Antifungal Agents

Systemic and Topical

Dr Khairani Idah Mokhtar (PhD) School of Dental Sciences USM Health Campus

Acknowledgement: Dr Asia Rehman (PPSG) Dr Mohd Suhaimi Ab. Wahab (Dept. of Pharmacology, PPSP)

Lecture Outline

Fungal Classification of antifungal drug Mechanism of actions Adverse effects

Fungi -eukaryotes Morphologically:

unicellular (yeasts) multicellular (molds/hyphae) alternate between the two forms (dimorphic fungi)

Tinea capitis or fungal of scalp

http://www.provlab.ab.ca/mycol/tutoria ls/derm/3case.htm

The Trichophyton fungus, photographed under an electron microscope at more than 4,000 times its original size, causes ringworm of the scalp (tinea capitis). The fungus is reproducing by flowering. Oliver Meckes/Photo Researchers, Inc. Read more: http://www.humanillnesses.com/original/EGa/Fungal-Infections.html#ixzz0cZ8Ktrb3

History of antifungal drug development

Drug Nystatin Amphotericin B deoxycholate Griseofulvin Miconazole, clotrimazole (topical) Flucytosine Miconazole (IV) Ketoconazole Approval 1954 1958 1959 1969 1972 1979 1981

Fluconazole
Itraconazole (capsules) Terbinafine (topical) Terbinafine (oral), ABLC ABCD, Liposomal Ampho B, Itraconazole (oral solution) Caspofungin Voriconazole Micafungin

1990
1992 1993 1996 1997 2001 2002 2005

Anindulafungin

2006

Fungal infections:

Superficial- skin, hair, nail, mucous membranes Systemic-affecting body as whole e.g in AIDS patients
Life-threatening Compromised host opportunistic mycoses Causative fungus: Candida*, Aspergillus, Cryptococcus Candida albicans-oral lesion, oral thrush (candidiasis), denture stomatitis

Antifungal drugs

2 categories:

Systemic drugs oral or parenteral

Systemic infections Mucocutaneous infections

> 8 agents. Most common:

amphotericin B, fluconazole, itraconazole, & ketoconazole

Topical therapy

>16 agents. Most common:

clotrimazole, miconazole & nystatin

Antifungals - classifications

Polyene
Amphothericin B Nystatin

Echinocandins
Caspofungin Micafungin Anidulafungin

Azoles
Imidazoles

Ketoconazole Miconazole Clotrimazole Itraconazole Fluconazole Voriconazole

Griseofulvin Terbinafine (allylamines) Flucytosine

Triazoles

Targets for antifungal drugs

Cell wall

Cell membrane

Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Cholesterol primarily in mammalian cell membrane, ergosterol predominant in many pathogenic fungal cell membrane

How do they work?

Polyenes and azoles -target ergosterol destroying the cell membranes integrity. Allylamines (terbinifine) - inhibit ergosterol synthesis. Echinocandins -3-glucan synthesis inhibitor block the production of the -(1,3)-glucan protein damaging the cell wall. flucytosine inhibit DNA/RNA synthesis griseofulvin inhibit fungal cell mitosis preventing cell proliferation and function. Nikkomycin and Polyoxin target chitin synthase.
Image from http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Mannoproteins are another potential target.

Polyene group; amphotericin B, nystatin

Mechanism of action:
Interact with ergosterol component of cell membrane Produce hydrophilic channels Leakage of cell contents and electrolytes
Intracellular ion loss Disrupt osmotic function of membrane

Alters cell metabolism

Mechanism of action Alteration of cell permeability by pores formation. Causing leakage of intracellular components. Leads to cell death.
http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Amphothericin B

Broad spectrum Powerful but toxic Candida spp., aspergillus, Histoplasma

capsulatum, C. imitis, Blastomyces dermatitidis, Cryptococcus neoformans

Amphothericin B

Intravenous Test dose Infusion over 6 hours 4 hrs vs 1 hr* Highly protein bound Poor CSF penetration (2-3%) May need intrathecal administration Slow release from peripheral compartment Slow excretion in urine and bile

*E C Oldfield et. Al., Randomized, double-blind trial of 1- versus 4-hour amphotericin B infusion durations. Antimicrob Agents Chemother. 1990 July; 34(7): 14021406

