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Clinical KHAIRANI's Antifungal Agents
Clinical KHAIRANI's Antifungal Agents
Clinical KHAIRANI's Antifungal Agents
Acknowledgement: Dr Asia Rehman (PPSG) Dr Mohd Suhaimi Ab. Wahab (Dept. of Pharmacology, PPSP)
Lecture Outline
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
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:
Topical therapy
Antifungals - classifications
Polyene
Amphothericin B Nystatin
Echinocandins
Caspofungin Micafungin Anidulafungin
Azoles
Imidazoles
Triazoles
Cell wall
Cell membrane
Cholesterol primarily in mammalian cell membrane, ergosterol predominant in many pathogenic fungal cell membrane
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
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
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
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
Liposomal Ampho B
liposome-encapsulated formulation
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
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.
forms lanosterol
Creates a leaky cell membrane. Impaired membrane function interferes with fungal replication.
Leads to altered cell metabolism & death.
Azoles- classification
Imidazoles (2 N atoms)
Ketoconazole
Triazoles (3 N atoms)
Miconazole, Clotrimazole
Itraconazole
Voriconazole
Azoles
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)
C. neoformans, Candida sp
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
Summary: