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1
 Antifungal drugs

Dr Devinder Arora
2020PHM; Pharmacology for Oral Health
Following this lecture you should be able to:
• Understand the main drugs used to treat fungal infections

• Describe the mechanism of action of major antifungal drugs and the main
clinically relevant points of considerations regarding them

• Understand the role of antifungal drugs in oral health

• Explain the regimens used in common oral fungal infections

 Antifungal drugs

• Yeasts
• e.g. Cryptococcus neoformans

• Yeast-like fungi that produce a structure resembling a mycelium

• e.g. Candida albicans
– the main fungal pathogen involved in oral disease.

• Filamentous fungi with a true mycelium

• e.g. Aspergillus fumigatus

• 'Dimorphic' fungi that, depending on nutritional constraints, may grow as

either yeasts or filamentous fungi
• e.g. Histoplasma capsulatum
Rang and Dale’s Pharmacology, 7th Edt.
Sites of action of antifungal drugs

β-glucan rich

Rang and Dale’s Pharmacology, 7th Edt.

 Polyene antifungal agents
❑ Nystatin
❑ Amphotericin
Mechanism of action:
• Polyenes bind to ergosterol in the cell wall of fungi → form
aqueous pores → leakage of intracellular ions and disruption of
membrane active transport mechanisms Lippincott's illustrated reviews: Pharmacology (4th ed.).

• they can be fungistatic or fungicidal

• Nystatin is particularly effective against infections with Candida species

• Amphotericin is active against all common fungi that cause systemic infection
(Candida, Aspergillus, Mucor and Cryptococcus species)
• Acquired resistance is rare (can occur in immunosuppressed people)
 Nystatin & Amphotericin
• Nystatin is too toxic for systemic use and is
not absorbed from G.I. tract
• therefore used topically
• as cream for skin infection or as vaginal pessaries,
or orally for buccal and bowel infections
• Amphotericin is poorly absorbed from the gut
and is usually given intravenously for
treatment of serious systemic fungal
infections
• An oral formulation is used for buccal and
intestinal candidiasis
• Amphotericin can also be given intrathecally
for fungal meningitis
Unwanted effects:
• Nystatin is virtually free of both toxic and
allergic unwanted effects when used topically
• used orally for intestinal infection, it can cause
G.I. upset
• Host toxicity with amphotericin is due to
binding to cholesterol rather than ergosterol
• IV infusion of amphotericin is commonly
associated with:
– fever and rigors during the first week of
therapy
– anorexia, nausea, vomiting, diarrhoea
– muscle and joint pain
– dose-related nephrotoxicity:
• reduced GFR, hypokalaemia and
hypomagnesaemia
Oropharyngeal candidiasis

• 100,000 units 4 times daily for 7-14 days for treatment

• 500,000 units 4 times daily can be used

• Best to use oral liquid after a meal or drink

• Swish the liquid around the mouth for as long as comfortable before
swallowing

• Continue to use for several days after the symptoms have disappeared

• Oral itraconazole or fluconazole is often required in

immunocompromised patients
Azole antifungals:
❑ Ketoconazole ❑ Itraconazole

❑ Miconazole ❑ Fluconazole

❑ Clotrimazole ❑ Voriconazole

❑ Econazole ❑ Posaconazole

• block the synthesis of ergosterol in fungi Lippincott's illustrated reviews: Pharmacology (4th ed.).

– inhibit lanosterol 14α-demethylase

– Inhibits ergosterol synthesis → altered cell membrane fluidity of fungi:
• alters cell membrane synthesis
• reduces the activity of membrane-associated enzymes
• increases cell wall permeability
• accumulation of ergosterol precursors in the cell causes growth arrest
• Although the human equivalent enzyme is much less sensitive to the effects of the drug, inhibition of
CYP enzymes can occur in human tissues, especially with ketoconazole.
Spectrum of activity
• Imidazoles are active against a wide variety of filamentous fungi and
yeasts, including Candida species.
• they are less active against Candida krusei.

• Clotrimazole and miconazole are used for:

• vaginal candidiasis and for dermatophyte infections
• e.g. ringworm (tinea) caused by:
• Trichophyton, Microsporon or Epidermophyton species

• Miconazole is also used to treat oral and intestinal fungal infections.

