DERMATOLOGY PHARMACOLOGY - NurseCe4Less.com
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DERMATOLOGY PHARMACOLOGY
KELLIE WILSON, PharmD
Kellie Wilson, is a Doctor of Pharmacy practicing in Anaconda, MT. She specializes in
retail pharmacy at an independent pharmacy. She attended the University of Montana
in Missoula, MT where she graduated in 2009 with a doctorate in pharmacy. She
then when on to work in Boise, ID as a retail pharmacist for one of the big
corporations for 2 years. She then moved home to Montana to work at a retail
pharmacy that is independently owned. In the 8 years she has worked as an
independent retail pharmacist she has become very involved in psychiatric pharmacy
for two major behavioral health organizations that are located around all of Montana.
Kellie loves working as a retail pharmacist because she enjoys the interaction with
her customers. Pharmacy is always changing and keeping up to date with new
medications is very challenging and very rewarding all at the same time and this is
why Kellie has chosen a career in pharmacy and is pursuing more towards psychiatric
pharmacy.
NOAH CARPENTER, MD
Dr. Noah Carpenter is a Thoracic and Peripheral Vascular Surgeon. He completed a
Bachelor of Science in Chemistry and medical school and training at the University of
Manitoba. Dr. Carpenter completed surgical residency and fellowship at the University
of Edmonton and Affiliated Hospitals in Edmonton, Alberta, and an additional Adult
Cardiovascular and Thoracic Surgery fellowship at the University of Edinburgh,
Scotland. He has specialized in microsurgical techniques, vascular endoscopy, laser
and laparoscopic surgery in Brandon, Manitoba and Vancouver, British Columbia,
Canada and in Colorado, Texas, and California. Dr. Carpenter has an Honorary
Doctorate of Law from the University of Calgary, and was appointed a Citizen
Ambassador to China, and has served as a member of the Native Physicians
Association of Canada, the Canadian College of Health Service Executives, the
Science Institute of the Northwest Territories, the Canada Science Council, and the
International Society of Endovascular Surgeons, among others. He has been an
inspiration to youth, motivating them to understand the importance of achieving
higher education.
1
NurseCe4Less.comABSTRACT
Many types of skin diseases can occur in people that range in onset and
severity. Health providers need to be informed of the varied skin conditions
and pharmacological therapy in order to appropriately inform patients of drug
benefits and risks and to deliver comprehensive medical treatment.
Dermatological treatment may be directed toward the management of an
inflammatory process, comorbid medical conditions, or it may be cosmetic.
There are evolving dermatology drug products and market factors that
providers will need to guide patients on when addressing their skin health
concerns and treatment choices. The effect of certain dermatological agents
in special populations, such as during pregnancy can range from inconclusive
to a known potential risk. When used in excessive amounts for prolonged
periods of time, there are product warnings related to certain drug treatments
for skin disease in pediatric, elderly and pregnant women. In pregnant women,
for example, topical steroids have been classified as category C drugs,
therefore caution must be observed to avoid harm to fetal health. More
research is needed to determine the benefits and risks of dermatological
agents used as cosmeceuticals and in the prevention and treatment of skin
disease.
2
NurseCe4Less.comPolicy Statement
This activity has been planned and implemented in accordance with the
policies of NurseCe4Less.com and the continuing nursing education
requirements of the American Nurses Credentialing Center's Commission on
Accreditation for registered nurses.
Continuing Education Credit Designation
This educational activity is credited for 4 hours at completion of the activity.
Pharmacology content is 4 hours.
Statement of Learning Need
The skin is an important body organ, and health providers need to be informed
about dermatology cosmeceuticals and medication used to treat various skin
diseases. Many factors ultimately determine the therapeutic benefit of
dermatology pharmaceuticals. A clinical knowledge of the many different
types and forms of dermatology medication, an awareness of patient
preferences for treatment, and the health benefits and risks of selected skin
products, are essential for health clinicians when recommending, initiating and
following the progress of skin treatment.
Course Purpose
To provide interdisciplinary health professionals who work in dermatology,
surgical, and general medicine areas of patient care with a general knowledge
of dermatology pharmacology for varied skin conditions and to support
clinician efforts to educate patients on appropriate medication use and
compliance.
Target Audience
Advanced Practice Registered Nurses, Registered Nurses, and other
Interdisciplinary Health Team Members.
Disclosures
Noah Carpenter, MD, Kellie Wilson, PharmD, William Cook, PhD, Douglas
Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures.
There is no commercial support.
3
NurseCe4Less.comSelf-Assessment of Knowledge Pre-Test:
1. _____________ is defined as a sudden, acute decrease in
response to a drug after the drug is administered.
a. Tapering down
b. Rebound effect
c. Tachyphylaxis
d. Topical nonadherence
2. Skin lesions are classified into two categories:
a. Primary and secondary skin lesions.
b. Site involvement and structure affected.
c. Congenital and acquired skin lesions.
d. Skin lesions caused by an infectious agent or an autoimmune
mechanism.
3. ____________ are at an increased risk of absorbing topical
corticosteroids.
a. Infants
b. Individuals who are overweight
c. Women
d. The elderly
4. ______________ is an antimitotic that reduces inflammation and
can help treat psoriasis.
a. Mupirocin
b. Clindamycin
c. Ketoconazole
d. Anthralin
5. The term ___________ refers to the inactive part of a topical
preparation that brings a drug into contact with the skin.
a. lidocaine
b. vehicle
c. prilocaine
d. astringent
4
NurseCe4Less.comIntroduction
Patients with a dermatological concern may report a condition ranging
from a serious diagnosis such as cancer to a cosmetic issue that impacts a
person's physical and emotional health. A health provider will need to
determine the cause of a skin disorder by evaluating whether there is a genetic
abnormality, an infection, or an autoimmune mechanism that is causing a skin
disorder. Identifying the site of involvement, the type of skin disorder, and
the structure that is mainly diseased will be needed before determining
treatment. Once a patient has been evaluated, there are topical medications,
as well as oral or injectable medications that may be used for dermatological
treatment. Topical treatments to select from are many and continue to grow
in the area of dermatology, which may include antibiotics, antifungals,
corticosteroids, retinoids and biologics. Depending on the patient’s condition,
an oral or injectable medication may be recommended. The treatment of an
infectious or inflammatory skin condition will sometimes require the use of an
antiviral or immunosuppressive agent. Dermatological treatment is presented
in the following sections with a primary focus on the most common
medications used. The important role of biologics in treating psoriasis and the
FDA-approved biologics used for psoriasis and psoriatic arthritis are discussed.
