Name : Sahroosh Hafeez
Roll no : 37 / 3 proff
rd
Subject : Pharmacology
Assignment topic : Antifungal drugs
Submitted to : Sir Izhar ullah
Department : Pharmacy
Date of submission : 25-09-2020
Content
Introduction to fungi
Classification of fungi
Antifungal drug classification
Mechanism of action and pharmacokinetics of antifungals
ANTIFUNGAL DRUGS
INTRODUCTION
■ Infectious diseases caused by fungi are called mycoses,
and they are often chronic in nature. Mycotic infections
may be superficial and involve only the skin (cutaneous
mycoses extending into the epidermis), while others may
be penetrate the skin, causing subcutaneous or systemic
infections.
■ In humans, fungal infections occur when an invading
fungus takes over an area of the body and is too much for
the immune system to handle.
■ Fungi can live in air, soil, water and plants. Some fungi live
naturally in human body .
CLASSIFICATION
■ Fungi may be classified as yeasts and Moulds.
■ Yeast : Blastomyces, candida, histoplasma, coccidiodes,
cryptococcus.
■ Moulds : Aspergillus species, Dermatophytes
■ Clinically classified as :
■ Superficial mycoses : Affect skin, hair and nails.
■ Subcutaneous mycoses ( tropical) : Affect the muscles and
connective tissues immediately below the skin.
■ Systemic (invasive) mycoses: Involve the internal organs .
■ Allergic mycoses : Affect lungs or sinuses.
■ Patients may have chronic asthma , cystic fibrosis, sinusitis.
Drugs for Subcutaneous and
systemic mycoses
■ Amphotericin B
■ Anidulafungin
■ Ketoconazole
■ Fluconazole
■ Itraconazole
■ Posaconazole
■ Flucytosine
■ Micafungin
Drugs for cutaneous mycoses
■ Butenafine
■ Butoconazole
■ Econazole
■ Nystatin
■ Terbinafine
■ Terconazole
■ Tolnaftate
■ Tioconazole
Classes of antifungal drugs
Azole antifungals
■ Azole antifungals are a group of medicines that contain an azole ring and inhibit the
growth of a wide range of fungi. They are classified into two groups: those with two
nitrogens in the azole ring (the imidazoles; examples include clotrimazole,
econazole, ketoconazole, miconazole, and tioconazole) and those with three
nitrogens in the azole ring (the triazoles; examples include fluconazole, itraconazole,
posaconazole, and voriconazole).
■ Azole antifungal agents can be used to treat fungal infections of the body and skin,
including athlete's foot, onychomycosis (fungal nail infections), ringworm, and
vaginal candidiasis.
Mechanism of action of azoles
The synthetic class of azole antimycotics constitutes the largest
group of antifungal agents currently in clinical use. Widespread
use of azoles has led to the rapid development of multiple drug
resistance, which poses a major hurdle in antifungal therapy. The
generally accepted mode of action of azoles is the inhibition of
14α-lanosterol demethylase, a key enzyme in ergosterol
biosynthesis, resulting in depletion of ergosterol and
accumulation of toxic 14α-methylated sterols in membranes of
susceptible yeast species. Depletion of ergosterol damages the
cell membrane resulting in cell death.
Drugs included in azole antifungals
1: Fluconazole :
It was the first member of the triazole class of antifungal agents. It is
the least active of all triazoles, with most of its spectrum limited to
yeasts and some dimorphic fungi. It is highly active against Cryptococcus
neoformans and certain species of Candida. It is used for prophylaxis
against invasive fungal infections in recipients of bone marrow
transplants.
Fluconazole is available in oral or IV dosage formulations.
Well absorbed after oral administration and distributes widely in tissues.
The majority of drug is excreted unchanged via the urine and dose
adjustment is needed in patients with renal dysfunction.
■ 2: Itraconazole :
■ It has broad antifungal spectrum compared to Fluconazole. It is drug of choice for treatment of
blastomycosis, histoplasmosis.
■ Oral solutions of itraconazole are used to treat Yeast infections of mouth, throat or of the esophagus .
■ Oral solutions should be taken empty stomach as food decreases absorption where as capsules
should be taken with food or beverage to increase absorption.
■ Drug distributes well in bones and adipose tissues. Extensively metabolised by liver.
■
3: Posaconazole :
■ A synthetic triazole structurally related to itraconazole. Available in oral tablets, oral suspensions and
IV formulations. Used in treatment of invasive fungal infections caused by Scedosporium and
Zygomycetes. Posaconazole has low bioavailability and should be given with food.
■ Drugs that affect the gastric pH may decrease the absorption of oral posaconazole. Contraindicated
with ergot alkaloids, citalopram, resperidone etc.
■ Common adverse effect of this class includes, skin rash, nausea, vomiting, headaches, diarrhea and
some times hepatotoxicity.
Polyene antifungal drug
Amphotericin B :
■ Naturally occurring polyene antifungal produced by Streptomyces
nodosus.
■ Mechanism of action : Amphotericin B binds to ergosterol, a
component of fungal cell membranes, forming pores that cause
rapid leakage of mono valent ions ( K, Na, Cl) and subsequent
fungal cell death. This is Amphotericin B primary effect as
antifungal agent.
