ANTIFUNGAL

ANGENTS

Antifungal agents :
Systemic
Topical

SYSTEMIC
ANTIFUNGAL
AGENTS

Amphotericin B
Amphotericin B a strain
of Streptomyces nodosus,
an aerobic actinomycete.

Chemistry
Amphoterixin B a family of
polyene macrolide
antibiotics.
Characteristic an internal
cyclic ester, poor aqueous
solubility, substantial
toxicity.

Drug Formulations
Amphotericin B insoluble in
water formulated intravenous
infusion.
Complex marketed as a
lyophilized powder containing
50 mg of amphotericin B, 41
mg, and small amount of
sodium phosphate buffer.

Antifungal Activity
Amphotericin B Candida
spp., Cryptococcus
neoformans, Blastomyces
dermatitidis, Histoplasma
capsulatum, Sporothrix
Aspergillus spp., Penicillium
marneffei, and the agents of
mucormycosis.

Mechanism of Action
Depends at least on its
binding ot a sterol moiety,
is present in the
membrane of sensitive
fungsi.

Their interaction with the

sterols of cell membranes, to
form pores or channels an
increase in the permeability
of the membrane, allowing
leakage of a variety of small
molecules.
Additional mechanisms of
action oxidative damage to
fungal cells.

Absorption, Distribution, Excretion

Absorption negligible.
Drug released from its
complex with deoxycholate in
the bloodstream, remains in
plasma is more than 90%
bound to proteins, largely Blipoprotein.

Approximately 2 - 5% of
each dose appears in the
urine.
Elimination unchanged in
anephric patients and in
patients receiving
hemodialysis.

Concentrations in fluids from

inflamed pleura, peritoneum,
synovium, and aqueous
humor approximately twothirds of tough concentratons
in plasma.

Therapeutic Uses
Usual therapeutic dose 0.5
0.6 mg/kg, administered in 5%
glucose over 4 hours.
Candida esophagitis in adults
responds to 0.15 0,2 mg/kg
daily.
Mucormycosis or invasive
aspergillosis treated with
doses of 1.0 1.2 mg\kg.

Intrathecal infusion useful in

patients with meningitis
caused by Coccidioides.
Treatment is begun with 0.05
0.1 mg, increased on a
three-times-a-week schedule
to 0.5 mg continued on a
twice-a-week.

Untoward Effects
Fever and chills.
Hypernea, respiratory
stridor or modest
hypotension.
Hypoxia or hypotension.
Azotemia.
Toxicity.
Renal tubular acidosis.

 Hypochromic, normocytic
anemia.
Headache, nausea,
vomiting, nausea, weight
loss, phlebitis at peripheral
infusion sites
Encephalopathy.
Thrombocytopenia, mild
leukopenia.

Flucytosine
Chemistry
Flycytosine
fluorinated pyrimidine
fluorouracil and
floxuridine.

Antifungal Activity
Clinically activity againts
Cryptococcus
neoformans, Candida
spp., and the agents of
chromomycosis.

Mechanism of Action
All susceptible fungi capable
of deaminating flucytosine to
5-fluorouracil, potent
antimetabolite.
Fluorouracil metabolized first
to 5-fluorouridylic acid by the
enzyme uridine
monophosphate (UMP)
pyrophosphorylase.

Absorption, Distribution, Excretion

Absorbed rapidly, well from
the gastrointestinal tract.
Widely distributed in the
body, with a volume of
distribution that
approximates total body
water.

The drug is minimally bound

to plasma protein.
Peak plasma concentration
approximately 70 80
ug/ml, achieved 1 2 hours
after a dose of 37,5 mg/kg.

Approximately 80% of a
given dose ix excreted
unchanged in the urine;
concentration in the urine
range from 200 500 ug/ml.
Half-life of the drug 3 6
hours in normal individuals.
In renal failure, the half-life
may be as long as 200 hours.

Flucytosine is cleared by
hemodialysis, patient
undergoing such treatment
receive a single dose of 37.5
mg/kg after dialysis, drug also
is removed by peritoneal
dialysis.
Flucytosine in CSF about 65
90%.
Drug appears into the aqueous
humor.

Therapeutic Uses
Flucytosine given orally in
amounts of 100 150
mg/kg/day, devided into 4
doses at 6-hours intervals.
Flucytosine used in
combination with
amphotericin B.

Untoward Effects
Depress the function of
bone marrow leukopenia
and thrombocytopenia.
Rash.
Nausea & vomiting.
Diarrhea.
Severe enterocolitis.

