Antifungal Drugs

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Antifungal Drugs By
Dr. Saad R. Abed
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Types of fungal infections

• 1- Superficial Affect skin mucous membrane.
  e.g.
• Tinea versicolor
• Dermatophytes Fungi that affect keratin layer
  of skin, hair, nail. e.g. tinea pedis , ring worm
  infection
• Candidiasis Yeast-like, oral thrush,
  vulvo-vaginitis.

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2- Deep infections/ Systemic

• Blastomyces
• Coccidiodes
• Cryptoccocus
• Histoplasma
• Sporotrichosis
• While Systemic affected Internal organs like
  brain, lung, GIT, liver, spleen, eye, etc.

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Classification of antifungal drugs

• Six groups
• 1- Antibiotics Amphotricin B,(AMB), Nystatin,
  Greiofulvin
• 2- Antimetabolities 5- Flucytosine,(5-FC),
  inhibition nucleic acid synthesis
• 3- Azoles a-Imidazoles Bifonazole,
  Clotrimazole, Econazole, Ketoconazole,
  Miconazol.
• b- Triazoles Fluconazole,
  Itraconazole, Voriconazole
• Inhibition of ergosterol synthesis.

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• 4- Allylamine Terbinafine, Naftifine
• Inhibition of Lanosterol and Ergosterol
  synthesis.
• 5- Echinocandins
• Inhibit fungal cell wall biosynthesis
• 6- Miscellaneous Antifungals Tolnaftant,
  Undecylenic acid, Benzoic acid, Ciclopirox
  olamine.

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• I. Antifungals damaging permeability
• of the cell membrane.
• Imidazoles Bifonazole, Clotrimazole, Econazole,
• Ketoconazole, Miconazole
• Triazoles Fluconazole, Itraconazole,
  Voriconazole
• Allylamines Terbinafine, Naftifine
• Morpholines Amorolfine
• Thiocarbamates Tolciclate, Tolnaftate
• Substituted pyridones Ciclopirox
• Polyene antibiotics Amphotericin B, Nystatin
• II. Antifungals inhibiting chitin synthesis in
  the cell wall.
• Caspofungin
• III. Antifungals inhibiting synthesis of nucleic
  acids
• Flucytosine

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Classification According to Route of
Administration

• Systemic
• Griseofulvin , Amphotericin- B , Ketoconazole ,
  Fluconazole , Terbinafine.
• Topical
• In candidiasis
• Imidazoles Ketoconazole , Miconazole.
• Triazoles Terconazole.
• Polyene macrolides Nystatin
• Gentian violet Has antifungal antibacterial.

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In Dermatophytes

• Squalene epoxidase inhibitors Terbinafine
• Naftifine.
• Tolnaftate.
• White field ointment 12 Benzoic acid 6
  Salicylic acid .
• Castellani paint.

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Antifungal Agents
1. Polyene Antifungal
Drugs These drugs interact with ergosterol in
the fungal cell membrane and form pores
Polyenes are related chemically to the
macrolide antibiotics with the large lactone ring
but have the distinctive characteristic of
conjugated double bonds and a lipophilic (a
chromophore of 4-7 conjugated double bonds) and
hydrophilic side (several alcohols, acids and
usually a sugar). The number of conjugated
double bonds correlates directly with antifungal
activity in vitro and inversely with the degree
of toxicity to mammalian cells. They are
unstable, only slightly soluble, and poorly
absorbed when taken orally. Amphotericin B
Nystatin (Natamycin) Pimaricin
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Mechanism of Action of Polyenes
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Amphotericin B
Amphotericin B, a polyene antibiotic, is produced
by Streptomyces nodosus. Discovered in 1956 has
been for 30 years the main available drug to
control serious fungal infections. Amp. B is
indicated for treatment of severe, potentially
life threatening fungal infections.
Unfortunately, it must be given IV and is toxic
(due to nonselective action on cholesterol in
mammalian cell membranes). Resistance is due
to lower production of membrane sterols or
altered sterols, but is relatively rare at
present. Target modification and reduced access
to target are other mechanisms of resistance.
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Amphotericin B
Disposition Amp. B deoxycholate ( Fungizone ) is
not absorbed orally. It is given by slow IV
infusion. It is highly bound to
cholesterol-lipoprotein and has a plasma T1/2 of
about 1 day and 1-2 weeks from tissues. It is
excreted in urine over a long time.
Penetration into the CNS is poor. However, for
fungal infections of the CNS, amphotericin B is
mixed with cerebrospinal fluid (CSF) that is
obtained from a spinal tap. The solution of
amphotericin is then reinjected through the tap.
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Products Amphotericin B. (Fungizone ?) 50
mg/vial with 41mg of sodium deoxycholate.
Reconstitute with water. Give a test dose and
gradually increase dose. Don't exceed
1.5mg/kg/d. Alternate day therapy is sometimes
used. Several months of therapy is usually
needed. Abelcet (Liposome Co.) 11 mixture of
amphotericin and lipid complex, 100 mg/20 ml.
Rationale for this lipid preparation is that
amphotericin B should have a greater affinity for
the lipid vehicle than for cholesterol in cell
membranes, thus lower toxicity. Lipid associated
amphotericin B is drawn into the
reticuloendothelial system, concentrating in
lymphatic tissues, spleen, liver and lungs where
infectious fungi concentrate. Lipases excreted
from fungi release drug from lipid carrier
allowing to bind to ergosterol in fungal cell
membranes to exert fungistatic and fungicidal
activities. Aphotec (Sequus Pharmaceuticals)
cholesteryl colloidal dispersion, 50 or 100 mg/20
ml. Supplied in variety of topical forms
including a 3 cream, lotion or ointment and
100mg/mL oral suspension to treat cutaneous and
mucocutaneous mycoses caused by Candida
albicans AmBiosome (Fujisawa) liposomal,
50mg/vial.
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Amphotericin B

