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DERMATOLOGY
PHARMACOLOGY
Jassin M. Jouria, MD
Dr. Jassin M. Jouria is a medical doctor,
professor of academic medicine, and medical
author. He graduated from Ross University
School of Medicine and has completed his
clinical clerkship training in various teaching
hospitals throughout New York, including
King’s County Hospital Center and Brookdale
Medical Center, among others. Dr. Jouria has
passed all USMLE medical board exams, and
has served as a test prep tutor and instructor for Kaplan. He has developed several medical
courses and curricula for a variety of educational institutions. Dr. Jouria has also served on
multiple levels in the academic field including faculty member and Department Chair. Dr.
Jouria continues to serves as a Subject Matter Expert for several continuing education
organizations covering multiple basic medical sciences. He has also developed several
continuing medical education courses covering various topics in clinical medicine. Recently,
Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s
Department of Surgery to develop an e-module training series for trauma patient
management. Dr. Jouria is currently authoring an academic textbook on Human Anatomy &
Physiology.
Abstract
Skin diseases range in types, onset and severity in individuals. Healthcare
providers need to be informed of the varied conditions and pharmacology
treatments in order to provide comprehensive care. Dermatology treatment
may be directed toward the treatment of an inflammatory process, comorbid medical condition, or it may be cosmetic to achieve a patient desire
outcome involving a change in physical appearance. The practice of
dermatology is a blending of traditional and market factors, which health
providers should be aware of when guiding patients in their health
management and medication treatment choices.
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Continuing Nursing Education Course Planners
William A. Cook, PhD, Director, Douglas Lawrence, MA, Webmaster,
Susan DePasquale, MSN, FPMHNP-BC, Lead Nurse Planner
Policy 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. It is the policy of NurseCe4Less.com to
ensure objectivity, transparency, and best practice in clinical education for
all continuing nursing education (CNE) activities.
Continuing Education Credit Designation
This educational activity is credited for 5 hours. Nurses may only claim credit
commensurate with the credit awarded for completion of this course activity.
Pharmacology content is 5 hours.
Statement of Learning Need
The skin is an important body organ to understand, especially while
considering the many factors that influence percutaneous medication use
and efficacy. Many factors ultimately affect therapeutic efficacy of
dermatology pharmaceuticals. Knowledge of the different forms and
properties of dermatology medication is essential to patient care outcomes;
and, of the market influences on patient cost and compliance.
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Course Purpose
To provide nursing professionals with knowledge of dermatology
pharmacology to support medication efficacy for varied skin conditions and
to improve patient understanding and compliance with medication use.
Target Audience
Advanced Practice Registered Nurses and Registered Nurses
(Interdisciplinary Health Team Members, including Vocational Nurses and
Medical Assistants may obtain a Certificate of Completion)
Course Author & Planning Team Conflict of Interest Disclosures
Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA,
Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures
Acknowledgement of Commercial Support
There is no commercial support for this course.
Activity Review Information
Reviewed by Susan DePasquale, MSN, FPMHNP-BC
Release Date: 1/1/2016
Termination Date: 10/18/2018
Please take time to complete a self-assessment of knowledge, on
page 4, sample questions before reading the article.
Opportunity to complete a self-assessment of knowledge learned
will be provided at the end of the course.
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1. _____________ is defined as the decrease in drug response due to the
use of a drug over a prolonged period of time.
a) Tapering down
b) Rebound effect
c) Tachyphylaxis
d) Topical nonadherence
2. There are two fields in dermatology:
a) medical and cosmetic dermatology.
b) surgical and cosmetic dermatology.
c) dermatology and general medicine.
d) dermatology and surgery.
3. ____________ are at an increased risk of absorbing topical
corticosteroids.
a) Infants
b) Individuals who are underweight
c) Women
d) The elderly
4. True/False: Cosmetic dermatologists are required to fulfill residency
requirements before they may offer cosmetic procedures.
a) True
b) False
5. Which of the following is a topical dermatologic treatment:
a) Oil
b) Liquids
c) Anti-infective agents
d) Powders
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Introduction
In the course of a day, dermatologists see a wide variety of patients with
concerns ranging from serious medical conditions like cancer to cosmetic
issues that impact the patient's physical and emotional health. As with most
other specialties, pharmacological agents can be a useful resource for
treating dermatological concerns involving the hair, nails, and skin. There
are a wide variety of pharmacological agents that can be utilized in treating
dermatological issues, and they are typically delivered either topically or
percutaneously. As with any medical treatment, the purpose of these
pharmacological agents is to provide relief for the patient's issue with a
minimal amount of pain and other side effects.
Medical And Cosmetic Dermatology
There are two fields in dermatology: medical dermatology and cosmetic
dermatology. Dermatologists are physicians trained in the medical, surgical,
and cosmetic care of the skin. To become a dermatologist, physicians must
spend an additional year of internship in general medicine, and then another
three years training in the specialty of dermatology after they complete
medical school.1 This training includes medical, surgical, and cosmetic
dermatology. Regardless of their career goals, all dermatologists receive
training in the following specialties:2

Medical dermatology: Diagnose, treat, and prevent diseases that affect
the skin, hair and nails.

Dermatopathology: Diagnose diseases that affect the skin, hair, and
nails by removing a sample and examining the sample with a
microscope.
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
Surgical dermatology: Treat diseases that affect the skin, hair, and
nails by using a surgical procedure.

Cosmetic dermatology: Treat the skin, hair, or nails using a treatment
that is meant to improve a patient's appearance rather than treat a
disease.
Many dermatologists do not specialize in one area; instead, they choose to
practice in all of these areas.
It is important to note that providers who do not receive training in cosmetic
procedures during their residency may also offer cosmetic procedures. There
are no residency requirements for cosmetic dermatologists. Even
aestheticians are able to offer some basic cosmetic procedures.
When a dermatologist chooses to specialize in cosmetic dermatology, he or
she will likely perform the following treatments:3

Surgery to diminish acne scars.

Injecting fillers and botulinum toxins to give an aging face a more
youthful appearance.

Laser surgery to diminish or remove small veins, age spots, tattoos,
or wrinkles.
Dermatology Treatment: Topical Agents
Topical dermatologic treatments include varied options. These are listed
below.4

Cleansing agents

Absorbent dressings (i.e., hydrocolloid patches or powder) and superabsorbent powders
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
Anti-infective agents

Anti-inflammatory agents

Astringents (drying agents that precipitate protein, shrink and contract
the skin)

Emollients (skin hydrators and softeners)

Keratolytics (agents that soften, loosen, and facilitate exfoliation of the
squamous cells of the epidermis)
Vehicles of Topical Therapies
Topical therapies can be delivered in various vehicles, which include:

Powders

Liquids

Combinations of liquid and oil
The vehicle influences a therapy’s effectiveness and may cause adverse
effects (i.e., contact or irritant dermatitis). Generally, aqueous and alcoholbased preparations are drying because the liquid evaporates are used in
acute inflammatory conditions.5 Powders are also drying. Oil-based
preparations are moisturizing and are preferred for chronic inflammation.
Vehicle selection is guided by location of application, cosmetic effects, and
convenience.6
Powders
Powders absorb moisture and decrease friction. Because they adhere poorly
to the skin, their use is mainly limited to cosmetic and hygienic purposes.
Generally, powders are used in the intertriginous areas and on the feet. The
adverse effects of powders include: caking (especially if used on weeping
skin), crusting, irritation, and granuloma formation.7 Furthermore, the user
may inhale powders. Most powders contain zinc oxide for its antiseptic and
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covering properties, talc (primarily composed of magnesium silicate) for its
lubricating and drying properties, and a stearate for improved adherence to
the skin. Calamine is a popular skin-colored powder composed of 98% zinc
oxide and 1% ferric oxide and acts as an astringent to relieve pruritus. Other
drugs formulated as powders include some over-the-counter antifungals.8
Poultices
A poultice, also referred to as a cataplasm, is a wet solid mass of particles,
sometimes heated, that is applied to diseased skin. Historically, poultices
contained meal, herbs, plants, and seeds. The modern poultice often
consists of porous beads of dextranomer. Poultices are used as wound
cleansers and absorptive agents in exudative lesions such as decubiti and leg
ulcers.9
Ointments
Ointments are semisolid preparations that spread easily. They are
petrolatum-based vehicles, capable of providing occlusion, hydration, and
lubrication. Drug potency is often increased from an ointment vehicle
because of the ointment’s enhanced permeability. Ointment bases used in
dermatology can be classified into five categories: (1) hydrocarbon bases,
(2) absorption bases, (3) emulsions of water-in-oil, (4) emulsions of oil-inwater, and (5) water-soluble bases.
Dermatologists commonly refer to the hydrocarbon bases and absorption
bases as ointments, and the water-in-oil or oil-in-water emulsion bases as
creams. In pharmaceutical terms, all of these preparations are ointments
and are specifically indicated for conditions affecting the glabrous skin
(palms and soles) and lichenified areas.10
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
Absorption Bases:
Absorption bases contain hydrophilic substances that allow for the
absorption of water-soluble drugs. The hydrophilic (polar) compounds
may include lanolin and its derivatives, cholesterol and its derivatives,
and the partial esters of polyhydric alcohols such as sorbitan
monostearate. These ointments are lubricating and hydrophilic, and
they can form emulsions. They function well as emollients and
protectants. They are greasy to apply but are easier to remove than
the hydrocarbon bases. They do not contain water. Examples include
anhydrous lanolin and hydrophilic petrolatum.11

Water-In-Oil Emulsions (Creams):
Emulsions are two-phase systems involving one or more immiscible
liquids dispersed in another, with the assistance of one or more
emulsifying agents. A water-in-oil emulsion, by definition, contains less
than 25% water, with oil being the dispersion medium. The two
phases may separate unless shaken. The emulsifier (or surfactant) is
soluble in both phases and surrounds the dispersed drops to prevent
their coalescence. Examples of surfactants used include sodium lauryl
sulfate, the quaternary ammonium compounds, Spans (sorbitan fatty
acid esters), and Tweens (polyoxyethylene sorbitan fatty acid esters).
Preservatives are frequently added to increase the emulsion’s shelf
life. Water-in-oil emulsions are less greasy, spread easily on the skin,
and provide a protective film of oil that remains on the skin as an
emollient, while the slow evaporation of the water phase provides a
cooling effect.7
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
Oil-In-Water Emulsions
An oil-in-water emulsion contains greater than 31% water. In fact, the
aqueous phase may comprise up to 80% of the formulation. This type
of formulation is the one most commonly chosen to deliver a
dermatologic drug. Clinically, oil-in-water emulsions spread very
easily, are water washable and less greasy, and are easily removed
from the skin and clothing. Invariably, they contain preservatives,
such as the parabens, to inhibit the growth of molds. Additionally, oilin-water emulsions contain a humectant (an agent that draws
moisture into the skin), such as glycerin, propylene glycol, or
polyethylene glycol (PEG), to prevent the cream from drying out. The
oil phase may contain either cetyl or stearyl alcohol (paraffin alcohols)
to impart a stability and velvety smooth feel upon application to the
skin. After application, the aqueous phase evaporates, leaving behind
both a small hydrating layer of oil and a concentrated deposit of the
drug.12

Water-Soluble Bases:
Water-soluble bases consist either primarily or completely of various
PEGs. Depending on their molecular weight, PEGs are either liquid
(PEG 400) or solid (PEG 4,000). These formulations are water soluble,
will not decompose, and will not support the growth of mold, and
therefore require no preservative additives. They are much less
occlusive than water-in-oil emulsions, nonstaining, greaseless, and
easily washed off of the skin. Without water, this ointment poorly
delivers its coformulated drug. Therefore, it will be useful in scenarios
where the practitioner desires a high surface concentration and low
percutaneous absorption of the drug. For example, topical antifungal
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drugs and topical antibiotics (i.e., mupirocin) are formulated in this
type of base.
Gels are made from water-soluble bases by formulating water,
propylene glycol, and/or PEGs with a cellulose derivative or carbopol. A
gel consists of organic macromolecules uniformly distributed in a
lattice throughout the liquid. After application, the aqueous or alcoholic
component evaporates, and the drug is deposited in a concentrated
form. This provides a faster release of the drug independent of its
water solubility. Gels are popular because of their clarity and ease of
both application and removal. They are suitable for facial or hairy
areas because after application little residue is left behind.
Nevertheless, they lack any protective or emollient properties. If they
contain high concentrations of alcohol or propylene glycol, they tend to
be drying or cause stinging.
Gels require preservatives. Newer gel formulations may contain the
humectant glycerin, the emollient dimethicone, or the viscoelastic
polysaccharide hyaluronic acid, which can mitigate some of the
associated irritation. Nonaqueous gels, with bases such as glycerol,
may be used for poorly solubilized therapeutics such as 5aminolevulonic acid. Microspheres, or microsponges, are formulated in
an aqueous gel. Medication, in this case tretinoin, is combined into
porous beads 10–25 μm in diameter. The beads are made up of
methyl methacrylate and glycol dimethacrylate.13
Pastes
Pastes are simply the incorporation of high concentrations of powders (up to
50%) into an ointment such as a hydrocarbon base or a water-in-oil
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emulsion. The powder must be insoluble in the ointment. Invariably, they
are “stiffer” than the original ointment. The powders commonly used are zinc
oxide, starch, calcium carbonate, and talc. Pastes function to localize the
effect of a drug that may be staining or irritating (i.e., anthralin). They also
function as impermeable barriers that serve as protectants or sunblock.
Pastes are less greasy than ointments, more drying, and less occlusive.14,15
Liquids
Liquids can be subdivided into solutions, suspensions, emulsions and foams.
These are described below.