Skin Disease Classifications and Treatments
Skin diseases are classified in various ways. The classifications and
subcategories of a skin condition are briefly listed here but these are evolving.1
It is useful to look at skin conditions by identifying the site of involvement,
the cause of the skin condition, and the main structure affected by the
disease.2,3
The site of involvement may include facial rashes or lesions on sun-
exposed sites. Skin lesions are classified into two categories: 1) Primary skin
lesions, which are abnormal skin conditions from birth or that are acquired
over a person’s lifetime, and 2) Secondary skin lesions, which are the result
of irritated or manipulated primary skin lesions, such as when a person
scratches a mole until it bleeds. In such instances, the resulting lesion, a crust,
5
NurseCe4Less.combecomes a secondary skin lesion.4 Pathogenesis may include genetic
abnormalities, infectious etiology or autoimmune mechanisms. The main
diseased structure may be epidermal disease, abnormalities of melanocytes,
and vascular changes.4
Many different medications are used to treat different skin infections or
conditions. There are topical medications as well as oral medications and
injectable medications.
Topical Agents
Topical medications use vehicles that are the inactive part of the topical
preparation and that help bring the drug into contact with the skin. The
vehicles that deliver topical therapies include inactive ingredients such as
powders, liquids, oils, or a combination of products. The location of application
of the topical medication, the cosmetic effects, and convenience determine
the choice of the vehicle. Some common topical treatments for skin conditions
include those listed in this section.2,5-10
● Antibacterials: Mupirocin or clindamycin, are often used to treat or prevent
infection.
● Anthralin: Anthralin is an antimitotic, is not often used because it can be
irritating and can stain, but is used to reduce inflammation and can help
treat psoriasis.
● Antifungal Agents: Clotrimazole (Lotrimin), ketoconazole (Nizoral), and
terbinafine (Lamisil AT), are a few examples
● Oral Antifungal Drugs: For the treatment of skin conditions such as
ringworm and athlete's foot.
● Benzoyl Peroxide: Creams, gels, washes, and foams containing benzoyl
peroxide are used to treat acne.
● Coal Tar: Available with/without a prescription, ranging from 0.5% to 5%
in strength. Coal tar is used to treat conditions including seborrheic
dermatitis (usually in shampoos) or psoriasis. Currently, coal tar is seldom
used because it can be slow acting and can cause severe staining of
personal clothing and bedding.
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NurseCe4Less.com● Corticosteroids: Used to treat skin conditions including eczema, and are
available in many different forms including foams, lotions, ointments, and
creams.
● Non-steroidal Ointment: The ointment crisaborole (Eucrisa) is used to treat
mild to moderate eczema.
● Retinoids: Retin-A and Tazorac are examples, and these are gels, foams
or creams derived from vitamin A used to treat conditions including acne.
● Salicylic Acid: Sold in lotions, gels, soaps, shampoos, washes, and patches.
Salicylic acid is the active ingredient in many skin care products for the
treatment of acne and warts.
Oral or Injection Treatments
Some common oral or injection treatments used for skin conditions may
include those listed here. A more detailed review of these treatments will be
included in later sections of this course.2,8-13
● Antibiotics: Oral antibiotics are used to treat many skin conditions.
Common antibiotics include dicloxacillin, erythromycin, and tetracycline.
● Antifungal Agents: Oral antifungal drugs include fluconazole and
itraconazole. These drugs can be used to treat more severe fungal
infections. Terbinafine is an oral antifungal medicine that may be used to
treat fungal infections of the nails.
● Antiviral agents: Common antiviral agents include acyclovir (Zovirax),
famciclovir (Famvir), and valacyclovir (Valtrex). Antiviral treatments are
used for skin conditions including those related to herpes and shingles.
● Corticosteroids: These medications, including prednisone, can be helpful
in treating skin conditions linked to autoimmune diseases including
vasculitis and inflammatory diseases such as eczema. Dermatologists
prefer topical steroids to avoid side effects; however, short-term use of
prednisone is sometimes necessary.
● Immunosuppressants: Immunosuppressants, such as azathioprine
(Imuran) and methotrexate (Trexall), can be used to treat conditions
including severe cases of psoriasis and eczema.
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NurseCe4Less.com● Biologics: These new therapies are the latest methods being utilized to
treat psoriasis and other conditions. Examples of biologics include
adalimumab (Humira), adalimumab-atto (Amjevita), a biosimilar to
Humira, brodalumab (Siliq), etanercept (Enbrel), etanercept-szzs (Erelzi),
a biosimilar to Enbrel, infliximab (Remicade), ixekizumab (Taltz),
secukinumab (Cosentyx), and ustekinumab (Stelara).
● Enzyme Inhibitors: Enzyme inhibitors such as apremilast (Otezla) shuts
down an enzyme in the immune system to fight inflammation. Eucrisa is
an enzyme inhibitor FDA approved for mild to moderate atopic
dermatitis/eczema.
● Retinoids: Acitretin (Soriatane) is specifically used to treat all types of
severe psoriasis. It reduces skin cell growth. It causes severe birth defects
and should not be used if a woman is planning to become pregnant, is
pregnant or is breastfeeding.
Antibacterial Agents and Antibiotics
Topical antibiotics play an important role in the management of many
common dermatologic conditions. Some antibiotics may be used as systemic
treatments through oral or injectable administration. They are prescribed
most often for the management of mild-to-moderate acne vulgaris or as
adjunctive treatment with oral agents. For localized superficial infections, such
as impetigo, the use of a topical agent (mupirocin or retapamulin) may
eliminate the need for oral antibiotics and the accompanying problems
of patient compliance, gastrointestinal side effects, and potential drug
interactions.2,18-15
Localized impetigo, superficial dirty abrasions, and secondarily infected
chronic dermatoses are commonly treated with topical antibiotics. However,
widespread impetigo, an infection of the lower extremities or disease occurring
in immunocompromised individuals should be treated with systemic antibiotics
to reduce the risk of serious complications.2,8-15
Topical antibiotics are used following minor surgical procedures.
