This document provides an overview of antifungal drugs. It begins with an introduction to fungi and fungal infections. It then covers the classification, mechanisms of action, pharmacokinetics, therapeutic uses, adverse effects, and drug interactions of various antifungal drug classes including azoles, polyenes, echinocandins, allylamines, and antimetabolites. It also discusses the screening of antifungal drugs and factors contributing to the spread of fungal diseases.

1. ANTIFUNGAL DRUGS
PRESENTED BY:
PARTH KHANDHERIA
M.PHARM SEM-1
DEPARTMENT OF PHARMACOLOGY
L.M. COLLEGE OF PHARMACY
AHMEDABAD.
1

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CONTENTS
 Introduction to fungi
 Fungal infection
 Antifungal drugs
-Classification
-M/A
-Pharmacokinetics
-Therapeutic use
-Adverse effects
-Drug Interaction
 Antifungal screening

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 Fungi are Eukaryotic cells. They possess
mitochondria, nuclei & cell membranes.
 They have rigid cell walls containing chitin as
well as polysaccharides, and a cell membrane
composed of ergosterol.
 While bacterial cells are prokaryotic. So,
antibacterial agents can exhibit Selective
toxicity.
 In contrast, similarity between fungal &
mammalian cells makes Antifungal drugs non-
selective.
 Thus, Antifungal drugs are in general more
toxic than antibacterial agents.

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Fungi can be divided into four classes
1. Yeasts
2. Yeast-like fungi
3. Dimorphic fungi
4. Moulds

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Type Characteristics Causitive Fungi Cause
Yeasts
reproduce by
budding
Cryptococcus
neoformans
meningitis
Yeast-like fungi
which partly grows
like yeast and
partly as filaments
called hyphae
Candida albicans
oral/ vaginal
thrush and
systemic
candidiasis.
Dimorphic fungi
which can grow as
filaments or as
yeast
Histoplasma
capsulatum
systemic
infections
Moulds
(Dermatophytes)
filamentous fungi
which reproduce
by forming spores
trichophyton sp
Microsporum sp
Epidermophyton sp
skin or nail
infections called
tines or
`ringworm'

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Factors aiding the spread of fungal disease
 Action of immunosuppressant drugs
 Acquired immunodeficiency syndrome (AIDS)
 Broad-spectrum antibiotics
 Chemotherapy agents

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OVERVIEW OF FUNGAL INFECTION
Fungi that can cause infections live
-In association with humans commensally,
-In Environment
 Fungal infections are termed as MYCOSES
 In the UK, the commonest fungal disease is
systemic Candidiasis

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Clinical classification of Mycoses:
I. Cutaneous mycoses- These diseases are restricted to the keratinized
layers of the skin, hair, and nails.
II.Subcutaneous mycoses-It involve the dermis, subcutaneous tissues,
muscle.These infections are difficult to treat and may require surgical
interventions such as debridement.
III Systemic mycoses due to opportunistic pathogens-
Systemic mycoses due to opportunistic pathogens are infections of
patients with immune deficiencies who would otherwise not be infected.
IV Systemic mycoses due to primary pathogens- originate
primarily in the lungs and may spread to many organ systems

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CUTANEOUS SUBCUTANEOUS OPPORTUNISTIC SYSTEMIC
Superficial
mycoses
Tinea
Piedra
Candidiasis
Chromoblastomycosis
Sporotrichosis
Mycetoma
(eumycotic)
Aspergillosis
Candidiasis
Cryptococcosis
Geotrichosis
Aspergillosis
Blastomycosis
Candidiasis
Dermatophytosis
Zygomycosis
Fusariosis
Trichosporonosis
Histoplasmosis
Cryptococcosis
Geotrichosis
Zygomycosis
Fusariosis
Trichosporonosis

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Classification of antifungal drugs based
on M/A
 Inhibition of fungal cell wall synthesis
(Echinocandins): Caspofungin, Micafungin & Anidulafungin
Bind to fungal cell membrane ergosterol and
increase membrane permeability:
(Polyene Group) Amphotericin-B.Nystatin
 Inhibition of ergosterol+lanosterol synthesis
(Allylamine Group) Terbinafine
Inhibition of ergosterol synthesis:(Triazole Group)
Inhibition of nucleic acid synthesis:5-Flucytosine
Disruption of mitotic spindle and inhibition
of fungal mitosis :Griseofulvin
Miscellaneous: Topical Agents Ciclopirox, Tolnaftate,
Naftifine, Butenafine and Topical Azoles