Solutions:
A solution involves the dissolution of two or more substances into
homogenous clarity. The liquid vehicle may be aqueous,
hydroalcoholic, or nonaqueous (alcohol, oils, or propylene glycol). An
example of an aqueous solution is aluminum acetate or Burow
solution. A hydroalcoholic solution with a concentration of alcohol of
approximately 50% is called a tincture. A collodion is a nonaqueous
solution of pyroxylin in a mixture with ether and ethanol, and is
applied to the skin with a soft brush. Flexible collodions have added
castor oil and camphor and are used, for example, to deliver 10%
salicylic acid as a keratolytic agent.
Liniments are nonaqueous solutions of drugs in oil or alcoholic
solutions of soap. The base of oil or soap facilitates application to the
skin with rubbing or massage. Liniments can be used as
counterirritants, astringents, antipruritics, emollients, and
analgesics.16-18
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
Suspensions (Lotions)
A suspension, or lotion, is a two-phase system consisting of a finely
divided, insoluble drug dispersed into a liquid in a concentration of up
to 20%. Nonuniform dosing can result in the suspended particles
coalescing and separating out of a homogeneous mixture, therefore
shaking of the lotion before application may be required. Examples
include calamine lotion, steroid lotions, and emollients containing urea
or lactic acid. The applied lotion leaves the skin feeling cooler via
evaporation of the aqueous component.
Lotions are easier to apply and allow for uniform coating of the
affected area, and are often the favorite preparation in treating
children. Lotions are more drying than ointments, and preparations
with alcohol tend to sting eczematized or abraded skin. Additionally,
lotions are suitable for application to large surface areas due to their
ability to spread easily.19

Shake Lotions
Shake lotions are lotions to which a powder is added to increase the
surface area of evaporation. As a result of the increased evaporation,
the application of shake lotions effectively dries and cools wet and
weeping skin. Generally, shake lotions consist of zinc oxide, talc,
calamine, glycerol, alcohol, and water, to which specific drugs and
stabilizers may be added. Shake lotions tend to develop sediment, and
derive their name from the need to shake the preparation before each
use to obtain a homogeneous suspension. In addition, after water has
evaporated from the lotion, the powder component may clump
together and become abrasive. Therefore, patients should be
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instructed to remove the residual particles before the reapplication of
shake lotions.20

Foams
Foams are triphasic liquids composed of oil, organic solvents and
water, which are kept under pressure in aluminum cans. Foams are
formulated with a hydrocarbon propellant, either butane or propane.
The foam lattice is formed when the valve is activated. Once in contact
with the skin, the lattice breaks down, the alcohol evaporates within
30 seconds, and leaves minimal residue on the skin. The alcohol
component of the foam is thought to act as a penetration enhancer,
momentarily altering the barrier properties of the stratum corneum
(outermost layer of the skin) and increasing drug delivery through the
intercellular route.
Previous studies have demonstrated that foam vehicles are highly
effective in delivering greater amount of active drug at an increased
rate when compared to other vehicles that traditionally depend upon
hydration of the intercellular spaces within the stratum corneum.
Foams have not been associated with an increase in adverse events
and compliance seems to be better with this formulation, especially for
localized conditions affecting the scalp.3,21
Aerosols
Topical aerosols may be used to deliver drugs formulated as solutions,
suspensions, emulsions, powders, and semisolids. Aerosols involve
formulating the drug in a solution within a pure propellant. Usually, the
propellant is a blend of nonpolar hydrocarbons. When applied to abraded or
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eczematized skin, aerosols lack the irritation of other formulations, especially
when the quality of the skin makes direct application painful or difficult.
Furthermore, aerosols dispense a drug as a thin layer with minimal waste,
and the unused portion cannot be contaminated.
Aerosol foams, a relatively new vehicle for drug delivery, are commonly used
to deliver corticosteroids such as betamethasone valerate and clobetasol
propionate. The foam contains the drug within an emulsion formulated with
a foaming agent (a surfactant), a solvent system (such as water and
ethanol), and a propellant. On application, a foam lattice forms transiently
until both the heat of the skin and the heat of rubbing the foam onto the
skin break it down. Foams that are alcohol based leave very little residue
within seconds of their application. Furthermore, a given corticosteroid
formulated in a foam vehicle demonstrates comparable potency when
compared with the same corticosteroid in other vehicles. Although aerosols
allow for the ease of application (especially to hair-bearing areas) and high
patient satisfaction, they suffer from the disadvantages of being expensive
and potentially ecologically damaging.
Penetration Enhancers
A penetration enhancer is a compound that is able to promote drug
transport through the skin barrier.

Chemical Enhancers:
Skin hydration and interaction with the polar head group of the lipids
are mechanisms for increasing penetration. Water, alcohols (mainly
ethanol), sulphoxides (dimethylsulphoxide/DMSO),
decylmethylsulphoxide/DCMS, azones (laurocapram), and urea are
some of the most commonly used compounds. Urea is thought to act
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as a penetration enhancer due to its keratolytic properties and by
increasing the water content in the stratum corneum. Other
substances that may also act as chemical enhancers include propylene
glycol, surfactants, fatty acids, and esters.
Vesicular systems are widely used in dermatologic and cosmetic fields
to enhance drug transport into the skin through the transcellular and
follicular pathways. Examples of vesicular systems include liposomes
(phospholipid-based vesicles), niosomes (nonionic surfactant vesicles),
proliposomes and proniosomes, which, respectively, are converted to
liposomes and niosomes upon hydration.5,22,23

Physical Enhancers:
Physical methods such as the application of a small electric current
(iontophoresis), ultrasound energy (phono- or sonophoresis) and the
use of microneedles increase cutaneous drug penetration.
Microdermoabrasion is the application of crystals (generally aluminum
oxide) on the skin and the collection of such crystals and skin debris
under vacuum suction. Microdermabrasion is a technique that
enhances drug permeation and facilitates drug absorption by altering
the architecture of the stratum corneum.24
Stabilizers
Stabilizers are nontherapeutic ingredients and include the preservatives,
antioxidants, and chelating agents. Preservatives protect the formulation
from microbial growth. The ideal preservative is effective at a low
concentration against a broad spectrum of organisms, nonsensitizing, odor
free, color free, stable, and inexpensive. Unfortunately, the ideal
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preservative does not exist. The parabens are the most frequently added
preservatives, and are active against molds, fungi, and yeasts, but less
effective against bacteria. Alternative agents include the halogenated
phenols, benzoic acid, sodium benzoate, formaldehyde, the formaldehydereleasing agents, and previously, thimerosal. Most commonly used
preservatives may act as contact sensitizers.25
Antioxidants or preservatives prevent the drug or vehicle from degrading via
oxidation. Examples include butylated hydroxyanisole and butylated
hydroxytoluene, used in oils and fats. Ascorbic acid, sulfites, and sulfurcontaining amino acids are used in water-soluble phases. Chelating agents,
such as sodium EDTA and citric acid, work synergistically with antioxidants
by complexing heavy metals in aqueous phases.26
Thickening Agents
Thickening agents increase the viscosity of products or suspend ingredients
in a formulation. Examples include bees-wax and carbomers. In addition to
functioning as an ointment vehicle, petrolatum may be added to an emulsion
to increase its viscosity. As in this example, an ingredient may have a
therapeutic effect as well as acting as part of a vehicle.27
Categories and Indications of Topical Agents
Major categories of topical agents are listed below.

Cleansing

Moisturizing

Drying

Anti-inflammatory
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
Antimicrobial

Keratolytic

Astringent

Antipruritic

Cleansing agents
The principal cleansing agents are soaps, detergents, and solvents. Soap is
the most popular cleanser, but synthetic detergents are also used. Baby
shampoos are usually well tolerated around the eyes and for cleansing
wounds and abrasions; they are useful for removing crusts and scales in
psoriasis, eczema, and other forms of dermatitis. However, acutely irritated,
weeping, or oozing lesions are most comfortably cleansed with water or
isotonic saline.28
Water is the principal solvent for cleansing. Organic solvents (i.e., acetone,
petroleum products, propylene glycol) are very drying, can be irritating, and
cause irritant or, less commonly, allergic contact dermatitis. Removal of
hardened tar and dried paint from the skin may require a petrolatum-based
ointment or commercial waterless cleanser.8,9,22,29-34
The following table highlights the various types of topical compounds,
recommended usage and applications.
Moisturizing
agents
Moisturizers (emollients) restore water and oils to the skin and help
maintain skin hydration. They typically contain glycerin, mineral oil, or
petrolatum and are available as lotions, creams, ointments, and bath
oils. Stronger moisturizers contain urea 2%, lactic acid 5 to 12%, and
glycolic acid 10% (higher concentrations of glycolic acid are used as
keratinolytics, i.e., for ichthyosis). They are most effective when
applied to already moistened skin (i.e., after a bath or shower). Cold
creams are moisturizing over the counter (OTC) emulsions of fats
(i.e., beeswax) and water.
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Drying agents
Excessive moisture in intertriginous areas (i.e., between the toes, and
in the intergluteal cleft, axillae, groin, and inframammary areas) can
cause irritation and maceration. Powders dry macerated skin and
reduce friction by absorbing moisture. However, some powders tend
to clump and can be irritating if they become moist.
Cornstarch and talc are most often used. Although talc is more
effective, talc may cause granulomas if inhaled and is no longer used
in baby powders. Cornstarch may promote fungal growth. Aluminum
chloride solutions are another type of drying agent (often useful in
hyperhidrosis).
Antiinflammatory
agents
Topical anti-inflammatory agents are either corticosteroids or
noncorticosteroids. Corticosteroids are the mainstay of treatment for
most noninfectious inflammatory dermatoses.
Lotions are useful on intertriginous areas and the face. Gels are useful
on the scalp and in management of contact dermatitis. Creams are
useful on the face and in intertriginous areas and for management of
inflammatory dermatoses. Ointments are useful for dry scaly areas
and when increased potency is required.
Corticosteroid-impregnated tape is useful to protect an area from
excoriation. It also increases corticosteroid absorption and therefore
potency. Topical corticosteroids range in potency from mild (class VII)
to superpotent (class I— Relative Potency of Selected Topical
Corticosteroids). Intrinsic differences in potency are attributable to
fluorination or chlorination (halogenation) of the compound.
Topical corticosteroids are generally applied 2 to 3 times daily, but
high-potency formulations may require application only once/day or
even less frequently. Most dermatoses are treated with mid-potency
to high-potency formulations; mild formulations are better for mild
inflammation and for use on the face or intertriginous areas, where
systemic absorption and local adverse effects are more likely.
All agents can cause local skin atrophy, striae, and acneiform
eruptions when used for > 1 mo. This effect is particularly problematic
on the thinner skin of the face or genitals. Corticosteroids also
promote fungal growth.
Contact dermatitis in reaction to preservatives and additives is also
common with prolonged use. Contact dermatitis to the corticosteroid
itself may also occur. Perioral dermatitis occurs with mid-potency or
high-potency formulations used on the face but is uncommon with
mild formulations. High-potency formulations may cause adrenal
suppression when used in children, over extensive skin surfaces, or
for long periods. Relative contraindications include conditions in which
infection plays an underlying role and acneiform disorders.
Noncorticosteroid anti-inflammatory agents include tar preparations.
Tar comes in the form of crude coal tar and is indicated for psoriasis.
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Adverse effects include irritation, folliculitis, staining of clothes and
furniture, and photosensitization. Contraindications include infected
skin. Several herbal products are commonly used in commercial
products, although their effectiveness has not been well established.
Among the most popular are chamomile and calendula.
Antimicrobials
Topical antimicrobials include:
 Antibiotics
Antibiotics have few indications. Topical clindamycin and
erythromycin are used as primary or adjunctive treatment for
acne vulgaris in patients who do not warrant or tolerate oral
antibiotics. Topical metronidazole and occasionally topical
sulfacetamide, clindamycin or erythromycin, are used for acne
rosacea. Mupirocin has excellent gram-positive (mainly
Staphylococcus aureus and streptococci) coverage and can be
used to treat impetigo when deep tissues are not affected.
OTC antibiotics such as bacitracin and polymyxin are often
used in postoperative care of a skin biopsy site and to prevent
infection in scrapes, minor burns, and excoriations. Topical
neomycin causes contact dermatitis more frequently than other
antibiotics. The use of topical antibiotics and washing with
antiseptic soaps in healing wounds may, however, actually slow
healing.

Antifungals:
Antifungals are used to treat candidiasis, a wide variety of
dermatophytoses, and other fungal infections.

Insecticides:
Insecticides (i.e., permethrin, malathion) are used to treat lice
infestation and scabies.