• Ketoconazole can be used for:
• systemic mycoses, resistant mucocutaneous candidiasis, resistant vaginal
candidiasis and resistant dermatophyte infections
Azoles:
• Fluconazole is used for candidiasis or for cryptococcal infection

– 1st line therapy for cryptococcal meningitis (easy CSF penetration)

– also used for oropharyngeal candida, blastomycosis and histoplasmosis

• Itraconazole is used for mucocutaneous candidiasis and for dermatophyte

infections

– such as pityriasis versicolor and tinea corporis or pedis (ringworms)

– Oropharyngeal candida

• Voriconazole is used for invasive aspergillosis, serious infections caused by

Scedosporium species, Fusarium species, or invasive fluconazole-resistant
Candida krusei.
Unwanted effects:
• Unusual with topical formulations, although oral miconazole can cause
gastrointestinal upset
• Oral ketoconazole causes:
• nausea, vomiting, abdominal pain
• rash, urticaria, pruritis
• hepatitis: asymptomatic elevation of liver enzymes is common;
• high doses of ketoconazole suppress androgen production in males and can
cause oligospermia or gynaecomastia
• Ketoconazole case inhibit the metabolism of other drugs which are metabolized by
CYP enzymes
• Nizoral has been de-registered & discontinued after consultation with TGA from Dec 2013 in
Australia.
Angular cheilitis(TGs)
• Miconazole
• 2% cream or gel

• Apply topically to the angles of the mouth

• 4 times daily for at least 14 days

OR

• Nystatin
• 100 000 units/g cream

• Apply topically to the angles of the mouth

• 2 – 3 times daily for at least 14 days

Predisposing factors in oral candidosis:

Local factors: Systemic factors:

• the wearing of dentures • immunosuppression
• salivary gland hypofunction • HIV infection

• incorrect use of corticosteroid • leukaemia

inhalers • the use of some drugs

• poor oral hygiene • inhaled and systemic
corticosteroids
• antibiotics
Oral candidosis (TGs)
• Amphotericin (adult and child)
– 10 mg lozenge sucked (then swallowed)
– 4 times daily, after food, for 7 to 14 days
OR

• Miconazole
– 2% gel 2.5 mL (child 6 months to 2 years: 1.25 mL) topically (then swallowed)
– 4 times daily, after food, for 7 to 14 days (measuring spoon supplied with pack).
Place directly in the mouth and on the tongue
OR

• Nystatin (adult and child)

– 100 000 units/mL suspension 1 mL topically (then swallowed)
– 4 times daily, after food, for 7 to 14 days. Place under the tongue or in the buccal
cavity.
Terbinafine:
• Terbinafine is an allylamine that inhibits squalene epoxidase, an enzyme that
converts squalene to ergosterol in the cell wall ➔ impaired cell wall synthesis
• resistance is rare, but similar to that for imidazole antifungals
• Terbinafine penetrates well into the stratum corneum and hair follicles after topical
use
• unwanted effects are unlikely with topical use of the drug
• nausea, taste disturbance, abdominal discomfort and diarrhoea, headache, rashes
(occasionally severe)
• Used to treat superficial dermatophyte infections
• Skin, groin, feet, when topical treatment is ineffective
• Onychomycoses (fungal infections of nails)
• also fungistatic against candida species
Caspofungin:
• Inhibits fungal cell wall synthesis, targeting the glucans that are found in
fungal but not human cell walls
• Inhibits the enzyme β1,3-glucan synthase ➔ prevents production of the main
structural polymer in the fungal cell wall

• Used to treat invasive aspergillosis as a second-line agent, and invasive

candidiasis
– also effective in oesophagial, oropharyngeal candidiasis

• Resistance is uncommon
• Nausea, vomiting, abdominal pain, diarrhoea, flushing, fever
• Headache, rashes
 Flucytosine:
Mechanism of action Resistance
• Flucytosine is converted to 5- • Occurs readily:
fluorouracil (5-FU) selectively in – mutation of the enzyme that metabolizes
fungal cells by the enzyme cytosine flucytosine.

deaminase – excessive synthesis of uracil which

competes with antimetabolite.
• acts as an antimetabolite that competes
with uracil for incorporation into fungal
• Flucytosine is only used in
RNA
combination with amphotericin or
fluconazole
• 5-FU is metabolised to compounds that
– Cryptococcal infections
inhibit thymidylate synthetase → inhibits
DNA synthesis

Unwanted effects
• Flucytosine is only active against
yeasts such as Candida, Aspergillus • Nausea, abdominal pain, diarrhea

and Cryptococcus species. It is used • Rashes

for systemic infections • Bone marrow depression in high doses

Lippincott's illustrated reviews: Pharmacology (4th ed.).

Griseofulvin:
• Inhibits dermatophyte mitosis
• impairs polymerization of mictotubule protein

• Active against dermatophytes Lippincott's illustrated reviews:

Pharmacology (4th ed.).

• Microsporum, Epidermophyton & Trichophyton species

• Well absorbed orally → concentrated in skin & nail beds

• Metabolized in liver and has a long half life
• Nausea, vomiting, headache, dizziness, fatigue
• Rashes, including photosensitivity

• Chances of drug interactions since griseofulvin induces CYP enzymes

• Has been largely replaced by oral terbinafine for dermatophytic infections of the nails
• still used for ringworm and dermatophytosis of the skin and hair