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Targets for antifungal therapy
11
Cell membrane
Polyenes , Azoles , Allylamines
Morpholines
DNA synthesis
E.g-Flucytosin
Griseofulvin
Cell wall
E.g-Echinocandins

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M/A of Antifungal drugs

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Chemical Classification of antifungal
drugs
1. Antibiotics
a)Polyenes: Amphotericin B(AMB),Nystatin, Hamycin,
Natamycin (Pimaricin)
b) Heterocyclic benzofuran: Griseofulvin
2. Antimetabolite: Flucytosine(5-FC)
3. Azoles:
a) Imidazoles (topical):Econazole,
Miconazole,Clotrimazole,Oxiconazole,
Ketonazole(Systemic)
b)Triazoles (systemic):Fluconazole, Itraconazole,
Voriconazole
4. Allylamine: Terbinafine
5. Other topical agent:Tolnaftate, Undecylenic acid,
Benzoic acid, Quiniodochlor, Ciclopirox olamine, Butenafine, Sod.
thiosulfate.

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Classification of antifungal drugs based
on treatment
 Drugs used to treat systemic fungal infection
1.Triazoles
2.Amphotericin-B
3.Ketoconazole(Imidazole)
4.Echinocandis
5.Flucytosine(5-FC)
 Drugs given systemically for treating Superficial
infections
1.Griseofulvin
2.Terbinafine
 Topically used Antifungal drugs
-Nystatin
-Clotrimazole,Miconazole,Butaconazole,Sertaconazole,Oxiconazole
-Ciclopirox
-Benzoic acid & Sodium Thiosulphate

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Echinocandins
 Three echinocandins are in current use:
caspofungin, micafungin and anidulafungin
 M/A- They cause fungal cell wall
lysis by inhibiting the synthesis of 1,3-β-glucan, an
essential component of the cell wall of susceptible
fungi
 Therapeutic Use-
-Treatment of invasive Aspergillus infection
 Pharmacokinetics-
Caspofungin is orally not absorbed and hence
infused slowly

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 Adverse Effects:
-Thrombophlebitis
-Abnormal liver function
-sensation of warmth, flushing,headache & rashes
 Drug Interactions:
- A combination of caspofungin with
cyclosporine should be avoided because of the risk of
hepatotoxicity.
- Enzyme inducers increase the clearance of
caspofungin while caspofungin increases the clearance of
tacrolimus.

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1. Antibiotics
A)Amphotericin-B (Polyene Group)
 Chemistry & M/A
- The polyenes possess a macrocyclic ring,
-one side of which has several conjugated double bonds and is
highly lipophilic,
-while the other side is hydrophilic with many OH groups.
-The polyenes have high affinity for ergosterol present in
fungal cell membrane: combine with it, get inserted into the
membrane.
-alters the permeability of the fungal cell membrane by
forming pores (channels) through which K+
. Na+
. H+
and other
macromolecules leak out, leading to cell death

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 Resistance:
Resistance to amphotericin-B is associated with a
replacement of ergosterol by other sterols in fungal plasma
membrane.
 Pharmacokinetics:
- It is poorly absorbed from GIT
-Oral administration is thus effective only against fungal
infections of intestine
-Not for treatment of systemic fungal infections
- Insoluble in water
- Therefore prepared as a colloidal suspension with sodium
desoxycholate for I.V. infusion.

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 Antifungal spectrum & Therapeutic uses:
-Yeast group and some mould group of fungal infections
-To treat superficial candidiasis
-Treatment of invasive aspergillosis
-Mucormycosis (an opportunistic fungal infection in lungs)
-Rapidly progressive blastomycosis , Histoplasmosis.
- Non-AIDS cryptococcal meningitis (used with fluconazole or
with flucytosine)
 Adverse effects :
- Acute toxicity- chills, fever, vomiting and modest
hypotension
- Long term toxicity- Hypochromic normocytic anaemia,
nephrotoxicity
- Intrathecal administration may lead to seizures
- Hepatic impairment with jaundice

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Preparations
21
Trade
name
Shape of
particles
Type of lipid
formulation
Generic Name
AmBisome Spheres
Has complex
liposomal mixture
Liposomal
Amphotericin B
(L-AmB)
Amphotec Disks
Has cholesteryl
sulfate
Amphotericin B
Colloidal Dispersion
(ABCD)
Abelcet Ribbons
Has two
phospholipids
Amphotericin B
Lipid Complex
(ABLC)

