Kwame Nkrumah University of

Science & Technology, Kumasi, Ghana

ANTIFUNGAL AGENTS

Prof. Dr. Christian Agyare

Department of Pharmaceutics
Faculty of Pharmacy and Pharmaceutical Sciences
College of Health Sciences

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Course Content/Objectives
Antifungal Agents
❖ Mechanisms of Action

❖ Indications

❖ Drug Interactions

❖ Contraindications/Cautions

❖ Side Effects/Adverse Reactions

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Reference Books/Reading List
❖Pharmacology by Rang, Dale, Ritter &
Gardner

❖Clinical Pharmacology Textbooks

❖British National Formulary (BNF)

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 Introduction
❖ Over 200,000 species of fungi identified

❖ Members include yeasts, moulds, mushrooms, smots, Aspergillus

spp, Candida spp, Penicillium spp. etc

❖ Fungal infections are termed as mycoses

❖ Infections caused by fungi can be life-threatening

❖ Immunocompromised individuals are most susceptible to fungal

infections

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 Some Fungal Infections
❖ Candidiasis/Thrush (mouth, vaginal and throat)

❖ Blastomycosis

❖ Histoplasmosis

❖ Cryptococcus meningitis

❖ Dermatophytosis

❖ Aspergillosis

❖ Mucormycosis
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Antifungals
❑Azoles

❑Allylamines

❑Polyenes

❑Echinocandin antifungals

❑Griseofulvin and Flucytosine

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AZOLES

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 Azoles
The azoles group consist of 2 broad classes distinguished by structure:

❑ Imidazoles (clotrimazole, miconazole, ketoconazole, econazole, butoconazole,

oxiconzole, sulconazole, sertaconazole)

❑ Triazoles (fluconazole, itraconazole, voriconazole, posaconazole, terconazole,

Isavuconazole)

Mechanism of Action
❑ Impair the biosynthesis of ergosterol by inhibiting 14-α-sterol demethylase
leading to the accumulation of 14-α-methylsterols in the cell membrane.

❑ Systemically, triazoles are slowly metabolized and have less effect on human
sterol synthesis

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Antifungal agents

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Azoles- Spectrum of Activity
Azoles show high sensitivity towards the following:

❑ Candida spp (albicans, tropicalis, parapsilosis, glabrata)

❑ Cryptococcus neoformas
❑ Blastomyces dermatitidis
❑ Histoplasma capsulatum
❑ Coccidiodes spp
❑ Paracoccidiodes brasiliensis
❑ Dermatophytes
❑ Aspergillus spp
❑ Scedosporium apiospermum

❑ Candida krusei and other agents responsible for mucormycosis are generally resistant to
azoles.

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Ketoconazole
✓ Administered orally and topically

CLINICAL INDICATIONS
❖ Fungal skin infection
❖ Tinea pedis
❖ Seborrhoeic dermatitis and dandruff
❖ Pityriasis versicolor
❖ Systemic fungal infection
❖ Endogenous Cushing’s syndrome (specialist use only)
❖ Vaginal and vulva candidiasis

Partially metabolized in the liver via CYP3A4

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Ketoconazole
DRUG INTERACTIONS SIDE EFFECTS
➢ Antacids ❖ Impotence
➢ Ethanol ❖ Gynaecomastia
➢ H2 blockers ❖ Reduced sperm count
➢ Phenytoin ❖ Decreased libido
➢ Omeprazole ❖ Hepatotoxicity
➢ Rifampicin ❖ Nausea/vomiting
➢ Isoniazid ❖ Pruritis
➢ Astemizole ❖ Dizziness
➢ Corticosteroids ❖ Photophobia
➢ Amphotericin B

• Contraindicated Acute
porphyria

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Miconazole
Administered topically, orally, intravaginally

CLINICAL INDICATIONS

❑ Vaginal and vulva candidiasis

❑ Oral candidiasis

❑ Intestinal candidiasis

❑ Fungal skin infection

❑ Nails infection

Metabolized by the liver

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Miconazole
DRUG INTERACTIONS SIDE EFFECTS
❑ Carbamazepine ❖ Dysmenorrhoea

