Antifungal Drugs

 FUNGAL INFECTIONS:
 They occur due to:
1- Abuse of broad-spectrum antibiotics
2- Decrease in the patient’s immunity
 Types of Fungal Infections:
1- Yeast:
a. Cryptococcus neoformans (Cryptococcosis)
b. Candida albicans (Candidiasis)
2- Filamentous Fungi:
a. Trichophyton
b. Epidermophyton
c. Aspergillus
d. Microsporum
3- Dimorphic Fungi:
a. Histoplasma (histoplasmosis)
b. Blastomyces (blastomycosis)
c. Coccidiomyces (coccidiomycosis)
d. Sporotrichomyces (sporotichosis)

 CLASSIFICATION OF ANTIFUNGAL DRUGS:

Systemic Drugs for Systemic Oral Drugs for Mucocutaneous Topical Drugs for Mucocutaneous
Infections Infections Infections
Amphotericin B Griseofulvin Nystatin
Topical Azoles (miconazole –
Flucytosine
clotrimazole)
Terbinafine
Topical Allylamines (terbinafine –
Azoles
naftifine)

 AMPHOTERICIN B:
 Amphotericin A & B are both antifungal antibiotics.
 Amphotericin A is not used clinically.
 It’s an amphoteric polyene macrolide antibiotic.
 It’s nearly insoluble in water.
 Pharmacokinetics:
1- It’s poorly absorbed orally; it’s effective against fungal GI infections.
2- It can be given as slow intravenous infusion in cases of systemic infections.
3- It’s highly bound to plasma proteins.
4- It poorly crosses the blood brain barrier.
5- It’s metabolized slowly in the liver.
6- It’s excreted slowly in urine over a period of several days.
7- It has a half-life of 15 days.
8- It’s not dialyzable.
9- It’s widely distributed in tissues except in CNS.
10- Only 2-3% of blood level is reached in CSF in cases of meningitis (intrathecal therapy in
fungal meningitis).
11- It DOES cross the placenta.

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 12- Hepatic dysfunction, renal impairment, and dialysis have little effect on the drug
concentration (NO dose adjustment is required).
 Pharmaceutical Formulations:
1- Conventional Formulation: Colloid suspension of amphotericin-B and sodium
desoxycholate for IV injection.
2- Lipid Formulation: Liposomal preparations (lipid-associated delivery system; IV)
 Liposomal Amphotericin-B:
1- It’s an active drug in lipid delivery vehicles.
2- Lipid vehicles serve as a reservoir that reduces binding to human cell membranes.
3- It’s given intravenously.
4- It has a shorter half-life.
5- Larger doses can be used with less toxicity.
6- It’s more expensive.
 Mechanism of Action:
1- It’s a selective fungicidal drug –acts only against fungal sterol.
2- It disrupts the fungal cell membrane by binding to ergosterol. Therefore, it alters the
permeability of the cell membrane by forming amphotericin B-associated pores leading to
leakage of intracellular ions and macromolecules (cell death).
3- Combination is avid.
4- Amphipathic characteristic.
5- Resistance may occur.
6- Binding to human membrane sterols may occur accounting for drug toxicity.
 Antifungal Activity: Fungicide with the widest spectrum

Yeast Molds
Candida Albicans
Cryptococcus neoformans
Histoplasma capsulatum Aspergillus fumigatus
Blastomyces dermatitidis
Coccidiodes immitis
 Resistance to Amphotericin-B:
1- Ergosterol binding is impaired by either:
a. decreasing the membrane concentration of ergosterol
b. Modifying the sterol target molecule
 Adverse Effects:
1- Immediate Reactions (Infusion-related toxicity):
a. Fever, chills
b. Muscle spasm
c. Headache
d. Vomiting
e. Hypotension

These side effects can be avoided by:

 Slowing the infusion
 Decreasing the daily dose
 Premedication with antipyretics, antihistaminics, or corticosteroids
 A test dose
2- Slower (Cumulative) Toxicity:
a. Nephrotoxicity is the most serious side effect (dose-dependent, reduced renal
perfusion, renal tubular injury)
b. Hypokalemia

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 c. Hypomagnesemia
d. Impaired liver function
e. Thrombocytopenia
f. Anemia due to reduced erythropoietin
g. Common practice to administer normal saline infusion with amphotericin B
h. After intrathecal therapy, seizures and neurological damage can happen.
 Clinical Uses:
1- It has broad-spectrum and fungicidal activities.
2- It’s the drug of choice for life-threatening mycotic infections.
3- It’s used for inducing regimen for serious fungal infections replaced later by azole drugs.
4- It’s used for chronic and preventive therapy of relapse.
5- It can be used for cancer patients with neutropenia who remain febrile on broad-spectrum
antibiotics.
6- It’s used for CNS infections not responding to other drugs.
7- Intrathecal therapy for fungal meningitis is poorly tolerated.
8- Mycotic corneal ulcers and keratitis cured by topical drops and subconjunctival injections.
9- Fungal arthritis (intra-articular injection)
10- Candiduria respond to bladder irrigation with no significant systemic toxicity.
 Routes of Administration:
1- Slow intravenous infusion for systemic fungal infections.
2- Intrathecal for CNS fungal infections.
3- Topical drops and direct subconjunctival injection for mycotic corneal ulcers and keratitis.
4- Local injection into the joint in cases of fungal arthritis.
5- Bladder irrigation in candiduria.

