ANTIFUNGAL DRUGS

DR.PADMAJA.S,
SENIOR RESIDENT,
DEPARTMENT OF PHARMACOLOGY, CHRI.
INTRODUCTION

 Fungi are eukaryotic organisms

 Rigid cell walls composed largely of chitin

 Fungal cell membrane contains ergosterol

 Infectious diseases caused by fungi are called Mycoses – cutaneous/subcutaneous/systemic

POLYENES – AMPHOTERICIN B

 Amphotericin B Amphotericin B binds with ergosterol

 Naturally occurring polyene - Streptomyces

Forms pores/channels in the cell membrane
nodosus

 Drug of choice for the treatment of several life-

Pores disrupt the membrane function & cellular
threatening mycoses contents leak out

Leading to cell death

 Amphotericin B – cidal /static
 Effective against - Candida albicans,
Histoplasma capsulatum, Cryptococcus
neoformans, Coccidioides immitis,
Blastomyces dermatitidis, and many strains of
Aspergillus.
 AMB is also active on various species of
Leishmania, a protozoa.
 PK – not absorbed orally; iv preparations
 Bound to plasma proteins, 60% metabolized in
liver, t1/2 15 days & Excretion occurs slowly
both in urine and bile.
 C-AMB is available as dry powder along with
deoxycholate (DOC)
 Liposomal amphotericin B (L-AMB)
L-AMB: SPECIAL FEATURES
 It produces milder acute reaction on i.v.
infusion.

 It can be used in patients not tolerating infusion

of conventional AMB formulation.

 It has lower nephrotoxicity & minimal

anaemia.

 It delivers AMB particularly to

reticuloendothelial cells in liver and spleen 
especially valuable for kala azar and in
immunocompromised patients
 USES:
 D-D interactions:

 Oral, vaginal & cutaneous candidiasis, fungal

 Flucytosine (5-FC) has supra additive action
corneal ulcer and otomycosis. with AMB (AMB increases the penetration of
 Systemic mycoses 5-FC into the fungus)
 Febrile neutropenia  Aminoglycosides, vancomycin, cyclosporine 
 Leishmaniasis increase renal toxicity
ECHINOCANDINS
(CASPOFUNGIN / MICAFUNGIN / ANIDULAFUNGIN)

MOA: Interfere with the synthesis of the fungal cell wall

inhibiting the synthesis of β(1,3)-d-glucan

lysis and cell death (fungicidal)

ECHINOCANDINS
 Not absorbed orally, so infused i.v.
 Extensive metabolism
 T1/2 10 hours
 Dose  70 mg loading dose infused i.v. over
one hour, followed by 50 mg i.v.
 Uses:
 Deep and invasive candidiasis
 Esophageal candidiasis and salvage therapy of
nonresponsive invasive aspergillosis
 Adverse effects:
 Phlebitis, rash, vomiting, dyspnoea,
hypokalemia and joint pain
HETEROCYCLIC BENZOFURAN - GRISEOFULVIN
 Fungistatic, active against Epidermophyton,
Trichophyton & Microsporum
 selective toxicity  Dermatophytes actively
concentrate it
 MOA: Griseofulvin interferes with mitosis—
multinucleated and stunted fungal hyphae are
produced
 It also causes abnormal metaphase
configurations.
 Binds to polymerized microtubules and
interferes with their function.
GRISEOFULVIN

 PK: Irregular absorption very low water  ADR: Headache, g.i.t. disturbances.
solubility.
 Rashes, photoallergy & Gynaecomastia
 Absorption is improved by taking along with
 Uses: Dermatophytosis
fats and by micro fining the drug particles
 Dose  125–250 mg QID with meals.
 Ultramicrofine preparations
 Interactions  induces CYP450 enzymes and
 Griseofulvin - deposits in keratin forming cells
of skin, hair and nails hastens warfarin metabolism.
 Efficacy of oral contraceptives may be lost.
ANTIMETABOLITE – 5 FLUCYTOSINE (5-FC)

 Synthetic pyrimidine antimetabolite

 Fungistatic
 5-FC is well absorbed by the oral route.
 Excretion – glomerular filtration, hence dose
adjustment is needed in renal disease.
 Chromoblastomycosis, Candidiasis &
cryptococcosis
 ADR: reversible neutropenia,
thrombocytopenia, and dose-related bone
marrow depression, GI disturbances &
reversible hepatic dysfunction
AZOLE DRUGS

 Two groups  Imidazoles & Triazoles

 Predominantly fungistatic

 Inhibit C-14 α-demethylase  blocking

the demethylation of lanosterol to
ergosterol  disrupts membrane structure
and function  inhibits fungal cell
growth
 TRIAZOLES

 Itraconazole - Broad spectrum activity  Uses:

 Absorption is increased by food and low

gastric pH, highly protein bound
 Well tolerated with doses < 200mg/day
Dizziness, pruritis, hypokalemia &
headache
 Drug interaction – Rifampicin
 Vaginal candidiasis – 200mg od for 3 days
 Dermatophytosis – 100-200mg od for 7-15 days
 Onychomycosis – 200mg/day for 3 months
 Pityriasis versicolor
 Rare infections – paracoccidioidomycosis &
chromomycosis
TRIAZOLES