❑ Disopyramide ❖ Skin reactions

❑ Fosphenytoin ❖ Vulvovaginal disorders

❑ Coumarins ❖ Diarrhoea (oral)

CONTRAINDICATIONS
✓ Hypersensitivity (oral)

✓ Milk protein allergy (oral)

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Clotrimazole
➢ Administered topically and Intravaginally

CLINICAL INDICATIONS

❑ Fungal infection in otitis externa

❑ Vaginal candidiasis

❑ Fungal skin infection

❖ Metabolized in the liver

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Clotrimazole
SIDE EFFECTS DRUG INTERACTIONS
✓ Oedema ❑ Lomitapide
✓ Pain ❑ Elagolix
✓ Paraesthesia ❑ Everolimus
✓ Skin reactions ❑ Warfarin
✓ Syncope ❑ Axitinib
✓ Abdominal pain ❑ Midazolam(intranasal)
✓ Vaginal haemorrhage

Contraindicated in hypersensitivity to
clotrimazole

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Fluconazole
Administered orally and parenterally

CLINICAL INDICATIONS
❑ Oropharyngeal and esophageal candidiasis
❑ Vaginal candidiasis
❑ Tinea pedis, Tinea corporis, Tinea cruris infections
❑ Pityriasis versicolor (dermal candidiasis)
❑ Invasive candidal infections (including candidaemia and disseminated
candidiasis)
❑ Cryptococcal infections (including meningitis)
❑ Prophylaxis of fungal infections in immunocompromised patients

Metabolised partially in the liver

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Fluconazole
SIDE EFFECTS DRUG INTERACTIONS
❑ Diarrhoea ❖ Disopyramide
❑ Vomiting ❖ Ergotamine
❑ Nausea ❖ Erythromycin
❑ Gastrointestinal discomfort ❖ Amiodarone
❑ Skin reaction ❖ Artemether/Lumefantrine
❑ Headache ❖ Clarithromycin
❑ Flatulence ❖ Clopidogrel
❑ Hepatic disorders ❖ Fentanyl
❑ Dizziness
❑ Seizure

Contraindicated in acute porphyria

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Itraconazole
Administered orally

CLINICAL INDICATIONS
❖ Oropharyngeal, vulvovaginal, systemic and esophageal candidiasis
❖ B. dermatitidis infection
❖ P. brasiliensis infection
❖ H. capsulatum infection
❖ Aspergillosis
❖ Onychomycosis
❖ Sporotrichosis
❖ T. corporis, T. versicolor, T. pedis infections
❖ Maintenance therapy in HIV-infected patients

Metabolized in the liver

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Itraconazole
DRUG INTERACTIONS SIDE EFFECTS
❖ Antacids ❑ Alopecia
❖ Barbiturate ❑ Constipation
❖ Carbamazepine ❑ Diarrhoea
❖ H2-antagonists ❑ Dyspnoea
❖ Rifampin ❑ GIT discomfort
❖ Rifabutin ❑ Headache
❖ Proton pump inhibitors ❑ Heart failure
❖ Ritonavir ❑ Nausea
❖ Quinidine ❑ Oedema
❖ Halofantrine ❑ Vomiting
❖ Levomethadyl ❑ Chest pain
❑ Skin reactions
Contraindications in acute porphyria

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Voriconazole
• Administered orally and parenterally

CLINICAL INDICATIONS
❑ Invasive aspergillosis
❑ Serious infections caused by scedosporium spp.
❑ Fusarium spp.
❑ Invasive fluconazole-resistant candida spp. (including C. krusei)

❖ Used as prophylaxis of invasive fungal infections in patients at high risk and

undergoing
❖ High-dose immunosuppressive therapy for haematopoietic stem cell transplantation or
receiving chemotherapy for acute myeloid leukaemia or myelodysplastic syndrome leads
to prolonged neutropenia