Approximately 5% of
patients, plasma levels of
hepatic enzymes increase.
Toxicity in patients with
AIDS or azotemia and
concentration in plasma
exceed 100 ug/ml.

Imidazoles & Triazole

Systemic triazoles
slowly metabolized less
effect on human sterol
synthesis.

Antifungal Activity
Azoles clinically activity
againts C.albicans,
C.tropicalis, C.glabrata,
C.neoformans, B.dermatitidis,
H.capsulatum, C.immitis,
Paracoccidioides brasiliensis,
ringworm fungi
(dermatophyes), Aspergillus
spp., S.schenckii.

Mechanism of Action
Inhibition of sterol 14-ademethylase, a microsomal
cytochrome P450-dependent
enzyme system impair the
biosynthesis of ergosterol for
the cytoplasmic membrane
accumulation of 14-amethylsterols.

Disrupt the close packing of

acyl chains of phospholipids,
impairing the functions of
certain membrane-bound
ensyme systems, enzymes of
the electron inhibiting
growth of the fungi.

Ketoconazole
Absorption, Distribution, Excretion
Oral
absorption
among individuals.

varies

Depressed :
1.Patient taking H2-histamine
receptor blocking
2.Simultaneous administration
of anticids.

After oral doses of 200, 400

& 800 mg, peak plasma
concentration of
ketoconazole approximately
4, 8 & 20 ug/ml.
The half-life of the drug
increases with dose, and as
long as 7 8 hours the
dose is 800 mg.

Ketoconazole metabolied
extensively, the inactive
products appear in the feces.
Concentration of active drug
in urine are very low.
In blood 84% of ketoconazole
is bound to plasma (albumin)
15% is bound to erythrocytes,
1% is free.

Concentration of ketoconazole in
the CSF of patients with fungal
meningitis less than 1% of the
total drug concentration in
plasma.
Rifampisin, isoniazid by
phenytoin eccelarates
metabolic clearance,
concentration of the antifungal
agent may be reduced by more
than 50%.

Therapeutic Uses
Effective in blastomycosis,
histoplasmosis,
coccidioidomycosis,
pseudallescheriasis,
paracoccidioidomycosis,
ringworm, tinea versicolor,
chronic mucocutanous
candidiasis.

Candida vulvovaginitis, and

oral & esophageal candidiasis.
Usually adult dose 400 mg
taken once daily.
Children 3.3 6.6 mg/kg/d.
Duration of therapy is 5 days
for Candida vulvovaginitis, 2
weeks of Candida esophagitis,
6 12 months for deep
mycoses.

Untoward Effects
Dose-dependent nausea,
anorexia, vomiting.
Allergic rash.
Hair loss.
Menstrual irregularities.
Gynecomastia and
decreased libido & potency.
Azoospermia.

 Hypertension & fluid

retention.
Elevation of
aminotransferase activity.
Symptomatic drug-induced
hepatitis.
Use durating pregnancy
not recommended.

Itraconazole
Absorption, Distribution, Excretion
Available as a capsule,
two solution formulation
oral, intravenous
administration.

Capsule form best absorbed

in the fed state, oral solution
better absorbed in the
fasting state, peak plasma
concentration >> 150% with
the capsule.
Intraconazole metabolized in
the liver, by the cytochrome
CYP3A4 isoenzyme system
inhibits the metabolism of
other drugs by CYP3A4.

Native drug and metabolite

99.8% and 99.5% bound to
plasma proteins.
Half-life 30 40 hours.
Liver disease increase
intraconazole plasma
concentration.
80 90% of intravenously
excreted in the urine.

Drug Interaction
Fatal cardiac arrhythmias
with cisapride, quinidine,
or astemizole.

Therapeutic Uses
The drug of choice for
patients with indolent,
nonmeningeal infections due
to B.dermatitidis,
H.capsulatum, P.brasiliensis,
C.immitis.

Intravenous formulation
the initial two weeks of
therapy with
blastomycosis,
histoplasmosis, and
indolent aspergillosis.

Approximately half the

patients with distal
subungual onychomycosis
respond well.
Itraconazole solution
effective in oropharyngeal
and esophageal candidiasis.

Interaction
of
itraconazole
with other
drugs

Dosage
Deep mycoses, two 100-mg
capsules given twice daily
with food.
For the first 3 days, 200 mg
three times daily as a
loading dose.

For maintenance therapy of

HIV-infected patients with
disseminated
histoplasmosis, 200 mg once
daily.
Onychomycosis 200 mg
once daily for 12 weeks, 200
mg twice daily for one week
out of each month pulse
therapy.

Patients with
fluconazole-resistant
oropharyngeal or
esophageal thrush 100
mg twice a day for 2-4
weeks.