Amphothericin B adverse effects

Immediate
Infusion related

Fever, rigors (6%), hypotension Premed with PCM or steroid may help

Delayed
Nephrotoxic

80% with cumulative dose of >4 mg Azotemia, RTA Saline loading may reduce the risk Hypokalaemia, hypomagnesemia

Electrolyte disturbance

Normochromic normocytic anaemia

Lipid formulation reduce side effects

Liposomal Ampho B
liposome-encapsulated formulation

Ampho B in lipid delivery vehicle Binding affinity

Act as Ampho B reservoir Reduce toxicity Formulations
AmBisome Amphotec Abelcet 5 X higher dose Less to host membrane More to fungal membrane

25 75 X more expensive

nystatin

Active against candida, cryptococcus, histoplasma Highly toxic Used mainly for superficial fungal infections candida Available as
tablets, suspension, vaginal pessaries, cream

Polyene: contains many double bonds

Amphotericin B

Nystatin

Available for I/V injection Used for local effect. Not absorbed from GIT & little from Not absorbed from skin or mucous broken skin. membranes. Uses; Uses; I/V for systemic fungal infections. For infections caused by Otherwise alternative to nystatin. Candida A. In dentistry; amphotericin B Thrush, denture stomatitis, lozenges / oral suspension for antibiotic stomatitis. local use. Side effects; Side effects; (with parenteral Nausea after oral use) administration.
Fever, nausea, vomiting, hypotension. Nephrotoxic; increase in blood urea. Neurotoxic; seizures & paresthesia.

Azoles synthetic compound

Mechanism of action Reduce ergosterol synthesis
inhibit fungal cytochrome P450 enzyme
14-alpha-demethylase

forms lanosterol

Creates a leaky cell membrane. Impaired membrane function interferes with fungal replication.
Leads to altered cell metabolism & death.

Mechanism of action Inhibits demethylation of lanosterol to ergosterol by 14-alpha-demethylase (P450 enzyme)

http://www.doctorfungus.org/thedrugs/antif_pharm.htm

Azoles- classification

Imidazoles (2 N atoms)
Ketoconazole

Triazoles (3 N atoms)

Miconazole, Clotrimazole

Given orally Systemic infection

Higher affinity for fungal enzyme Less toxic than imidazoles

For local application

Fluconazole (oral, IV)

Good GIT absorption Good CSF penetration

Itraconazole

*Triazoles safer than imidazole, flucanazole is widely use

Voriconazole

Good absorption Poor CSF penetration Visual disturbance in 30% of patients

Azoles

Oral and iv administration Less toxic than Ampho B

Clinical Use: many Candida species Cryptococcus neoformans endemic mycoses such as blastomycoses, histoplasmosis dermatophytes Aspergillus:itraconazole

Adverse effects

relatively nontoxic Most common: minor gastrointestinal upset Very rare: hepatitis

Drug Interactions: Azoles-- drug interactions due to effects on cytochrome P450 enzyme systems

Flucytosine (5-FC)

Not commonly used Derived from fluorouracil (5-FU) Mechanism of action:

Taken up by fungal cell; believes it to be cytosine It is then deaminated to 5-fluorouracil; an antimetabolite.

Interferes with DNA synthesis & cell death.

No anticancer property Narrow spectrum Oral formulation Adverse effects

C. neoformans, Candida sp

Marrow suppression Hepatitis

Griseofulvin

Mechanism of actions:
Binds to microtubules. Disrupts cells mitotic spindle structure. Arrest of cell division. Results in inhibition of fungal mitosis (reproduction).

Effective only against tinea (ring worm) infections in skin, hair & nails. Use for systemic treatment of dermatophytosis Bound to keratin in newly form epidermis, protect the skin Need to be given for 2-6 weeks Replaced by itraconazole and terbinafine

Echinocandins

Caspofungin, Micafungin, Anidulafungin New antifungals Mechanism of action:

Available only in intravenous form Single daily dose Use for resistant infection Not much of side effects

Blocks the synthesis of a major fungal cell wall component, 1-3-beta-D-glucan

-specific target to fungal cell wall

Summary:

Amphothericin B Azoles- fluconazole

Drug formulations Side effects

Thank you for your attention

References Katzungs Basic and Clinical Pharmacology, 11th Ed. 2008