 FLUCYTOSINE:
 It’s a water-soluble pyrimidine analog (cytotoxic drug) related to the chemotherapeutic agent –
fluorouracil. It’s often given in combination with amphotericin-B and itraconazole.
 It has a systemic fungistatic action.
 Mechanism of Action:
1- The drug is taken up by fungal cells via cytosine permease and converted by cytosine
deaminase to an active metabolite -5-Fluorouracil (5-FU).
2- F-dUMP inhibits thymidylate synthase leading to the inhibition of DNA synthesis.
3- F-UTP replaces uracil leading to the inhibition of RNA and protein synthesis.
4- Amphotericin-B increases its permeability, allowing more 5-FC to penetrate the cell. Both
amphotericin-B and 5-FC act synergistically.
 Pharmacokinetics:
1- It’s rapidly and well absorbed orally.
2- It’s widely distributed (even in CSF).
3- It’s mainly excreted unchanged through the kidneys by glomerular filtration.
4- It’s removed by hemodialysis.
5- It has a half-life of 3-4 hours.
6- It has poor protein binding.
7- TDM is important in renal insufficiency (50-100 mg/ml).
 Spectrum of Activity: Narrower than Amphotericin-B
1- It’s restricted to some Candida species, Cryptococcus neoformans, and molds causing
chromoblastomycosis.
2- It’s not used as a single agent.
3- Resistance develops rapidly.
4- Synergism between 5-FC and amphotericin-B both in-vitro and in-vivo.
5- Synergism between 5-FC and azoles in-vitro.

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  Clinical Uses:
1- Use is confined to combination therapy.
2- 5-FC and amphotericin B are used for cryptococcal meningitis.
3- 5-FC and itraconazole are used for chromoblastomycosis.
 Adverse Effects:
1- Nausea, vomiting, diarrhea, toxic enterocolitis
2- Reversible neutropenia, thrombocytopenia, anemia, and bone marrow depression
3- Alopecia
4- Elevation in liver enzymes
5- Some adverse effects related to 5-FU formed by intestinal organisms from 5-FC
6- Narrow therapeutic window

Synthetic Fungicides
 AZOLES:

Imidazoles Triazoles
Ketoconazole Itraconazole
Miconazole (topical) Fluconazole
Clotrimazole (topical) Voriconazole
 A group of fungistatic drugs with a broad-spectrum activity.
 They have antibacterial, antiprotozoal, antihelminthic, and antifungal actions.
 They are classified into imidazole and triazole groups.
 Mechanism of Action:
1- They interfere with cell membrane permeability by decreasing ergosterol synthesis via
inhibition of fungal cytochrome p450 enzyme (14--demethylase) which is responsible for
converting lanosterol to ergosterol (the main sterol in fungal cell membranes).
2- They have greater affinity to fungal cytochrome than human cytochrome.
3- Imidazoles have lesser degree of specificity than triazoles.
4- Imidazoles have more drug interactions and side effects.
5- Resistance is common.
6- They inhibit the mitochondrial cytochrome oxidase leading to accumulation of peroxides
that cause autodigestion of the fungus.
7- Imidazoles may alter DNA and RNA metabolism.
 Spectrum of Activity:
1- Candida
2- Cryptococcus neoformans
3- Endemic mycosis (blastomycosis & histoplasmosis)
4- Dermatophytes
5- Infections caused by aspergillus (voriconazole & itraconazole)
 Adverse Effects: Relatively not toxic
1- Minor GIT upset
2- Liver enzyme abnormalities
3- Drug interactions (vary according to the drug)

 KETOCONAZOLE:
 It’s the first oral azole.
 It’s less selective for fungal p450 than newer drugs.
 It has greater propensity to inhibit mammalian cytochrome p450.
 It’s well absorbed orally; it’s best absorbed at low gastric pH.