Petrolatum, commonly called petroleum jelly, may also be used. It acts as an
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NurseCe4Less.comointment or moisturizer to prevent dry, rough, scaly skin. When comparing
bacitracin and petrolatum in minor surgical procedures bacitracin does not
statistically decrease the already low rate of infection. Some patients are
allergic to bacitracin. Petrolatum has been found to be of equal efficacy with
fewer side effects than bacitracin. When clean wounds are made during minor
surgery, there is no need to use antibacterial ointment to aid in healing or
prevent infection.2,8-15 Because burns produce a fertile ground for life-
threatening secondary infection, prophylactic topical therapy is often used.2,8-
15
Topical antibiotics, recommended uses and administration are listed next.
Mupirocin
Mupirocin, which was formerly known as pseudomonic acid A, is a topical
antibiotic agent derived from Pseudomonas fluorescens. The drug reversibly
binds to isoleucyl-tRNA synthetase and inhibits bacterial protein synthesis.5
The activity of mupirocin is limited to Gram-positive bacteria, especially
staphylococci and most streptococci. Its activity is enhanced in an acid pH
environment (5.5), which is the normal pH of the skin. Mupirocin is somewhat
temperature-sensitive, and thus loses efficacy if exposed to high
temperatures.5
Mupirocin ointment 2% is applied three times daily and is principally
indicated for the treatment of localized impetigo caused by S. aureus and
Streptococcus pyogenes.5 Prolonged use of mupirocin ointment to control
methicillin-resistant S. aureus (MRSA) carriage, especially in bedridden
patients with decubitus ulcers, led to significant resistance.
Low serum concentrations of mupirocin are achieved after intranasal
application, which might explain the selection of mupirocin-resistant strains of
S. aureus.6 A small intranasal application of a combination antibiotic ointment
containing bacitracin, polymyxin B, and gramicidin can successfully decolonize
more than half of MRSA-positive patients who remain clear after an average
follow-up of a few months. Mupirocin-sensitive MRSA has a high chance of
9
NurseCe4Less.combeing eradicated; however, in cases that are mupirocin-resistant it is much
harder to successfully treat S. aureus infection.6
New formulations that involve the use of the calcium salt of mupirocin
(the calcium salt aids in chemical stability in the intranasal preparation) are
available for intranasal use as a 2% ointment and a 2% topical cream.6
Retapamulin
Retapamulin is approved for the topical treatment of impetigo in patients
older than 9 months of age.17 It is a semisynthetic pleuromutilin antibiotic
derived from fermentation in Clitopilus paseckerianus with activity against
staphylococci. The antibacterial mechanism of action is inhibition of protein
synthesis. Allergic contact dermatitis to the active ingredient has been
reported.7
Bacitracin
Bacitracin is a topical polypeptide antibiotic originally isolated from the
Tracy-I strain of Bacillus subtilis.18 Bacitracin is a cyclic polypeptide with
multiple components (A, B, and C). Bacitracin A is the major component of
commercial products and is often used as the zinc salt. Bacitracin interferes
with bacterial cell wall synthesis by binding to and inhibiting the
dephosphorylation of a membrane-bound lipid pyrophosphate.8 It is active
against Gram-positive cocci such as staphylococci and streptococci. Most
Gram-negative organisms and yeast are resistant to the drug. It is available
as bacitracin ointment and as zinc bacitracin, with 400 to 500 units per gram.8
Topical bacitracin is effective for the treatment of superficial bacterial
infections of the skin such as impetigo, furunculosis, and pyodermas. It is
often combined with polymyxin B and neomycin as a triple antibiotic ointment
applied several times daily for the treatment of secondarily infected
eczematous dermatitis such as atopic dermatitis, nummular dermatitis, or
stasis dermatitis.8 Unfortunately, the topical application of bacitracin carries
10
NurseCe4Less.comwith it the risk of allergic contact sensitization and, rarely, anaphylactic
shock.8
Polymyxin B
Polymyxin B is a topical antibiotic derived from a spore-forming soil
aerobe B. polymyxa.8 Polymyxin B is a mixture of polymyxin B1 and B2, which
are both cyclic polypeptides. They function as cationic detergents that interact
strongly with bacterial cell wall membrane phospholipids, thus disrupting the
integrity of the cell membrane.8
Polymyxin B is active against a wide range of Gram-negative organisms,
including P. aeruginosa, Enterobacter, and Escherichia coli.18 Polymyxin B is
available in ointment form (5,000 to 10,000 units per gram) in combination
with bacitracin or as triple antibiotic ointment with bacitracin and neomycin.
It should be applied one to three times a day.8
Topical Aminoglycosides (Neomycin and Gentamicin)
The aminoglycosides are an important group of antibiotics used topically
and systemically to treat infections caused by Gram-negative bacilli.
Aminoglycosides exert their bactericidal effects by binding to the 30S
ribosomal subunit and interfering with protein synthesis.9,10
Neomycin sulfate, the aminoglycoside most often used topically, is a
fermentation product of Streptomyces fradiae. Commercial neomycin is a
mixture of neomycin B and C, whereas framycetin, used in Canada and some
European countries, is pure neomycin B.9,10 Neomycin sulfate has activity
against aerobic Gram-negative bacteria and is used most commonly for
prophylaxis against infection in superficial abrasions, cuts, and burns. It is
available in ointment form (3.5 mg/g) and is also packaged in combination
with other antibiotics such as bacitracin, polymyxin, and gramicidin.9,10 Many
dermatologists do not recommend neomycin because it is responsible for a
large number of cases of allergic contact dermatitis.9,10
11
NurseCe4Less.comOther agents, such as lidocaine, pramoxine, or hydrocortisone are
available in combination with neomycin.9,10 Neomycin sulfate (20%) in
petrolatum is used to assess for contact allergy. Gentamicin sulfate is derived
from the fermentation of Micromonospora purpurea. It is available as a topical
0.1% cream or ointment.9,10 Gentamicin sulfate is used by some dermatologic
surgeons to provide prophylaxis against malignant otitis externa due to P.
aeruginosa when operating on the ear, especially on diabetic or other
immunocompromised patients. The ophthalmic formulation is useful in caring
for operative wounds in the periorbital area.9,10
Sulfonamides (Silver Sulfadiazine and Mafenide Acetate)
Silver sulfadiazine and mafenide acetate are broad-spectrum
antibacterials useful in the treatment of acne vulgaris, acne rosacea, and
burns.11 Sulfacetamide is available as a 10% lotion and in combination with
5% sulfur in a gel, cream, suspension, cleanser, cloths, and mask.11
Most sulfonamides are structurally similar to PABA and compete with it
during the synthesis of folic acid and their antibacterial mechanism of action
is to compete with para-aminobenzoic acid (PABA) during the synthesis of folic
acid; however, the mechanism of action of mafenide is not the typical
sulfonamide mechanism of action since PABA does not antagonize mafenide’s
performance.11 The mechanism of action of sulfonamides for topical treatment
of rosacea is not understood.