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Nystatin (fungicidin)
 Similar to amphotericin B but more toxic
than amphotericin-b
• Used only for superficial candidiasis of
Skin, Mouth, Vagina, Intestine
 Available as tablets and ointments (1 to 5
lacs U) – also vaginal tablets
22

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Other polyenes
23
Hamycin:
 Water soluble
 Absorption from GIT not reliable
 Not used for systemic fungal infections
 Used topically for Aspergillus, Candida,
Monilial, Trichomonas vaginalis infections
Natamycin:
 Broad spectrum
 Used topically for – Keratitis, Monilial
infections, Trichomonas vaginalis

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b)Heterocyclic benzofuran
Griseofulvin
 Extracted from Penicillium griseofulvum
 Active against most dermatophytes,including
Epidermophyton , Trichophyton , Microsporum
but not against Candida & other fungi causing
deep mycosis
 M/A-
Disruption of the mitotic spindle & eventually
arrests fungal mitosis at metaphase.
 It also binds io newly synthesised keratin
making it resistant to fungal invasion.

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 Pharmacokinetics
-Ineffective topically
-Administered orally but it is variably absorbed from GIT
-Micronisation of the drug particles and ingestion with a
fatty meal improves its bioavailability.
 Therapeutic Uses
- in the systemic treatment of dermatophytosis
-Terbinafin & azoles are more eficacious
 Adverse effects & Interactions:
-Headache, nausea, vomiting. photosensitivity and
peripheral neuritis
-As an inducer of cytochrome P-450 it can decrease the
effectiveness of warfarin and oral contraceptives.
-It causes disulfiram-like reaction with ethanol

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2. Antimetabolite:
Flucytosine(5-FC)
 5-FC is a fluorinated analogue of cytosine and is
structurally related to the antineoplastic agent 5
fluorouracil.
 Mechanism of Action:
- Flucytosine is transported into the fungal cells with
the help of cytosine permease enzyme
- Where it is converted to 5- fluorouracil by the
fungal cytosine deaminase enzyme
- 5-FC is then further metabolised to 5-
fluorodeoxyuridine monophosphate
-Which is competitive inhibitor of thymidylate
synthetase
-blocks the formation of thymidine monophosphate
from Deoxyuridine monophosphate
- inhibits the fungal DNA synthesis

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Pharmacokinetics Therapeutic Uses: Adverse Effects:
-orally well absorbed
-plasma half-life of 3-6
hrs
-Levels rise rapidly in
renal impairment
leading to toxicity.
-used as a part of
combination therapy for
candidiasis & cryptococcal
meningitis(with
amphotericin-B) or for
chromoblastomycosis (with
itraconazole).
-in monotherapy,
resistance and therapeutic
failure are common
-Bone marrow depression
leading to leukopenia &
thrombocytopenia
-An elevation of hepatic
enzymes and reversible
hepatomegaly
-Nausea, vomiting,
epigastric distress and
skin rash

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3. Azoles:
 Imidazoles:
- Topical: Clotrimazole, econazole,miconazole,
tioconazole, sulconazole
- Systemic: Ketoconazole
 Triazoles:
- Fluconazole, itraconazole and voriconazole

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 Fungistatic or fungicidal properties depending upon
drug concentration
 Azoles can be divided into two groups: the imidazole
group (2 nitrogen in the azole ring) & triazole group(3
nitrogens in the azole ring).
 M/A- -bind to the fungal
cytochrome P-450 dependent 14-α demethylase
enzyme
-that is responsible for the demethylation of
lanosterol to ergosterol synthesis,
-The ergosterol synthesis is therefore hindered.
which results in damaged leaky fungal cell membrane.

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Acetyl CoA
Squalene
Lanosterol
(ergosterol)
Allylamine
drugs
Azoles
Squalene-2,3 oxide
Squalene
epoxidase
14-α-demethylase
31
LanosterolLanosterol
rol
Squalene
Squalene epoxide

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Ketoconazole
 Pharmacokinetics:
-Acidic pH required for the absorption of Ketoconazole.
- bioavailability is reduced in achlorhydria. Such patients should
be given acidifying agents (like orange juice) before
ketoconazole administration.
-Plasma half-life is 8-10hours
- penetration into CSF is negligible; hence it is ineffective in
the treatment of fungal meningitis
 Therapeutic Uses:
-Histoplasmosis
- coccidioidomycosis
- non -CNS blastomycosis

