3. Fungal infections (Superficial)
z Dermatomycosis (bcc cup)
z Tinea pedis (athlete’s foot)
z Tinea corporis (skin ringworm)
z Tinea cruris (groin)
z Tinea capitis (scalp)
z Tinea unguium (nails)
z Tinea barbae (beard)
z Tinea mannum(hand)
z Candidiasis – skin, mouth, vagina
oropharynx
8. Antifungal drugs- Classification
3. AZOLES
z Imidazoles: (Topical): Clotrimazole,
Econazole, Miconazole, Oxiconazole
(Systemic): Ketoconazole
Trizoles: ( Systemic) Itraconazole, Fluconazole,
Voriconazole
Inhibition of ergosterol synthesis
4. ALLYLAMINE: Terbinafine
Inhibition of lanosterol and ergosterol synthesis
5. OTHER TOPICAL AGENTS:
Tolnaftate, Undecylenic acid, Benzoic acid,
Quiniodochlor, Ciclopirox olamine, Sod. thiosulfate.
9. Amphotericin B - MOA
z In fungi: ergosterol in membranes: higher
affinity than mammalian cholesterol for AmB
z Ergosterol: Only present in fungal cell
membrane and not in animal cell
z Ergosterol: Polyenes combine with it, get
inserted into the membrane and several
molecules together orient themselves and
form a micropore.
13. Antifungal Spectrum
z Candida albicans, Histoplasma capsulatum, Cryptococcus
neoformans, Blastomyces dermatitidis, Coccidioides immitis,
Aspergillus, Rhodotorula.
z Resistance is rare and slow to develop
z Pharmacokinetics
z Poorly: crosses cell membranes, absorbed from the gut and
penetration into the eye, CSF, and joint capsules
z For treatment of meningitis, it must be given intrathecally
Given only via IV injection or intrathecally Selective distribution
into deep tissue sites, with slow release of drug
Kidney > liver > spleen > lung > heart > skeletal muscle > brain > bone > CSF > eye
14. z Classic amphotericin B deoxycholate (Fungizone™)
formulation: serious toxic side effects.
Less toxic preparations:
1) Liposomal amphotericin B
2) Amphotericin B colloidal dispersion
3) Amphotericin B lipid complex
z milder acute reaction
z better tolerated
z lower nephrotoxicity
z minimal anaemia
z targeted delivery-liver & Spleen
15. ADVERSE EFFECTS (AMB)
z Acute: Infusion-related
z Chills, fever, dyspnea, nausea, vomiting,
bronchospasm, hypotension, convulsions
z Chronic
z Nephrotoxicity
z impaired concentration, impaired urinary
acidification, K & Mg wasting with hypokalemia
and hypomagnesemia
z Normochromic, normocytic anemia
z (↓ erythropoietin)
17. Griseofulvin
z Fungistatic
z A systemic antifungal used to treat topical
ringworm infections, e.g., onychomycosis,
Tinea capitis, Tinea pedis, etc.
z many Trichophyton spp., Microsporum spp.
and Epidermophyton spp. are susceptible
z Dermatophyte infections
z Oral absorption (better with small particle size)
z Enzyme inducer
18. Mode of Action - Griseofulvin
z disrupts mitotic spindle during
metaphase by interacting with fungal
microtubules------ (-) fungal mitosis
(metaphase arrest)
z sufficient to inhibit growth of fungi (drug
is static), preventing them from invading.
19.
20. Griseofulvin-Adverse actions
z GI disturbances
z Allergic reactions
z Skin rash
z Headache
z Photosensitivity
z Angioedema
z Peripheral neuritis
21. Griseofulvin-Adverse effects (CNS)
z Lethargy
z Mental confusion
z Blurring of vision
z Vertigo
z Being an antimiototic--bone marrow
suppression, leucopenia, neutopenia
23. 2. ANTIMETABOLITES:
5-Flucytosine (5-FC)
z Flucytosine is
converted into 5-
flurouracil, which
inhibits thymidylate
synthetase leading to
inhibition of DNA
synthesis
(antimetabolite action)
z All susceptible fungi are
capable of deaminating
flucytosine to 5-
flurouracil
24. 3. AZOLES
‰ Better CSF
penetrability
‰ High volume of
distribution
‰ Dermatophytes,
candida and other
deep mycoses
‰ Triazoles are greater
efficacy/lesser side
effect and drug
interaction
25. 14- α demethylase
Mechanism of Action:
Acetyl CoA Squalene
Lanosterol
Ergosterol
Azoles
Squalene-2,3 oxide
Squalene-2,3
epoxidase
29. Ketoconazole
z Spectrum: yeasts and moulds - poor absorption
limits its role for severe infections, generally
used in mucosal infections only
z Pharmacokinetics
z Variable oral absorption, dependent on pH (often
given with cola or fruit juice)
z T1/2 7-10 hours
z Protein binding > 99%
z Hepatic, bile and kidney elimination
z H2 blockers, antacids--- decrease absorption
30. 9Hepatoxicity (2-8%)- increase in
transaminases, hepatitis
9Dose related inhibition of CYP
P450- responsible for
testosterone synthesis
9Dose-related inhibition of CYP
P450 -responsible for adrenal
cortisol synthesis
31. 4. ALLYLAMINE: Terbinafine
z It causes non-
competitive inhibition
of squalene epoxide
enzyme, which is
involved in the
synthesis of
ergosterol by fungi
Squalene-2-3- epoxidase
32. Mechanism of Action:
14-α demethylase
Acetyl CoA Squalene
Lanosterol
Ergosterol
Squalene-2,3 oxide
Squalene-2,3
epoxidase
Allylamines
33. 4. ALLYLAMINE: Terbinafine
z A highly lipophilic, keratinophilic
z Effective orally against dermatophytes
and candida
z Useful in fungal infections of nails (6-12
weeks)
z Adverse effects:- gastric upset, rashes
and taste disturbances
z Rarely hepatotoxicity
34. 5. OTHER TOPICAL AGENTS:
z White field’s ointment = Benzoic acid
(6%) + Salicylic acid (3%)
z Tolnaftate: Tinea corporis, cruris
z Ciclopirox: Dermatophytes, candida
Malassezia furfur
z Selenium Sulfide: Malassezia furfur
z Haloprogin: Dermatophytes, candida
36. What are the targets for antifungal
therapy?
Cell membrane
Fungi use principally ergosterol
instead of cholesterol
Cell Wall
Unlike mammalian cells, fungi
have a cell wall
DNA Synthesis
Some compounds may be
selectively activated by fungi,
arresting DNA synthesis.
Atlas of fungal Infections, Richard Diamond Ed. 1999
Introduction to Medical Mycology. Merck and Co. 2001