Silver sulfadiazine is thought to release silver slowly. Silver sulfadiazine
exerts its effect on the bacterial cell walls and membranes. Mafenide acetate,
if used over large areas of skin, has the potential to cause metabolic acidosis,
and intense pain on topical administration. Candida superinfection may also
be a problem with mafenide cream.11
Nitrofurazone
Nitrofurazone (Furacin) is a nitrofuran derivative used for the treatment
of burns.12 The mechanism of action involves the inhibition of bacterial
12
NurseCe4Less.comenzymes involved in aerobic and anaerobic degradation of glucose and
pyruvate. Nitrofurazone is available as a 0.2% cream, solution, or soluble
dressing, and its spectrum of activity includes staphylococci, streptococci, E.
coli, Clostridium perfringens, and Proteus spp.12
Gramicidin
Gramicidin is a topical antibiotic derived from B. brevis.13 The
gramicidins are linear peptides that form stationary ion channels in susceptible
bacteria. The antibiotic activity of gramicidin is restricted to Gram-positive
bacteria.13
Clioquinol
Clioquinol (also known as iodochlorhydroxyquin) is a broad-spectrum
antibacterial/antifungal topical that is currently indicated for the treatment of
inflammatory skin disorders and tinea pedis and has been used for minor
bacterial infections. It is a synthetic hydroxy-quinoline whose mechanism of
action is unknown.14
The disadvantages of clioquinol include discoloration of clothing, skin,
hair, and nails and the potential to cause irritation. Clioquinol may interfere
with thyroid function determination when taken orally and possibly topically if
used extensively.14 The iodine moiety interferes with tests that rely on iodine
uptake (this effect can last for up to 3 months after application). However,
clioquinol does not interfere with testing for T3 or T4.14
Erythromycin
Erythromycin belongs to the group of macrolide antibiotics and is active
against both Gram-positive cocci and Gram-negative bacilli. It is used
principally as a topical agent in the treatment of acne.15
Erythromycin binds to the bacterial 50S ribosomes and blocks
translocation of the peptidyl-transfer RNA (tRNA) molecule from the acceptor
13
NurseCe4Less.comto the donor site, interfering with the formation of the polypeptide chain and
inhibiting protein synthesis. In addition to its antibacterial properties,
erythromycin has anti-inflammatory activity.15
Erythromycin is available as a 1.5% to 2.0% solution, gel, pledgets, and
ointment as a single agent. It is also available in combination with benzoyl
peroxide.15
Clindamycin
Clindamycin is a semisynthetic lincosamide antibiotic that is derived
from lincomycin. The mechanism of action is very similar to that of
erythromycin, with binding to the 50S ribosome and suppression of bacterial
protein synthesis.16 Clindamycin is used topically as a 1% gel, solution,
suspension (lotion), and foam primarily for the treatment of acne. It is also
available as a combination with benzoyl peroxide, which may slow the
development of antibiotic resistance to clindamycin. Pseudomembranous
colitis rarely has been reported to occur with the topical use of clindamycin.16
Metronidazole
Metronidazole, a topical nitroimidazole, is currently available as a 0.75%
gel, cream, or lotion and as a 1% cream or gel for the topical treatment of
rosacea.17 In the lower strength, it is applied twice daily, and in the higher
strength, it is used once daily. Orally, metronidazole has broad-spectrum
activity against many protozoal organisms and anaerobes.17
Antifungals
Superficial fungal infections, including dermatophytosis, candidiasis,
and pityriasis versicolor, are most often restricted to the epidermis.18-20 In
treating these infections, the clinician must select between topical or systemic
management. Factors guiding management may include the 1) extent and
severity of the infection, 2) site of involvement, 3) any comorbid conditions
14
NurseCe4Less.comor potential drug interactions, 3) anticipated efficacy of treatment, cost and
access to medication, and 4) ease of use.18-20
Patients with limited fungal infections confined to glabrous skin are
usually best treated with topical agents. Conversely, those with extensive or
recalcitrant disease, or with involvement of terminal hair or nails, may be
better suited for systemic management. In some cases, either treatment
option may be reasonably chosen.18-20
Treatment with topical antifungal therapy enjoys several advantages
over systemic management, including: fewer side effects, fewer drug
interactions, localization of treatment, and generally lower cost.18-20 Numerous
topical antifungal medications are available. For the most part, specific
antifungal agents have replaced nonspecific topical treatments, such as
keratolytics (salicylic acid) or antiseptics (gentian violet or Castellani paint),
which were once the first choice for management. The ideal topical antifungal
is efficacious, inexpensive, well tolerated, and has low resistance within
targeted fungi.18-20
Despite widespread availability, few topical antifungal agents have been
directly compared with one another in clinical trials. Studies sponsored by the
manufacturer often compare the active agent in the antifungal to the delivery
vehicle. Extrapolation between studies is further complicated due to
differences in study design, duration of therapy, site of infection, selection
methodology, or treatment endpoint. Topical antifungals typically fall into one
of three classes: 1) imidazoles, 2) allylamines and benzylamines, and
3) polyenes.18-20
Imidazoles
Imidazoles represent a broad class of antifungal medications. Certain of
these, such as clotrimazole, have been around for decades, while others, such
as sertaconazole, have only become available recently.20-22 Imidazoles impede
synthesis of a component of the fungal cell wall through inhibition of lanosterol
14α-demethylase, a cytochrome P450-dependent enzyme, which converts
15
NurseCe4Less.comlanosterol to ergosterol.20-22 Depletion of ergosterol results in membrane
instability and hyperpermeability; changes incompatible with growth and
survival of the fungus. Imidazoles are considered fungistatic in practical
application, with the possible exception of sertaconazole when used to treat
some Candida species.20-22 While all imidazoles possess the same mechanism
of action, in-vitro studies demonstrate that not all dermatophytes are
uniformly susceptible to an imidazole at an equivalent concentration, and this
may explain some treatment failures.20-22
Topical imidazoles possess anti-inflammatory activity via inhibition of
neutrophil chemotaxis, calmodulin activity, synthesis of leukotrienes and
prostaglandins, and histamine release from mast cells. Some agents, such as
ketoconazole, yield anti-inflammatory effects equivalent to 1%
hydrocortisone.20-22 Topical imidazoles also demonstrate limited antibacterial
properties, particularly with respect to gram-positive organisms.20-22 All
marketed imidazoles demonstrate excellent penetration of the stratum
corneum with strong keratinophilic behavior. Sulconazole may be detected in
the stratum corneum up to 96 hours after application. Similarly,
sertaconazole, the newest of all marketed imidazoles, has a half-life within the
stratum corneum of more than 60 hours.20-22
Because of this high affinity for keratin, systemic absorption of
imidazoles is low, with urinary excretion usually in the range of 0.3%–1.0%
of the applied dose.20-22 Even when applied to inflamed skin, absorption of
imidazoles does not usually exceed 4% of the applied dose. Again, sulconazole
is unique in that percutaneous absorption in the range of 8%–11% of the
applied dose exceeds that of all other imidazoles.20-22
Due to inherent antibacterial activity, some topical imidazoles have
demonstrated modest efficacy in treating erythrasma, impetigo, and ecthyma.