Nonspecific antiseptic agents:
Nonspecific antiseptic agents include iodine solutions (i.e.,
povidone iodine, clioquinol), gentian violet, silver preparations
(i.e., silver nitrate, silver sulfadiazine), and zinc pyrithione.
Iodine is indicated for presurgical skin preparation. Gentian
violet is used when a chemically and physically stable
antiseptic/antimicrobial is needed and must be very
inexpensive.
Silver preparations are effective in treating burns and ulcers
and have strong antimicrobial properties; several wound
dressings are impregnated with silver. Zinc pyrithione is an
antifungal and a common ingredient in shampoos used to treat
dandruff due to psoriasis or seborrheic dermatitis. Healing
wounds should generally not be treated with topical antiseptics
other than silver because they are irritating and tend to kill
fragile granulation tissue.
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Keratolytics
Keratolytics soften and facilitate exfoliation of epidermal cells.
Examples include 3 to 6% salicylic acid and urea. Salicylic acid is used
to treat psoriasis, seborrheic dermatitis, acne, and warts. Adverse
effects are burning and, if large areas are covered, systemic toxicity.
It should rarely be used in children and infants.
Urea is used to treat plantar keratodermas and ichthyosis. Adverse
effects are irritation and intractable burning. It should not be applied
to large surface areas.
Astringents
Astringents are drying agents that precipitate protein and shrink and
contract the skin. The most commonly used astringents are aluminum
acetate (Burow solution) and aluminum sulfate plus Ca acetate
(Domeboro solution). Usually applied with dressings or as soaks,
astringents are used to treat infectious eczema, exudative skin
lesions, and weeping pressure ulcers.
Witch hazel is a popular OTC astringent.
Antipruritics
Doxepin is a topical antihistamine that is effective in treating itching of
atopic dermatitis, lichen simplex chronicus dermatitis, and nummular
dermatitis. Topical benzocaine and diphenhydramine (present in
certain OTC lotions) are sensitizing and not recommended. Other
antipruritics include camphor 0.5 to 3%, menthol 0.1 to 0.2%,
pramoxine hydrochloride, and eutectic mixture of local anesthetics
(EMLA), which contain equal parts lidocaine and prilocaine in an oil-inwater vehicle.
Topical antipruritics are preferred over systemic drugs (i.e., oral
antihistamines) when smaller surface areas of skin are affected and
pruritus is not intractable. Calamine lotion is soothing but not
specifically antipruritic.
Factors Affecting Absorption
Several kinds of medications have systemic effect when applied
transdermally. Rate of medication absorption depends on drug form, size of
molecules (smaller molecules are more rapidly absorbed), and medication
base (oil-based or more readily absorbed water-based vehicles). Such
medications as hormones, antianginals, antihypertensives, analgesics, and
antihistamines may be specifically applied transdermally for prolonged
release for systemic therapy. General goals of therapy are to remove causes
of skin disorders, find measures to restore and maintain normal skin
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function, and relieve symptoms such as itching, dryness, pain, or
inflammation.35
Many forms of dermatologic preparations - such as liquids, ointments, gels,
beads, pastes, plasters, creams, powders, foams, and sprays - are available
to treat skin disorders. The selected form depends on the desired
therapeutic effect and the ability of the person's skin to absorb medication.
Skin keratin, when moisturized, provides a waterproof barrier for the body;
therefore, skin must be hydrated for absorption of water-based drugs.
Some drugs are placed in dressings to trap perspiration and prevent water
loss and to assist with hydration and absorption. Water-soluble drugs are
more readily absorbed and excreted, whereas fat-soluble drugs in a lipid
base have slower excretion rates. In some body areas, such as the eyelids or
behind the ears, the thinness of skin allows rapid absorption of medication,
whereas areas such as the palms of the hands and soles of the feet are
thick, making them almost impenetrable by medications. Some products
contain lanolin to smooth skin and apply moisture in a lipid-soluble base.
Other products, in alcohol bases, dry skin.
Product use dictates the medication base needed, its method and site of
application, and ability to be absorbed. Just as with medications taken by
other routes, the patient's medical record should be checked for allergies to
medications to prevent skin irritation or other allergic reactions. Skin should
be clean and dry for optimal absorption. If medication is for a specific site,
such as a topical anti-infectant for an infected wound, it should be applied to
the specific site without spreading onto surrounding tissues. If patches are
used for systemic medications, sites should be rotated to avoid skin irritation
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and prevent decreased absorption occurring because of skin sensitization to
medication.36-38
Primary Factors Affecting Absorption
This section covers the primary factors affecting skin absorption of
dermatology topical products.
Stratum Corneum:
The stratum corneum is the rate-limiting barrier to percutaneous drug
delivery. This cornified layer is composed of ceramides, free fatty acids, and
cholesterol in a 1:1:1 molar ratio. By weight, the stratum corneum consists
of 50% ceramides (acylceramides being the most abundant), 35%
cholesterol, and 15% free fatty acids. The stratum corneum thickness and,
thus, drug penetration will vary depending on body site.
There are two main routes for permeation through the stratum corneum: 1)
the transepidermal, and 2) the transappendageal pathways. The
transappendageal, or shunt route, involves the flow of molecules through
the eccrine glands and hair follicles via the associated sebaceous glands. In
the transepidermal route, molecules pass between the corneocytes via the
intercellular micropathway, or through the cytoplasm of dead keratinocytes
and intercellular lipids, defined as the transcellular micropathway. The
intercellular pathway is considered the most important route for cutaneous
drug delivery.
An important consideration in topical therapy is that diseased skin may have
an altered (increased, decreased, or absent) stratum corneum, thus
changing the body sites’ barrier function. Abraded or eczematized skin
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presents less of a barrier. Solvents, surfactants, and alcohols can denature
the cornified layer and increase penetration; as a result, topical medications
with these components may enhance absorption. Importantly, simple
hydration of the stratum corneum enhances the absorption of topically
applied steroids by four to five times.2,4,21
Occlusion:
Occlusion via closed, airtight dressings or greasy ointment bases increases
the hydration and temperature of the stratum corneum, limits rub-off/washoff of the drug and, consequently, enhances drug penetration. Occlusion
techniques range from application under an airtight dressing, such as vinyl
gloves, plastic wrap, and hydrocolloid dressings to occlusion with cotton
gloves or socks at night for treatment of hands and feet, to application of a
medication already impregnated into an airtight dressing, as seen in
flurandrenolide tape. To derive the greatest benefit from occlusion, the
patient should hydrate the skin by immersion in water for approximately 5
minutes before the application of a cream or ointment. Clinically, this may
correspond to application immediately after bathing and before drying
completely.
With many drugs, occlusion increases drug delivery by 10 – 100 times the
amount of drug delivered when not occluded. This approach can lead to
more rapid onset times and increased efficacy when compared with topical
application alone. On the other hand, occlusion may also lead to a more
rapid appearance of the drug’s adverse effects, such as the ability of topical
corticosteroids to induce local skin atrophy or suppression of the
hypothalamus-pituitary–adrenal (HPA) axis. Occlusion may promote
infection, folliculitis, or miliaria. In the case of topical anesthetics such as
lidocaine and prilocaine, occlusion hastens absorption into both the skin and
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the bloodstream, which has led in rare cases to cardiac complications from
lidocaine toxicity or methemoglobinemia from prilocaine toxicity.26,28,36,39
Frequency of Application:
The frequency of drug application likely has little effect on increasing a
topical drug’s overall efficacy. One daily application is enough for most
topical glucocorticoids, for example, but the nonspecific emollient or
protective effect of creams and ointments are likely enhanced by more
frequent applications. Regardless, increasing the contact time for a topical
drug augments its total absorption.29
Quantity of Application:
The quantity of the drug applied likely has a negligible effect on drug
absorption. Obviously enough of the drug must be dispensed and spread to
cover the affected areas. Furthermore, the quantity of drug applied might
affect patient adherence to the prescribed regimen. For example, too much
applied drug might negatively alter the subjective experience of having a
medication on the skin, i.e., the drug may feel “wrong” (greasy, caked,
chalky, etc.) or is cosmetically unattractive (shiny, white color). Regardless,
the amount prescribed must be adequate to treat the affected body surface
area for the necessary length of time. In this regard, patient education is
critical to prevent wasteful overuse or ineffective underuse of the
medication.
For topical medications like sunscreens that are used over large areas, under
application is a problem for most patients. However, for smaller areas,
patients may apply a large amount of an ointment, for example, leading to
complaints of greasiness or rubbing off on clothing, which can be minimized
by using an appropriate amount.2
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Adherence:
Topical medication adherence is a critical although often overlooked aspect
of medication efficacy. Generally, adherence to a treatment regimen is
associated with female gender, employment, being married, and low
prescription costs. Lower adherence is seen for patients with extensive
disease and, paradoxically, disease on the face. One 8-week survey using
electronic monitoring showed that adherence to treatment for a twice-daily
topical prescription decreased from 84% the first week to 51% during the
eighth week, with topical nonadherence being especially notable on
weekends. Furthermore, adherence is negatively affected by depression,
which is common in people with chronic skin conditions and found in up to
20% of patients with psoriasis.
Tachyphylaxis:
Defined as the decrease in drug response when used over a prolonged
period of time, tachyphylaxis is commonly observed during corticosteroid
topical therapy. It is now thought that adherence may be a contributing
factor, rather than loss of corticosteroid receptor function.
Increase in adherence may be achieved by asking patients to use it only on
weekends (weekend therapy) or specific days of the week (pulse therapy).
Rebound Effect:
Worsening of preexisting dermatoses can occur in patients who have been
using topical potent corticosteroids for prolonged regimens. Either tapering
down the corticosteroid strength to moderate- or low-potency corticosteroids
or increasing the duration of time between applications of the topical drug
might prevent the rebound effect.9,13,40
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Miscellaneous Factors:
Vigorous rubbing or massaging of the drug into the skin not only increases
the surface area of skin covered, but also increases blood supply to the area
locally, augmenting systemic absorption. It may cause a local exfoliative
effect that will also enhance penetration. The presence of hair follicles on a
particular body site also enhances drug delivery, with the scalp and beard
areas presenting less of a barrier when compared with the relatively hairless
body sites.
Although having a thinner stratum corneum, the skin of older individuals is
poorly hydrated, with fewer hair follicles and, therefore, may impede drug
delivery. Reducing the particle size of the active ingredient increases its
surface area–volume ratio, allowing for a greater solubility of the drug in its
vehicle. This forms the basis for the increased absorption of certain
micronized drugs.23,24,41
Inactive Components in Topical Formulations
The vehicle is the inactive part of a topical preparation that brings a drug
into contact with the skin. The vehicle of a topical formulation often has
beneficial nonspecific effects by possessing cooling, protective, emollient,
occlusive, or astringent properties. Rational topical therapy matches an
appropriate vehicle that contains an effective concentration of the drug. The
vehicle functions optimally when it is stable both chemically and physically
and does not inactivate the drug. The vehicle also should be nonirritating,
nonallergenic, cosmetically acceptable, and easy to use. Additionally, the
vehicle must release the drug into the pharmacologically important
compartment of the skin.
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Finally, the patient must accept using the vehicle or else compliance will be
poor. For example, although ointments are often pharmacodynamically more
effective than creams, patients generally prefer creams to ointments, and
thus, it is no surprise that more prescriptions are written for cream-based
formulations.33,36,42,43
The following is a list of the most commonly used ingredients in topical
preparations. Many of these compounds may serve more than one function
in a particular formulation.7

Emulsifying Agents
o Cholesterol
o Disodium monooleamidosulfosuccinate
o Emulsifying Wax
o Polyoxyl 40 stearate
o Polysorbates
o Sodium laureth sulfate
o Sodium lauryl sulfate

Auxiliary emulsifying agents or emulsion stabilizers
o Carbomer
o Catearyl alcohol
o Cetyl alcohol
o Glyceryl monostearate
o Lanolin and lanolin derivatives
o Polyethylene glycol
o Stearyl alcohol

Stabilizers
o Benzyl alcohol
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o Butylated hydroxyanisole
o Butylated hydroxytoluene
o Chlorocresol
o Citric Acid
o Edetate disodium
o Glycerin
o Parabens
o Propyl gallate
o Propylene glycol
o Sodium bisulfite
o Sorbic acid/potassium sorbate

Solvents
o Alcohol
o Diisopropyl adipate
o Glycerin
o 1,2,6 - Hexanetriol
o Isopropyl myristate
o Propylene carbonate
o Propylene glycol
o Water

Thickening Agents
o Beeswax
o Carbomer
o Petrolatum
o Polyethylene
o Xanthum gum
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
Emollients
o Acprylic/capric triglycerides
o Cetyl alcohol
o Glycerin
o Isopropyl myristate
o Isopropyl palmitate
o Lanolin and lanolin derivatives
o Mineral oil
o Petrolatum
o Squalene
o Stearic acid
o Stearyl alcohol