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  Its bioavailability is decreased in the presence of antacids, H 2 blockers, proton pump inhibitors,
and food.
 Cold drinks improve its absorption in patients with achlorhydria.
 Its half-life increases with the dose; it has a half-life of 7-8 hours.
 It’s inactivated by the liver, and it’s excreted in bile (feces) and urine.
 It does NOT cross the blood brain barrier.
 Clinical Uses: It’s used topically or systemically (oral route only) to treat:
1- Oral and vaginal candidiasis
2- Dermatophytosis
3- Systemic mycoses and mucocutaneous candidiasis
 Adverse Effects: It has a narrow therapeutic range.
1- Anorexia, nausea, vomiting
2- Hepatotoxicity
3- Inhibition of human p450 enzymes
4- Inhibition of adrenal and gonadal steroid synthesis which may lead to:
a. Menstrual irregularities
b. Loss of libido; infertility
c. Impotence
d. Gynecomastia in males
 Contraindications and Drug Interactions:
1- It’s contraindicated in pregnancy, lactation, and hepatic dysfunction.
2- It increases the plasma levels of oral anticoagulants, oral hypoglycemic drugs, phenytoin,
and cyclosporine.
3- It enhances the arrhythmogenic effects of antihistamine drugs, astimazole, and
terfenadine.
4- Cimetidine increases gastric pH thereby interferes with the absorption of ketoconazole
(decrease plasma level).
5- Rifampin increases the hepatic metabolism of the azole drugs (decreasing plasma levels).
6- H2 blockers and antacids decrease its absorption.

 FLUCONAZOLE:
 It’s water soluble.
 It’s completely absorbed from the GIT.
 It has an excellent bioavailability after oral administration.
 Its bioavailability is not affected by food or gastric pH.
 It has the same plasma concentrations if it’s given by intravenous route.
 It has the least effect on hepatic microsomal enzymes (lack of endocrine effects).
 Drug interactions are less commonly encountered with fluconazole.
 It has the widest therapeutic window which permits more aggressive dosing.
 It penetrates the blood brain barrier; therefore, it’s the drug of choice in treating cryptococcal
meningitis.
 It’s safely given to patients receiving bone marrow transplants (reducing fungal infections).
 It’s excreted mainly through the kidneys (dose should be decreased in renal insufficiency).
 It has a half-life of 25-30 hours.
 Resistance is not a problem.
 Clinical Uses:
1- Esophageal and oropharyngeal candidiasis (effective against all forms of mucocutaneous
candidiasis)
2- Cryptococcal meningitis in immunocompromised patients.
3- Histoplasmosis, blastomycosis, and ring worm infection
4- It’s NOT effective against aspergillosis.
 Adverse Effects:

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 2- Abdominal pain, nausea, vomiting, diarrhea
3- Headache
4- Reversible alopecia
5- Skin rashes
6- Hepatic failure may lead to death
7- Highly teratogenic (as are other azoles)
8- Inhibition of p450 microsomal enzymes
9- NO endocrine side effects

 ITRACONAZOLE:
 It lacks endocrine side effects.
 It has a broad-spectrum activity.
 It can be given orally and intravenously.
 Food and low gastric pH increase its absorption.
 Cyclodextran enhances bioavailability.
 It inhibits cytochrome p450 (less than ketoconazole).
 Drug interactions are less than ketoconazole.
 Reduced bioavailability with rifamycins.
 It’s metabolized in the liver to active metabolites.
 It’s highly lipid-soluble.
 It’s well distributed to bones, adipose tissue, and sputum.
 It CANNOT cross the blood brain barrier.
 It has a half-life of 30-40 hours.
 It’s the drug of choice in systemic infections caused by dimorphic fungi (histoplasma,
blastomyces, sporothrix).
 It’s the drug of choice in the treatment of dermatophytoses.
 It’s active against aspergillus (replaced by voriconazole).
 It’s used intravenously only in serious infections.
 It’s effective against AIDS-associated histoplasmosis.
 Side Effects:
2- Nausea, vomiting
3- Hypokalemia, hypertension, edema
4- Inhibition of many drug metabolisms (oral anticoagulants)

 VORICONAZOLE:
 It’s the newest triazole; it has a broad-spectrum antifungal activity.
 It’s given orally or intravenously.
 It is well absorbed; it has high oral bioavailability.
 Less protein binding than itraconazole.
 It penetrates tissues well including the CSF.
 It inhibits p450 microsomal enzymes (weak inhibition).
 It’s the MOST potent azole.
 It has a spectrum of activity similar to that of itraconazole.
 It’s has excellent activity against invasive aspergillosis, candidiasis, and dimorphic fungi.
 It causes reversible visual disturbances, rashes, and elevated liver enzymes.