Metabolized in the liver via CYP2C19, CYP2C9, CYP3A4

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Voriconazole
DRUG INTERACTIONS SIDE EFFECTS
✓ Clopidogrel ❑ Acute kidney injury
✓ Amobarbital ❑ Anaemia
✓ Carbamazipine ❑ Arrhythmias
✓ Erythromycin ❑ Bone marrow disorders
✓ Lomitapide ❑ Constipation
✓ Lovastatin ❑ Depression
❑ Diarrhoea
❑ Dizziness
❑ Dyspnoea
❑ Electrolyte imbalance
Contraindicated in acute porphyria ❑ Eye inflammation
❑ Fever
❑ Gastrointestinal discomfort
❑ Vomiting

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Posaconazole
Administered orally and parenterally

CLINICAL INDICATIONS
✓ Invasive aspergillosis refractory to, or patients intolerant of, itraconazole or
amphotericin,
✓ Fusariosis either refractory to, or patients intolerant of, amphotericin,
✓ Chromoblastomycosis and mycetoma refractory to, or in patients intolerant of,
itraconazole,
✓ Coccidioidomycosis refractory to, or in patients intolerant of, amphotericin, itraconazole,
or fluconazole
✓ Oropharyngeal candidiasis (severe infection or in immunocompromised patients only)
✓ Prophylaxis of invasive fungal infections in patients at high risk and undergoing high-
dose
❖ Immunosuppressivetherapy for haematopoietic stem cell transplantation or receiving
chemotherapy for acute myeloid leukaemia ormyelodysplastic syndrome leads to prolonged
neutropenia

Metabolized primarily by glucuronide conjugates

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Posaconazole
SIDE EFFECTS DRUG INTERACTION
❖ Loss of appetite ❑ Lovastatin
❖ Constipation ❑ Simvastatin
❖ Diarrhoea ❑ Amiodarone
❖ Dizziness ❑ Colchicine
❖ Dry mouth ❑ Disopyramide
❖ Electrolyte imbalance ❑ Erythromycin
❖ Gastrointestinal discomfort ❑ Fentanyl
❖ Headache ❑ Oxycodone
❖ Hypertension
❖ Nausea
❖ Skin reactions
❖ Altered taste
❖ Vomiting

Contraindicated: acute porphyria

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Isavuconazole
Administered orally and intravenously

CLINICAL INDICATIONS

✓ Invasive Aspergillosis
✓ Mucormycosis in patients for whom Amphotericin B is in appropriate

CONTRAINDICATIONS
✓ Pregnancy
✓ Breast feeding
✓ Hepatic impairment

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Isavuconazole
SIDE EFFECTS
❖ Decreased appetite
❖ Gastrointestinal discomfort
❖ Asthenia
❖ Headache
❖ Chest pain
❖ Hepatic disorders
❖ Delirium
❖ Nausea
❖ Diarrhoea
❖ Skin reactions
❖ Drowsiness
❖ Thrombophlebitis
❖ Electrolyte imbalance

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ALLYLAMINES

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Allylamines
MECHANISM OF ACTION
❖ Inhibit ergosterol synthesis at the level of squalene epoxidase

❖ These agents are highly selective for fungal enzyme and have a minimal effect on
mammalian cholesterol level.

❖ Drugs in this class are Naftifine and Terbinafine

CLINICAL INDICATIONS
➢ Dermatophytosis of the skin and the nails

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Allylamines
❖Naftifine
Available in a 1% cream and gel for topical treatment of ringworm, athlete’s foot and jock
itch

❖Terbinafine
Available in a 1% cream for topical administration for the treatment of
T. pedis, T. corporis and T. cruris.