Because there are more potent antibacterial agents, this is not a preferred
indication for imidazole use.20-22 Cure rates for superficial fungal infection
treated with imidazoles are variable and often depend upon study design. A
thorough review of the literature provides no compelling evidence that
significant differences in cure or relapse exist among the various topical
16
NurseCe4Less.comimidazoles; however, other considerations may dictate the selection of a
particular imidazole.20-22
Topical imidazoles are available as a cream or lotion. Although lotions
are better suited for use over large areas or upon hair-bearing skin, limited
studies suggest a cream may be marginally more effective. In studies
performed by the manufacturer, oxiconazole cream yielded a clinical and
mycologic cure in an approximate half of tinea pedis cases while the lotion
yielded the same cure.20-22 Additionally, the potential for irritancy must be
considered. Topical clotrimazole for the treatment of tinea cruris has shown
erosive reactions in patients while sulconazole did not cause any erosion in
the reviews.20-22
Topical imidazoles are available in a multitude of forms. Econazole,
ketoconazole, and oxiconazole are approved for once-daily dosing but twice-
daily dosing is recommended for the remainder. Although twice-daily dosing
is recommended for sulconazole, a study comparing once-daily to twice-daily
dosing in tinea corporis and tinea cruris reported an identical rate of cure.20-
22
This might have been predicted based upon the 60-hour half-life within the
stratum corneum. Application of all topical antifungals, including imidazoles,
should include normal skin for a radius of 2 cm beyond the affected area.
Duration of treatment with imidazoles has varied. In general, tinea corporis
and tinea cruris require treatment for approximately 2 weeks, whereas tinea
pedis may require treatment for up to 4 weeks. Treatment should be continued
for at least 1 week after all symptoms have abated.20-22
Risks associated with the use of topical imidazoles include those
inherent to all topical medications, and consist chiefly of irritant and allergic
reactions. Additionally, clotrimazole is marketed in combination with the
topical glucocorticoid, betamethasone dipropionate. It was initially assumed
that the addition of the steroid would more rapidly relieve inflammation,
scaling, and pruritus.20-22 The combination has been found to be more effective
than clotrimazole alone in alleviating symptoms. However, betamethasone
dipropionate is a potent topical steroid, and striae and other cutaneous side
effects from the steroid component may occur.
17
NurseCe4Less.comIt is likely that overuse by non-specialists occurs because of the
mistaken assumption either that the steroid agent is mild, or that the
combination will be a better choice when the differential diagnosis is
unresolved. The U.S. Food and Drug Administration (FDA) has twice revised
the product warnings for clotrimazole-betamethasone dipropionate,
discouraging use on thin skin, for prolonged periods, or when the diagnosis is
in doubt.20-22
Use of topical imidazoles is associated with few complications. Because
of low systemic absorption, drug reactions with topical imidazoles are rare.20-
22
Concerns of resistance must also be considered. Resistance of Candida
albicans to clotrimazole has been described in human immunodeficiency virus-
positive patients with mucocutaneous candidiasis. There has also been
documentation of low levels of in-vitro resistance of various Candida species
to other topical imidazoles. Often, this resistance is associated with resistance
to oral fluconazole.20-22
Allylamines and Benzylamines
Allylamines and benzylamines are closely related compounds. Currently,
two topical allylamines and single topical benzylamine are marketed in the
United States. Allylamines and benzylamines impede synthesis of ergosterol
through inhibition of squalene epoxidase, an enzyme that converts squalene
to squalene oxide.23
Depletion of ergosterol results in membrane instability and
hyperpermeability. Allylamines and benzylamines are considered fungicidal
because the accumulation of intracellular squalene leads directly to cell death.
The clinical significance of this cidal action is unclear.23 Unlike imidazoles, the
activity of allylamines and benzylamines is independent of the cytochrome
P450 enzyme system. When compared to naftifine, terbinafine demonstrates
a 10- to 100-fold increased potency in vitro, although this does not appear to
be relevant in clinical use.23
18
NurseCe4Less.comLike imidazoles, allylamines, and benzylamines demonstrate anti-
inflammatory activity. Naftifine inhibits adhesion of polymorphonuclear cells
to endothelium, interrupts chemotaxis, and inhibits the 5-lipoxygenase
proinflammatory pathway.23,24 It is assumed that terbinafine and butenafine
yield anti-inflammatory effects through similar mechanisms. Allylamines and
benzylamines also demonstrate limited antibacterial properties.23
Allylamines and benzylamines are highly lipid soluble and efficiently
penetrate the stratum corneum, where they may persist for extended
durations.23,24 Butenafine has been detected within the stratum corneum at
minimum inhibitory concentration for at least 72 hours after application, and
terbinafine may persist at a similar level for up to 7 days after application.
Systemic absorption of these agents is quite low, with typical urinary excretion
in the range of 3%–5% of the applied dose.23,24
Despite antibacterial properties, terbinafine has proven inferior to
mupirocin for treatment of impetigo, and a traditional antibacterial agent
should be used. Similarly, although allylamines and benzylamines do
demonstrate activity against fungi involved in systemic infection, such as
Sporothrix schenckii, Blastomyces dermatitidis, and Histoplasmosis
capsulatum, topical therapy is inappropriate.23,24
Limited evidence suggests that topical allylamines or benzylamines may
be preferred over topical imidazoles for certain dermatophyte infections. In
cases of tinea pedis one week of topical terbinafine may be as effective as four
weeks of topical imidazoles, with a high rate of cure.23,24 Use of this
abbreviated treatment with terbinafine has been confirmed in trials using the
active agent versus vehicle alone.