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 Adverse Effects:
-Nausea, vomiting and anorexia occur commonly but these
adverse effects can be minimized by taking ketoconazole
with food
-Allergic dermatitis
-Reversible elevations in liver enzymes
- inhibits the synthesis of testosterone and estradiol which may
lead to gynaecomastia and irregular menstrual cycles
 Drug Interactions:
-Ketoconazole inhibit mammalian cytochrome P450 (CYP3A4)
more than fungal cytochrome P450.
1. Increases the serum concentrations of cisapride,
terfenadine, astemizole and quinidine, warfarin,
cyclosporine, tacrolimus,
HMG-CoA reductase inhibitors
2. Rifampicin and phenytoin accelerate ketoconazole
metabolism and reduce its efficacy
-H2 receptor blockers, proton pump inhibitors and antacids
decrease ketoconazole absorption by decreasing gastric acidity

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Triazole Drug Fluconazole Itraconazole
Pharmacokinetic
-Does not need acidic pH for
its absorption from GIT
-The half-life is 27-37 hrs
- Dosage reductions are
required in the presence of
renal insufficiency.
-Administeretion-oral ,
parenteral
- requires low gastric pH for its
absorption
-highly protein bound (99%)
- Oral bioavailability is variable
- metabolised in liver & excreted in
bile
-Half-life-30-35 hrs.
- more specific for fungal
cytochrome P450
Therapeutic uses
-Vulvovaginal candidiasis
-Oropharyngeal candidiasis
-Mucocutaneous candidiasis
-Systemic candidiasis
-Fungal meningitis
-Histoplasmosis
-non-meningeal blastomycosis
-cutaneous and extracutaneous
sporotrichosis
- oropharyngeal & cutaneous
candidlase
-Ringworm,Fungal nail infection
Adverse Efeect
-nausea,vomiting,diarrhoea,
headache
-Increase in serum transaminase
-HyPokalaemia. hypertension &
oedema
-Transaminase enzyme level may
rise
Drug interaction
least effect on mammalian Same as Ketoconazole

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Voriconazole
Pharmacokinetics:
2nd
second generation triazole that has some distinguishing
features
-High oral bioavailability (96%)
- Low protein binding (55%)
-Good CSF penetration
-Plasma half-life is only 6 hrs
 Therapeutic Use:
-Invasive aspergiliosis
-Esophageal candidiasis

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 Adverse effect:
- visual changes such as blurred vision, altered colour
perception and photophobia.
-Nausea
-Elevated Hepatic Enzyme
 Drug Interactions:
- Rifampicin.ritabutin.phenytoin end ritonavir accelerate
voriconazole metabolism and reduce its efficacy.
- Metabolism of Tacrolimus, cyclosporine and warfarin is
retarded by Voriconazole

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4. Allylamine:
Terbinafine(fungicidal)
 M/A
-squalene epoxidase converts squalene to lanosterol
-Terbinafine inhibits fungal enzyme squalene epoxidase
- Leads to reduction in lanosterol production that
decreases ergosterol production which affects fungal
cell membrane integrity and function.
 Pharmacokinetics:
- highly lipophilic and keratophilic resulting in high
concentrations in stratum corneum,sebum, hair and
nails.
-A prolonged terminal half-life of about 15 days
because of the very slow release of the drug from skin,
nails and adipose tissue.

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 Therapeutic Uses:
-It can be used systemically as well as topically.
- Orally it is specifically used to treat onychomycosis
- Unlabeled use includes topical treatment of cutaneous
candidiasis
 Adverse Effects:
-Headache
- GIT upset
- Liver enzymes elevation
-Hepatobiliary dysfunction (but rarely)

41. Antifungal screening
 The purpose of antifungal screening is not to
define the therapeutic properties of an individual
compound, but rather to indicate which of a large
number of compounds or samples are worthy of
further study.
41

42. Types of Screening
A. General in vitro screens
Agar dilution, Agar diffusion, Broth dilution
B. Selective screening
Cell wall synthesis in Candida albicans,
Protoplast regeneration in Neurospora crassa,
Morphology screens, Ergosterol biosynthesis
C. In vivo screening
Mouse Protection test, Multiple Infection model
42

43. References
 Pharmacology by Rang H.P, Dale M.M, 6th
edition,2007
 Tripathi K.D, Essentials of Medical
Pharmacology, 6th Edition, Jaypee brother
publisher, New Delhi,
 HL Sharma, KK Sharma, Principal of
Pharmacology, 1st edition,2010

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