Untoward Effects
Gastrointestinal distress,
nausea, vomiting,
hypertriglyceridemia in 9%,
hypokalemia, increased serum
aminotransferase, rash,
hepatoxicity.
Anaphylaxis several rash,
including Stevens-Johnson
syndrome.

Fluconazole

A flluorinated bistriazole.

Absorption, Distribution, Excretion

Complete absorbed.
Concentration in plasma
same orally or intravenous.
Peaks plasma
concentration 4-8 ug/ml
after repetitive doses of
100 mg.

 Renal excretion 90% of

elimination, elimination
half-time is 25-30 hours.
Fluconazole diffuse
sputum and saliva;
concentration in CSF
50-90%.
About 11-12% of plasma
drug is protein boundg.

Interactions
Increases plasma
concentration of
astemizole, cisapride,
cyclosporine, rifampin,
rifabutin, sulfonylureas,
theophylline, tracrolimus,
warfarin.

Therapeutic Uses
Candidiasis
Fluconazole, 200 mg first
day, 100 mg daily for least
2 weeks oropharyngeal
candidiasis.
Esophageal candidiasis
100-200 mg daily.

 A single dose of 150 mg

vaginal candidiasis.
A dose of 400 mg daily
incidence of deep
candidiasis.

Cryptococcus
Fluconazole, 400 mg daily
initial 8 weeks in
cryptococcal meningitis of
AIDS.
After the 8 weeks dose
decreased 200 mg daily for
life.

Other Mycosis
Fluconazole drug of
choice for coccidioidal
meningitis.
Fluconazole activity
againts histoplasmosis,
blastomycosis,
sporotrichosis, ringworm.

Untoward Effects
Nausea, vomiting.
Headache.
Skin rash.
Abdominal pain.
Diarrhea.
Reversible alopecia.
Hepatic failure.
Steven-Johnson syndrome.

Griseofulvin
Untifungal Activity
Griseofulvin
fungistatic in vitro for
Microsporum,
Epidermophyton,
Trichophyton.

Mechanism of Action
Production of
multinucleate cells as the
drug inhibits fungal mitosis
distruption of the
mitotic spindle by
interacting with
polymerized microtubles.

Absorption, Distribution, Excretion

0.5-g dose of griseofulvin
peak plasma
concentration 1 ug/ml in
about 4 hours.
Half-life in plasma 1 day,
50% of the oral dose in
the urine within 5 days.

Therapeutic Uses
Microsporum, Trichophyton or
Epidermophyton respons to
griseofulvin.
Daily fose of griseofulvin 515 mg/kg for children, 500 mg
to 1-g for adults.
Doses of 1.5 2.0 g daily
used for short periods in
severe or extensive infectons.

Untoward Effects
Headache.
Nervous system
manifestations.
Nausea.
Vomiting.
Diarrhea.

 Heartburn.
Flatulence.
Dry mouth.
Angular stomatitis.
Hematologic effects.
Increasing metabolism
of warfarin.

Terbinafine
Synthetic allylamine.
Well absorbed,
bioavailability, decreased
about 40%.
Drug accumulates in skin,
nails, fat.
Half-life about 12 hours.

 Found in plasma for 4 8

weeks after prolonged
therapy.
A low incidence of
gastrointestinal distress,
headache, diarrhea, or rash.
Hepatotoxicity, severe
neutropenia, Steven-Johnson
syndrome, toxic epidermal
necrolysis.

 Mechanism of action
inhibition of fungal squalene
epoxidase, blocking
ergosterol biosynthesis.
250-mg tablet daily
effective for oncychomycosis
of nails.
Duration of treatment the
nail 3 months.

TOPICAL
ANTIFUNGAL
AGENTS

Imidazole & Triazole

Indications for topical
use ringworm, tinea
versicolor,
mucocutaneous
candidiasis.

Cutaneous Applications
Effective for tinea corporis,
tinea pedis, tinea cruris,
tinea versicolor, cutaneous
candidiasis.
Applied twice a day for 3
6 weeks.

Vaginal Applications
Vaginal cream, suppositories,
tablets choice for vaginal
candidiasis.
Used once a day, at bedtime
administered in 5-g.
Approximately 3-10% of the
vaginal dose absorbed.
Side effect vaginal burning
or itching.

Clotrimazole
Absorption less than 0.5%
after application to the
intact skin; from the
vagina, it is 3-10%.
Fungicidal concentration
remain in the vagina 3
days after application.

 Clotrimazole
stinging, erythema,
edema, vesication,
desquamation,
pruritus, urticaria.