 Fluconazole - Higher degree of water solubility  Voriconazole - Oral BA is 90% and less protein
& good CSF penetration bound
 Oral BA is high – 94% & fewer drug interactions
 Inhibitor of CYP3A4 enzyme
 Wide therapeutic range – aggressive dosing
 Rashes, elevated hepatic enzymes and visual
 Uses: oropharyngeal candidiasis – 100mg/day disturbances
for 2 weeks  DOC – invasive aspergillosis
 Esophageal candidiasis – 100mg/day for 2-3
 Uses – fluconazole resistant candida,
weeks
histoplasmosis & blastomycosis
 Disseminated candidiasis, cryptococcal or
 Therapeutic levels should be between 1 and 5
coccidioidal meningitis – 200 to 400mg/day for
4-12 weeks mcg/mL.
 Fungal keratitis – 0.3% eye drops
 Posaconazole - Oral liquid formulation
 Absorption increases with fatty meals
 Intravenous and sustained acting tablet forms
are available now
 Drug interactions – increases the levels of drugs
metabolized by CYP3A4
 Therapeutic levels should be 0.5 – 1.5 mcg/ml
 First azole active against mucormycosis
 Currently licensed for therapy in invasive
aspergillosis
 prophylaxis induction chemotherapy for
leukemia & allogeneic bone marrow transplant
 Isavuconazole - New triazole and prodrug
 Available as oral & iv formulations with high
BA
 Coadministration with strong 3A4 inhibitors
(eg, ritonavir) or inducers (eg, rifampin) is not
recommended.
 Currently licensed for invasive aspergillosis
and invasive mucormycosis.
IMIDAZOLES - TOPICAL

 Clotrimazole - Most commonly used in  Econazole - Similar to clotrimazole

treatment of tinea infections  Highly effective in dermatophytosis,
 60 -100% cure rate with 2-4 weeks application otomycosis & oral thrush
 Vaginitis – once daily application for 7 days  Local irritation is the only mild adverse effect

 Oropharyngeal candidiasis – 10mg troche in the  Available as 1% ointment & 1% cream &
mouth 3-4 times/day 150mg vaginal tablet
 Local irritation and mild burning sensation
 Available as 1% cream/lotion/powder, 1% ear
drops
IMIDAZOLES

 Miconazole - Highly efficacious in tinea,  Oxiconazole - Newer topical imidazole

pityriasis versicolor, otomycosis, cutaneous &
vulvovaginal candidiasis
 Effective in tinea and vaginal candidiasis

 Good penetration through skin layers – single

application  Only local irritation is the adverse effect

 Mild cutaneous and vaginal irritation is reported  Available as 1% oxiconazole with benzoic acid
0.25% cream/lotion

 Available as 2% powder/gel/lotion/dusting
powder, 1% ear drops
IMIDAZOLE – KETOCONAZOLE (KTZ)

 Orally effective broad-spectrum antifungal drug
 Useful in both dermatophytosis and deep
mycosis.
 The oral absorption of KTZ is facilitated by
gastric acidity because it is more soluble at
lower pH.
 t½ varies from 1½ to 6 hours.
 Therapeutic concentrations are attained in the
skin and vaginal fluid.
 ADR:
 Loss of appetite, headache, paresthesia, rashes
and hair loss.
 It decreases androgen production from testes,
and displaces testosterone from protein binding
sites.
 Gynaecomastia, loss of hair and libido, and
oligozoospermia
 Menstrual irregularities in some- decrease in
estradiol
 USES
 Drug interactions: enzyme inhibitor
 Dermatophytosis
 H2 blockers & antacids reduce its absorption
 Monilial vaginitis
 Rifampicin, Phenytoin  induce its
 Dermal leishmaniasis
mettabolism
ALLYLAMINE - TERBINAFINE

 Orally and topically active against dermatophytes & candida

 Fungicidal due to accumulation of squalene within fungal cell

 Inhibits squalene epoxidase – early step

 BA < 50%, strongly plasma protein bound and has high affinity for keratin

 Concentrated in sebum, stratum corneum & nails

 T ½ is 11-16 hrs, excreted mainly via urine

 ADR: GI upset, headache, rashes & altered
taste sensation

 Topical – itching, dryness, irritation & rashes

 Uses: 1% cream twice daily in tinea

pedis/cruris/corporis & pityriasis versicolor for
2-4 weeks

 Onychomycosis and tinea capitis – orally with

250mg tablet od
OTHER TOPICAL ANTIFUNGALS

 Tolnaftate: tinea cruris/corporis: responds in 1-3 weeks

 Relapses are common; local irritation occurs
 Tinaderm 1% cream/lotion

 Ciclopirox olamine: new drug effective in tinea/dermal candidiasis/pityriasis versicolor

 Higher cure rates
 Onychomycosis – 8% nail lacquer (cure rate is low)
 Vaginal candidiasis – 1% ciclopirox cream
 Butenafine: topically used in dermatophytosis
 Efficacy is similar to topical terbinafine

 Undecylenic acid: fungistatic used topically with combination of zinc salts

 Inferior to other drugs; still used in tinea pedis/cruris & nappy rashes

 Benzoic acid: weak antifungal & antibacterial;

 Prolonged use eradicates the fungus