Download 1- Systemic antifungals

ANTIFUNGALS
IHAB YOUNIS,M.D.
Classification
1- Systemic antifungals
2-Topical antifungals
1- Systemic antifungals
Oral antifungal medications may be
required for a fungal infection if :
• It is extensive or severe
• It resists topical antifungal therapy
• It affects hair-bearing areas (tinea
capitis and tinea barbae)
Medications only suitable for
dermatophyte infections
• Griseofulvin
• Terbinafine
Griseofulvin
)Ultragriseofulvin® , Fulvin ® 125 mg)
• It has been available since 1958
• It comes from the mould, Penicillium
griseofulvum
• It is fungistatic i.e. stops fungal cells
dividing but does not kill them outright.
This means treatment needs to be
continued for several weeks or months
• It is not very well absorbed from the
gut so, should be taken after a meal or
milk as fat increases the absorption
• The medication is carried into the skin
by sweat and within a couple of weeks
is concentrated in the outer skin layers
• Half the medication is cleared from the
blood stream in 10 to 20 hours. This
means that:
– the medication can be taken once daily
– Griseofulvin should be continued until the
fungal infection has completely gone
because the medication is quickly cleared
from skin and hair when it is stopped
Dose regimen
• Adults: 330-375 mg daily
• Children: 10: 25 ultramicrosize/kg/d
Duration:
• Tinea pedis, Tinea cruris, tinea
manuum, tinea corporis etc. for 2: 6
weeks
• Tinea capitis for at least 6: 8 weeks
(longer for M canis)
• Tinea unguium for 12: 18 months until
all signs of nail infection have gone
Drug interactions
• H2 antagonists should not be taken for
2 hours after griseofulvin because they
might otherwise stop its absorption
• Griseofulvin reduces the action of:
– Warfarin
– Oral contraceptives (increasing the chance
of pregnancy)
Side effects
• Headaches
• Gastrointestinal upset
• Rashes including urticaria,LE
• Urinary frequency, bed wetting
• Blurred vision, dizziness, depression
• Menstrual disturbance
• Liver disturbance
• Males should not father children within
6 months of treatment with griseofulvin
as it may damage sperm cells
• C - Safety for use during pregnancy:
has not been established.It was found to
be teratogenic to pregnant rats; therefore, so
should not be prescribed for women
contemplating pregnancy
Terbinafine
(Lamisil ®, Turbin ® 125, 250 mg)
• It is an allylamine medicine
• It inhibits a fungal enzyme, squalene
epoxidase, and stops the cells making
ergosterol, the main component of the cell
wall
• It is absorbed well, with or without food
• It may persist in the skin for up to 8 weeks
after the drug has been discontinued and in
the nails for up to a year
Dose regimen
• The oral dose for adults is 250 mg daily
• For children:
– Weight 10-20 kg, 62.5 mg per day
– Weight 20-40 kg, 125 mg per day
– Weight >40 kg, 250 mg per day
• Duration
• Tinea corporis, tinea cruris, tinea
pedis, tinea manuum: 1 to 4 weeks
• Tinea unguium: for 6-8 weeks
(fingernails) or 3-4 months (toenails)
Side effects
• GIT: Nausea, feeling of fullness, diarrhoea,
abdominal pain, taste disturbance, loss of
appetite
• Headache
• Dizziness
• Abnormal liver function tests
• Reduced neutrophil white blood cell count
• Allergic skin rash including urticaria and
erythema multiforme major (toxic epidermal
necrolysis)
• Terbinafine should not be taken in pregnancy
or during breast-feeding
• Terbinafine does not generally alter the
concentration of other medications
Broad spectrum
antifungals (Azoles)
Ketoconazole
(Nizoral,Kizole,200 mg tab)
• Ketoconazole was introduced in 1981
• It is a broad-spectrum synthetic antifungal
• Its use has now been limited because other
drugs available are less hepatotoxic
• It binds to the fungal p450 enzymes and
stops the cells making ergosterol, the main
component of the cell wall
• It is better absorbed orally when it is
taken with a fatty meal or acidic drink
(e.g. orange juice)
• It takes three to ten hours for half of
the medication to be cleared from the
blood stream
• It reaches the surface of the skin
through normal blood circulation, sweat
and sebum in very high concentrations
Dose regimen
• In adults is 200 - 400 mg daily are
• The dose in children is usually 50 mg per day
for those weighing less than 20 kg and
100mg daily for those 20-40 kg
Duration
• Taken for two to eight weeks
• A single dose may be effective for pityriasis
versicolor
• Nail infections are treated for up to twelve
months
Side effects
• Hepatotoxicity is reported to occur in 1 of
12,000 patients
• Abnormal liver function tests (15%)
• The main side effects are gastro-intestinal and
occur in 5-10% of patients
• Testosterone
gynecomastia
• C - Safety for use during pregnancy has