Echinocandins Glucan Synthesis Inhibitors

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 Caspofungin – Micafungin - Anidulafungin

 GENERAL FEATURES:
 The newest class.
 They’re active against Candida and Aspergillus; they’re NOT effective against Cryptococcus
neoformans.
 They block the synthesis of a major fungal cell wall component –Beta 1,3 glucan- leading to
disruption of cell wall and ultimately cell death.
 They’re used in mucocutaneous candidal infections.
 Mechanism of Action:
They block fungal cell wall synthesis by inhibiting the enzyme -1,3-beta glucan synthase. This
leads to depletion of glucan polymers in the fungal cell and weakness of the cell wall that
makes it unable to withstand osmotic stress; death of cells occur.
 Echinocandins:
1- They have minor GIT effects and some drug interactions.
2- Caspofungin causes elevation of liver enzymes if taken in combination with cyclosporine;
therefore, combination should be avoided.
3- Micafungin increases the plasma levels of cyclosporine, sirolimus, and nifedipine.
4- Anidulafungin causes the release of histamine when it’s given by IV infusion.

Oral Antifungal Drugs Used for Mucocutaneous Infections

Griseofulvin - Terbinafine
 GRISEOFULVIN:
 It’s very insoluble fungistatic drug derived from penicillium.
 It’s has a narrow-spectrum activity.
 It’s given orally (absorption increases with fatty meals).
 It has a half-life of 24 hours.
 It’s taken selectively by newly formed skin, and it becomes concentrated in the keratin layers.
 It induces cytochrome p450 microsomal enzymes; it’s excreted through biliary routes.
 Available oral formulations (micronized, ultramicrosized)
 It should be given for 2-6 weeks for skin and hair infections to allow replacement of infected
keratin by the resistant structure.
 It should be given for longer periods (months) to treat nail infections.
 It inhibits fungal mitosis by disrupting the mitotic spindle through interaction with polymerized
microtubules.
 It’s used to treat systemic dermatophyte infections (ring worm of skin, hair, and nail).
 It’s highly effective in treating athlete’s feet.
 It’s ineffective topically.
 It’s NOT effective against subcutaneous or deep mycosis.
 Adverse Effects:
1- Peripheral neuritis, headache, mental confusion, fatigue, vertigo, blurred vision
2- GIT upset; hepatitis
3- Increase of alcohol intoxication
4- Skin eruptions and photosensitivity
5- Serum-sickness-like syndrome
6- It’s a microsomal inducer (decreases the anticoagulant effects of warfarin).

 TERBINAFINE:

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  It’s a synthetic allylamine drug.
 It’s available in oral formulations as well as creams.
 It’s a keratophilic medication, but it has a fungicidal action.
 It’s the drug of choice for the treatment of dermatophytes (onychomycosis); it’s more
effective than itraconazole or griseofulvin.
 It’s well tolerated, and it needs shorter duration of therapy.
 It inhibits fungal squalene epoxidase.
 It acts by interfering with the synthesis of ergosterol through inhibition of fungal squalene
epoxidase enzyme (accumulation of squalene which is toxic to the organism causing death of
the fungal cell).
 Its activity is limited to Candida albicans and dermatophytes.
 Terbinafine cream is effective in the treatment of tinea cruris and tinea corporis.
 It’s well absorbed orally, and its bioavailability decreases due to first-pass metabolism in
the liver.
 It’s highly bound to proteins.
 It accumulates in the skin, nails, and adipose tissue.
 It’s severely hepatotoxic because it can cause liver failure and even death.
 It accumulates in the breast milk; therefore, it should not be given to a nursing mother.
 It causes GIT upset (diarrhea, dyspepsia, and nausea)
 It causes taste and visual disturbances.

Topical Antifungal Drugs

 TOPICAL AZOLES (CLOTRIMAZOLE, MICONAZOLE):
 They are used in superficial fungal infections (dermatophytosis, candidiasis, and fungal
keratitis)
 They are not effective against mycoses of the nails, hair, or subcutaneous mycoses.
 The preferred formulation for cutaneous application is cream or solution.
 Their absorption is negligible, and they have rare side effects.
 Azoles for Topical Use: In the form of creams, solution, lotion, and suppositories.
 They are used for treating oral thrush and vulvovaginal candidiasis.
 They are effective against dermatophytic infections (tinea cruris, tinea corporis, tinea pedis).
 Topical Ketoconazole: It’s used in the treatment of seborrheic dermatitis and tinea versicolor.
It’s available in the forms of cream and shampoo.

 TOPICAL ALLYLAMINES (TERBINAFINE,

NAFTIFINE):
 Creams and gel can be used for dermatophytic infections (tinea corporis and tinea cruris).

 NYSTATIN:
 It’s a polyene macrolide antibiotic.
 It’s too toxic for parenteral administration.
 It’s used only topically.
 It’s available in the form of creams, ointments, suppositories, and other preparations.
 It’s not significantly absorbed from the skin, mucus membrane, or GIT.
 Clinical Uses:
2- Prevention or treatment of superficial candidiasis in the mouth, esophagus, and intestinal
tract.
3- Vaginal candidiasis
4- It can be used in combination with antibacterial agents and corticosteroids.

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Pharmacology Team 9