection of the skin
which causes abscesses)
Colonial Morphology of Fungi

Cryptococcus Trichophyton Wangiella

neoformans tonsurans dermatitidis
Candida T. menta- Aspergillus
albicans grophytes fumigatus
The Fungal Cell Wall

mannoproteins

1,3
1,6
glucans

Cell 1,3 glucan chitin

membrane synthase
ergosterol
a. Polyene antibiotics: Amphotericin B

 A polyene antibiotic isolated from

Streptomyces nodosus.
 It contains a macrolide ring and an
aminosugar, mycosamine.
a. Polyene antibiotics: Amphotericin B

 Several conjugated double bonds and is highly

lipophilic
 Other side is hydrophilic with many OH groups
 A polar aminosugar and a carboxylic acid group at
one end
Amphotericin B - MOA
 In fungi: ergosterol in membranes: higher
affinity than mammalian cholesterol for AmB
 Ergosterol: Only present in fungal cell
membrane and not in animal cell
 Ergosterol: Polyenes combine with it, get
inserted into the membrane and several
molecules together orient themselves and
form a micropore.
Amphotericin B - MOA
 The hydrophilic side forms the interior of the
pore through which ions, amino acids and other
water soluble substances move out (leakage of
cell contents)
 The micropore is stabilized by membrane
sterols which fill up the spaces b/n the AMB on
the lipophilic side
 Alters cell permeability selectively to K+ and
Mg2+.
 Ergosterol

Ergosterol with
pore

Polyene
 Antifungal Spectrum

 Candida albicans, Histoplasma capsulatum, Cryptococcus

neoformans, Blastomyces dermatitidis, Coccidioides immitis,
Aspergillus, Rhodotorula.

 Resistance is rare and slow to develop

 Pharmacokinetics
 Poorly: crosses cell membranes, absorbed from the gut and
penetration into the eye, CSF, and joint capsules

Kidney > liver > spleen > lung > heart > skeletal muscle > brain > bone > CSF > eye

 For treatment of meningitis, it must be given intrathecally

Given only via IV injection or intrathecally Selective distribution

into deep tissue sites, with slow release of drug
 Classic amphotericin B deoxycholate (Fungizone™)
formulation: serious toxic side effects.
Less toxic preparations:

1) Liposomal amphotericin B
2) Amphotericin B colloidal dispersion
3) Amphotericin B lipid complex

 milder acute reaction

 better tolerated
 lower nephrotoxicity
 minimal anaemia
 targeted delivery-liver & Spleen
Amphotericin B (Cont)
Uses:
 IV: Serious systemic fungal infections
 Topically for oral, vaginal & cutaneous
candidiasis
 Leishmaniasis: Reserve drug for Kala azar

The drug of choice for:

 Cryptococcal meningitis
 Mucormycosis (zygomycosis)
 Invasive fungal infection, not responding to
other therapy
ADVERSE EFFECTS (AMB)
 Acute: Infusion-related
 Chills, fever, dyspnea, nausea, vomiting,
bronchospasm, hypotension, convulsions
 Chronic
 Nephrotoxicity
 azotemia, impaired concentration,
impaired urinary acidification, K & Mg wasting
with hypokalemia and hypomagnesemia
 Normochromic, normocytic anemia
 (↓ erythropoietin)
Drug interactions

 Synergism
 Flucytosine

 Rifampicin Amphotericin B

 Enhanced renal toxicity

 Aminoglycosides
Drug interactions
Nystatin

 Streptomyces noursei
 Polyene antibiotic
 Same mechanism as Amphotericin B
used against candida and dermatophytes
(Epidermophyton, Trichophyton, Microsporum).
 Used only for topical use
 Oral tablets and vaginal tablets
 Eye drops
 HAMYCIN