• Adverse Effects
• Reactions on infusion - headache, fever, chills,
  anorexia, vomiting, muscle and joint pain. Pain
  at site of injection and thrombophlebitis are
  frequent complications of intravenous
  administration. Drug must never be given
  intramuscular. Can give aspirin, meperidine,
  steroids, antiemetics etc to prevent some of
  these.
• Nephrotoxicity - chronic renal toxicity in up to
  80 of patients taking the drug for prolonged
  periods. It is reversible but can be
  irreversible in high doses. Test for kidney
  function regularly. This is the most common
  limiting toxicity of the drug.
• Hematologic - hemolytic anemia due to effects on
  RBC membrane.
• Other less common reactions - cardiac,
  convulsions, neuropathy, hearing loss, allergic,
  etc.
• Some decrease in adverse effects particularly
  nephrotoxicity with liposomal preparations the
  idea with the lipid preps is to decrease
  nonspecific binding to mammalian membranes.

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Nystatin
Nystatin Isolated from streptomyces noursei in
1951. A conjugated tetraene, is the first
clinically useful polyene antifungal antibiotic.
Available in oral tablets, powder for suspension,
vaginal tablets, pastilles. This polyene is used
for local therapy only (not absorbed).
No significant adverse effects with these uses.
Combined with tetracycline to prevent monilial
overgrowth caused by the destruction of bacterial
microflora of the intestine during tetracycline
therapy. (Mycostatin ? and other generic
products)
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Natamycin
Natamycin (Pimaricin Natacyn) Polyene
antibiotic obtained from cultures of Streptomyces
natalensis. Structures consists of 26-membered
lactone instead of the 38 for Nystatin and
Amphotericin B. The 26-membered polyenes cause
both K leakage and cell lysis at same
concentration. Natamycine supplied as a 5
ophthalmic suspension intended for the treatment
of fungal conjunctivitis, blepharitis and
keratitis.
Natamycin
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Griseofulvin Antifungal antibiotic produced from
Penicillium griseofulvin. Effects on
microtubules to inhibit cell division . Inhibits
fungal mitosis by interfering with microtubule
function, distrupts mitotic spindle during
metaphse ( metaphse arrest ). Therapy must
continue until new tissue replaces old diseased
tissue. When given orally, plasma-borne
griseofulvin becomes incorporated into keratin
precursor cells and ultimately into keratin which
cannot then support fungal growth.
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Griseofulvin(cont.)

• Used to treat dermatophyte infections ( ring worm
  of skin, hair, nails ).
• Ineffective topically.
• Not effective in subcutaneous or deep mycosis.
• Fungistatic, has a narrow spectrum.
• Present as microsize and ultramicrosize
• Given orally (Absorption increases with fatty
  meal )
• Half-life 24 hours
• Taken selectively by newly formed skin
  concentrated in the keratin.
• Induces cytochrome P450 enzymes
• Should be given for 6-8weeks for skin hair
  infections to allow replacement of infected
  keratin by the resistant structure.
• Is category c in pregnancy.