Humectants
o Glycerin
o Propylene glycol
o Sorbitol solution
Risks Associated with Topical Agents
Local Effects
Either the vehicle or its active ingredients may cause local toxicity to the
applied site. Local adverse effects are usually minor and reversible. Major
cutaneous side effects include irritation, allergenicity, atrophy,
comedogenicity, formation of telangiectases, pruritus, stinging, and pain.
The mechanism of toxicity may be as simple as the desiccation of the
stratum corneum (for example, the removal of sebum and oils by the
preparation’s emulsifiers), or involve a more complex effect on either the
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cells of the epidermis or dermis and the structures these cells comprise (i.e.,
epidermis, adnexae). Local damage may occur either directly at, or within
close proximity to, the treated site. In addition, irritation and damage may
appear even after a drug has been discontinued. Often the therapeutic
effects of the active ingredient mask or immediately treat the toxic effects of
the formulation so that acutely toxic effects are transient.28,44
Irritant Contact Dermatitis:
Irritation is driven less by drug penetration and more by drug concentration.
Thus, lowering the concentration of an irritating drug may lower the risk of
side effects. However, a change in formulation may reduce the preparation’s
efficacy. Nevertheless, often using a less concentrated preparation over a
greater period of time is as therapeutically efficacious while minimizing
adverse effects; for example, the use of benzoyl peroxide 2% to 5%
preparations in contrast to 10% preparations. In some instances, though,
skin irritancy might be central to drug efficacy. For example, although not
conclusively shown, the power of immunomodulating agents such as
imiquimod might rely on an increased innate (inflammatory or irritant)
immune response.
Subjective or Sensory Irritant Contact Dermatitis:
Patients may detect burning or stinging sensations without any signs of
cutaneous irritation after applying a topical medication. Several compounds
may induce sensory irritant contact dermatitis in predisposed individuals,
such as tacrolimus, sorbic acid, propylene glycol, benzoyl peroxide hydroxy
acids, mequinol, ethanol, lactic acid, azelaic acid, benzoic acid, and tretinoin.
Allergic Contact Dermatitis:
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In contrast to local irritation, contact allergy development depends on local
penetration. Allergy, of course, is driven by antigen recognition and
presentation and, thus, percutaneous absorption of the drug must be at a
level that guarantees interaction with the immune effector cells of the skin.
Therefore, the contact allergenicity of a drug relates most significantly to
percutaneous absorption. In some instances, cutaneous allergy may be
therapeutic, for example, the treatment of patients with cutaneous T-cell
lymphoma with topical nitrogen mustard. The shift in malignant T cells from
T helper (Th) 2 to Th1-type cytokine expression is believed to lead to
apoptosis of the malignant T cells and tumor regression.
Malignancies:
Rarely, topical therapy may result in neoplasia. For example, the risk of
secondary malignancies, such as keratoacanthomas, basal and squamous
cell carcinomas, lentigo maligna and primary melanoma have been reported
with the long-term use of nitrogen mustard.
Other Effects:
The application of topical corticosteroids to the periorbital skin has been
reported both to induce cataracts and increase in intraocular pressure.24,26,31
Systemic Effects
One should be aware of the potential systemic toxicities of topical drugs.
Although generally safer than the other routes of administration, topical
application can result in systemic toxicities ranging from end-organ toxicity
(central nervous system, cardiac, renal, etc.), teratogenicity, and
carcinogenicity to drug interactions. These outcomes may relate to the drug
itself, its metabolites, or even a component of the vehicle.
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The kinetics of topically applied drugs differ significantly from those
administered by other routes. One important consideration is the lack of
hepatic first-pass metabolism of a topical drug. This is especially relevant to
drugs such as salicylic acid that are relatively innocuous when given
enterally, but may manifest central nervous system toxicity when applied
topically. Additionally, acting as a reservoir, the stratum corneum may store
large amounts of a topical drug, and a subsequently long diffusion period of
many days may ensue, delivering a steady supply of drug to the systemic
circulation.45-47
Percutaneous toxicity directly relates to percutaneous absorption. Therefore,
factors that modulate absorption also influence toxicity. These include the
following: the concentration of the drug, its vehicle, the use of occlusion, the
body site and area treated, frequency of use, the duration of therapy, and
the nature of the diseased skin. For example, 6% salicylic acid in Eucerin
used for 11 days in the treatment of psoriasis has been associated with
epistaxis and deafness, while the same concentration of salicylic acid in
hydrophilic cream under occlusion for 4 days for the treatment of dermatitis
(involving the same amount of body surface area) may result in
hallucination. Similar to their effect on systemically administered drugs,
renal and hepatic diseases, by influencing drug clearance, also contribute to
an increased potential for drug toxicity.5
Young children have a greater surface area – volume ratio, and thus are at
greater risk of percutaneous toxicity than adults. This phenomenon
necessitates alternative drugs, formulations, and dosing schedules for
children with widespread cutaneous disease. Patients with acute fares of
cutaneous illness (for example, psoriasis or atopic dermatitis) may require
the treatment of a larger body surface area in a relatively abbreviated period
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of time. These patients may also increase their dose and frequency of
application during such fares.
Coupled with the likely increased percutaneous absorption of the diseased
skin, these scenarios exponentially increase the possibility of systemic
toxicity, and patient education is vital to prevent adverse outcomes. To
reduce the risk of toxicity from topical drugs and to increase treatment
efficacy, many practitioners will rationally advocate systemic approaches
(i.e., methotrexate, cyclosporine, injectable or infusible biologics, or
ultraviolet radiotherapy) to patients whose disease involves an extensive
body surface area.48,49
Type I Hypersensitivity Reactions:
In rare instances, anaphylactic shock can be precipitated by topical drug
application. For example, when applied to diseased or abraded skin,
bacitracin ointment can induce an immediate-type (type I) hypersensitivity
reaction in susceptible individuals. Such reactions might be represented by a
local and then subsequently generalized pruritus leading to cardiopulmonary
arrest. Nonimmunologic acute toxicity results from substances such as
pesticides and chemical warfare agents that rapidly diffuse through the skin
and reach target organs.
Malignancies:
Systemic calcineurin inhibitors have been associated with increased risk of
lymphoma and nonmelanoma skin cancer. But the topical use of such drugs
does not appear to be related to cancer. In fact, the risk for lymphoma with
the use of topical calcineurin inhibitors was assessed in animal studies that
demonstrated an increased risk only when blood levels were 30 times higher
than those measured after topical application in human subjects.
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Numerous studies have demonstrated the efficacy and safety of topical
calcineurin inhibitors. More than 50 cases of lymphoma have been reported,
although the topical calcineurin inhibitor use may be coincidental.
Nevertheless, there is a clear need for additional follow-up information to
establish the long-term safety profile of this class of drugs. Two long-term
trials currently being conducted might help address these concerns.
Endocrine System:
Topical corticosteroids can rarely cause hypothalamic–pituitary–adrenal axis
suppression, growth retardation, hyperglycemia, iatrogenic Cushing
syndrome and femoral head osteonecrosis. Factors that enhance drug
absorption are directly related to an increase in these side effects; therefore,
carefully monitoring must be ensured when prescribing usage in large
surfaces areas, prolonged use of potent corticosteroids, usage under
occlusion, high potency corticosteroids, or use for the pediatric age group
(due to their increased surface to body mass ratio).
Transdermal drug delivery, in contrast to topical drug delivery, uses topical
application of therapeutic drug as a delivery system for systemic therapy.
The most commonly used patches are for nitroglycerin and fentanyl.
Advantages of this approach include controlled release, a steady blood-level
profile with zero-order kinetics, lack of a plasma peak, and, in some cases,
improved patient compliance. These patches remain on the skin for 12 hours
to 1 week. A patch consists of a plastic backing, a reservoir of medication,
either a rate-controlling membrane or a polymer matrix system for
controlled diffusion, followed by an adhesive facing the skin. The most
common adhesives used are acrylates, silicones, and polyisobutylenes.
These patches have been tested and are approved for use on the thighs,
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buttocks, lower abdomen, upper arms, and chest; application to other sites
can lead to either subtherapeutic or supratherapeutic blood levels.
Adverse effects of patches include local irritation and allergic contact
dermatitis to either an adhesive or to the drug itself and may necessitate
discontinuation. Topical therapies are a mainstay of treatment for the
dermatologist. An understanding of the interactions between a drug’s
concentration, penetration, availability, and treatment of diseased skin
allows providers to maximize both efficacy and tolerability of topical therapy.
Also, an understanding of local and systemic toxicities allows selection of
appropriate, safe therapy for patients and minimizes unwanted effects.
Appropriate selection of topical agents and patient education on proper use
can optimize therapeutic outcomes.2,3,20,26,39,50
Specific Types of Topical Agents
Topical Antibiotics
Topical antibiotics play an important role in the management of many
common dermatologic conditions. They are prescribed most often by
dermatologists 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 (i.e., mupirocin or retapamulin)
may eliminate the need for oral antibiotics and the accompanying problems
of compliance, gastrointestinal side effects, and potential drug interactions.
Topical antibiotics are still frequently prescribed as prophylactic agents after
minor surgery or cosmetic procedures (chemical peel or laser resurfacing) to
reduce the risk of postoperative wound infection and to speed wound
healing. The use of topical antibiotics for prophylaxis after such minor
procedures has been proven to be unnecessary and incurs risk of inducing
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allergy. Petrolatum is recommended for use after clean surgical
procedures.51
Agents Used In the Topical Treatment of Acne and Rosacea
The efficacy of topical antibiotics for the treatment of acne vulgaris and
rosacea may be due to their direct antibiotic effect, but many of the topical
antibiotics exhibit anti-inflammatory properties by suppressing neutrophil
chemotactic factor or by other mechanisms. There are concerns about the
use of topical antibiotics in the treatment of acne vulgaris because of the
increasing levels of antibiotic resistance. Combining the antimicrobial
benzoyl peroxide with antibiotics reduces the development of antibiotic
resistance.45 The following table outlines topical antibiotics with antiinflammatory properties 28,52-57
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. Erythromycin
binds to the bacterial 50S ribosome and blocks translocation of the
peptidyl-transfer RNA (tRNA) molecule from the acceptor to 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.
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.
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. 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.
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.
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In the lower strength, it is applied twice daily, and in the higher
strength, it is used once daily. Orally, metronidazole has broadspectrum activity against many protozoal organisms and anaerobes.
Azeliac Acid
Azelaic acid is a dicarboxylic acid found in food (whole-grain cereals
and animal products). There is a normal human plasma level (20–80
ng/mL); topical application does not significantly alter this level. The
mechanism of action is thought to be normalization of the
keratinization process (decreased thickness of the stratum corneum,
decreased number and size of keratohyaline granules, and decreased
amount of filaggrin).
There are reports of in-vitro activity against Propionibacterium acnes
and Staphylococcus epidermidis, which may be due to protein
synthesis inhibition. In aerobic microorganisms, there is inhibition of
oxidoreductive enzymes (such as tyrosinase, mitochondrial enzymes of
the respiratory chain, 5α-reductase, and DNA polymerases).
In anaerobic bacteria, there is disruption of glycolysis. Azelaic acid is
used principally in the treatment of acne vulgaris and rosacea,
although there are some advocates for its use in the treatment of
hyperpigmentation (such as melasma for which it was initially
developed). However, the US Food and Drug Administration has not
approved the drug for this indication. Azelaic acid is available as a 15%
gel or 20% cream preparation.
Sulfonamides
Sulfacetamide is a topical sulfonamide used in the treatment of rosacea
and acne. The antibacterial mechanism of action for most sulfonamides
is competition with para-aminobenzoic acid (PABA) during the
synthesis of folic acid. The mechanism of action for topical treatment of
rosacea is not understood.
Sulfacetamide is available as a 10% lotion and in combination with 5%
sulfur in a gel, cream, suspension, cleanser, cloths, and mask.
Dapsone
Topical 5% dapsone gel is approved by the FDA for the topical
treatment of acne. The mechanism of action of dapsone in acne
vulgaris is not known at this time; however, it is possible that
inhabitation of neutrophils activity may be important. If benzoyl
peroxide is applied after topical dapsone, temporary orange/yellow
discoloration of skin and facial hair has been noted.
Corticosteroids
Topical corticosteroids are used to relieve inflammation and pruritus of
contact dermatitis, insect bites, minor burns, seborrheic dermatitis,
psoriasis, and eczema. These medications contain a drying agent or
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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.
Systemic toxicity may be a side effect with long-term therapy using highpotency topical preparations. Site of application influences the medication
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.58
Corticosteroids have specific and nonspecific effects that are related to
different mechanisms of action, including anti-inflammatory,
immunosuppressive, antiproliferative, and vasoconstrictive effects. 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. 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.58-59
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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 the
arachidonic acid pathway. 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. Lipocortin I inhibits phospholipase A2, reducing the release
of arachidonic acid from phospholipids. Corticosteroids also decrease the
release of 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.58,60
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. 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.
Corticosteroids reduce eosinophilia in patients with asthma. They also reduce
T-cell proliferation and induce T-cell apoptosis, in part from inhibition of the
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T-cell growth factor IL-2. In addition, several cytokines are directly affected
by corticosteroids, including IL-1, tumor necrosis factor-α, granulocytemacrophage colony-stimulating factor, and IL-8. These effects may also be a
result of the steroid action on antigen presenting cells.11,61
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.62
Vasoconstriction:
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. 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.
Corticosteroids have a basic skeletal structure comprising 17 carbon atoms
arranged in three six-membered rings and one five-membered ring.36,60
Modifications of cortisol, by addition or alteration of functional groups at
certain positions, have led to compounds with variable anti-inflammatory
potency, glucocorticosteroid versus mineralocorticoid activity, and adverse
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effects. Before choosing a topical glucocorticoid preparation, one must
consider the patient-related and drug-related factors that can affect its
systemic absorption. 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, greatly affect the activity of the topical agent.23,24
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. 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.
Areas of the body where the skin is inherently thin not only allow for
increased penetration of the drug but also are more susceptible to develop
side effects 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. 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.21
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. 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
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efficacy of oral corticosteroid therapy may be due in part to poor patient
compliance with topical therapy.28
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. 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.63,64
Increasing hydration of the stratum corneum can enhance absorption of
topical corticosteroids by four to five times. Absorption is also enhanced by
ten times with occlusion. A retrospective study of wet dressings used with
topical corticosteroids (hydrocortisone 1% cream to the face and folds and
triamcinolone 0.1% cream from the neck down) for adults with recalcitrant
pruritic dermatoses of different etiologies, alleviated the pruritus in 98% of
the patients. The enhanced corticosteroid penetration is only one of the
numerous benefits of the wet dressings.64
Topical corticosteroids are recommended for their anti-inflammatory activity
in inflammatory skin diseases, but they can also be used for their antimitotic
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effects and their capacity to decrease the synthesis of connective tissue
molecules. Certain variables must be considered when treating skin
disorders with topical glucocorticoids. For example, the responsiveness of
diseases to topical glucocorticoids varies. In this setting, diseases can be
divided into the three categories: (1) highly responsive, (2) moderately
responsive, and (3) least responsive.65
Topical glucocorticoids are highly effective, and few side effects are observed
when a low-potency preparation is used for brief periods of time without
occlusion in children. However, children and, in particular, infants, are at an
increased risk of absorbing topical corticosteroids for several reasons. They
have a higher ratio of skin surface area to body weight and application to a
given area results in a greater potentially systemic dose of steroid. Infants
may also be less able to metabolize potent glucocorticoids rapidly.
Premature infants are especially at risk because their skin is thinner and the
penetration rate of topically applied drugs is greatly increased. Application of
topical steroids to the diaper area results in occlusion of the steroid by the
diaper, and increased penetration occurs. Excess absorption of topical
glucocorticoids can suppress endogenous cortisol production. Consequently,
subsequent cessation of topical steroid therapy after an extended treatment
period can, albeit rarely, result in an Addisonian crisis. Deaths from
Addisonian crisis have been reported with the use of topical steroids, and the
risk of this occurring is greater in children.61,66
Chronic suppression of cortisol production can also lead to growth
retardation. A morning plasma cortisol level can be performed to screen for
adrenal suppression, although adrenocorticotropic (ACTH) stimulation testing
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with cosyntropin is more accurate. If suppression is present, the child should
be slowly weaned from the steroids to prevent these complications.
Corticosteroids have been used with success for atopic dermatitis for several
decades. Placebo-controlled trials have found them effective in 75% or more
of patients with atopic dermatitis when compared with fewer than 30% of
placebo-treated patients. They are important for managing acute changes.
As with other skin conditions, selecting the appropriate strength according to
the body site, the extent of involvement and the intensity of change is
essential for treatment success.63,67
Education of the patients and caregivers is critical to improve adherence to
the prescribed medication and optimize compliance. Results from large-scale
surveys show that patients or caregivers overestimate the actual risks of
topical corticosteroids leading to treatment noncompliance. Adequate time
should be spent transmitting the important role of intermittent topical
corticosteroid therapy, and the beneficial risk-benefit ratio with their
appropriate use.68
Hemangiomas of infancy show a good or partial response to treatment with
ultrapotent topical glucocorticoids in 74% of infants. The majority reported
accelerated cessation of growth. Small, superficial hemangiomas,
particularly at sites prone to ulceration, disfigurement or both, and small
periocular lesions that have not yet caused significant visual impairment are
the best candidates for therapy. Corticosteroids act in hemangiomas to
decrease proliferation but the mechanism of this action is unknown.
Intralesional corticosteroid injection of hemangiomas before and after
treatment, have revealed an increase in mast cells, reduced transcription in
several cytokines and enhanced transcription of cytochrome b gene.36
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Elderly patients similarly can have thin skin, which allows for increased
penetration of topical glucocorticoids. They are also more likely to have
preexisting skin atrophy secondary to aging and may be diaper dependent,
so the same precautions used in the treatment of infants should be used
when treating elderly patients.69
Uses in Pregnancy:
Appropriate human studies using topical glucocorticoids in pregnancy have
never been undertaken. Studies in animals, however, show that topical
steroids are systemically absorbed and may cause fetal abnormalities,
especially when used in excessive amounts, under occlusive dressings, for
prolonged periods of time, or when the more potent agents are used. The
U.S. Food and Drug Administration (FDA) rates most topical steroids as
category C drugs, which implies that caution must be exercised when used
in pregnancy. A recent, systematic review of the safety of topical
corticosteroids in pregnancy performed by Chi et al., found that the current
data is inconclusive and limited and unable to detect an association between
topical corticosteroids and congenital abnormalities, preterm delivery, mode
of delivery or stillbirth.70
The current evidence shows no statistically significant effects for pregnant
women who use topical corticosteroids as compared with unexposed women.
However, in a small cohort study of participants from a single maternity
center, there appears to be an association of highly potent corticosteroids
with low birth weight. Most of the previous studies only assessed the risk for
congenital abnormality or orofacial cleft. Further cohort studies with
comprehensive outcome measures (including fetal growth, preterm birth,
and birth death), consideration of corticosteroid potency, dosage and
indications, and a large sample size are required in order to detect a small
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risk. It is currently unknown whether topical glucocorticoids are excreted in
breast milk; however, they should be used with caution in breastfeeding
mothers and should never be used on the breasts before breastfeeding.71-73
Dosing Regimen:
The frequency of topical application of corticosteroids was developed in an
empirical manner, with most textbooks and physicians recommending twicedaily use. For superpotent corticosteroids, once-daily application is
considered as beneficial as twice-daily application. Likewise, there is at best
a slight difference with once versus twice daily application of potent or
moderately potent corticosteroids. These observations suggest that oncedaily application of topical corticosteroids may be as effective as twice daily,
while decreasing the risks of side effects, tachyphylaxis, and cost of therapy,
and improving patient compliance.
Tachyphylaxis has been demonstrated in experimental conditions by
diminished vasoconstriction, rebound of DNA synthesis, and recovery of
histamine wheals after application of topical steroids in patients with a
history of long-term topical steroid usage. As a working rule in adults, no
more than 45 g/week of potent or 100 g/week of weak or moderately potent
topical corticosteroid should be applied (without occlusion) if systemic
absorption is to be avoided.58,60,74
Monitoring Therapy:
Application of corticosteroids to large surface areas, occlusion, higher
concentrations, or more potent derivatives directly increases the risk of
hypothalamic–pituitary–axis suppression. If the latter is suspected,
laboratory analyses that include a complete blood cell count, a chemistry
panel, and a baseline morning cortisol level should be performed. In a
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patient with confirmed HPA suppression, gradual reduction of potency and
amount of topical steroid, and possibly the simultaneous institution of oral
steroid supplementation, are needed.63
Risks and Precautions:
Local as well as systemic side effects have been documented with the use of
topical corticosteroids. Under normal conditions, up to 99 % of the applied
topical corticosteroid is cleared from the skin, and only 1 % is
therapeutically active. Cutaneous adverse effects can result from the small
percentage of percutaneously absorbed corticosteroid or may also result
from its transient presence onto the skin. Continued use of topical
corticosteroids may also lead to tachyphylaxis. Considerations for prescribing
topical corticosteroids to prevent side effects should be followed.31,64
Complications:
Local adverse effects of topical corticosteroid use are more prevalent than
systemic reactions. They are largely due to the antiproliferative effects of
these agents.

Atrophic Changes:
Skin atrophy is the most prominent cutaneous adverse effect, and
involves both the epidermis and dermis. Dermal atrophy develops from
the direct antiproliferative effects of topical corticosteroids on
fibroblasts, with inhibition of collagen and mucopolysaccharide
synthesis, resulting in loss of dermal support. Decreased synthesis of
types I and III collagens after topical glucocorticoid use has been
shown in numerous studies. Reduction of glycosaminoglycan
production has also been described. Levels of hyaluronan, the major
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glycosaminoglycan in the skin, are also rapidly decreased after shortterm glucocorticoid treatment, because of decreased hyaluronan
synthesis.
Fragmentation and thinning of elastic fibers develop on the upper
layers, whereas deeper fibers form a compact and dense network. As a
result of these atrophic changes, there is vascular dilatation,
telangiectasias, purpura, easy bruising, stellate pseudoscars (purpuric,
irregularly shaped, and hypopigmented atrophic scars), and ulceration.
Although atrophy is, to some extent, reversible, formation of striae,
visible linear scars that form in areas of dermal damage presumably
during mechanical stress, are permanent.

Acneiform Reactions:
The development or exacerbation of dermatoses of the face, including
steroid rosacea, acne, and perioral dermatitis, is a well-known side
effect of topical corticosteroids. Although steroids initially lead to the
suppression of inflammatory papules and pustules, patients become
addicted because they notice that the lesions change when treatment
is withdrawn. This frequently leads to the continued use of greater
potency topical corticosteroids. For these reasons, steroid use should
be discouraged in the treatment of rosacea and perioral and periocular
dermatitis.
Prolonged corticosteroid treatment can also result in “steroid acne,”
which is characterized by crops of dense, inflamed pustules in the
same developmental stage. These lesions occur on the face, chest, and
back. Patients with psoriasis are also susceptible to a papulopustular
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change after withdrawal of high-potency, topical corticosteroid therapy
to an extensive surface area for a prolonged period of time.