 S.pimprina developed by Hindustan

Antibiotics at Pimpri similar to Nystatin
but more water soluble

 NATAMYCIN
b. HETEROCYCLIC BENZOFURAN
GRISEOFULVIN
 derived from Penicillium griseofulvum
 is poorly water soluble and requires bile
salts for solubilization in the gut
Griseofulvin
 Fungistatic
 A systemic antifungal used to treat topical
ringworm infections, e.g., onychomycosis,
Tinea capitis, Tinea pedis, etc.
 many Trichophyton spp., Microsporum spp.
and Epidermophyton spp. are susceptible
 Dermatophyte infections
 Oral absorption (better with small particle size)
 Enzyme inducer
Mode of Action - Griseofulvin

 disrupts mitotic spindle during

metaphase by interacting with fungal
microtubules------ (-) fungal mitosis
(metaphase arrest)
 sufficient to inhibit growth of fungi (drug
is static), preventing them from invading.
Griseofulvin
Mode of Action - Griseofulvin
Griseofulvin-Adverse actions
 GI disturbances
 Allergic reactions
 Skin rash
 Headache
 Photosensitivity
 Angioedema
 Peripheral neuritis
Griseofulvin-Adverse effects (CNS)

 Lethargy
 Mental confusion
 Blurring of vision
 Vertigo
 Being an antimiototic--bone marrow
suppression, leucopenia, neutopenia
Griseofulvin-Drug Interactions
 Griseofulvin+ Warfarin/Oral contraceptives---+
Hepatic microsomal enzymes-----?
 Phenobarbitone reduces the oral absorption
and induces the metabolism of Griseofulvin ----
failure of therapy.
 Griseofulvin + alcohol---- intolerance.
 Duration of action--- site of infection, thickness
of the infected keratin and its rate of sheding.
Griseofulvin-Uses
 2. ANTIMETABOLITES:
5-Fluorocytosine (5-FC)
 A flurorinated pyrimidine related to flurouracil
and fluoxyridine
 Given orally/iv
 Reaches good levels in CSF
 With AMP-B in cryptococcal meningitis
 Not alone because of risk of development of
resistance.
2. ANTIMETABOLITES:
5-Flucytosine (5-FC)
 Flucytosine is
converted into 5-
flurouracil, which
inhibits thymidylate
synthetase leading to
inhibition of DNA
synthesis
(antimetabolite action)
 All susceptible fungi are
capable of deaminating
flucytosine to 5-
flurouracil
2. ANTIMETABOLITES:
5-Flucytosine (5-FC)
 2. ANTIMETABOLITES:
5-Flucytosine (5-FC)
 Resistance due to decrease activation of
the drug by the fungal cell.
 Absorbed rapidly from GIT
 t ½ 3-6 hrs.
5-Fluorocytosine (5-FC)
Amphotericin B Vs Flucytosine
Amphotericin B Flucytosine
1. Active Drug 1. Prodrug
2. Broad spectrum 2. Narrow spectrum
3. Antifungal antibiotic 3. Antimetabolite
4. Fungicidal 4. Fungistatic
5. Not absorbed through GIT 5. Well absorbed from the GI
tract tract
6. Highly bound to plasma 6. Poorly bound to plasma
proteins and sterols in tissues proteins
7. Does not cross the BBB 7. Freely crosses the BBB and
8. Metabolized in liver and reaches high concentratin in
excreted slowly in urine and CSF
bile 8. Excreted in urine mainly in
9. Highly efficacious and highly unchanged form
toxic drug 9. Less effective and less toxic
10. Given intravenously, than AMB
intrathecally and topically 10. Given orally
3. AZOLES
 Better CSF penetrability
 High volume of
distribution
 Dermatophytes,
candida and other deep
mycoses
 Triazoles are greater
efficacy/lesser side
effect and drug
interaction
3. AZOLES
 In fungi, the cytochrome
P450-enzyme lanosterol
14-demethylase is
responsible for the
conversion of lanosterol
to ergosterol
 Azoles bind to lanosterol
14-demethylase
inhibiting the production
of ergosterol
 Mechanism of Action:

Acetyl CoA Squalene

Squalene-2,3 oxide
Squalene-2,3
epoxidase
Lanosterol

14- α demethylase Azoles

Ergosterol
14- α demethylase
3. AZOLES
Effect of azoles on C. albicans

Before exposure After exposure

Ketoconazole

 Spectrum: yeasts and moulds - poor absorption

limits its role for severe infections, generally
used in mucosal infections only
 Pharmacokinetics
 Variable oral absorption, dependent on pH (often
given with cola or fruit juice)
 T1/2 7-10 hours
 Protein binding > 99%
 Hepatic, bile and kidney elimination
 H2 blockers, antacids--- decrease absorption
Hepatoxicity (2-8%)- increase in
transaminases, hepatitis
Dose related inhibition of CYP
P450- responsible for
testosterone synthesis
Dose-related inhibition of CYP
P450 -responsible for adrenal
cortisol synthesis
Ketoconazole –Drug interactions

 Hepatic enzyme inhibitors

 Ketoconazole + Sulfonylureas(Hypoglycaemia)
 Ketoconazole + Phenytoin (Phenytoin toxicity)
 Ketoconazole + Warfarin (Bleeding)
 Ketoconazole + Cyclosporine (Potentiates
nephrotoxicity)

Increase plasma levels

4. ALLYLAMINE: Terbinafine
 It causes non-
competitive inhibition
of squalene epoxide
enzyme, which is
involved in the
synthesis of
ergosterol by fungi

Squalene-2-3- epoxidase
 Mechanism of Action:
Acetyl CoA Squalene

Squalene-2,3 oxide
Squalene-2,3
epoxidase
Allylamines

Lanosterol
14-α demethylase

Ergosterol
4. ALLYLAMINE: Terbinafine

 A highly lipophilic, keratinophilic

 Effective orally against dermatophytes
and candida
 Useful in fungal infections of nails (6-12
weeks)
 Adverse effects:- gastric upset, rashes
and taste disturbances
 Rarely hepatotoxicity
5. OTHER TOPICAL AGENTS:

 White field’s ointment = Benzoic acid

(6%) + Salicylic acid (3%)
 Tolnaftate: Tinea corporis, cruris
 Ciclopirox: Dermatophytes, candida
Malassezia furfur
 Selenium Sulfide: Malassezia furfur
 Haloprogin: Dermatophytes, candida
4 3
1a

1b

2
 Table : Properties of the important antifungal agents.

Target Chemical group Examples Mode of action

Cell membrane
Synthesis Azoles Miconazole, Inhibition of ergosterol
Ketonazole,
Fluconazole

  Function Polyenes Nystatin Bind to sterols in cell

Amphotericin B membrane ,causing
leakage of cellular
components and cell
death.
Table : Properties of the important antifungal agents
(continued).

Target Chemical group Examples Mode of action

Nucleic acid
Synthesis Pyrimidines Flucytosine Deaminated in cell to
(5-FC) 5- fluorocil which
ultimately inhibits
DNA synthesis.

  Function Benzofurans Griseofulvin Appears to inhibit

nucleic acid synthesis,
microtubule assembly,
chitin synthesis.
New Drugs

The Future is Now (almost):

Newer Azoles (Triazoles)
and Echinocandins
(Caspofungin) instead of or in
combination with Amphotericin
B.
The Fungal Cell Wall

mannoproteins

1,3
1,6
glucans

Cell 1,3 glucan chitin

membrane synthase
ergosterol
New Drugs
New Drugs
New Drugs
 What are the targets for antifungal
therapy?
Cell membrane
Fungi use principally ergosterol
instead of cholesterol

DNA Synthesis
Some compounds may be
selectively activated by fungi,
arresting DNA synthesis.

Cell Wall
Unlike mammalian cells, fungi
have a cell wall

Atlas of fungal Infections, Richard Diamond Ed. 1999

Introduction to Medical Mycology. Merck and Co. 2001
Cell Membrane Active Antifungals

Cell membrane
• Polyene antibiotics
- Amphotericin B, lipid
formulations
- Nystatin (topical)

• Azole antifungals
- Ketoconazole
- Itraconazole
- Fluconazole
- Voriconazole
- Miconazole, clotrimazole (and
other topicals)
THANK YOU