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DOSAGE AND ADMINISTRATION
Adults Daily administration of 375 mg (as a
single dose or in divided doses) will give a
satisfactory response in most patients with tinea
corporis, tinea cruris, and tinea capitis. For
those fungal infections more difficult to
eradicate, such as tinea pedis and tinea unguium,
a divided dose of 750 mg is recommended.
Pediatric Use Approximately 7.3 mg per kg of
body weight per day of ultramicrosize
griseofulvin is an effective dose for most
pediatric patients. On this basis, the following
dosage schedule is suggested 16-27 kg 125 mg to
187.5 mg daily. over 27 kg 187.5 mg to 375 mg
daily. Children and infants 2 years of age and
younger - dosage has not been established. So
from 20 25 mg per kg per day ( microsize ) or
15 20 mg per kg per day ( ultramicrosize ).
Clinical experience with griseofulvin in children
with tinea capitis indicates that a single daily
dose is effective. Clinical relapse will occur if
the medication is not continued until the
infecting organism is eradicated.
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Griseofulvin

• Adverse effects
• Headache is a common adverse effect. May cause
  aplastic anemia.
• Peripheral neuritis, mental confusion, fatigue,
  vertigo, GIT upset,enzyme inducer, blurred
  vision, allergic reaction, photosensitivity,
  angioedema.
• Being an antimiototic-bone marrow suppression,
  leucopenia, neutropenia.
• Increases alcohol intoxication.

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2-Allylamine (Terbinafine)

• The drug is primarily a fungicidal agent and
  highly active against dermatophytes, but less
  active against molds, dimorphic fungi, and
  various yeasts. Drug of choice for treating
  dermatophytes (onychomycoses).
• Terbinafine inhibits the enzyme squalene
  epoxidase in the fungal cell membrane, thereby
  blocking the biosynthesis of ergosterol.
  (Squalene epoxidase, a complex, microsomal
  non-cytochrome P450 enzyme, catalyzes the first
  enzymatic step of ergosterol synthesis the
  conversion of squalene into squalene epoxide).
  Consequently, terbinafine causes an abnormal
  intracellular accumulation of squalene and a
  deficiency in ergosterol.
• (Accumulation of squalene ,which is toxic to
  the organism causing death of fungal cell).

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• Fungicidal , its activity is limited to candida
  albicans dermatophytes.
• Effective for treatment of onychomycoses
• 6 weeks for finger nail infection 12 weeks for
  toe nail infections . Terbinafine is well
  absorbed from the gastrointestinal tract, mostly
  in chylomicrons. The distribution half-life is
  1.5 hours, and the elimination half-life is
  approximately 22 hours. Terbinafine is highly
  lipophilic and keratophilic in nature and,
  therefore, is widely distributed.
• upon absorption throughout skin and adipose
  tissue. Terbinafine is extensively biotransformed
  by the liver, mostly through oxidation by a very
  small fraction of P450 isoenzymes. More than 80
  percent of the drug is excreted in urine the
  rest is eliminated with feces.

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Side Effect Contraindication

• Highly protein binding
• Accumulates in skin , nails, fat.
• Severely hepatotoxic, liver failure even death.
• Accumulate in breast milk , should not be given
  to nursing mother.
• GIT upset (diarrhea, dyspepsia, nausea )
• Taste visual disturbance.
• Terbinafine is a pregnancy category B.

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Dosage Schedules and Formulations

• Terbinafine is supplied as a 250-mg tablet
  and should be taken once daily for all regimens
  except twice-daily pulse dosing.
• Table for treatment schedules.

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TABLE Terbinafine Dosing Regimen
PEDIATRIC ADULT Onychomycosis Tinea capitis Tinea corporis, tinea cruris Tinea pedis (moccasin) Seborrheic dermatitis
3-6 mg/kg/day 6-12 wk Trichophyton infections 3-6 mg/kg/day 2-4 wkMicrosporum infections 3-6 mg/kg/day 6-8 wk 3-6 mg/kg/day 1-2 wk Fingernails 250 mg/day 6 wkToenails 250 mg/day 12 wk 250 mg/day 2-8 wk 250 mg/day 1-2 wk 250 mg/day 2 wk 250 mg/day 4-6 wk Onychomycosis Tinea capitis Tinea corporis, tinea cruris Tinea pedis (moccasin) Seborrheic dermatitis