Therapeutic Uses
Available as a 1% cream,
lotion, solution, 1% or
2% vaginal cream or
vaginal tablets of 100,
200, or 500 mg.

 For the vagina, 100-mg

tablet once a day at
bedtime for 7 days, 200-mg
tablet daily for 3 days, 500mg tablet inserted only
once, 5-g of cream once a
day for 3 days (2% cream)
or 7 days (1% cream).

Econazole
Econazole nitrate
available as a watermiscible cream (1%) to
be applied twice a day.

Miconazole
Miconazole penetrates
the stratum corneum of
the skin, persists more
than 4 days.
Less than 1% is
absorbed into the blood.

 Absorption is 1.3% from

the vagina.
Adverse effects topical
application the vagina
burning, itching or
irritation.
Miconazole safe for use
during pregnancy.

Therapeutics Uses
Available as a dermatologic
ointment, cream, solution,
spray, powder, or lotion as
2% and 4% vaginal cream, as
100-mg suppositories,
applied in the vagina at
bedtime for 7 days, 200-mg
vaginal suppositories for 3days therapy.

Terconazole & Butoconazole

Mechanism of action is
similar imidazole.
80-mg vaginal suppository
at bedtime for 3 days, 0.4%
vaginal cream 7 days, 0.8%
cream for 3 days.
Butoconazole nitrate available
as a 2% vaginal cream, used at
bedtime for 3 days.

Tioconazole
A single 4.6-g dose of
ointment containing
6.5% drug at bedtime.

Ciclopirox Olamine
Ciclopirox olamine
broad-spectrum
antifungal activity.
Fungicidal C.albicans,
E.floccosum, M.canis,
T.mentagrophytes,
T.rubrum.

 Less than 1.5% absorbed

into the systemic
circulation.
Half-life is 1.7 hours.
Available as a 1% cream &
lotion for the treatment of
cutaneous candidiasis and
for tinea corporis, cruris,
pedis, versicolor.
Not topical toxicity.

Haloprogin
Halorogin halogenated
phenolic.
Fungicidal
Epidermophyton,
Pityrosporum,
Microsporum,
Trichosporum, Candida.

 Irritation, pruritus,
burning sensation,
vesiculation, maceration,
sensitization occur.
Poorly absorbed through
the skin.
Applied twice a day for 2
4 weeks.

Tolnaftate
Thiocarbamate.
Effective T.rubrum,
T.mentagrophytes,
T.tonsurans, E.floccosum,
M.canis, M.audouinii,
M.gypseum, M.furfur,
ineffective candida.

 Availble in a 1%
concentration as a cream,
gel, powder, aerosol
powder, topical solution
or as a topical aerosol
liquid.
Applied : twice a day.

Naftifine
Allylamine.
Naftifine inhibit
squelene-2,3-e[pxodase
inhibit fungal biosythesis
of ergosterol.
Available as a 1% cream or
gel twice-daily
application.

Terbinafine
Terbinafine cream
applied twice daily,
effective in tinea
corporis, tinea cruris,
tinea pedis.
Less active againts
Candida species and
M.furfur.

Polyene Antifungal
Antibiotics
Nystatin
Nystatin is similar to
amphotericin B.
Nystatin not absorbed
from the gastrointestinal
tract, skin, or vagina.

 Nystatin useful only for

candidiasis.
Topical preparation,
ointment, creams,
powders, contain 100,000
U/g.
Applied two or three times
a day.

 Vaginal tablets containing

100,000 U once daily
for 2 weeks.
Oral suspension
contains 100,000 U of
nystatin per mililiter is
giver four times a day.
Oral tablets containing
500,000 U.

Miscellaneous Antifungal
Agents
Undeclyenic acid
10-undercenoic acid, 11carbon unsaturated.
A yellow liquid a
characteristic rancid
odor.

 Undeclyenic acid
available in a foam,
ointment, cream,
powder, spray powder,
soap, liquid.
Zinc undecylenate
combination with other
ingredients.

 Compound undecylenic
acid ointment contains
undecylenic acid (about
5%), zinc undecylenate
(about 20%).
Undecylenic acid
preparation used in the
treatment of various
dermatomycoses,
especially tinea pedis.

 Also for use in the

treatment of diaper
rash, tinea cruris, and
other minor
dermatologic
conditions.

Benzoic acid and Salicylic acid

Known as whitefields
ointment combines
the fungistatic action of
benzoate with the
keratolytic action of
salicylate.

 Benzoic acid and salicylic

acid in a ratio of 2 to 1
(usually 6% to 3%).
Used mainly in the
treatment of tinea pedis.
Also used to treat tinea
capitis.