Antifungal Agents
Introduction:
➢ Used to kill or inhibit
the growth of fungus in
the body of the host.
➢ Produced in a
remarkable number
because of broad
spectrum, oral
bioavailability and low
toxicity.
Amphotericin-B
• Toxic systemic antifungal antibiotics produced
by Streptomyces nodosus in 1950.
• Has no antibacterial action.
• Highly protein bound drug.
• Can’t cross the BBB.
Chemistry:
• An amphoteric polyene macrolide.
• Heptane macrolide containing seven conjugated
double bonds in the trans position & 3-amino-3,6-
dideoxymannose connected to the main ring by a
glycosidic bond.
• Insoluble in water.
Antifungal Spectrum:
❑ Fungicidal or fungistatic
❑ Effective against a wide range of fungi including -
Candida albicans
c
h Histoplasma capsulatum
c Cryptococcus neoformans
c
b Coccidioides immitis
Blastomyces dermatitidis.
❑ Many stains of aspergillus.
Mechanism of Action:
Amphotericin + Ergosterol (sterol found in cell
membranes of fungi)
(Fungal cell membrane)
Deformity of fungal cell membrane
Forms a pore in the membrane
(transmembrane ion channels)
Leakage of intracellular ions and enzymes
Fungal cell death
Pharmacokinetics:
➢ Administration: Oral, Parenteral and topical
➢ Absorption:
Poorly absorbed: GIT
➢ Distribution:
Extensively bound to plasma protein (90%)
High conc. : inflammatory exudates liver and
spleen
Low conc.-Kidney, lungs, CSF, vitreous humor or
amniotic fluid
Metabolism: Hepatic
➢ Excretion:
2%-5% appears in the urine. Some are eliminated
via bile.
Indication:
✓ All life-threatening mycotic infections.
✓ Fungal meningitis.
✓ Cutaneous candidiasis
✓ Candida cystitis
✓ Fungal injection in the gut
✓ Thrombocytopenia
✓ Arachnoiditis
Adverse Effect:
• Nephrotoxicity • Weight loss
• Hypocalcemia • Joint pain
• Fever with chill • Thrombophlebitis
• Headache • Anemia
• Nausea • Hypertension
• Vomiting • Renal impairment
• Malaise • Tachypnea
Resistance:
• Infrequent
• Associated with decreased ergosterol content
of the fungal membrane or replace ergosterol
with steroids.
• Some isolates of Candida lusitaniae and
Aspergillus terreus are resistant to
amphotericin B.
Dosage:
Parental:
Conventional Formulation: 50mg powder
injection
Tablet Formulation:
Abelect: 100mg/20ml suspension for injection.
Ambiosome: 50mg powder for injection.
Amphotec: 50, 100mg powder for injection.
Topical: 3% cream, lotion, ointment
Ketoconazole
• First orally active azole
• Available for the treatment of systemic
mycoses
• Inhibit mammalian cytochrome p450 enzyme.
Antifungal Spectrum:
❑ Active against many fungi, including histoplasma
Blastomyces
Candida and coccidioides.
❑ Inactive against aspergillus species
❑ Mucocutaneous candidiasis.
Mechanism of Action:
Ketoconazole
Inhibits cytochrome p450 dependent enzyme 14α-
demethylase
Blocks the demethylation of lanosterol to
ergosterol
This inhibition disrupts membrane structure and
function
Inhibits fungal cell growth.
Pharmacokinetics:
Properties Ketoconazole Itraconazole Fluconazole Voriconazole
1. Spectrum Narrow Expanded Expanded Expanded
2. Routes of Oral Oral Oral, IV Oral, IV
administration
3. t1/2 (hours) 7-10 24-42 22-31 6
4. CSF penetration No No Yes
5. Renal excretion No No Yes
6. Water solubility Low Low High High
7. Absorption Variable Variable High High
8. Elimination Hepatic Hepatic Renal Hepatic
9. Interaction with Frequent Occasional Occasional
other drugs
10. Inhibition of Dose dependent No inhibitor No inhibitor
mammalian sterol inhibitory effect
synthesis
Adverse Effects:
✓ Allergies
✓ gastro-intestinal disturbances
✓ Nausea
✓ Anorexia
✓ Vomiting
✓ Gynecomastia
✓ decreased libido
✓ menstrual irregularities
Resistance:
• Particularly in the protracted therapy (HIV
infection)
• Mutations in the C-14 α-demethylase gene, which
cause decrease in azole binding.
• Some strains of fungi have developed the ability
to pump the azole out of the cell.
Drug Interactions:
• Ketoconazole can potentiate the toxicities of drugs such
as cyclosporine, phenytoin, tolbutamide, warfarin by
inhibiting cytochrome p450.
• Rifampin can shorten the duration of action of
Ketoconazole & the other azoles by inducing the
cytochrome p450 system.
• H2 blockers, antacids, proton- pump inhibitors as well as
sucralfate can decrease absorption of Ketoconazole.
• Ketoconazole & amphotericin B should not be used
together because the decrease in ergosterol in the
fungal membrane reduces the fungicidal action of
amphotericin B.
• Ketoconazole teratogenic in animals & should not be
given during pregnancy.
Terbinafine
• Terbinafine is a synthetic alkylamine
• Highly lipophilic, keratinophilic agent
• Active against wide range of skin pathogens.
• discovered in 1990.
Mechanism of Action:
Inhibits fungal squalene epoxidase (monooxygenase)
Decreases the synthesis of ergosterol
Accumulation of toxic amounts of squalene
Fungal cell becomes death
Pharmacokinetics:
1) Administration: Oral, Cutaneous
2) Bioavailability: Only 40%, due to first pass
metabolism
3) Distribution: 99% bound to plasma protein
Deposited in the skin, nails & fat
4) t1/2: 12hrs
5) Metabolism: Liver
6) Excretion: Urine
Antifungal Spectrum:
• Fungicidal
• Limited to Candida albicans & Dermatophytes
Drug Interactions:
Terbinafine + Rifampin - Decreases blood level
Terbinafine + Cimetidine - Increases blood level
Indications:
• Dermatophytoses (skin infection)
• Onychomycoses (nail infection)
• Ring worm.
Contraindications:
• Nursing mother
• Moderate renal impairment
• Hepatic cirrhosis
Adverse Effects:
1)Gastrointestinal disturbances
✓Diarrhoea
✓Dyspepsia
✓Nausea
2) Headache
3) Rash
4) Taste & Visual disturbance
5) Hepatotoxicity
6) Neutropenia
Dose:
• oral- 250 mg tablet daily
• Topical- 1% cream gel
Thank you