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3-Azole Antifungal Agents
Azole antifungal agents are the largest class of
synthetic antimycotics. About 20 agents on the
market today. Some used topically to treat
superficial dermatophytic and yeast infections.
Others used systemically to treat severe fungal
infections. Antifungal activity stems from the
presence of an aromatic five member heterocyclic,
either an imidazole (two nitrogen atoms) or a
triazole (three nitrogen atoms)
The first members of the class were highly
substituted imidazoles (clotrimazole, miconazole)
were not absorbed orally. Ketoconazole
introduced in 1984 was the first effective oral
therapy for Candida. Itroconazole and
Fluconazole are more potent, less toxic and
provide effective oral therapy for many systemic
fungal infections. These two are triazoles.
Another triazole has been recently introduced
(voriconazole).
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Examples of Azole agents


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A- Imidazoles

• Broad class of antifungal. Impede synthesis
  of a componentof the fungal cell wall through
  inhibition of Lanosterol 14a demthylase
• Ketoconazole
• Miconazole
• Clotrimazole
• They lack selectivity ,they inhibit human gonadal
  and steroid synthesis leading to decrease
  testosterone cortisol production.
• Also, inhibit human P-450 hepatic enzyme.

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Ketoconazole

• Well absorbed orally .
• Bioavailability is decreased with antacids, H2
  blockers , proton pump inhibitors food .
• Cola drinks improve absorption in patients with
  achlorhydria.
• Half-life increases with the dose , it is (7-8
  hrs).
• Inactivated in liver excreted in bile (feces )
  urine.
• Does not cross BBB.
• Clinical uses
• Used topically or systematic (oral route
  only ) to treat
• 1- Oral vaginal candidiasis.
• 2- Dermatophytosis.
• 3- Systemic mycoses mucocutaneous candidiasis.

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Adverse Effects
Nausea, vomiting ,anorexia Hepatotoxic Inhibits
human P 450 enzymes Inhibits adrenal gonadal
steroids leading to Menstrual
irregularities Loss of libido Impotence Gynaecomas
tia in males Contraindications Drug
interactions Prgnancy, lactation ,hepatic
dysfunction Interact with enzyme inhibitors ,
enzyme inducers. H2 blockers antacids decrease
its absorption
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B-Triazoles

• Itraconazole
• Fluconazole
• Voriconazole
• They are
• Selective
• Resistant to degradation
• Causing less endocrine disturbance

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Itraconazole

• Lacks endocrine side effects
• Has a broad spectrum activity
• Given orally IV
• Food increases its absorption
• Metabolized in liver to active metabolite
• Highly lipid soluble ,well distributed to bone,
  sputum ,adipose tissues.
• Can not cross BBB. Half-life 30-40 hours
• Used orally in dermatophytosis vulvo-vaginal
  candidiasis.
• IV only in serious infections.
• Effective in AIDS-associated histoplasmosis
• Side effects
• Nausea, vomiting, hypokalemia, hypertension,
  edema, inhibits the metabolism of many drugs as
  oral anticoagulants.

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TABLE Itraconazole Dosing Regimen
PEDIATRIC ADULT Onychomycosis Tinea capitis Tinea corporis, tinea cruris, tinea pedis
Fingernails 5 mg/kg/day 1 wk/mo 2 pulses Toenails 5 mg/kg/day 1 wk/mo pulsed 3 pulses Trichophyton infections 5 mg/kg/day 2-4 wkMicrosporum infections 5 mg/kg/day 4-8 wk Dose by weight 1-4 wk Fingernails 200 mg bid 1 wk/mo 2 pulses Toenails 200 mg/day 12 wkor200 mg bid 1 wk/mo 3 pulses 250 mg/day 2-8 wk 200 mg bid 1 wkor100-200 mg/day 2-4 wk Onychomycosis Tinea capitis Tinea corporis, tinea cruris, tinea pedis
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Cont
PEDIATRIC ADULT Oropharyngeal candidiasis Pityriasis versicolor
Swallow solution by weight Swallow solution 100-200 mg/day 200 mg/day 5-7 days, prevent recurrence with 200 mg bid once/mo Oropharyngeal candidiasis Pityriasis versicolor
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Fluconazole

