MECHANISM OF ACTION

AND INTERACTIONS OF
ANTIFUNGALS

Dr. Ayesha Mirza

STRUCTURE OF FUNGUS
 CLASSIFICATION

• POLYENES • ECHINOCANDINS
Amphotericin B, Nystatin Caspofungin, anidulafungin,
micafungin
• AZOLES • OTHER
Imidazoles: Ketoconazole.. Griseofulvin
Triazoles: Fluconazole,
itraconazole, voriconazole,
posaconazole, ravuconazole
• ALLYLAMINES
Terbinafine, butenafine
• FLUORINATED
PYRIMIDINE
Flucytosine
 AMPHOTERACIN B
• Naturally occurring polyene antifungal
• Available as plain, lipid complex and liposomal formulation.
• Administered via I.V infusion.
• Extensively bound to plasma proteins and distributed
throughout the body.
• Renal excretion less then 3%and some eliminated via bile.
 AMPHOTERACIN B
MECHANISM OF ACTION

• Bind to ergosterol in cell membrane.

• Formation of pores or channels.

• Increased permeability to monovalent and

divalent cations.

• Leading to cell death

MECHANISM OF ACTION OF
AMPHOTERACIN B
 INDICATIONS OF
AMPHOTERICIN B
Systemic mycosis
Candidosis
Aspergillosis
Mucormycosis
Cryptococcosis

Dose
0.4 – 1 mg/ kg /day
 SIDE EFFECTS
• Nephrotoxicity.
• Nausea.
• Vomiting .
• Headache.
• Hypotention.
• Electrolyte imbalance.
• Drowsiness.
• Generalized weakness.
 AZOLES

• FLUCONAZOLE

– Triazole antifungal.
– Availble in oral and I.V preparations.
– Absorption excellent, not gastric acidity
dependent.
– Minimal binding to plasma
proteins.
– Poorly metabolized by liver.
– Excretion via kidney.
 AZOLES
• ITRACONAZOLE
– Triazole antifungal.
– Available in oral prep.
– Well absorbed orally.
– Food increases bioavailability.
– Extensively bound to plasma proteins.
– Metabolized by liver
– 54% excreted in feces
and 34% in urine
 AZOLES
• KETOCONAZOLE

– Imidazole antifungal.
– Available in oral, shampoo and cream form.
– Food, antacids,cimitidine and rifampicin impair
absorption.
– Highly bound to plasma proteins.
– Extensively metabolized in liver .
– Inhibition of Cyt p 450 enzyme.
– Excretion mainly through bile.
 AZOLES
Mechanism of action
• Inhibition of C-14 alpha demethylase.

• Interruption of ergosterol synthesis.

• Accumulatioun of toxic intermediate sterols.

• Impaired membrane permeability ond

membrane bound enzyme activity.

• Arrest of fungal growth.

MECHANISM OF ACTION OF
AZOLES
 Indications of Fluconazole
• U.S. Food and Drug Administration indications
– Vaginal candidiasis
– Oropharyngeal and esophageal candidiasis
– Cryptococcal meningitis
– Prophylaxis against candidiasis
• Other common uses
– Onychomycosis
– Mucocutaneous canidiasis
– Tinea corporis
– Tinea pedis
– Tinea capitis
– Pityriasis versicolor
– Sporotrichosis
 Indications of itraconazole
• U.S. Food and Drug Administration
indications
– Onychomycosis due to dermatophytes
– Systemic mycoses
– Oropharyngeal candidiasis
– Esophageal candidiasis
• Other common uses
– Onychomycosis due to Candida sp.
– Tinea corporis and its sub-types
– Tinea cruris
– Tinea pedis
– Tinea capitis
 Side effects of azoles

FLUCONAZOLE
• Nausea
• Vomitting
• Hepatotoxicity
• Cardiac arrythmias

ITRACONAZOLE
• Nausea
• Vomiting
• Hepatotoxicity
• Pulmonary edema
 Side effects of azoles (cont..)

KETOCONAZOLE
• Endocrine abnormalities
• Gastrointestinal disturbance
• Hepatotoxicity
 ALLYLAMINES
TERBINAFINE
• Synthetic allylamine
antifungal.
• Available in tablet, cream and shampoo form.
• Highly lipophilic ,accumulates in skin, nails and
fatty tissue.
• Well absorbed after oral administration.
• Highly bound to plasma proteins.
• Extensively metabolized through cyt p450.
 ALLYLAMINES
Mechanism of action

• Act at an earlier step in synthesis of ergosterol.

• Inhibit enzyme squalene epoxidase

• Accumulation of toxic
sterols.

• Fungal cell death.

 MECHANISM OF ACTION
TERBINAFINE AND AZOLES
 INDICATIONS OF
TERBINAFINE
• U.S. Food and Drug Administration indications
– Onychomycosis due to dermatophytes

• Other common uses

– Onychomycosis due to Candida sp.
– Tinea corporis
– Tinea cruris
– Tinea pedis
– Tinea capitis
 Side effects of terbinafine

• Gastrointestinal disturbance

• Hepatotoxcity

• Allergic reaction
 FLUCYTOSINE
• Synthetic pyramidine.
• Originally used as an antineoplastic agent.
• Only used in combination with amphoteracin B.
• Well absorbed orally.
• Distributed through the body.
• Eliminated mainly through kidney.

