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Pharmacology-4 PHL 425
Sixth Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Antifungal Agents
Antifungal Agents, Overview
 Fungi are plant-like organisms but, unlike plants, they cannot turn sunlight
into food (photosynthesis)
 Fungi may exist in colonies of single cells (yeast) or filamentous
multicellular aggregates (molds or hyphae)
 Many types of fungi live harmlessly in the soil, on food or on our skin
 However, some types of fungi can thrive and multiply on the surface of the
body, to cause infection of the skin, nails, mouth or vagina
 Human fungal infections have increased dramatically in incidence and
severity in recent years, due mainly to:
 Cancer treatment and the HIV epidemic (why? Is immune system
involved?)
 Critical care accompanied by increases in the use of broad-spectrum
antimicrobials
 Immunosuppressive therapy (organ transplantation)
Antifungal Agents,
Overview
 Fungal infections (Mycosis): can be divided into:
1. Superficial infections (mucocutaneous); affecting skin, nails, scalp or
mucous membranes)
2. Systemic infections (affecting deeper tissues and organs)
 Fungal infections of the skin, nails, vagina and mouth are quite common,
but are rarely serious and do not usually spread deeper into the body (with
a normal immune system)
 It is rare for fungi to affect internal organs. These internal fungal infections
can be serious and, sometimes, life-threatening
 Systemic mycoses due to primary pathogens originate primarily in the lungs
and may spread to many organ systems
 Organisms that cause systemic mycoses are virulent “dimorphic”
 Infection occurs in patients with immune deficiencies
Superficial fungal infections
 Fungi that cause superficial skin infection are called
dermatophytes ( e.g.ring worm);
 Tinea infections (scalp, body, foot)
 Candidiasis (thrush)
Tinea Versicolor
Tinea corporis
Onychomycosis
Superficial fungal infection
• Fungi that cause superficial skin infection are called
dermatophytes ( e.g.ring worm);
• Tinea infections (scalp, body, foot)
• Candidiasis (thrush)
Tinea pedis and onychomycosis
Tinea Capitis
Antifungal drugs
 Oral or parenteral drugs
 For systemic infections
 For nail or scalp or massive skin infection
 For refractory or intractable cases
 Topical and oral for mucocutaneous
infections
Antifungal preparations
 They are used to treat various fungal infections in the form
of creams, shampoos, pessaries (topical) and medicines
to take by mouth, and injections for systemic effects
 The length of treatment depends on the type of the
offending fungi and severity of infection
 Some courses of treatment can be as short as a few days
(vaginal thrush), other can be for ten weeks
(ringworm infection of the scalp) or months for
onychomycosis
 Topical antifungal creams and shampoos: usually cause
no side effects and are easy to use
Systemic Antifungal Drugs
1- Amphotericin B
2- Flucytosine
3- Azoles
1- Amphotericin B
 Amphotericin B is a polyene antifungal
antibiotic produced by Streptomyces
nodosus
 It is poorly absorbed from the GIT
 Oral amphotericin B is thus effective
only on fungi within the lumen of the
GIT and cannot be used for treatment
of systemic disease
 For systemic infections, it can be given by slow i.v.
injection
 Intrathecal for fungal meningitis
 It can also be applied topically
Amphotericin B
 Mechanism of Action of Amphotericin B
Amphotericin B is selective in its fungicidal effect because it exploits
the difference in lipid composition of fungal and mammalian cell
membranes
Amphotericin B binds to ergosterol (a fungal cell membrane sterol)
and alters the permeability of the cell by forming amphotericin Bassociated pores in the cell membrane …..how?