➢ It is more potent than naftifine and has demonstrated oral activity against
onchomycosis (ringworm of the nails)

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 Allylamines
METABOLISM
❖ Highly lipophilic and keratophilic, thus it accumulates in the stratum corneum of skin
and the nails.
❖ Metabolism of terbinafine is not dependent on CYP450 mediated enzyme activity

DRUG INTERACTION
❑ No pharmakinetic or pharmcodynamic interactions have been observed
with the concomitant administration of terfenadine

❖ Contraindicated in patients with chronic or active liver disease and history of allergic
reaction to oral allyamines

❖ Possible risk of anaphylaxis

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Allylamines
SIDE EFFECTS
❑ Nausea
❑ Taste disturbances and anorexia
❑ Abdominal discomfort and diarrhea
❑ Headache
❑ Rashes which are occasionally severe
❑ Fatigue
❑ Myalgia
❑ Arthralgia

CAUTIONS
✓ Autoimmune diseases
✓ Use with caution in pregnancy
CONTRAINDICATIONS
✓ Avoid in lactating mothers
✓ Avoid oral use in patients with hepatic impairment

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POLYENE ANTIFUNGALS

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Polyene antifungals
❖ Possess a system of conjugated double bonds in large macrocyclic lactone rings
❖ Polyenes have series of hydroxyl groups on the acid-derived portion of the
macrocycle
❖ Linked to the macrocycle is a glycosidically linked deoxyaminohexose called
mycosamine

Mechanism of Action
❖ Bind with ergosterol causing membrane disruption, cessation of membrane
enzymatic activities and loss of cellular constituents especially potassium ions.
❖ 3-dimensional shape enable penetration the fungal cell membrane, acting as false
membrane components

Two classes of clinically important polyenes:

❖ 26-membered-ring such as Natamycin
❖ 38-membered-ring macrocycles such as Amphotericin B and Nystatin

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Polyenes
❖ Polyenes are broad spectrum antifungals agents effective against pathogenic
yeasts, molds and dermatophytes

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Polyenes
Systemic use of polyenes is limited due to:
✓ Relative toxicities of these agents

✓ Low water solubility

✓ Poor chemical stability

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Nystatin
❖ A 38-membered macrocyclic lactone ring first isolated from Streptomyces noursei

❖ Nystatin is not absorbed when given by the oral route

❖ It is also too toxic to be given by the parenteral route hence used as a topical agent.

CLINICAL INDICATIONS
➢ Oral, oropharyngeal and perioral infections by local application in the mouth.
➢ Candida albicans infections of the skin

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Nystatin
SIDE EFFECTS
❑ Nausea
❑ Vomiting
❑ Skin reactions
❑ Stevens-Johnson Syndrome
❑ Angioedema
❑ Diarrhoea

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 Amphotericin B
❖ 38-membered macrocyclic lactone ring isolated from Streptomyces nodosus

MECHANISM OF ACTION
❖ It interacts with membrane sterols (ergosterol in fungi) forming a transmembrane
channel allowing leakage of cytoplasmic contents

ADMINISTERED ONLY BY INTRAVENOUS ROUTE

✓ Like nystatin, it is poorly absorbed from the gut

✓ Relatively less toxic than nystatin hence given by parenteral administration

✓ It is highly protein bound and penetrates poorly into body fluids and tissues

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Amphotericin B
CLINICAL INDICATIONS (mainly for systemic infections)
✓ Candidiasis
✓ Cryptococcidiosis
✓ Aspergillosis
✓ Mucormycosis

SIDE EFFECTS
❑ Anaemia
❑ Abnormal hepatic function
❑ Renal tubular acidosis
❑ Skin reactions
❑ Hypotension
❑ Nausea and vomiting

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ECHINOCANDIN ANTIFUNGALS

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Echinocandins
MECHANISM OF ACTION
❖Inhibit fungal cell wall synthesis by inhibiting β-(1,3)
glucan synthesis

✓ Fungicidal against most Candida spp

✓ Fungistatic against Aspergillus spp

Examples: Caspofungin, Micafungin, Anidulafungin

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Caspofungin
❖ Parenteral administration only

CLINICAL INDICATIONS
❑ Invasive aspergillosis and candidiasis
❑ Empirical treatment of systemic fungal infections in patients with neutropenia