• Dose 150 mg /kg /day

 FLUCYTOSINE
(5-fluorocytosine)
Cytosine permease 5-FC cytosine deaminase
5-FU
5-fluorodeoxyuridine
5-FU monophosphate
thymidylate synthase inhibitor
inhibits DNA synthesis

5-FU uracil phosphoribosyl 5-fluorouridilic acid

(FUMP)
5-fluoro-UTP
transferase (UPRTase) incorporated into RNA
disrupts protein synthesis
FUMP phosphorylation
 INDICATIONS AND SIDE
EFFECTS OF FLUCYTOSINE
• Indications
– Candidsis
– Cryptococcosis
– Chromoblastomycosis

• Side effects
– Gastrointestinal toxicity
– Hepatotoxicity
– Haematologic toxicity
 ECHINOCANDINS

Newest class of antifungal agent.

Caspofungin is the only licensed agent.

Given via intravenous route.

Metabolites excreted both via kidney and bile.

 ECHINOCANDINS
Mechanism of action

• Glucan synthesis inhibitor.

• Inhibits enzyme 1,3 beta glucan synthatase.

• Depletion of glucan polymer in fungal cell wall.

• Weak fungal cell wall ,cell death.

MECHANISM OF ACTION OF
ECHINOCANDINS
 INDICATIONS AND SIDE
EFFECTS
INDICATIONS
• Mucocutaneous candidosis
• Aspergillosis

SIDE EFFECTS
• Gastrointestinal disturbance
• Hepatotoxicity
• Flushing
 GRISEOFULVIN
• Derived from penicillin
species.
• Affective after oral
ingestion and reaches
skin and hair.
• Ingestion with high fat
diet promotes
absorption.
• Deposited in keratin
precursor cells.
• Excretion via kidneys.
MECHANISM OF ACTION OF
GRISEOFULVIN

• Accumulates in newly synthesized keratin.

• Interacts with microtubules ,disrupts mitotic spindle and

inhibits mitosis.

DOSE
• 10 mg / kg /day
 INDICATIONS AND SIDE
EFFECTS

INDICATIONS
• Dermatophytic infections

SIDE EFFECTS
• Headache
• Dizziness
• Insomnia
• Precipitation of SLE
• Photo allergic reactions
 TOPICAL ANTIFUNGALS
• IMIDAZOLES
• Clotrimazole
• Miconazole
• Ketoconazole
• ALLYLAMINE
• Terbinafine
• POLYENES
• Nystatin
• CICLOPIROX OLAMINE
 INTERACTIONS
Effects Mechanism Anti Fungal clinical Suggested
involvement management
Decreased serum concentration Decreased Ketoconazole Use solution
of azole dissolution/absor formulation of
ption of solid ketoconazole or other
Antacids H2 Receptor dosage form azole if indicated (i.e.
antagonism voriconazole)
Proton Pump Inhibitors
Sulcrafate Avoid taking antacids
within 2 hours of oral
azole therapy
Increased metabolism of azole Induction of Ketoconazole, Avoid concomitant use
Isoniazid mammalian itraconazole, of these agents if
Rifampin cytochrome-P450 fluconazole, possible. May require
Phenytoin mediated voriconazole, switch to amphotericin
Carbamazepine metabolism of posaconazole B formulation or
Phenobarbital azole echinocandin
Ritonavir (voriconazole)
 INTERACTIONS
Effects Anti Fungal Suggested clinical
Mechanism
involvement management
Increased serum Inhibition of Ketoconazole, Avoid concomitant use
concentration of if possible.
cytochrome P450 itraconazole,
co-administered voriconazole >
drug or metabolite Severity of possible
fluconazole (usual interaction is drug-
Oral hypoglycemics doses) dependent.
Wafarin
Cyclosporin
Tacrolimus
Phenytoin
Carbamezepine
Triazolam,
alprazolam,
midazolam
Diltiazem
Isoniazid
Rifampin
Quinidine
Cyclophosphamide
Digoxin
Loratidine
 INTERACTIONS
Effects Mechanism Anti Fungal Suggested clinical
involvement management
Increased Decrease filtration in Amphotericin B Most drug dosages can
accumulation of glomerular be adjusted based on
renally-cleared drugs estimates of glomerular
and/or drug vehicles filtration (i.e. creatinine
Flucytosine clearance).
Fluconazole Use of a lipid
Beta-lactams amphotericin B
and many others... formulation may help
stabilize or slow declines
in renal function.
Enhanced Enhanced glomerular Amphotericin B Minimize co-
nephrotoxicity and tubular toxicity in administration of
Aminoglycosides the kidney nephrotoxic agents
Cyclosporine whenever possible.
Intravenous Contrast Consider first-line use of
Dye lipid amphotericin B
Foscarnet and others... formulation.