 Amphotericin B combines avidly with ergosterol along the double bondrich side of its structure and associates with water molecules along the
hydroxyl-rich side
 This amphipathic characteristic facilitates pore formation by multiple
amphotericin molecules, with the lipophilic portions around the outside of
the pore and the hydrophilic regions lining the inside
The pore allows the leakage of intracellular ions and
macromolecules, eventually leading to cell death
Mechanism of action of
Amphotericin
Fungal Cytoplasmic membrane
Fungal 
cell death
D
Ergosterol
K+,Na+
Amphotericin binds to ergosterol and forms pores in the membrane
Amphotericin B
 Antifungal Activity
Despite its high toxicity, amphotericin B remains standard therapy for
most life-threatening systemic mycoses
 It is used intravenously in the treatment of many systemic mycoses
Amphotericin B remains the antifungal agent with the broadest spectrum
of action
It has activity against the clinically significant yeasts, including Candida
albicans, but ineffective against dermatophytes
 Adverse Effects: Toxicity of amphotericin B can be divided into two broad
categories: immediate reactions, related to the infusion of the drug, and slow
reactions
Infusion-Related Toxicity: These reactions consist of fever, chills, muscle
spasms, vomiting, headache and hypotension
They can be ameliorated by slowing the infusion rate or decreasing
the daily dose
Amphotericin B
Slower Toxicity:
Renal damage is the most significant toxic reaction
A varying degree of anemia due to reduced
erythropoietin production by damaged renal tubular
cells is occasionally seen
Abnormalities in liver function tests
Neurotoxicity, seizures: intrathecal administration
Flucytosine (5-FC)
 A synthetic pyrimidine antimetabolite
 It is a prodrug that is converted by fungi to 5 fluorouracil; the latter inhibits
thymidine synthesis
 5-FC needs certain enzymes in the fungi to enter the cell and be transformed to
5- FU
Permease
5-FC
Deaminase
5-FC
5-FU
5-FdUMP
inhibits thymidylate
RNA & DNA synthesis
Flucytosine
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FC has a selective toxicity because mammalian cells have low levels
of permease and deaminase
It is given by the oral route
Penetrates well into CSF
Flucytosine must not be used as a sole agent in life-threatening
fungal infections due to relatively weak antifungal effects and fast
development of resistance
Resistance is due to changes in the sensitivity of the target enzymes
(decreased activity of fungal permease and deaminase)
Flucytosine with amphotricin B are synergistic, as amphotricin
increases cell permeability allowing more 5-FC to penetrate the cell
Adverse effects of 5-FC includes; reversible myelosuppression;
anemia, leucopenia, thrombocytopenia, elevated hepatic enzymes,
alopecia, GI disturbances; nausea, vomiting and diarrhea
3- Azoles
 Azoles are synthetic compounds that can be classified as
either imidazoles or triazoles according to the number of
nitrogen atoms in the five-membered azole ring
 The imidazoles consist of ketoconazole, miconazole, and
clotrimazole. The latter two drugs are now used only in
topical therapy
 The triazoles include itraconazole and fluconazole
 Mechanism of Action
The antifungal activity of azole drugs results from the reduction of
ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes
• The specificity of azole drugs results from their greater affinity for
fungal than for human cytochrome P450 enzymes
• Imidazoles (e.g., ketoconazole) exhibit a lesser degree of specificity
than the triazoles, accounting for their higher incidence of drug
interactions and side effects
MOA of azoles
Lanosterol
Fungal P450
Ergosterol
Blocked by azole
Azoles
 Clinical Use
The spectrum of action of these medications is quite broad, ranging
from many candida species, the dermatophytes, to the endemic
mycoses
They are also useful in the treatment of intrinsically amphotericinresistant cases
 Adverse Effects
As a group, the azoles are relatively nontoxic. The most common
adverse reaction is relatively minor gastrointestinal upset
All azoles have been reported to cause abnormalities in liver enzymes
and, very rarely, clinical hepatitis
1- Ketoconazole
 Oral route, it requires gastric acid for absorption (cola drinks
increase acidity)
 Does not penetrate into the CSF
 Less selective for fungal cytochrome enzymes (can inhibit host
cyp450, can inhibit cortisol and testosterone synthesis)
 Side effects:
- Allergy, GI disturbances most common
- It inhibits cytochrome P450 isoenzymes responsible for the synthesis of
adrenal and gonadal steroids leading to gynecomastia, menstrual
irregularity and impotence
- liver enzymes
2- Fluconazole
 Wide therapeutic window (few interactions and better GIT tolerance)
 High oral bioavailability and good CSF penetration
 It lacks the endocrine side effects of ketoconazole (no inhibition of
cytochrome P450)
3- Itraconazole
 It is the most potent azole
 Itraconazole has a broader spectrum of activity
 Oral or I.V.