In some instances, resolution of tinea pedis using terbinafine has
occurred with as few as three doses.23,24 Generic terbinafine 1% cream is more
expensive than an equivalent amount of clotrimazole 1%, but considering the
frequency of application, the amount of medication required, the likelihood of
patient compliance and ease of use, and the rapidity of results, some experts
recommend topical terbinafine over topical imidazoles for tinea pedis.23,24
19
NurseCe4Less.comTopical allylamines and benzylamines are available in a number of
forms. Each agent has a slightly different dosing regimen based upon the
formulation and the location and severity of infection. Risks associated with
the use of topical allylamines and benzylamines are those inherent to all
topical medications.23,24 A possible interaction between topical terbinafine and
acenocoumarol may exist, however complications arising from the use of
topical allylamines or benzylamines are few.23,24
Polyenes
Polyenes were among the first agents discovered to possess specific
antifungal properties. The two major topical polyene antifungals are nystatin
and amphotericin B.25 Only topical nystatin is actively marketed in the United
States. Like all polyenes, nystatin binds irreversibly to membrane sterols
present in susceptible species of Candida.25 The polyene molecules
demonstrate a higher affinity for fungal sterols, including ergosterol, than for
human sterols, yielding imperfect selective toxicity. This irreversible binding
alters membrane permeability, causing leakage of essential intracellular
components and fungal death. In low concentrations, nystatin is fungistatic,
but, at high concentrations, it may be fungicidal.25
Nystatin is insoluble in water and is not absorbed from intact skin, the
gastrointestinal tract, or the vagina. Topical nystatin is used to treat
mucocutaneous candidiasis caused by C. albicans, and other susceptible
species such as C. parapsilosis, C. krusei, and C. tropicalis.25,36 Repeated
studies have demonstrated that topical imidazoles are more effective than
nystatin in treating vulvovaginal candidiasis, and use of nystatin for this
indication has diminished in recent years. Nystatin is not effective against
dermatophytes or Pityrosporum; and, hence, it is not indicated for treatment
of tinea or pityriasis versicolor.25,26
Nystatin is available as a powder, cream, ointment, suspension, and
pastille. To treat oral candidiasis (thrush), the suspension or pastille is used
four to five times daily, usually for 2 weeks.26 To treat cutaneous infection,
20
NurseCe4Less.comthe powder, cream, and ointment are used twice daily for approximately two
weeks. Risks associated with the use of topical nystatin are those inherent to
all topical medications. A significant number of cases of allergic contact
dermatitis attributed to nystatin alone have been reported. These reactions
have been reported with topical and oral use. Anaphylaxis has been described
with the use of nystatin-containing vaginal suppositories but the reaction was
attributed to ingredients other than nystatin.26
A combination agent consisting of nystatin and triamcinolone acetonide
is widely marketed.27 The addition of triamcinolone may provide additional
benefit over nystatin alone during the first few days of treatment when
inflammation is maximal.27 After this initial period, the manufacturer
recommends a transition to nystatin alone or to other topical antifungal
agents. Although triamcinolone acetonide is only a mid-potency agent,
cutaneous sequelae, including striae, skin atrophy, and steroid-induced acne,
has been reported. Because candidiasis often involves thin and fragile skin,
such as that of the intertriginous areas, the risk of damage is likely
potentiated. Many of the combined formulations contained, or may still
contain, ethylenediamine, a sensitizer that may cause allergic contact
dermatitis. As with clotrimazole-betamethasone dipropionate, the
combination agent of nystatin triamcinolone acetonide is more often
prescribed by non-dermatologists.27
Complications with topical polyenes are few. Nystatin resistance may be
encountered in some Candida. This resistance may either be seen in wild
strains (primary type) or it may be induced during therapy (secondary type).24
Although C. albicans maintains a low rate of spontaneous resistance to
nystatin, particularly in comparison to resistance to imidazoles, other species,
such as C. tropicalis, C. guilliermondii, C. krusei, and C. stellatoidea, rapidly
acquire resistance upon exposure to nystatin.24
Ciclopirox Olamine
Ciclopirox olamine is a hydroxypyridone antifungal agent with a unique
structure and mode of action. Unlike most other topical antifungals, ciclopirox
21
NurseCe4Less.comolamine does not interfere with sterol synthesis.28-30 Instead, it interrupts
active membrane transport of essential cellular precursors, particularly
trivalent cations. Ultimately, this disrupts cellular function, leading to the
demise of the fungus. If concentrations of the drug are high enough, the
membrane integrity of the fungus may actually be impaired.28-30
Ciclopirox olamine also has inherent anti-inflammatory activity exerted
through inhibition of prostaglandin and leukotriene synthesis within
polymorphonuclear cells. Broad-spectrum antibacterial properties have also
been attributed to ciclopirox olamine. In one study, topical ciclopirox olamine
had broader coverage against Gram-positive and Gram-negative organisms
than did topical imidazoles or topical allylamines.28-30
When applied to the skin, ciclopirox olamine remains in high
concentration within the epidermis and upper dermis. Ciclopirox Olamine
penetrates keratin easily, with cadaveric skin demonstrating concentrations in
the epidermis that were 10–15 times the minimum inhibitory concentration
for a sensitive species.28-30 This ability to penetrate keratin recommends use
for onychomycosis, as the drug is also capable of penetrating the nail plate
material. Studies of drug metabolism have demonstrated that, with typical
use, approximately 10% of the administered dose is excreted in the urine.28-
30
Ciclopirox olamine is indicated for the treatment of dermatophytoses
and onychomycosis, candidiasis, pityriasis versicolor, seborrheic dermatitis,
and even cutaneous infections with unusual saprophytes. In tinea pedis, a
mycologic cure rate of up to 85% has been observed, and in seborrheic
dermatitis, a significantly larger percentage of users had >75% improvement
within 2 weeks of use than those using the shampoo vehicle alone.28-30
Although treatment with ciclopirox olamine for tinea pedis and seborrheic
dermatitis has yielded results on par with other modalities, use in
onychomycosis has met with more modest success.28-30
Often, an assessment of efficacy depends upon whether a mycologic
cure (culture-negative) or clinical cure (a disease-free nail) defines success.