• Water soluble
• Completely absorbed from GIT
• Excellent bioavailability after oral
  administration
• Bioavailability is not affected by food or
  gastric PH
• Conc. in plasma is same by oral or IV route
• Has the least effect on hepatic microsomal
  enzymes.
• Drug interactions are less common
• Penetrates well BBB so, it is the drug of choice
  of cryptococcal meningitis
• Safely given in patients receiving bone marrow
  transplants (reducing fungal infections)
• Excreted mainly through kidney
• Half-life 25-30 hours
• Resistance is not a problem

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Clinical uses
Candidiasis ( is effective in all forms of
mucocutaneous candidiasis) Cryptococcus
meningitis Histoplasmosis, blastomycosis, , ring
worm. Not effective in aspergillosis
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Side effects

• Nausea, vomiting, headache, skin rash , diarrhea,
  abdominal pain , reversible alopecia.
• Hepatic failure may lead to death
• Highly teratogenic ( as other azoles)
• Inhibit P450 cytochrome
• No endocrine side effects

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New azole agent more recently approved
Posaconazole Novel trizole antifungal recently
approved for use as an oral suspension to treat
invasive fungal infections. Fungistatic against
Candida and fungicidal against Asperigillus
species. Similar structure to Itraconazole,
absorbtion greatly affected by food. Mainly
metabolized by phase II glucuronide conjugation
and has little interaction with P450 enzymes.
Posoconazole
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4- Nucleoside Antifungals
Orally active antifungal with a very narrow
spectrum of activity Flucytosine was
synthesized in 1957 as an antitumor agent. It
was inactive but it was found to have antifungal
activity. Drug inters fungal cell through active
transport on ATPases that normally transport
pyrimidines. Once inside cells, fungal cytosine
deaminase convert the drug to active
5-fluorouracl (5FU) which is incorporated into
RNA causing faulty RNA synthesis. It is also is
a strong, non-competitive inhibitor of
thymidylate synthesis interrupting the one carbon
pool substrate. Mammalian cells do not contain
cytosine deaminase.
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Nucleoside Antifungals
Resistance develops rapidly and occurs on many
levels e.g. transport into the cell and cytosine
deaminase steps. After a few dosing intervals
the drug is essentially useless. To avoid rapid
resistance, combination with Amphotericin B, and
the combination is synergistic. It is also
synergistic with itraconazole and fluconazole,
and interest in these combinations for treatment
of systemic Candida infections is increasing.
Amphotericin B damaged membranes are thought to
allow better entry of flucytosine. Used (with
Amp. B) for Cryptococcal meningitis, systemic
Candida infections, and some other systemic
fungal infections. Adverse Effects 1)GI upset
- very common. 2)Hepatic - 5 have increased
transaminases. 3)Hematologic - anemia,
leukopenia, thrombocytopenia this is the major
complication of therapy and may be due to low
levels of 5-FU circulating. 4)adverse effects
seen when plasma levels reach gt100 mcg/ml
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5- Cell wall inhibitors
Echinocandins, a group of cyclic peptides with
long lipophillic sidechains have been under
investigation for a number of years. They
interfere with cell wall biosynthesis through
inhibition of the enzyme ß-1,3-glucan synthase.
Reduction of in the glucan content weakens the
cell wall and leads to rupture of fungal cells.
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Echinocandins
Micafungin
Caspofungin (parenteral)
approved for invasive aspergillosis in patients
refractory to or intolerant of other therapies .
IV use only
Anidulafungin
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Caspofungin

• Inhibits the synthesis of fungal cell wall by
  inhibiting the synthesis of ß(1,3)-D-glucan,
  leading to lysis cell death.
• Given by IV route only
• Highly bound to plasma proteins
• Half-life 9-11 hours
• Slowly metabolized by hydrolysis N-acetylation.
• Elimination is nearly equal between the urinary
  fecal routes.

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6- Miscellaneous Antifungals
Undecylenic Acid H2CCH(CH2)8COOH Wide
ly used as the zinc salt in OTC preparations for
topical treatment of infections by dermatophytes.
A fungistatic acting through non-specific
interaction with components in cell
membrane. Can be used in concentrations up
to 10 in solution, powder and emulsions.
Traditionally used for athletes foot (tinea
pedis) although cure rates are low.
Ciclopirox Olamine A hydroxylated pyridinone used
for superficial dermatophytic infections mainly
onychomycosis. It caused inhibition of polyvalent
cations (Fe3) and caused inhibition of metallic
enzymes in the fungal cell this distrupt cellular
function lead to demise of the fungus. A new
formulation of an 8 lacquer has been recently
introduced for treating nail infections.
Ciclopirox