Introduction to antifungal drugs

1. Antifungal Drugs
Antibiotics
Dr. S. Parasuraman

2. Antifungal Drugs
• Human fungal infections have increased dramatically in recent
years, owing mainly to advances in surgery, cancer treatment, and
critical care accompanied by increases in the use of broad-spectrum
antimicrobials and the HIV epidemic. These changes have resulted
in increased numbers of patients at risk for fungal infections.
• Antifungal drugs are used for superficial and deep (systemic) fungal
infections.
• Important antibiotics: amphotericin-B, griseofulvin
• Novel antifungal agent: Terbinafine
• Recently added drug: Echinocandins

3. Antifungal Drugs- Classification
• Antibiotics
– Polyenes: Amphotericin B
– Echinocandins: Caspofungin
– Heterocyclic benzofuran: Griseofulvin
• Antimetabolite: Flucytosine (5-FC)
• Azoles
– lmidazoles
• topical: Clotrimazole, Econazole, Miconazole, Oxiconazole
• systemic: Ketoconazole
– Triazoles (systemic): Fluconazole, Itraconazole, Voriconazole,
Posaconazole
• Allylamine: Terbinafine
• Other topical agents: Undecylenic acid, Benzoic acid

4. Antifungal Drugs- Mechanism of action

5. Antifungal Drugs- Polyene antibiotics
• Polyene is derived from their highly double-bonded structure.
• Prototype: Amphotericin B (AMB)
• Source: Streptomyces nodosus
• MOA:
– The polyenes have high affinity for ergosterol present in
fungal cell membrane.
– This Polyenes are combine with membrane protein and
form a 'micropore‘ and increase the cell permeability (ions,
amino acids and other water soluble substances move out
through hydrophilic side forms) allowing leakage of a
variety of small molecules.
– Cholesterol, present in host cell membranes, closely
resembles ergosterol; the polyenes bind to it as well,
though with lesser affinity.

6. Antifungal Drugs- Polyene antibiotics
• Pharmacokinetics: Amphotericin B is not absorbed orally. For
intestinal candidiasis it can be given orally. The serum t1/2 is
approximately 15 days. About 60% of the drug (amphotericin B)
metabolized in liver and is excreted slowly in the bile and urine
over a period of several days.
• Therapeutic Uses:
• Broad spectrum of activity and fungicidal action
• Used for the treatment of treatment of systemic fungal disease
• Amphotericin B is most effective drug for resistant cases of kala
azar and mucocutaneous leishmaniasis

7. Adverse Effects
• Acute reaction:
– Chills, fever, aches, pain all over, nausea, vomiting and
dyspnea. Injection of hydrocortisone 0.6 mg/kg with the
infusion may reduce the intensity of reaction.
– Thrombophlebitis of the injection vein can occur.
• Long-term reaction:
– Nephrotoxicity
– Anaemia
– CNS toxicity (only on intrathecal injection)
Antifungal Drugs- Polyene antibiotics

8. • Caspofungin
– MOA: Inhibiting the enzyme β-1, 3-glucan synthase and
thereby disturbing the integrity of the fungal cell wall.
– Use: Approved for deep and invasive candidiasis,
esophageal candidiasis and salvage therapy of
nonresponsive invasive aspergillosis
– ADR: Rash, vomiting, dyspnoea, hypokalemia and join
pain.
Antifungal Drugs- Echinocandins

9. • Griseofulvin
– Griseofulvin is a very insoluble fungistatic drug derived from a
species of Penicillium griseofulvum. Its only use is in the
systemic treatment of dermatophytosis.
– MOA: Bind to microtubules and prevents spindle formation and
mitosis in fungi.
– PK: The absorption of griseofulvin from g.i.t. is somewhat
irregular because of its very low water solubility. Fatty food may
increase the absorption of griseofulvin.
– ADR: Toxicity is low and not serious. Headache, GIT disturbance,
CNS symptoms and peripheral neuritis.
Antifungal Drugs- Heterocyclic Benzofuran

10. Imidazoles and triazoles
• Mechanism of action: Imidazoles and triazoles on fungi is
inhibition of 14-α-sterol demethylase and impair the biosynthesis of
ergosterol in cytoplasmic membrane and accumulates the 14-α-
methylsterols.
• Clotrimazole: It is effective in the topical treatment of tinea
infections like ringworm.
• Econazole: It is similar to clotrimazole. Effective in
dermatophytosis, otomycosis and oral thrush.
• Miconazole: Highly efficacious (>90% cure rate) drug for tinea,
pityriasis versicolor, otomycosis, cutaneous and vulvovaginal
candidiasis.
• Route of administration: Topical.

11. Ketoconazole (Systamic)
• First orally effective broad-spectrum antifungal drug, useful in
both dermatophytosis and deep mycosis.
• Ketoconazole sometimes is used to inhibit excessive
production of glucocorticoids in patients with Cushing's
syndrome.
• ADR: Ketoconazole is much less toxic than AMB, most
common side effects are nausea and vomiting.
Gynaecomastia, loss of hair and libido, and oligozoospermia
may be the manifestations.
• Use:
– Effective in dermatophytosis, monilial vaginitis, Systemic mycosis
– KTZ is occasionally used in dermal leishmaniasis and kala azar
– High-dose KTZ has been used in Cushing's syndrome to decrease
corticosteroid production.

12. Fluconazole (systemic)
• It is a water-soluble triazole having a wider range of activity
than KTZ. It has good cerebrospinal fluid penetration.
• ADR: Mostly nausea, vomiting, abdominal pain, rash and
headache. Elevation of hepatic transaminase has been noted in
AIDS patients.
• Use: vaginal candidiasis, oropharyngeal candidiasis,
disseminated candidiasis, cryptococcal/ coccidioidal meningitis;
eye drop is useful in fungal keratitis.

13. TERBINAFINE
• MOA: Terbinafine inhibits the fungal enzyme squalene
epoxidase. This leads to the accumulation of the sterol
squalene, which is toxic to the organism.
• ADR:
– Adverse effects are rare, consisting primarily of
gastrointestinal upset and headache.
– Topical terbinafine can cause erythema, itching, dryness,
irritation, urticaria and rashes.
• Dose: One tablet given daily for 12 weeks achieves a cure rate
of up to 90% for onychomycosis and is more effective than
griseofulvin or itraconazole.

14. stinging
erythema
vesication
desquamation
pruritus
urticaria
ADR of Antifungal agents

15. Thank you

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Visceral leishmaniasis (VL)/ kala-azar/ black fever/ Dumdum fever
caused by protozoan parasites of the Leishmania genus.
This disease is the second-largest parasitic killer in the
world (after malaria), responsible for an estimated 500,000
infections each year worldwid

17. oropharyngeal candidiasis
esophageal candidiasis
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onychomycosis