not been established
• Although only excreted in tiny amounts from
breast milk, it should only be taken by a breastfeeding mother if essential
Drug interactions
• As ketoconazole needs acid for its absorption,
antacids, H2 antagonists should not be taken
for 2 hours after it
• Ketoconazole may increase the concentration
of these drugs and enhance their effect:
• Warfarin,methyl prednisolone, ciclosporin,
antidiabetic sulphonylurea medication
(tolbutamide, glibenclamide, gliclazide,
glipizide)
• The following drugs markedly decrease
the concentration of ketoconazole:
Rifampicin, isoniazid, phenytoin
Ketoconazole is not thought to interact
with the oral contraceptive pill
Itraconazole
(Sporanox, Itrapex, 100 mg)
• Mode of action :Like ketokonazole
• The medication is better absorbed orally
when it is taken with a fatty meal or acidic
drink (e.g. orange juice)
• It is bound to proteins such as albumin in the
circulating blood and becomes concentrated
in fat cells and within skin and nails
• It takes one to three days for half of the
medication to be cleared from the blood
stream
• Skin concentrations may be 3 to 10-fold
higher than those in the blood. It may persist
in the skin for up to 4 weeks after the drug
has been discontinued and in the nails for up
to a year
Dose regimen
• Tinea corporis, tinea cruris , tinea pedis, tinea
manuum : 200 mg daily for one week OR
100mg daily for 2 weeks
• Vulvovaginal candidiasis: 200 mg twice daily
for one day OR 200 mg daily for 3 days
• Oral candidiasis: 100 mg daily for two weeks
• Tinea unguium: 200 mg/day for 6-8 weeks
(fingernails) or 3-4 months (toenails), OR 200
mg twice daily for 7 days, repeated monthly
for 2 months (fingernails) or 3-4 months
(toenails)
Side effects
• Nausea, vomiting and constipation (5%)
• Headache
• Abnormal liver function tests (up to 5% for
those on long term therapy, 2% for pulse
therapy); significant liver disease is rare
• Allergic skin rash including urticaria
• Endocrine effects gynecomastia
• Should be used with caution in those with
heart problems
• Itraconazole should not be taken in
pregnancy. Although only excreted in tiny
amounts from breast milk, it should only be
taken by a breast-feeding mother if essential
Drug interactions
• The dose of these drugs should be
reduced:
– Warfarin
– Digoxin
– Methyl prednisolone
– Ciclosporin
– Tacrolimus
• The dose of these drugs may need
reducing if side effects arise:
– Quinidine
– Calcium channel blockers
– Antidiabetic sulphonylurea medication
(tolbutamide, glibenclamide, gliclazide,
glipizide)
• The following drugs decrease the
concentration of itraconazole:
–
–
–
–
Rifampicin
Isoniazid
Phenytoin
Carbamazepine
• Itraconazole is not thought to interact
with the oral contraceptive pills
Fluconazole
(Difflucan, Flucoral,
50 & 150 mg cap)
• Fluconazole binds to the fungal p450
enzymes and stops the cells making
ergosterol, the main component of the cell
wall
• Oral absorption is not altered by gastric
pH. It takes 22 to 30 hours for half of the
medication to be cleared from the blood
stream and may take several days of
continuous treatment to reach a steady
concentration
• The drug is eliminated unchanged in the
urine so doses should be reduced if there is
kidney disease
Drug interactions
• As itraconazole
Side effects
• As itraconazole
Dose regimen
• For vulvovaginal candidiasis, a single oral
dose of fluconazole 150 mg is usually
effective. It can be repeated
• For dermatophyte infections and pityriasis
versicolor, either 50 mg daily or 150 mg once
weekly is taken for two to six weeks
• Larger doses (up to 400 mg daily) are
required for systemic infections.
• Fluconazole is not normally used in children
but doses of 5 mg/kg/day have been safely
prescribed for serious infection
2-Topical antifungals
• They are applied to the affected area
twice daily
• For two to four weeks and continued for
one or two weeks after the last visible
rash has cleared
• Including a margin of several
centimetres of normal skin
• Repeated treatment is often necessary
Types
I- Azoles
They inhibit synthesis of ergosterol,which is
necessary for the formation of fungal cell
membranes. They are fungistatic
•
•
•
•
•
•
Clotrimazole (Canesten, Dermatine)
Miconazole (Daktarin, Miconaz)
Tioconazole (Trosyd, Tiocon)
Ketoconazole (Nizoral, Ketoderm)
Econazole (Pevaryl, ecoderm)
Seratoconazole (Dermofix)
II- Allylamines
These also act by inhibiting the formation
of ergosterol but block synthesis at an
earlier stage in the pathway than
imidazoles, namely between squalene and
squalene epoxide
• Terbinafine (Lamisil, Terbin)
• Naftifine )Exoderil)
III- Others
• Ciclopirox (Batrafen)
• Whitefield ointment (Salicylic acid3%
Benzoic acid 6%(
• Tolnaftate (Tinea cure)