Hypertrichosis:
Hypertrichosis occurs rarely in women and children who apply potent
corticosteroids to the face. The mechanism is still unknown.

Pigmentary Changes:
Decreased pigmentation is a common side effect of topical steroid use.
The pigment generally returns after discontinuation of therapy.

Development of Infections:
Topical corticosteroids are responsible for exacerbating and/or
masking cutaneous infectious diseases. The incidence of skin infection
during corticosteroid therapy varies but is probably between 16% and
43%. Tinea versicolor, disseminated Alternaria infection, and
dermatophytosis, including tinea incognito (masked dermatophyte
infection), can develop.
Granuloma gluteale infantum, characterized by reddish–purplish
granulomatous lesions on the diaper area, is a well-known
complication of diaper dermatitis that is being treated with
corticosteroids. Candida albicans is commonly recovered in these
patients. Topical corticosteroids have also an effect on prolongation or
worsening of herpes simplex, molluscum contagiosum, and scabies
infection.
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
Allergic Reactions:
Allergic contact dermatitis from steroids should be suspected when its
use worsens the dermatitis, does not lead to improvement or changes
the clinical pattern of disease. It occurs more commonly in patients
with an impaired barrier function, such as patients with stasis
dermatitis, leg ulcers and atopic dermatitis. The prevalence of topical
corticosteroid sensitization ranges between 0.2% and 6.0%, and
increases with prolonged exposure and selection of certain drugs.
In a 6-year retrospective study, 127 of 1,188 patients (10.7%) patch
tested with topical corticosteroids showed a positive reaction to at
least one agent, with 56 patients reacting to multiple topical
corticosteroids. Topical corticosteroids were recognized as the
American Contact Dermatitis Society’s 2014 allergen of the year based
on their prevalence. A classification has been created to determine
cross-reactivity among the various available preparations.
This classification has four groups on the basis of structure and crossreactivity patterns. Each class is represented by an agent. Class A is
represented by the hydrocortisone type, class B by the acetonide
steroids, class C by the betamethasone type and class D, subdivided
into two groups, includes D1 represented by betamethasone
dipropionate and D2 by methylprednisolone aceponate. Patch-test
reactions to class A steroids are most common, whereas patch-test
reactions to class C steroids are extremely rare.
When an allergy to a topical corticosteroid is highly suspected and
patch testing is not available, the clinician should prescribe a class C
steroid with a vehicle that contains no allergens. Desoximethasone
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0.25% ointment and 0.05% gel are the only two products that meet
these criteria. The vehicle or the preservative can also be responsible
for the allergy to the corticosteroid preparation. A systematic review of
ingredients in corticosteroid vehicles was recently published. The
authors found seven vehicle ingredients that are commonly used in
topical corticosteroid preparations and are well-known allergens: (1)
propylene glycol, (2) sorbitan sesquioleate, (3) formaldehyde-releasing
preservatives (imidazolidinyl urea and diazolidinyl urea), (4) parabens,
(5) methylchloroisothiazolinone/methylisothiazolinone, (6) lanolin, and
(7) fragrance. Of 166 topical corticosteroids, 128 (including all creams)
had at least one of these vehicle components. More generic products
were free of allergens than were the branded products. Solutions and
ointments were the least allergenic vehicles. The most commonly
present potential allergens were propylene glycol and sorbitan
sesquioleate.36,46,67,75-79
Relative Potency of Topical Corticosteroids80
Class*
I
Drug
Betamethasone dipropionate 0.05% ointment
Clobetasol propionate 0.05% cream or ointment
Diflorasone diacetate 0.05% ointment
Halobetasol propionate 0.05% cream or ointment
II
Amcinonide 0.1% ointment
Betamethasone dipropionate 0.05% cream
Betamethasone dipropionate 0.05% ointment
Desoximetasone 0.25% cream, 0.05% gel, 0.25% ointment
Diflorasone diacetate 0.05% ointment
Fluocinonide 0.05% cream, gel, ointment, or solution
Halcinonide 0.1% cream
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Class*
Drug
Mometasone furoate 0.1% ointment
III
Amcinonide 0.1% cream or lotion
Betamethasone dipropionate 0.05% cream
Betamethasone dipropionate 0.05% lotion
Betamethasone valerate 0.1% ointment
Desoximetasone 0.05% cream
Diflorasone diacetate 0.05% cream
Fluocinonide cream 0.05%
Fluticasone propionate 0.005% ointment
Halcinonide 0.1% ointment or solution
Triamcinolone acetonide 0.1% ointment
IV
Fluocinolone acetonide 0.025% ointment
Flurandrenolide 0.05% ointment
Mometasone furoate 0.1% cream or lotion
Triamcinolone acetonide 0.1% cream or ointment
V
Betamethasone valerate 0.1% cream
Desonide 0.05% ointment
Fluocinolone acetonide 0.025% cream
Flurandrenolide 0.05% cream
Fluticasone propionate 0.05% cream
Hydrocortisone butyrate 0.1% cream, ointment, or solution
Hydrocortisone valerate 0.2% cream or ointment
Triamcinolone acetonide 0.1% lotion or 0.025% ointment
VI
Alclometasone dipropionate 0.05% cream or ointment
Betamethasone valerate 0.1% lotion
Desonide 0.05% cream
Flumethasone pivalate 0.03% cream
Fluocinolone acetonide 0.01% cream or solution
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Class*
Drug
Triamcinolone acetonide 0.1% cream
Triamcinolone acetonide 0.025% cream or lotion
VII
Hydrocortisone 1% or 2.5% cream, 1% or 2.5% lotion, 1% or 2.5%
ointment
Hydrocortisone acetate (1% or 2.5% cream, 1% or 2.5% lotion, 1% or
2.5% ointment) and pramoxine hydrochloride 1%
*Class I is the most potent, and class VII is the least potent. Potency depends on
many factors, including the drug’s characteristics and concentration and the base
in which it is used.
Therapy of Superficial Bacterial Infections and Burns
Localized impetigo, superficial dirty abrasions, and secondarily infected
chronic dermatoses are commonly treated with topical antibiotics. However,
widespread impetigo, infection of the lower extremities, or disease occurring
in immunocompromised individuals should be treated with systemic
antibiotics to reduce the risk of serious complications. Topical antibiotics are
still at times used following minor surgical procedures. The result of a large
study comparing bacitracin and petrolatum in more than 1,200 minor
surgical procedures demonstrated that bacitracin did not statistically
decrease the already low rate of infection. Several patients were, however,
shown to be allergic to bacitracin. Petrolatum proved to be cheaper, of equal
efficacy and to have 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. Because burns produce a
fertile ground for life-threatening secondary infection, prophylactic topical
therapy is often used.29 The table below lists topical antibiotics,
recommended uses and administration.20,29,53,81-83
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Mupirocin
Mupirocin, which was formerly known as pseudomonic acid A, is a
topical antibiotic agent derived from Pseudomonas fuorescens. The
drug reversibly binds to isoleucyl-tRNA synthetase and inhibits
bacterial protein synthesis.
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.
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. One study in the
Tennessee Veterans’ Affairs Hospital demonstrated that prolonged
use of mupirocin ointment to control methicillin-resistant S. aureus
(MRSA) carriage, especially in bedridden patients with decubitus
ulcers, led to significant resistance.
Furthermore, Japanese researchers found that low serum
concentrations of mupirocin are achieved after intranasal
application and postulated that this might explain the selection of
mupirocin-resistant strains of S. aureus. A small pilot study using
intranasal application of a combination antibiotic ointment
containing bacitracin, polymyxin B, and gramicidin successfully
decolonized 80% (9 out of 11) of MRSA-positive patients who
remained clear after a mean follow-up of 2 months. All cases of
mupirocin-sensitive MRSA were eradicated, whereas only three of
five cases of mupirocin-resistant were eliminated.
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.
Retapamulin
Retapamulin is approved for topical treatment of impetigo in
patients older than 9 months of age. It is a semisynthetic
pleuromotilin antibiotic derived from fermentation in Clitopilus
paseckerianus with activity against staphylococci. The antibacterial
mechanism of action is inhibition of protein synthesis via 50S
bacterial ribosomes at protein L3, near the peptidyl tranferase
center. Retapamulin binding inhibits peptidyl tranferase and partial
inhibition of binding of initiator tRNA to P-site of ribosome. Allergic
contact dermatitis to the active ingredient has been reported.
Bacitracin
Bacitracin is a topical polypeptide antibiotic originally isolated from
the Tracy-I strain of Bacillus subtilis. 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 membranebound lipid pyrophosphate.
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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.
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.
Unfortunately, the topical application of bacitracin carries with it the
risk of allergic contact sensitization and, rarely, anaphylactic shock.
Polymyxin B
Polymyxin B is a topical antibiotic derived from a spore-forming soil
aerobe B. polymyxa. 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.
Polymyxin B is active against a wide range of Gram-negative
organisms, including P. aeruginosa, Enterobacter, and Escherichia
coli. 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.
Topical
Aminoglycosides
(Neomycin and
Gentamicin)
The aminoglycosides are an important group of antibiotics used
both topically and systemically for the treatment of infections
caused by Gram-negative bacilli. Aminoglycosides exert their
bactericidal effects by binding to the 30S ribosomal subunit and
interfering with protein synthesis. Neomycin sulfate, the
aminoglycoside most often used topically, is a fermentation product
of Streptomyces firadiae.
Commercial neomycin is a mixture of neomycin B and C, whereas
framycetin, used in Canada and some European countries, is pure
neomycin B.9 Neomycin sulfate has activity against aerobic Gramnegative 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.
Other agents, such as lidocaine, pramoxine, or hydrocortisone, also
are available in combination with neomycin. Many dermatologists
do not recommend neomycin because it is responsible for a large
number of cases of allergic contact dermatitis. The prevalence of
contact dermatitis is high, with 6% to 8% of patients undergoing
patch testing being positive. Neomycin sulfate (20%) in petrolatum
is used to assess for contact allergy. Gentamicin sulfate is derived
as a fermentation product from Micromonospora purpurea. It is
available as a topical 0.1% cream or ointment.
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Gentamicin sulfate is used by some dermatologic surgeons when
operating on the ear, especially in diabetic or other
immunocompromised patients, to provide prophylaxis against
malignant otitis externa due to P. aeruginosa. The ophthalmic
formulation is useful in caring for operative wounds in the
periorbital area.
Sulfonamides
(Silver
Sulfadiazine and
Mafenide
Acetate)
The sulfonamides are structurally similar to PABA and compete with
it during the synthesis of folic acid. Sulfonamides are used to treat
acne vulgaris, acne rosacea, and burns. Silver sulfadiazine is
thought to release silver slowly and exerts its effect on the bacterial
cell walls and membranes. The mechanism of action of mafenide is
not the typical sulfonamide mechanism of action because PABA
does not antagonize its performance.
Mafenide acetate, if used over large areas of skin, has the potential
to cause metabolic acidosis, and it can cause intense pain on topical
administration. Both agents are broad-spectrum antibacterials
useful in the treatment of burns. Candida superinfection may be a
problem with mafenide cream.
Nitrofurazone
Nitrofurazone (Furacin) is a nitrofuran derivative used for the
treatment of burns. The mechanism of action involves the inhibition
of bacterial enzymes involved in the 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
perfiringens, and Proteus sp.
Miscellaneous Agents
Gramicidin
Gramicidin is a topical antibiotic derived from B. brevis. The
gramicidins are linear peptides that form stationary ion channels in
susceptible bacteria. The antibiotic activity of gramicidin is
restricted to Gram-positive bacteria.
Clioquinol
Clioquinol (also known as iodochlorhydroxyquin) is a broadspectrum 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.
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. 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.
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Topical Retinoids
In topical preparations, retinoids are widely used as prescription drugs as
well as cosmeceuticals. In some of these products, retinoids are naturally
occurring compounds while others are synthetic molecules. Until recently,
clinical use of topical retinoids has been limited to all-trans-retinoic acid,
which is approved in the U.S. for the treatment of acne, photo-aged skin,
and melasma. Topical adapalene and tazarotene have also received approval
for acne; tazarotene has received approval for psoriasis and photo-aging.
More recently, bexarotene was approved for management of cutaneous Tcell lymphoma and alitretinoin was approved for patients with Kaposi
sarcoma. It is widely accepted that topical retinoids are extremely effective
for acne therapy, especially for comedonal (mild acne) lesions.84
Of the different classes of antiacne medications, retinoids are thought to be
the best, if not the only, agents to normalize the abnormal follicular
epithelial differentiation or desquamation important in the pathogenesis of
acne lesions. Therefore, the use of retinoids can also provide protection
against the development of new lesions. This prophylactic property is the
basis for including topical retinoid in almost all antiacne regimens. A
potential for aggravating inflammation exists in treating inflammatory acne
(i.e., papules and pustules) with topical retinoids, but when properly
administered, this type of acne also responds well to retinoids.85
Fine wrinkles and dyspigmentation are two features of photo-aged skin that
are improved by topical tretinoin or tazarotene. Several weeks of treatment
are required before clinical improvement is appreciated. For the effacement
of fine wrinkles by topical tretinoin, partial restoration of markedly reduced
levels of collagen in sun-exposed skin toward those seen in sun-protected
skin appears to be responsible. Tretinoin’s ability to improve photo-aging is
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specific and does not result from the irritation or retinoid dermatitis
frequently produced by this compound. Topical adapalene is not approved
for the treatment of photo-aging; however, a recent study indicates that it
also holds promise in ameliorating the clinical features of photo-damage.17,86
Many other skin disorders have been reported to improve by topical
retinoids, but most of these have not been rigorously studied; thus, their
therapeutic claims should be interpreted with caution. Molluscum
contagiosum, warts, and various forms of ichthyosis may be improved by
topical retinoids to a variable degree. In psoriasis, especially, irritation of
treated skin has limited the use. Topical tazarotene, which is approved for
psoriasis, does not appear to have fully overcome the irritation problem;
thus, it is typically used in combination with topical steroids.87
With such a wide variety of skin conditions treatable by topical retinoids,
their use has included all age groups, perhaps with the exception of
neonates. The use of topical retinoids in pregnancy is an emotional issue.
Because none of the dermatologic conditions seen in pregnancy that may
respond to topical retinoids (i.e., acne, melasma, stretch marks) is lifethreatening to the mother or the fetus, it seems prudent to delay the
treatment until after delivery. In a study that demonstrated that early,
inflammatory stretch marks were improved by topical tretinoin, all
pregnancy-related stretch marks were treated postpartum. Therefore, even
in this pregnancy-associated condition, the therapeutic benefit could be
achieved by instituting the treatment after delivery.88
Dosing Regimen:
For decades, tretinoin was the only topical retinoid available for clinical use
sold under the trade name Retin-A. Now, tretinoin is also available in other
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formulations. Adapalene is also available in varying formulations and, more
recently, combination medications have been introduced. For acne and
psoriasis, topical tazarotene is available and for photo-aging treatment,
tretinoin and tazarotene are approved for use.
Tretinoin 0.05%/hydroquinone 4%/fuocinolone 0.1% is a topical
combination approved for the treatment of melisma (a common condition of
grey-brown patches on the face).17 Different formulations allow some
flexibility in terms of tailoring the therapy to an individual’s skin dryness or
oiliness. Finally, more recently approved topical retinoids include bexarotene
and alitretinoin, sold in gel formulations.89
Regardless of the retinoid preparation or the patient’s age, the most
important element in topical therapy is patient/guardian education. It must
be clearly explained to each patient that, as part of the treatment, local skin
irritation, characterized by redness and peeling, can be expected. The
concept that clinical improvement correlates with the degree of irritation has
been erased through a large, controlled clinical study in which 0.025% and
0.1% tretinoin were shown to be equally efficacious, but the former was
significantly less irritating than the latter.90 Therefore, unlike most
medications for which the dosing schedule may be set as once or twice daily,
administration of a topical retinoid should be titrated depending on the skin
reaction. For some individuals, it may be applied only twice a week, for
others four times a week, and this can be increased, as tolerated, to a oncedaily regimen. This method of individualizing topical therapy minimizes
unwanted acute retinoid dermatitis.91
Under the nonprescription category, there are countless “natural retinoid”
preparations with various claims (mostly anti-aging) being sold throughout
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the world. Most of these contain retinyl esters, especially retinyl palmitate,
retinaldehyde, or retinol. Whether any of these products can deliver retinoid
activity to human skin is subject to question. Percutaneous absorption
(especially for retinyl esters), adequate concentrations, and stable
formulations (especially for retinol) are some of the important unknowns for
this group of products.10 Based on human in-vivo work, all-trans-retinol and
all-trans retinaldehyde hold the most promise of these natural retinoids in
being biologically active, provided the stability of the compound can be
maintained with a proper formulation.
When the sun-protected skin of individuals older than 80 years of age was
treated for 7 days with 1% retinol, fibroblast growth and dermal collagen
were increased significantly. Concomitantly, retinol markedly reduced the
levels of matrix-degrading metalloproteinases that are elevated in aged skin.
These findings suggest that retinol may reverse and partially prevent skin
atrophy that accompanies intrinsic aging. A recent clinical study has
confirmed that topical retinol improves the fine wrinkles associated with
atrophic, naturally aged skin of the elderly.92
Risks and Precautions or Adverse Effects:
By far the most common adverse effect associated with topical retinoid use
is local skin irritation characterized by erythema, peeling, dryness, tightness,
and burning sensation. This predictable skin response is temporary, but
troubling, for many patients. It tends to peak within the first month of
treatment and diminishes thereafter. It responds to a temporary reduction in
the frequency or amount of retinoid application and to liberal use of
emollients. Retinoid activation of the receptors is followed by subsequent
induction of HB-EGF and AR in human skin in vivo.93
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The importance of this signaling pathway in the hyperplastic response of the
epidermis to topical retinoids was recently demonstrated when
pharmacologic antagonists of EGF receptor tyrosine kinase activity blocked
retinoid-induced epidermal thickening in human skin organ culture and in
vivo. This observation suggests that it may be possible to reduce the
clinically undesirable effects of retinoids on epidermal keratinocytes.
However, the erythema response following topical retinoic acid may not be
retinoid-receptor mediated because all-trans-retinol, which induces
epidermal hyperplasia and CRABP-II mRNA-like retinoic acid (two indicators
of receptor activation), is minimally associated with clinical erythema.20
For bexarotene and alitretinoin, local irritation is also the most common side
effect. With alitretinoin, the local erythema can increase to edema and
vesiculation with continued use. However, most reactions are mild-tomoderate with only 7% of patients requiring treatment withdrawal in clinical
trials. Finally, the central hypothyroidism seen with systemic bexarotene is
not observed in the gel formulation. Systemic retinoid exposure has been
well documented and established as a cause of embryonic death and
congenital malformation and, understandably, there is concern about
potential teratogenicity from long-term topical retinoid use.32
Systemic absorption of retinoids from topical application is negligible, and
the levels of endogenous retinoic acid in the blood are not increased by twice
daily application of 0.025% tretinoin to more than 40% of body area over 1
month. Furthermore, controlled topical administration of tretinoin at doses
used for acne therapy (2 g of 0.025% gel applied daily to the face, neck, and
upper part of the chest for 14 days) has less influence on plasma levels of
endogenous retinoids than diurnal and nutritional factors. Indeed, a large,
population-based study demonstrated no excess risk of birth defects in
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offspring born to mothers who were exposed to topical tretinoin during
pregnancy. Therefore, no evidence exists for teratogenicity of topical
tretinoin in humans.17,94
“Sun sensitivity” is a frequently discussed subject with topical retinoid use
and requires clarification. When formally tested in humans, topical tretinoin
does not lower the minimal erythema dose of ultraviolet B (UVB) light.
Because its presence in human skin does not increase the likelihood of
sunburn reaction, tretinoin is not a phototoxic agent. The patients, who
complain of such sun sensitivity, describe an uncomfortable skin sensation
that is felt within minutes of being in the sun rather than hours later. This
timeline is not consistent with a typical sunburn reaction, which takes a few
hours to be noticed. Furthermore, this sensation often is reported as
accentuated in warmer temperatures, which suggests participation of
infrared irradiation (heat). Related to sun sensitivity is the issue of
photocarcinogenesis. In an animal model of photocarcinogenesis, topical
tretinoin has caused skin cancer. However, when human skin was grafted
onto mice with severe combined immunodeficiency disease, gross
inadequacy of the commonly used rodent model of photocarcinogenesis was
demonstrated. Specifically, the traditional rodent models significantly
overestimate the human carcinogenic potential of tested agents.86,87
Topical retinoids appear to have a protective effect against UV-induced
premalignant and malignant lesions. In those predisposed by nevoid basal
cell carcinoma syndrome or xeroderma pigmentosum to the development of
nonmelanoma skin cancer, systemic retinoids have provided effective
protection. In this regard, topical tretinoin’s ability to prevent UV induction
of c-Jun is relevant; c-Jun is a proto-oncoprotein that is minimally detectable
in normal human skin in vivo. Its partner c-Fos; however, is constitutively
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expressed. Ultraviolet irradiation to human skin does not affect the level of
c-Fos expression, but it markedly induces c-Jun protein, which can then
heterodimerize with c-Fos, forming a complete active AP-1 transcription
factor.95,96
The critical importance of AP-1 in mediating carcinogenic transformation of
papillomas has been demonstrated. In human squamous cell carcinomas, cJun expression is elevated, and systemic retinoids prevent carcinomas of the
head and neck. Mechanisms involved in this chemopreventive effect of the
retinoid likely include c-Jun suppression. These clinically observed
anticarcinogenic activities of retinoids are also supported by in vitro data,
demonstrating that tretinoin treatment of human skin upregulates the
antigen-presenting activity of Langerhans cells without concomitant increase
in autoreactivity. Such a retinoid effect would improve cutaneous immune
responsiveness to tumor antigens. Therefore, topical retinoic acid is not a
carcinogen in humans.97
Drug Interaction and Compatibilities:
Retinoids, in general, are photo-labile and therefore can be photoinactivated. Based on this chemistry, it is recommended to apply the agents
in the evening rather than before the start of the day. Because the major
avenue of tretinoin inactivation is through CYP26, drugs that modulate the
activity of this enzyme can potentially cause drug interactions. Ketoconazole
and liarozole are effective inhibitors of CYP26 and, therefore, are RAMBAs.
Concurrent use of these azoles and topical tretinoin can increase the amount
and prolong the half-life of tretinoin locally in the skin, thereby aggravating
local side effect. Other than retinoids, no other compounds have been shown
to induce CYP26. The use of vitamin D3 and its analogs has increased in
dermatology, and, in particular, for psoriasis. Vitamin D effects in human
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skin are largely mediated via its nuclear receptor VDR. Like RAR, VDR
functions in human skin mainly as a heterodimer with RXR (VDR-RXR). In
contrast with retinoid signaling via RAR-RXR, in which the presence of RXRligand confers no additional effect, RXR-ligand provides a synergistic effect
with VDR-ligand in vitamin D signaling. Therefore, topical retinoids that
possess or, through metabolic conversion, acquire RXR selectivity can
positively influence vitamin D pharmacology in human skin.88,90,92,98
Antifungals
Superficial fungal infections, including dermatophytoses, candidiasis, and
pityriasis versicolor, are most often restricted to the epidermis. In treating
these infections, the clinician must select between topical or systemic
management. Factors guiding management include, but are not limited to,
the 1) extent and severity of the infection, 2) site of involvement, 3) any
comorbid conditions or potential drug interactions, 3) anticipated efficacy of
treatment, cost and access to medication, and 4) ease of use.8
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.99
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.7 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
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once the first choice for management. The ideal topical antifungal is
efficacious, inexpensive, well tolerated, and has low resistance within
targeted fungi.
Despite widespread availability, few topical antifungal agents have been
directly compared with one another in clinical trials. Studies sponsored by
the manufacturer often compare just the active agent to the vehicle.
Extrapolation between studies is further complicated due to differences in
study design, duration of therapy, site of infection, selection methodology,
or treatment endpoint. Most topical antifungals belong to one of three
classes: (1) imidazoles, (2) allylamines and benzylamines, and (3)
polyenes.100,101
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. Imidazoles
impede synthesis of a component of the fungal cell wall through inhibition of
lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme, which
converts lanosterol to ergosterol. 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. 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.102,103
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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. Topical imidazoles also demonstrate limited antibacterial
properties, particularly with respect to gram-positive organisms. 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.
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. 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.104-106
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. Cure rates for superficial fungal
infection treated with imidazoles are variable and often depend upon study
design. For example, topical miconazole has demonstrated a 63%–100%
cure rate, depending upon the study quoted. A thorough review of the
literature provides no compelling evidence that significant differences in cure
or relapse exist among the various topical imidazoles; however, other
considerations may dictate selection of a particular imidazole.99,103,105
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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 52% of tinea pedis cases while the lotion yielded the same
cure in just 41% of cases. Additionally, the potential for irritancy must be
considered. In one study of topical clotrimazole for treatment of tinea cruris,
erosive reactions developed in 4 of 27 patients while sulconazole did not
cause any erosions in the same population.102
Topical imidazoles are available in a multitude of forms. Econazole,
ketoconazole, and oxiconazole are approved for once-daily dosing but twicedaily 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.
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.103,104,107,108
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. Early studies demonstrated the combination was indeed more
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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. Longer-term
studies also reported a higher relapse rate (36%) with the combination
product. This combination product may comprise 50% or more of antifungal