■ Antifungal spectrum : It may be fungicidal or fungistatic,
depending on the organism and concentration of the drug.
Effective against wide range of fungi, including Candida albicans,
Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides
immitis, Aspergillus species.
■ Pharmacokinetics : Administered by slow, intravenous infusion.
Amphotericin B is insoluble in water so it should be coformulated
with either sodium deoxycholate or artificial lipids to form
liposomes. Not absorbed orally, half life is 15 days. Metabolised in
liver and excreted in urine and bile.
Adverse effects of
Amphotericin B includes :
Fever
chills
Hypotension
Anemia
Renal impairment
Echinocandins
■ Echinocandins are a class of antifungal drugs that target the
fungal cell wall. They are lipopeptide molecules that
noncompetitively inhibit (1,3) beta-d-glucan synthase enzyme. This
enzyme forms glucan, a major component of the fungal cell wall
therefore by inhibiting its synthesis fungal cell walls are damaged.
■ 1: Caspofungin : Caspofungin is an antimycotic echinocandin
lipopeptide. This agent is active against Aspergillus and Candida
species. Not active orally, given IV. Highly bound to serum proteins.
About 97% drug is bound to albumin. Well distributed in tissues
not in CSF .Primarily metabolised by liver and excreted in urine.
Dose adjustment is required in patients with hepatic dysfunction.
■ 2:Mucifungin and Anidulafungin :
■ Is an echinocandin antifungal drug used to treat and prevent invasive fungal
infections including candidemia, abscesses and esophageal cacandidiasis.
■ The metabolism of micafungin occurs hepatically as the drug molecule is a
substrate of CYP3A4, a liver enzym.
The metabolism of micafungin occurs hepatically as the drug molecule is a
substrate of CYP3A4, a liver enzyme. Anidulafungin significantly differs from
other antifungals in that it undergoes chemical degradation to inactive forms at
body pH and temperature. Because it does not rely on enzymatic degradation or
hepatic or renal excretion, the drug is safe to use in patients with any degree of
hepatic or renal impairment.
Drugs for cutaneous mycotic
infections
■ Mould like fungi that cause cutaneous infections are called
Dermatophytes.
■ These infections are classified by the affected site e.g tinea pedis (
which refers to an infection in feet). The three different fungi that
cause the majority of cutaneous infections are Trichophyton,
Microsporum and Epidermophyton.
■ Squalene Epoxidase Inhibitors
■ The allylamine terbinafine acts by inhibiting squalene epoxidase, an
enzyme in the pathway leading to the synthesis of ergosterol in the
fungal cell membrane.
■ Terbinafine is available as both a topical preparation and an oral
tablet. Topical terbinafine is at least as effective as other topical
antifungal agents. Topical terbinafine is used to treat tinea pedis and
tinea cruris. Duration of treatment is 1 week. Oral terbinafine is drug
of choice for treating Dermatophyte onychomycosis ( fungal infection
of nails). It is better tolerated, requires shorter duration of therapy.
Pharmacokinetics of terbinafine : Following oral administration terbinafine
is well absorbed 70%). In plasma, terbinafine is > 99% bound to plasma
proteins and there are no specific binding sites.
Terbinafine is distributed to the sebum and skin. A terminal half-life of
200-400 hours may represent the slow elimination of terbinafine from
tissues such as skin and adipose. Approximately 70% of the administered
dose is eliminated in the urine.
2: Griseofulvin :
Griseofulvin is fungistatic, however the exact mechanism by which it
inhibits the growth of dermatophytes is not clear. It is thought to inhibit
fungal cell mitosis and nuclear acid synthesis. It also binds to and
interferes with the function of spindle and cytoplasmic microtubules by
binding to alpha and beta tubulin. It binds to keratin in human cells, then
once it reaches the fungal site of action, it binds to fungal microtubes thus
altering the fungal process of mitosis.
Absorption
Poorly absorbed from GI ranging from 25 to 70% of an oral dose.
Absorption is significantly enhanced by administration with or after a fatty
meal.
■ 3: Ciclopirox :
■ Ciclopirox is a synthetic antifungal agent for topical dermatologic treatment of
superficial mycoses. It is most useful against Tinea versicolor.
■ Ciclopirox is indicated for the treatment of tinea pedis and tinea corporis due
to Trichophyton rubrum, Trichophyton mentagrophytes and Epidermophyton
floccosum, as well as seborrheic dermatitis. It is not to be used in the eyes or
vagina, and nursing women should consult their doctors before use.
■ In addition to other formulations, ciclopirox is used in lacquers for topical
treatment of onychomycosis (fungal infections of the nails).
REFERENCE
https://en.m.wikipedia.org/wiki/Ciclopirox
https://www.slideshare.net/mobile/nasertadvi/antifungal-drugs-14709424
https://www.slideshare.net/mobile/rahulbhati5095/antifungal-drugs-
196036223
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC352226/#:~:text=The%20phar
macokinetics%20of%20amphotericin%20B,term%20therapy%20for%20dissemi
nated%20histoplasmosis.&text=The%20elimination%20phase%20half%2Dlife,B
%20from%20a%20peripheral%20compartment.
Pharmacology lippincott sixth edition
THANK YOU!