22
NurseCe4Less.comAlthough a disease-free nail is often the patient’s true goal, ciclopirox olamine
achieved such a response in just 5.5%–8.5% of those treated with a standard
48-week course.28-30 Use of oral terbinafine in combination with topical
ciclopirox olamine is more effective as compared to treatment with oral
terbinafine alone.28-30
Debate regarding the use of ciclopirox olamine as an independent or
adjunct treatment for onychomycosis is ongoing. Ciclopirox Olamine is
available in a wide range of forms.28-30 Cutaneous candidiasis,
dermatophytosis, and pityriasis versicolor should be treated twice daily for 2
weeks to 1 month, but treatment for tinea pedis should continue 1 month or
longer.28-30 When using ciclopirox shampoo for seborrheic dermatitis,
treatment may continue twice weekly for an indefinite duration. Improvement
is generally noted in 2–4 weeks. Finally, in treating onychomycosis, nail
lacquer is applied daily to the nail and hyponychium for 48 weeks and excess
medication is removed weekly with alcohol.28-30
Risks associated with the use of topical ciclopirox olamine are those
inherent to all topical medicaments. Allergic contact dermatitis has been
reported only rarely, and ciclopirox olamine is considered a weak sensitizer.
In patients with an allergic reaction to ciclopirox, imidazoles may be used with
relative safety because of a markedly different chemical structure. Serious
complications with topical ciclopirox olamine are few.28-30
Tolnaftate
Tolnaftate is a thiocarbamate is contained in over-the-counter antifungal
remedies. The precise mechanism of action of tolnaftate is unknown.32 It is
thought to impair ergosterol synthesis via inhibition of squalene epoxidase but
in a different manner than that of allylamines and benzylamines. Tolnaftate
may be fungistatic or fungicidal, depending upon the concentration. No
antibacterial properties have been attributed to tolnaftate. Little data exists
regarding the pharmacokinetics of tolnaftate.32
23
NurseCe4Less.comLike other topical antifungals, systemic absorption is assumed to be
negligible from a clinical standpoint. Tolnaftate is indicated for the treatment
of dermatophytosis and pityriasis versicolor. Early studies demonstrated a
cure rate for tinea pedis as high as 73 percent to 93 percent, but later studies
demonstrated lower efficacy, essentially equivalent to undecylenic acid.32
Although direct comparisons are lacking, topical tolnaftate is widely
considered less effective than topical imidazoles, allylamines, and
benzylamines. Tolnaftate is ineffective for candidiasis.32
Tolnaftate is available in a variety of formulations. Twice-daily use for
at least 2 to 4 weeks, and up to 6 weeks on hyperkeratotic skin, is
recommended. To diminish the incidence of recurrence, others simply
recommend treatment be continued 2 weeks beyond apparent resolution.32
Risks associated with the use of topical tolnaftate are those inherent to all
topical medicaments. Allergic contact dermatitis has been reported on
occasion. Serious complications with the use of topical tolnaftate are few.32
Undecylenic Acid
The mechanism of action for undecylenic acid is largely unknown. It
appears that the organic acid interacts with components in the fungal cell wall.
In C. albicans, the inhibition of germ tube formation has been recently
identified, and a similar effect has been noted in conidia formation in
Trichophyton rubrum.33
Undecylenic acid is available as zinc, calcium, or copper salt. As tissue
pH rises, this salt fails to dissociate, and antifungal properties of the
medication diminish. The acid is practically insoluble in water, but is miscible
in ethanol, water, or ether. With topical use, systemic absorption is
negligible.33 The zinc contained in the zinc undecylenate form, the most
common in clinical use, provides some astringent action that may aid in
reducing rawness and irritation. Topical undecylenic acid is used for the
treatment of dermatophytosis and candidiasis.33
24
NurseCe4Less.comAlthough early studies indicated a cure rate in excess of 80 percent,
subsequent studies demonstrated cure rates of 53 percent or less. Undecylenic
acid and its salts are widely considered less effective than miconazole,
clotrimazole, or tolnaftate in the treatment of tinea pedis.33 A trial of topical
undecylenic acid for herpes labialis demonstrated a decreased incidence and
duration of viral shedding, with a decrease in pain and tenderness. The
antiviral effect was of short duration and most pronounced when acid was
applied during the prodrome.33
Other long chain alcohols enjoy specific approval for abbreviation of
herpes labialis and appear more effective. Undecylenic acid and its salts are
available as a powder, aerosol, cream, and solution. Standard dosing for
children and adults is twice-daily for 4 weeks of use.33 Risks associated with
the use of topical undecylenic acid are those inherent to all topical
medicaments. Allergic contact dermatitis has been recently reported, and a
protocol for patch testing exists if such an allergy is suspected.33
Topical forms of undecylenic acid may yield an unpleasant “fishy smell”
that discourages use. Complications with topical undecylenic acid are few.