prescriptions by primary care providers, compared to less than 7% among
dermatologists. It is likely that overuse by nonspecialists 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 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.20,103,105
Use of topical imidazoles is associated with few complications. Because of
low systemic absorption, drug reactions with topical imidazoles are rare.
However, in a single study, increased serum tacrolimus levels were observed
in renal transplant recipients who used clotrimazole troches for
mucocutaneous candidiasis. For this reason, use of nystatin may be
preferred when treating thrush in transplant patients using tacrolimus.
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.20,50
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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. 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. 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.109,110
Like imidazoles, allylamines, and benzylamines demonstrate antiinflammatory activity. Naftifine inhibits adhesion of polymorphonuclear cells
to endothelium, interrupts chemotaxis, and inhibits the 5-lipoxygenase
proinflammatory pathway. It is assumed that terbinafine and butenafine
yield anti-inflammatory effects through similar mechanisms. Allylamines and
benzylamines also demonstrate limited antibacterial properties. A recent
study showed lowered minimum inhibitory concentrations for both bacteria
and fungi when terbinafine was used in combination with benzoyl
peroxide.111
Allylamines and benzylamines are highly lipid soluble and efficiently
penetrate the stratum corneum, where they may persist for extended
durations. 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.
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Systemic absorption of these agents is quite low, with typical urinary
excretion in the range of 3%–5% of the applied dose. 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.110,112,113
Limited evidence suggests that topical allylamines or benzylamines may be
preferred over topical imidazoles for certain dermatophyte infections. Some
trials for tinea pedis indicate that 1 week of topical terbinafine is as effective
as 4 weeks of topical imidazoles, with cure resulting in 53%–95% of cases.
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. 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.107,114,115
Topical 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
use of topical allylamines and benzylamines are those inherent to all topical
medications. A recent case report highlighted a possible interaction between
topical terbinafine and acenocoumarol, and speculated this might be due to
high protein binding of terbinafine, with displacement of the anticoagulant,
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but this is likely exceptional; complications arising from use of topical
allylamines or benzylamines are few.109,110,116
Polyenes
Polyenes were among the first agents discovered to possess specific
antifungal properties. The two major topical polyene antifungals are nystatin
and amphotericin B. 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. 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.106,117
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. 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.106,118
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. To treat cutaneous infection, the
powder, cream, and ointment are used twice daily for approximately two
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weeks. Risks associated with 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 use of nystatin-containing vaginal suppositories but the
reaction was attributed to ingredients other than nystatin.119,120
A combination agent consisting of nystatin and triamcinolone acetonide is
widely marketed. The addition of triamcinolone may provide additional
benefit over nystatin alone during the first few days of treatment when
inflammation is maximal. After this initial period, the manufacturer
recommends a transition to nystatin alone or to other topical antifungal
agents. Although triamcinolone acetonide is only a midpotency 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. Finally, 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 nystatintriamcinolone acetonide is more often
prescribed by nondermatologists.107,121,122
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).
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. guilliermondi, C. krusei, and C. stellatoides,
rapidly acquire resistance upon exposure to nystatin.117
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Other Agents
Some topical antifungals, such as ciclopirox olamine, tolnaftate, and
undecylenic acid, do not fit well into the major classes and are instead
discussed separately.1,2,8,82,99,106,114,121,123-125
Ciclopirox
Olamine
Ciclopirox olamine is a hydroxypyridone antifungal agent with a unique
structure and mode of action. Unlike most other topical antifungals,
ciclopiroxolamine does not interfere with sterol synthesis. Instead, it
interrupts active membrane transport of essential cellular precursors,
particularly trivalent cations. Ultimately, this disrupts cellular function,
leading to demise of the fungus. If concentrations of the drug are high
enough, the membrane integrity of the fungus may actually be impaired.
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.
When applied to the skin, ciclopirox olamine remains in high
concentration within the epidermis and upper dermis. Ciclopiroxolamine
penetrates keratin easily, with cadaveric skin demonstrating
concentrations in the epidermis that were 10–15 times the minimum
inhibitory concentration for a sensitive species. 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.
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 with 2 weeks of use than those using the shampoo
vehicle alone. 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.
Often, an assessment of efficacy depends upon whether a mycologic
cure (culture-negative) or clinical cure (a disease-free nail) defines
success. Although a disease-free nail is often the patient’s true goal,
ciclopiroxolamine achieved such a response in just 5.5%–8.5% of those
treated with a standard 48-week course. Two recent trials demonstrated
increased efficacy when using oral terbinafine in combination with topical
ciclopirox olamine, as opposed to oral terbinafine alone.
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Debate regarding the use of ciclopiroxolamine as an independent or
adjunct treatment for onychomycosis is ongoing. Ciclopiroxolamine is
available in a wide range of forms. Cutaneous candidiasis,
dermatophytoses, 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. 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, the nail lacquer is applied daily to the nail and
hyponychium for 48 weeks and excess medication is removed weekly
with alcohol. Risks associated with 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.
Tolnaftate
Tolnaftate is a thiocarbamate first developed in the 1960s but now
contained only in over-the-counter anti-fungal remedies. The precise
mechanism of action for tolnaftate is unknown. 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.
Like 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. Although direct comparisons are lacking,
topical tolnaftate is widely considered less effective than topical
imidazoles, allylamines, and benzylamines. Tolnaftate is ineffective for
candidiasis.
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. Risks associated with use of topical tolnaftate are those
inherent to all topical medicaments. Allergic contact dermatitis has been
reported on occasion. Serious complications with use of topical tolnaftate
are few.
Undecylenic
Acid
Despite more than 60 years of use, 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.
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Undecylenic acid is available as a zinc, calcium, or copper salt. As tissue
pH rises, this salt fails to dissociate, and the 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. 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.
Although 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. 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.
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. Risks associated
with 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.
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.
Cosmetic Dermatology
Cosmetic dermatology is often referred to as desire dermatology and
supports individuals to achieve the appearance they want. While
dermatology is often a combination of medical and desire treatment, there is
more of an evolving marketplace influence and overlapping of dermatology
specialties that come together in the field of cosmetic dermatology. This
section considers the integrated medical and surgical practices of
conventional dermatology and the key practices involved in a rapidly
evolving model of cosmetic practice.
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Botulinum Toxin (Botox) Injections
Botulinum toxin (Botox), an exotoxin
produced by the bacteria Clostridium
botulinum, occurs naturally in
nature. The use of C. botulinum A
exotoxin, commonly known as
botulinum toxin type A (Botox-A),
has emerged over the last decade as
one of the most popular methods of
combating cutaneous signs of aging,
particularly the dynamic wrinkles of
the face. The therapeutic application
of this potent neurotoxin has carved
a comfortable niche in the cosmetic
realm of dermatology practice for
practical reasons. Results appear within several days of administration, the
procedure itself is short in duration and relatively uncomplicated, and side
effects are minimal.126
Although medicinal use of Botox by physicians is widespread, professional
opinions vary as to the best ways to administer the treatment. For instance,
the ideal dilution of the toxin, the number of units to inject, and the
longevity of prepared and refrigerated Botox remain debated issues. The
methods described in this section are those used most frequently by the
primary author. The novice injector should try the various methods espoused
by experienced specialists to determine which yields the best results in his or
her own practice.127
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Mechanisms of Action
Acetylcholine (ACh) is the neurotransmitter associated with induction of
muscle movement. Botox achieves chemical denervation of striated muscles
by cleaving one or more of the proteins required for the release of ACh. The
target protein depends on the serotype of toxin used. The result is
temporary flaccid paralysis of the injected muscles, which persists
approximately 3 to 5 months. As new neuromuscular junctions form, muscle
function returns. There are seven Botox serotypes (A–G). Serotype A is the
most potent and was the first to be made available in the United States for
medical use. Botox Cosmetic™ (Allergan Inc., Irvine, CA) and Dysport™
(Ipsen Products, Maidenhead, Berkshire, UK) are both formed from serotype
A, which functions by cleaving the SNAP-25 protein, a component of the
SNARE (Soluble N-ethylmaleamide-sensitive factor Attachment protein
Receptor) complex. The presence of an intact SNARE complex, composed of
synaptobrevin, SNAP-25, and syntaxin, is necessary for vesicles containing
ACh to fuse with the cell membrane and to release ACh into the
neuromuscular junction. Botox-B, now available in the United States as
Myobloc™ (known as Neurobloc in Europe), cleaves synaptobrevin, thus
preventing the release of Ach.127,128
Clinical Uses of Botox
Dynamic Wrinkles:
Botox can be injected into specific muscles to induce temporary paralysis
resulting in an inability to move and wrinkle the skin overlying the treated
muscle. Botox is only beneficial for dynamic wrinkles, also known as
“wrinkles in motion.” It is not as effective for static wrinkles, although
prolonged use of Botox may help prevent wrinkles in motion from becoming
wrinkles at rest. Botox can be combined with dermal fillers and resurfacing
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techniques to optimize patient satisfaction. The upper part of the face
contains distinct muscle groups that can be selectively paralyzed by a
knowledgeable injector. In the lower part of the face, the muscle groups are
less distinct and thus more difficult to inject accurately. The paralytic effects
of Botox appear approximately 3 to 7 days after injection. However, the
effects may increase for up to 2 weeks.129,130
To use Botox, 2.5 cc of preservative-free saline diluent is added to the 100-U
vial. This yields 4 U per 0.1 cc. To use Reloxin/Dysport, 2.5 mL of 0.9%
preservative-free saline diluent is added to the 500-U vial. This provides 20
U per 0.1 mL. To use Myobloc, 1.2 cc of saline diluent is added to the 2500U vial. This yields 200 U per 0.1 cc, which is injected with a 1-cc syringe and
a 30-gauge needle.131
Glabellar Region:
To treat the glabellar region (skin
between the eyebrows and above
the nose), 0.1 cc (4 U of Botox or
200 U Myobloc) is injected into each
corrugator muscle along with 0.1 cc
into the procerus muscle. Glabellar
injections are currently the only
injections approved by the FDA for
cosmetic use. The glabellar
indication is also the only one under
consideration by the FDA for
Reloxin. In men or patients with
stronger musculature, two sites
superior to the corrugator muscle
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may need to be injected. Doses of 20 U in the glabella work for most men
while retaining a natural look; one study showed that 40 to 60 U in the
glabellar area was more effective in males.
The injector should avoid the periosteum as this can induce post-injection
headache. After injecting the procerus muscle, massage the area laterally
across the bridge of the nose to ensure that the toxin enters the depressor
supercilii portion of the corrugator muscle, which will subtly lift the patient’s
medial brow, resulting in a more youthful appearance. Proper treatment of
the glabellar area or “brow furrow” prevents the patient from frowning,
leading to a more relaxed, less angry look. In addition, relaxation of these
muscles for long periods of time may prevent or reduce wrinkle formation in
the brow area.132,133
Forehead Region:
Botox-A is clinically used more broadly than its FDA indication of glabellar
treatment. Expanded use is permissible for licensed providers and is referred
to as “off label” use. To treat wrinkles of the forehead, 0.1 cc (4 U Botox,
200 U Myobloc) is injected across the forehead.
Injection of the forehead is an art as well as a science as it can dramatically
affect eyebrow shape. Therefore, prior to injecting the forehead, the provider
should consider whether she or he wants to enhance the arch of the eyebrow
to create a more horizontal eyebrow shape. Generally, women prefer a more
arched brow because it imparts a more feminine look, while men prefer a
more horizontal brow. The forehead should be injected about every two
square centimeters where movement of the muscles is seen on eyebrow
elevation.
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It is important not to inject all patients in the same way. Forehead injections
should be tailored or customized to the patient’s forehead size and shape. In
addition, one must take into consideration the placement of the eyebrow
over the superior orbital rim. Low brows will become even lower after
injections of Botox to the forehead; therefore, forehead injections should be
avoided in some patients. Alternately, injections can be performed in the
higher regions of the forehead in patients with low brows.
The major pitfalls with forehead injections are the following: (1) unwanted
eyebrow shape (2) brow ptosis, (3) missed areas and (4) drooping eyelids.
It is important not to over-inject the forehead area as this may lead to brow
ptosis. Additionally, one must take care to avoid the area 1 cm above the
eyebrows to reduce the chances of brow ptosis. The provider should warn
the patient with low forehead wrinkles within this 1-cm area that these
wrinkles cannot be treated with Botox, and will remain after
treatment.131,134,135
Care must be taken to avoid forehead injections in individuals with low-set
brows and/or excessive eyelid skin. In older patients and patients with
excess eyelid skin, overtreatment of the forehead area may result in
drooping eyelids. Hooding of the upper eyelids by the descending eyebrow
tissue results in a neural reflex that increases the activity of the frontalis
muscle in an effort to keep the vision clear of the descending tissue that
would otherwise obstruct vision or interfere with eyelid function. In this
population the upward pulling of the frontalis muscle is needed to raise the
baggy upper eye skin. These patients are better treated with blepharoplasty
first, then with Botox. The ideal patient for Botox treatment in the forehead
is a young patient (20s–40s) with no excess upper eyelid skin.126,136,137
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Crow’s Feet:
To treat crow’s feet with Botox, 0.1 cc is injected 1 cm lateral to the lateral
canthus. Then 0.05 cc is injected 1 cm above the first injection and 0.1 cc 1
cm below. If wrinkles progress medially, one can inject 0.05 cc
approximately 1 cm apart along the orbital rim to the midpupillary line.
When using Dysport, fewer injection sites may be required because of
increased diffusion. Injecting medial to the midpupillary line does not correct
medial wrinkles and can lead to an ectropion; therefore, this area should be
avoided. Most patients do not notice these wrinkles prior to Botox injections
and sometimes mistakenly believe that Botox “caused” these previously
unobserved wrinkles. When used properly, Botox can temporarily erase the
lateral crow’s feet lines.138
Brow Lift and the Microdroplet Technique:
Botox has been used to elevate the eyebrow position by treating between
the eyebrows as well as the lateral eyebrow with relatively few injection
sites, and with relatively large quantities of Botox (1.5–2.5 U Botox-A). This
technique is limited by the possibility of inducing the undesired side effect of
upper eyelid ptosis caused by the unwanted diffusion of Botox into the
levator palpebrae superioris muscle, which is responsible for eyelid
elevation.139
The position and appearance of the eyebrows is determined at rest and
dynamically by the opposing action of several groups of muscles that act on
the eyebrow. The frontalis muscle primarily performs eyebrow elevation.
Brow elevation is opposed by the septal and orbital portions of the
orbicularis oculi muscle; including, the depressor supercilii component of the
orbicularis oculi muscle, and the procerus muscle. The medial position of the
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eyebrow is also influenced by the activity of the corrugator supercilii muscle.
Additionally, the shape of the brows is affected by the activities of the
eyebrow elevators and the eyebrow depressor muscles where they
interdigitate along the eyebrow to create facial expression.134,140
With age there is a gradual fall in the position of the eyebrows, which is
known as brow ptosis, resulting in smaller appearing eyes that is not
aesthetically desirable. Botox can also be used to elevate the brows,
resulting in a more youthful appearance. This is referred to as a chemical
brow lift. The technique of lifting the brow includes injection of the glabellar
area as described above. After injecting the procerus muscle with 0.1 cc of
Botox the nasal bridge should be massaged in order to ensure that the toxin
enters the depressor supercilii portion of the corrugator muscle. This can be
used to try and correct an asymmetry of the medial brow. Injecting 0.05 cc
of Botox into the lateral brow depressor muscles can raise the lateral aspect
of the eyebrow.131,141
Treatment of the lateral depressors of the brow results in an average brow
elevation of 4.83 mm when measured from the lateral canthus. Injections of
Botox into the glabellar area and lateral brow have also been shown to yield
brow elevations of 1 to 3 mm when measured from the eyebrow to the
midpupillary point. However, the lateral brow lift with Botox provides
inconsistent results and leads to lateral brow lowering in some patients. (The
procerus injection consistently raises the brows). Therefore, it is preferred to
use a dermal filler injected into the lateral brow to achieve a brow lift.142
A novel technique that has been recently introduced is intended to
temporarily elevate the eyebrows without provoking any undesirable side
effects. This “microdroplet technique” uses small quantities of Botox
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dissolved in micro droplets of injectable saline carrier to treat the septal and
orbital orbicularis muscles on each side of the patient’s face. The provider
treats the frontalis at and below the brow by injecting very small volumes of
fluid in multiple locations. These micro droplets have volumes of 10 to 50 L
of injectable saline containing as small as 0.001 to 1 U Botox. Treatment is
based on 100 U Botox and 3 mL of injectable saline, which equals
approximately 0.33 U of Botox per 10 L.143,144
A typical treatment involves a total of approximately 100 micro droplets
placed in double or triple rows just above, in, and below the brow, stopping
around the level of the lowest brow cilia. The microdroplet injections are
placed superficially approximately 1 mm into the skin to trap the Botox at
the interface between the orbicularis oculi and the skin. For crow’s feet, the
needle is inserted before the midline of the lateral palpebral raphe. The
glabellar area is also treated. The combination of these treatments produces
a uniform brow-lift effect.145
Bunny Lines:
The upper nasalis muscle across the bony dorsum of the nose causes
fanning wrinkles (“bunny lines’’) at the radix of the nose and can lead to
medial wrinkling around the eyes. Two to four units of Botox can be injected
into the nasalis muscle to reduce or eliminate these lines.
Many physicians inject into the wrinkles rather than into the nasalis muscle
resulting in an incomplete correction. The correct injection points are in the
belly of the muscle, inferior to the angular vein. If the injection is too low,
the levator labii superioris will be relaxed, which leads to an unwanted upper
lip ptosis.137
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Treating Nasal Tip Ptosis/Nasal Tip Lift:
Botox has been used for lifting the nasal tip. More than one technique exists
but there is no consensus on an optimal method. The main muscles that
influence the nasal tip are the nasalis, the depressor septi nasi, the levator
labii superioris, and the alaeque nasi muscle.
Atamoros in 2003 described the injection of 4 U of Botox into each of the
alar portions of the nasalis and 4 U into the depressor septi. Dayan and
Kempiners later described the injection of 5 U of Botox into each depressor
septi nasi and 3 U into each levator labii superioris. Ghavami et al.
demonstrated similar results as Dayan and Kempiners with only 1 to 2 U
injected to each of the depressor septi nasi and further stressed that proper
studies excluding confounding variables, such as concomitant rhinoplasty or
chemodenervation of synergistic muscles, are required before Botox
injection alone can be recommended as a treatment for dynamic nasal tip
ptosis. It is recommended to use 2 to 3 U injected at the base of the
columella. This procedure is most effective for those with a short- or normalsized upper lip. Those with a long length between the top of the columella
and the top of the lip, that is, long upper lip, do not receive good results
from this procedure. Those with a long upper lip will benefit from a dermal
filler to raise the nasal tip.134,140,145
Cosmetic Use of Botulinum Toxin Type A in the Lower Face:
Cosmetic treatments with Botox-A have focused mainly on the upper face,
particularly the glabellar, forehead, and periocular areas. With the huge
increase in the number of cosmetic Botox injections delivered each year and
its clinical effectiveness, a variety of off-label interventions using Botox-A for
the lower face have emerged. However, this area has an increased incidence
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of side effects and should only be treated by experienced Botox users. As
such, Botox-A is now more widely used in lower face and neck rejuvenation,
in treating the chin and corners of the mouth as well as in recontouring of
the jawline.
Yet another area where Botox-A has shown promise cosmetically is in the
treatment of facial and chest wall flushing. The response of the lower facial
muscles to Botox-A is greater than upper facial muscles. Moreover, it has
been established that the lower facial muscles will have a longer-lasting
response to Botox-A than upper facial musculature. The dose for the lower
muscles therefore needs to be adjusted to the muscle size and patient
gender to be approximately half or one-third the dose injected in the upper
facial muscles.142,146,147
Upper Gum Show:
The levator labii superioris alaeque nasi muscle retracts the upper lip. In
some individuals, this muscle is overactive and pulls the lip back excessively,
allowing visualization of the upper gums and upper incisors. Injecting 1 - 2 U
into the levator labii superioris alaeque nasi muscle on each side of the bony
nasal prominence will slightly drop the lip, preventing the upper gum show.
This procedure works better in young patients because it causes vertical
elongation of the lip. This can be used in combination with fillers such as
CosmoPlast in the vermilion border to prevent the elongated lip.148
Melomental Folds:
The melomental folds are also called marionette lines. They extend from the
downturned corner of the mouth to the lateral chin. The depressor anguli
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oris pulls down the corner of the mouth in opposition to the zygomaticus
major and minor contributing to these folds.
Dermal fillers often correct marionette lines; however, some physicians
prefer to combine dermal fillers with Botox injections. Botox can be injected
into the depressor anguli oris to weaken it, allowing the zygomaticus to
elevate the corners of the mouth and return them to a horizontal position.
For reducing the melomental folds, a dose of 2 - 4 U should be injected at
the depressor anguli oris immediately above the angle of the mandible and 1
cm lateral to the lateral oral commissure. Care must be taken not to use too
high of a dose as this can lead to drooping of the lateral lower lip, flaccid
cheeks, an incompetent mouth, or an asymmetric smile.129,139
Perioral Lines:
Many factors are implicated in the formation of perioral lines. Smoking,
photo-aging, loss of subcutaneous tissue in the lower face, and the purse
string-like action of the orbicularis oris muscles are the most important
causes. Botox-A injection is usually reserved for deep perioral lines
worsened with muscular pursing of the lips. The dosage is dependent on the
depth of lines but generally 1 U of Botox-A injected into each site with a
total of 2 U per half of the upper lips. The middle upper lip should be avoided
in patients wanting to retain their cupid bow.
It is critical to measure the placement on the upper lips first so that the
sides are treated in exactly the same spot to preserve symmetry. The best
results occur when Botox is combined with laser resurfacing or lip fillers to
enhance the vermillion border and smooth the surface of the skin.145,149
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Mentalis Muscle and Chin Puckering:
Relaxing the hyperkinetic muscle fibers of the chin and the mentalis muscle
with Botox-A can reduce and eliminate chin puckering. A single dose of 4 to
6 U of Botox-A placed in the exact center of the point of the chin is effective.
An overdose in this area can result in the inability to approximate the lower
lips tightly against the teeth, ultimately leading to involuntary dribbling from
the lip when drinking or drooling from the corners of the mouth.150,151
Neck Lines and Platysma:
Brandt and Bellman were the first to report using Botox to treat aging of the
neck. Platysmal bands and neck vertical lines represent an accurate gauge of
chronological age specifically for those people with exaggerated outdoor sun
exposure. Separation of the platysma anteriorly occurs with aging, resulting
in banding or “turkey neck.” Vertical platysmal bands may be successfully
treated with Botox-A. The extended or marked platysmal bands are grasped
between the thumb and index fingers and the needle is vertically inserted
into the muscle band. The dose is usually 2 to 4 U spaced 4 cm apart with an
overall cumulative dose of 8 to 12 U per band and a total maximum in the
neck of 25 to 30 U.
Because of the nature of the muscle and the site of injection, complications
such as dysphagia and dysphonia can be encountered. Patients should be
warned about the possibility of such untoward effects.129, 152
Nefertiti Lift:
The platysma muscle pulls downward with age, leading to jowl formation and
frequent rhytides. Jawline redefinition with neurotoxin has not been widely
exposed in the literature and there exists a discrepancy in the exact dosing
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and techniques to best define this area. A technique described recently by
Levy was named the “Nefertiti Lift” (after the perfect jawline of the ancient
queen). This technique releases the downward tension of the depressor
effect of the aging platysma and releases the skin to the elevator muscles
for lifting action. The “mini-lift” technique requires an injection of 2 to 3 U of
Botox-A along and under each mandible and to the upper part of the
posterior platysmal band for a total of 15 to 20 U per side.153
Chest:
The upper area of the chest is a site of predilection for photodamage.
Textural, pigmented, and photodamage changes are frequently seen in the
V- shaped area of the chest. Both photodamage and muscular sagging of the
upper chest cause static and dynamic wrinkles. Anatomically, the platysma
is known to originate at the second rib; however, it can still present as far
down as the fourth rib after which it traverses the pectoralis major and
inserts in the mandible.
To date there is no consensus or indication for upper chest injection of
Botox-A; however, there are various ways to inject Botox in the upper chest.
The techniques used are the curved, the “V,” and the triangular approaches,
during which Botox is injected over a curved, V-shaped area, or a triangular
area with “5 to 10” sites identified within, each targeted with 2 to 8 U of
Botox.145,154
Other Uses of Botulinum Toxin:

Hyperhidrosis Hyperhidrosis is a troublesome problem leading to awkward social
situations for those affected. Unfortunately, topical and oral
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medications, iontophoresis, and surgery have not proven efficacious in
the majority of patients. Sympathetic nerves that use ACh as the
neurotransmitter innervate the eccrine glands. Therefore, Botox is
effective in temporarily reducing or abolishing sweat production. Botox
is the only medication that is approved by the FDA for axillary
hyperhidrosis.
Botox for hyperhidrosis is diluted with 5.0 cc of preservative-free
saline, yielding 2 U per 0.1 cc. Reloxin/Dysport can also be diluted with
5.0 cc of preservative-free saline, providing 10 U per 0.1 cc. To use
Myobloc, 5000-U vial has 2.1 cc of saline diluent added. This yields
200 U per 0.1 cc. Using a 1-cc tuberculin syringe with a 30-gauge
needle, 0.05 cc is subcutaneously injected with an approximate depth
of 3 mm with care to avoid intramuscular injections. The palm or sole,
including the webs of the hands and feet, should be injected every
square centimeter.
When treating the axilla, patients should be asked which areas bother
them to determine how far beyond the hair bearing area to inject. A
starch-iodine test may be performed prior to injections to ascertain
which areas need to be injected. The iodine solution is applied to the
affected area and then covered with starch. The areas that produce
sweat will turn black, indicating which areas to inject. Although this
test is messy, it is a useful technique for evaluating the efficacy of the
injections and for determining which areas to inject.
It is recommended to inject the tips of the fingers and toes as well to
avoid compensatory sweating in these areas. It is usually necessary to
inject 100 U Botox or 5000 U Myobloc per palm or sole and 50 U Botox
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or 2500 U Myobloc per axilla. The effects last approximately 4 months
although there are reports in the literature of longer lasting
results.155-157