SIDE EFFECTS
✓ Arthralgia
✓ Diarrhoea
✓ Dyspnoea
✓ Electrolyte imbalance
✓ Fever
✓ Headache
✓ Hyperhidrosis
✓ Nausea
✓ Skin reactions
✓ Vomiting
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Capsofungin
❖Metabolized slowly by hydrolysis and N-
acetylation

DRUG INTERACTION
✓ Antiepileptics (carbamazepine, fosphenytoin,
phenytoin)
✓ Ciclosporin
✓ Corticosteroids (dexamethasone)
✓ Efavirenz
✓ Nevirapine
✓ Rifampicin

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Micafungin
❖ Parenteral administration only

CLINICAL INDICATIONS
✓ Invasive candidiasis
✓ Oesophageal candidiasis
✓ Prophylaxis of candidiasis in patients undergoing bone marrow
transplantation or who are expected to become neutropenic for over
10 days

Metabolized by the liver to catechol and methoxy forms

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Micafungin
SIDE EFFECTS
❑ Anaemia
❑ Loss of Appetite
❑ Arrhythmias
❑ Confusion
❑ Constipation
❑ Diarrhoea
❑ Headache
❑ Hepatic toxicity

DRUG INTERACTIONS
✓ Amphotericin B

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Anidulafungin
❖ Administered parenterally only

Clinically indicated for invasive candidiasis

SIDE EFFECTS
✓ Bronchospasm
✓ Cholestasis
✓ Diarrhoea
✓ Dyspnoea
✓ Headache
✓ Hyperglycaemia
✓ Hypertension
✓ Nausea
✓ Seizure
✓ Skin reactions
✓ Vomiting

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Anidulafungin
CONTRAINDICATIONS

❖ Pregnancy and breast feeding

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 OTHER ANTIFUNGALS

GRISEOFULVIN and FLUCYTOSINE

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Griseofulvin
MECHANISM OF ACTION
❖ Binds to tubulin to interfere with microtubule function thus inhibiting mitosis

Administered oral route only

CLINICAL INDICATIONS
✓ Dermatophyte infections of the skin, hair, nails and scalp where topical
therapy has failed or inappropriate
✓ Tinea capitis caused by Trichophyton tonsurans

METABOLISM
❖ Occurs in the liver by oxidative demethylation and glucuronification to
6-desmethylgrseofulvin (an active metabolite)
❖ Less than 1% of the drug is excreted unchanged

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Griseofulvin
CONTRAINDICATIONS DRUG INTERACTIONS
✓ Chronic or active liver disease ❑ Warfarin
✓ People with lupus ❑ Itraconazole
erythematosus ❑ Amoxicillin
✓ Porphyria ❑ Ketoconazole
✓ Pregnancy ❑ Aspirin
❑ Vitamins
❑ Contraceptives
SIDE EFFECTS
❖ Headache
❖ GIT disturbances
❖ Cutaneous eruption

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Flucytosine
MECHANISM OF ACTION
❖ Disrupts protein synthesis by inhibiting RNA synthesis in the fungal
cell

Administered intravenously only

CLINICAL INDICATIONS
✓ Systemic yeast and fungal infections

✓ Adjunct to Amphotericin in severe systemic candidiasis and in

other severe or long-standing infections

✓ Cryptococcal meningitis (adjunct to amphotericin B)

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Flucytosine
CAUTIONS
✓ Blood disorders
✓ Elderly CONTRAINDICATIONS
❑ Pregnancy
SIDE EFFECTS ❑ Breast feeding
✓ Agranulocytosis
✓ Aplastic anaemia
✓ Blood disorder ✓ Leucopenia
✓ Cardiotoxicity ✓ Nausea
✓ Confusion ✓ Rash
✓ Diarrhoea ✓ Sedation
✓ Hallucination ✓ Seizure
✓ Headache ✓ Vertigo
✓ Hepatic disorder ✓ Vomiting
✓ Thrombocytopenia

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Thanks for your attention

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