Because undecylenic acid is widely accepted to be less effective than
imidazoles, clinical monitoring for treatment failure is indicated.33
Corticosteroids
Topical corticosteroids are used to relieve inflammation and pruritus of
contact dermatitis, insect bites, minor burns, seborrheic dermatitis, psoriasis,
and eczema.34 These medications contain a drying agent or conversely an
emollient and are usually found in creams, ointments, lotions, and gels to
facilitate absorption at the site of action. Absorption is high in areas of thin
skin, but penetration is poor with thick skin. These preparations vary widely
in strength, with those available over the counter (OTC) being of low
potency.34
Systemic toxicity may be a side effect with long-term therapy using
high-potency topical preparations. Site of application influences the
25
NurseCe4Less.commedication form choice. Gels and lotions are used in hairy areas. Creams rub
easily into tissue if needed for weepy, wet tissue lesions. Lipid-based
ointments are more occlusive and moisturizing and are best for application on
dry or scaly areas.34
Corticosteroids have specific and nonspecific effects that are related to
different mechanisms of action, including anti-inflammatory,
immunosuppressive, antiproliferative, and vasoconstrictive effects.34 Most of
their actions are mediated by an intracellular receptor called the glucocorticoid
receptor. The glucocorticoid receptor α-isoform is located in the cytosol, binds
glucocorticoids, and translocates to a region of the nuclear DNA known as the
corticosteroid responsive element, where it is then able to stimulate or inhibit
transcription of the adjacent genes, thus regulating the inflammatory
process.34
The glucocorticoid receptor β-isoform does not bind glucocorticoids, but
is able to bind the antiglucocorticoid/antiprogestin compound RU-486 to
regulate gene expression. The glucocorticoid receptor β can attenuate the
ligand-mediated transactivation of hormone-sensitive genes by the α-isoform
and may be an important marker of steroid insensitivity.34
Anti-Inflammatory Effects
Corticosteroids are thought to exert their potent anti-inflammatory
effects by inhibiting the release of phospholipase A2, an enzyme responsible
for the formation of prostaglandins, leukotrienes, and other derivatives of
arachidonic acid pathway.35 Corticosteroids also inhibit transcription factors,
such as activator protein 1 and nuclear factor κβ, which are involved in the
activation of proinflammatory genes. Genes known to be upregulated by
corticosteroids and that play a role in the resolution of inflammation include
lipocortin and p11/calpactin-binding proteins, both involved in the release of
arachidonic acid.35
Lipocortin I inhibits phospholipase A2, reducing the release of
arachidonic acid from phospholipids. Corticosteroids also decrease the release
26
NurseCe4Less.comof interleukin-1α (IL-1α), an important proinflammatory cytokine, from
keratinocytes. Other proposed mechanisms for the anti-inflammatory effects
of corticosteroids include inhibition of phagocytosis and stabilization of
lysosomal membranes of phagocytizing cells.35
Immunosuppressive Effects
The effectiveness of corticosteroids is, in part, also due to their
immunosuppressive properties. Corticosteroids suppress the production and
effects of humoral factors involved in the inflammatory response, inhibit
leukocyte migration to sites of inflammation, and interfere with the function
of endothelial cells, granulocytes, mast cells, and fibroblasts.35-37 Several
studies have shown that corticosteroids can cause mast cell depletion in the
skin. Experiments have also shown that topical corticosteroids cause local
inhibition of chemotaxis of neutrophils in vitro, and decrease the number of
Ia+ Langerhans cells in vivo.35-37
Corticosteroids reduce eosinophilia in patients with asthma. They also
reduce T-cell proliferation and induce T-cell apoptosis, in part from inhibition
of the T-cell growth factor IL-2. In addition, several cytokines are directly
affected by corticosteroids, including IL-1, tumor necrosis factor-α,
granulocyte-macrophage colony-stimulating factor, and IL-8. These effects
may also be a result of steroid action on antigen presenting cells.35-37
Antiproliferative Effects
The antiproliferative effect of topical corticosteroids is mediated by
inhibition of DNA synthesis and mitosis, partly explaining the therapeutic
action of these drugs in scaling dermatoses. They are known to reduce the
keratinocyte size and proliferation. Fibroblast activity and collagen formation
are also inhibited by topical corticosteroids.35-37
27
NurseCe4Less.comVasoconstriction
The mechanism by which corticosteroids induce vasoconstriction is not
yet completely clear. It is considered related to inhibition of natural
vasodilators such as histamine, bradykinins, and prostaglandins. Topical
steroids cause capillaries in the superficial dermis to constrict, thus reducing
erythema.35-37 The ability of a given corticosteroid agent to cause
vasoconstriction usually correlates with its anti-inflammatory potency and,
thus, vasoconstriction assays are often used to predict the clinical activity of
an agent. These assays, in combination with double blind clinical trials, have
been used to separate the topical corticosteroids into seven classes based on
potency. Class 1 includes the most potent, while class 7 contains the least
potent.35-37
Modifications of Cortisol and Preparation Choice
Modifications of cortisol, by addition or alteration of functional groups,
have led to the development of compounds with variable anti-inflammatory
potency, glucocorticosteroid versus mineralocorticoid activity, and adverse
effects.35-37 Before choosing a topical glucocorticoid preparation, patient-
related and drug-related factors that can affect its systemic absorption should
be taken into account. This would include the age of the patient, the extent
and location of the body surface area to be treated and the presence or
absence of skin inflammation, which greatly affect the activity of the topical
agent.35-37
Penetration of the glucocorticoid varies according to the skin site, which,
in turn, is related to the thickness of the stratum corneum and the vascular
supply to the area.35-37 For example, penetration of topical steroids through
the eyelids and scrotum is four times greater than for the forehead and 36
times greater than for the palms and soles. Inflamed, moist, and denuded skin
also shows increased penetration.35-37
Areas of the body where the skin is inherently thin allow for increased
penetration of the drug and are also more susceptible to developing side
28
NurseCe4Less.comeffects than other areas where the skin is thick. Potent topical steroids (classes
1 and 2) should rarely, if ever, be used in the areas with the highest level of
penetration, such as the eyelids.35-37 The concentration of the therapeutic
agent used, the duration of the application, the use of occlusive dressings, the
elected vehicle, and the intrinsic characteristics of the chosen molecule, can
also affect the absorption and the degree of adverse effects.35-37
The target site for topical corticosteroids is the viable epidermis or
dermis, and clinical response to a formulation is directly proportional to the
concentration of corticosteroid achieved at the target site.35-37 A comparison
study of skin concentrations after topical versus oral corticosteroid treatment
found that most topical corticosteroids have the potential to achieve greater
effective drug levels in the superficial layers of the skin than those achieved
with standard doses of oral prednisone. Therefore, the apparently greater
efficacy of oral corticosteroid therapy may be due in part to poor patient
compliance with topical therapy.35-37
Topical corticosteroids are compounded in several formulations and with
varying strengths. Recent research has emphasized the importance of
treatment adherence in the management of skin conditions. As such, newer
formulations including spray, foam, lotion, hydrogel, and shampoo
formulations have been developed to improve patient convenience and
acceptance, without sacrificing the efficacy, safety and tolerability of the
traditional ointment and cream formulations.35-37 A recent systematic review
of the literature found that while there are few direct comparison studies
between clobetasol propionate, a class 1 steroid, in different vehicles, the
efficacy rates for more recent formulations is roughly comparable to that of
clobetasol ointment in the treatment of psoriasis. The most common adverse
effect was mild and transient stinging or burning at the lesion site, which may
be due to the alcohol content found in these formulations. None of the clinical
trials directly compared these formulations with one another.35-37
Increasing hydration of the stratum corneum can enhance absorption of
topical corticosteroids by four to five times.35-37 Absorption is also enhanced
by ten times with occlusion. A retrospective study of wet dressings used with
29
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