 More selective for fungal enzymes no endocrinal
disturbances
 Itraconazole is over 99% protein bound and has
virtually no penetration into CSF. Therefore, it should
never be used to treat meningitis and other CNS
infections
 It should be taken after meal, preferably with an acidic
drink such as orange juice
Azoles: Pulse dosing
 Pulse dosing refers to taking medicine daily for 1 week
a month (1 week treatment and 3 weeks without drug)
for 2, 3, or 4 months
 Pulse dosing with itraconazole tablets is as effective for
treatment of onychomycosis as continuous dosing
 The drug persists in nail for several months
 Some people find it easier, cheaper and less toxic
Antifungal Agents for
superficial fungal infections
 The treatment of superficial fungal infections caused by
dermatophytic fungi may be accomplished with:
1. Topical antifungal agents, e.g. clotrimazole, miconazole, terbinafine,
ketoconazole
2. Orally administered agents, e.g., griseofulvin, fluconazole, terbinafine,
ketoconazole
 Superficial infections caused by candida species may be
treated with topical applications of clotrimazole, miconazole,
ketoconazole, nystatin or amphotericin B
 Chronic generalized mucocutaneous candidiasis is responsive
to long-term therapy with oral ketoconazole
Oral Drugs for cutaneous
mycotic infection
 Azoles; ketoconazole, fluconazole,
itraconazole
 Griseofulvin
 Terbinafine
Griseofulvin
• Fungistatic
• Treat fungal infections of the skin and nails
• Ineffective topically
• Replaced by new agents which are more
tolerated & with less side effects & interactions
(terbinafine)
• Griseofulvin is reserved for cases with nail, hair
or large body surface involvement
Griseofulvin: MOA
The drug binds to tubulin, Disrupts the mitotic spindle,
inhibits fungal mitosis
Griseofulvin: adverse effects
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Headache, confusion, dizziness, fatigue
Allergic reactions; urticaria
GIT irritation (N, diarrhea, dyspepsia)
Impairment of liver enzyme activity
Can reduce the effectiveness of oral
contraceptives as it is a cytochrome p450
enzyme inducer
Terbinafine
 Synthetic allylamine, keratophilic fungicidal drug
 It is deposited in skin and nails
 For treatment of dermatophytes , especially
onychomycoses (fungal infection of the nails)
 It is more effective than griseofulvin and
itraconazole
 It is also used for candida albicans infection
Terbinafine: MOA
Terbinafine
inhibits
Fungal cell
death
Squalene
epioxidase
Squalene
Lanosterol
Squalene
Ergosterol
Side effects of Terbinafine
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GIT; nausea, constipation , diarrhea
Rashes, urticaria
CNS; headache, dizziness, vertigo
Hepatobiliary dysfunction: elevated liver
enzymes
• Changes in taste sensation
• Visual disturbances
Topical drugs for mucocutaneous
fungal infections
• Polyenes
– Nystatin (Nilstat ; Mycostatin)
• Azoles
– Clotrimazole (Canesten)
– Ketoconazole (Nizoral); Antifungal shampoo
– Miconazole (Daktarin)
• Allylamine
– Terbinfine (Lamisil)
Nystatin
 Nystatin is a polyene antifungal drug
to which many molds and yeast
infections are sensitive, including
Candida spp.
 MOA: Like amphotericin B, nystatin
binds to ergosterol, a major
component of the fungal cell
membrane. When present in
sufficient concentrations, it forms
pores in the membrane that lead to
K+ leakage and death of the fungus
Nystatin
 Nystatin is too toxic for parenteral administration and is only
used topically
 It is currently available in creams, ointments, suppositories
and other forms for application to skin and mucous
membranes
 Nystatin is not absorbed to a significant degree from skin,
mucous membranes, or the gastrointestinal tract. As a result,
it has little toxicity
 Nystatin is active against most candida
species and is most commonly used for
suppression of local candidal infections
 Some common indications include
oropharyngeal thrush and vaginal candidiasis
Miconazole
 An azole used only topically for treatment of
oropharyngeal and vaginal candidiasis
 It is a potent inhibitor of warfarin metabolism and
causes bleeding in warfarin – treated patients
even when applied topically
Preparations for vaginal infections
• Nystatin (Nilstat® vaginal cream & pessaries)
• Clotrimazole (Canesten® vaginal cream & ovules)
• Miconazole
Failure of therapy could be due to:
 Diabetes Mellitus
 Broad spectrum antibiotics
 Immunosupression
Mechanisms of action of antifungal drugs
Thank You