Inguinal Hyperhidrosis Inguinal hyperhidrosis (IH) is a focal and primary form of
hyperhidrosis in which the individual has intense sweating in the
inguinal region. Appearing in adolescence, usually not later than the
age of 25, the condition continues into adulthood. Inguinal
hyperhidrosis is characterized by chronic, intense sweating in the
inguinal region, a situation that is potentially embarrassing for the
patient. It is a condition that symmetrically affects the groin region,
including the suprapubic area, the shallow depression that lies
immediately below the fold of the groin (corresponding to the femoral
triangle), the medial surfaces of the upper inner thighs, and the
genital area. It may also include the lower part of the gluteus
maximus, gluteal fold, and natal cleft.150,158

No study to date has described the ideal doses of Botox for the
treatment of IH. The threshold doses of Botox-A for the treatment of
hyperhidrosis depend on the severity of the condition. Two or three
units of Botox-A per square centimeter can be used to treat the
hyperhidrotic area in the inguinal region. The only side effects reported
are those related to the injections, such as rare small hematomas and
temporary edema.157

Other Neuroglandular Disorders The effects of Botox-A at the neuroglandular junction have not been
explored as extensively as those occurring at the neuromuscular
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junction. Clinical studies examining the effect of intracutaneous Botox
for focal hyperhidrosis found complete abolition of sweating in the
injected area within 3 to 7 days. No adverse effects were reported,
and in a 5-month follow-up there were no clinical recurrences of the
hyperhidrosis.
Gustatory sweating is another area of neuroglandular dysfunction in
which Botox-A has proven effective. Gustatory sweating (or Frey’s
syndrome) is a disabling disorder in which the cheek skin sweats
profusely during eating. The syndrome may occur after parotidectomy,
and is likely due to the misdirection of regenerating parasympathetic
fibers that innervate the sweat glands of the face. Intracutaneous
Botox-A has been reported to significantly decrease or prevent
sweating for more than 6 months, with no clinical evidence of facial
weakness in any patients. Botox-A injected into the submandibular
glands has been reported to significantly decrease salivation resulting
from stimulation of the lingual nerves. The decreased salivation was
temporary, and did not appear to be directly toxic to the acinar cells of
the gland. Canine studies have also shown that vasomotor rhinorrhea,
a parasympathetically controlled phenomenon, responds favorably to
topical Botox-A.133,150,159
While the duration of action of Botox-A at the neuromuscular junction
appears to be approximately 3 months, a longer-lasting effect may
occur at the glandular level. Botox-A has produced anhydrosis for
more than 12 months in patients with gustatory sweating. The reason
for the difference in duration of action is uncertain; hypotheses include
a higher rate of resynthesis of SNAP-25 (the protein cleaved by Botox)
in neuromuscular synapses, and a higher area of axonal sprouting and
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consecutive reinnervation of muscle fibers as compared to that in
glandular tissue.140

Botulinum Toxin in Persistent Facial Flushing Facial flushing is not an uncommon problem in fair-skinned individuals
of Celtic and northern European descent. A vasomotor phenomenon
that results in increased erythema, persistent facial flushing can be
accompanied by facial telangiectasias and gustatory sweating. Facial
flushing is categorized as either autonomic neural-mediated (wet) or
direct vasodilator-mediated (dry). The method by which Botox-A works
to affect vasodilation is unknown, and the results regarding its efficacy
for this indication are inconclusive.
One theory is that Botox might work through reduction of local
subclinical inflammation, which contributes to persistent erythema.
Moreover, the anti-inflammatory role of Botox-A in blocking substance
P, vanilloid receptor 1 (TRPV-1), and calcitonin gene-related peptide
(CGRP) is important in decreasing the subclinical inflammation that
might present as erythema. Only Yuraitis et al. have described an
improvement related to facial flushing in limited case reports.
Alexandroff as well as Kranendonk et al. failed to show an effective
response to Botox-A for facial flushing in three published cases.
Further studies are required to better assess the safety and efficacy of
this procedure.135,145

Botulinum Toxins and Acne Vulgaris Acne, which most commonly occurs during adolescence, is influenced
by several factors. The pathology centers on the pilosebaceous follicle
(comprising the sebaceous gland), the follicle (pore), and vellus hair.
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Factors that promote the formation of comedones (whiteheads or
blackheads) include the following: (1) increased sebum production; (2)
inflammation of the dermis and follicles by inflammatory mediators;
(3) hyperkeratinization and obstruction of the upper region of the
follicle; and, (4) colonization of the follicle by the bacterium
Propionibacterium acnes.131
Adolescence is marked by an
increase in levels of circulating
androgens, particularly
dehydroepiandrosterone sulfate
(DHEAS). The increased androgen
levels are thought to cause
sebaceous glands to enlarge and
increase sebum production. While
most acne patients have normal
hormone levels, increased sebum
production plays an important
role in acne.
A correlation exists between the rate of sebum production and the
severity of acne. In addition, acne patients typically produce sebum
that is deficient in linoleic acid, which is a potential cause of abnormal
keratinization and follicular obstruction. Increased sebum levels can
also irritate keratinocytes, causing the release of interleukin-1, which
in turn can cause follicular hyperkeratinization. The final common
pathway in each of these acne-causing routes, which are not mutually
exclusive, is follicular obstruction.
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Botox may inhibit the cascade of events leading to acne. This is likely
achieved through parasympathetic effects, inhibiting sweat gland
activity, and sebaceous gland secretion as well as stimulating
keratinocyte locomotion. Associated anti-inflammatory and
antiandrogenic effects may also contribute.127,132
It is thought that Botox-A toxin inhibits the formation of acne through
at least three different pathways. First, Botox inhibits sebum
production by sebaceous glands through cholinergic inhibition and
sebocyte differentiation. Botox injections results in a lowered sebum
potential across the ducts and skin, which inhibits cholinergic
secretions normally attributed to increased sebum production.
Moreover, decreased sebocyte promoter differentiation and lower
sebum levels may clinically improve acne by decreasing the growth of
P. acnes. Thus, the ability to decrease sebum production decreases P.
acnes growth and acne development. Additionally, Botox inhibits sweat
production by sweat glands. Decreased perspiration may clinically
improve acne by reducing the growth of P. acnes.133,160
Follicular occlusion by keratinocytes is the final common pathway in
each of the various routes leading to acne. Keratinocyte migration is
inhibited by the high-dose stimulation of nicotinic ACh receptors. By
inhibiting the release of ACh, Botox may indirectly increase the
migration of keratinocytes, thus reducing follicular occlusion. The
androgen surge during puberty is a known instigator of acne, and
studies have shown that androgens increase the number of ACh
receptors. Interestingly, androgen receptors are found on
pilosebaceous duct keratinocytes, which are important in follicular
occlusion. It is postulated that during puberty androgens increase the
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number of ACh receptors on the pilosebaceous keratinocytes, leading
to further inhibition of keratinocyte locomotion through increased ACh
stimulation. By inhibiting the release of ACh, Botox decreases the
number of ACh receptors on the pilosebaceous keratinocytes, thereby
increasing keratinocyte locomotion through decreased ACh
stimulation.161,162
Finally, results from recent research have shown that holocrine gland
secretions are controlled by various neuropeptides, with substance P
playing a significant role. Botox-A blocks substance P, TRPV-1, and
CGRP, which are important mediators in inflammation, and therefore
helps decrease the inflammatory aspect of acne development.163

Botulinum Toxin and Chemical Liposuction:
Obesity is a medical problem with obvious cosmetic implications.
Liposuction, gastric volume reduction, laparoscopic banding, lipase
inhibitors, and mesotherapy are all methods employed in the
treatment of obesity. Fat distribution and its physiology are partly
known to be under the control of the autonomic nervous system.
Multiple research studies have revealed that lipoatrophy and
degradation of adipocytes was noticed after denervation. There is
disagreement regarding whether or not nervous system innervation
plays a role in fat accumulation. Bilbao et al. showed that vagotomy
reduced fat accumulation in rats and postulated that vagotonia plays a
role in the development of obesity. On the other hand, Jones et al.
showed that muscle action-related sympathetic activity is associated
with advancing age and increased abdominal adiposity. This disparity
was linked to a high sympathetic to parasympathetic ratio.139 Following
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observations of coincidental lipoatrophy after Botox injections, it has
been:
“postulated that Botox injected in subcutaneous fat might
achieve fat loss for cosmesis. Lim et al., suggested a scheme by
which subcutaneous fat denervation and hence focal lipoatrophy
could be achieved. They recommended a maximum injectable
total dose of 200 U for the intended area of fat reduction with an
even distribution of each injection. Further research in this area
is required to establish a better risk–benefit ratio of this potential
Botox use and to provide a guided consensus for its optimal
use.”164

Botulinum and Hair Growth Control Focal hair loss following Botox-A treatment for blepharoplasm and
oromandibular dystonia has been reported, but remains controversial.
Several theories have been suggested to explain this observation,
specifically the fact that hair follicles contain cholinergic receptors,
which are essential signaling elements for nerve transmission that
send growth signals to hair follicles. When inhibited by Botox, those
receptors may lead to hair loss. Hair loss has also been described in
conditions related to peripheral nerve dysfunction such as diabetic
peripheral neuropathy, myxoma of the nerve sheath, and after
occipital nerve block with corticosteroid.
Botox could have the same effect through chemodenervation. Some
studies have actually reported regrowth of hair rather than loss after
Botox was administered for alopecia areata, extending the debate over
whether Botox actually causes hair regrowth or loss.129,131
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
Botox-A and Cosmetic Surgery Botox-A can be used before or after the surgical manipulation to either
enhance or sustain benefits. If injected in the pre-operative period, the
toxin may allow improved tissue manipulation and reduced incisional
tension leading to improved healing. Prior to endoscopic brow lift or a
face-lift using endoscopy, Botox-A injections help in raising the
position of the brow and can reduce the amount of surgical
manipulations necessary. Finally, when used after surgery, Botox-A
weakens the musculature, prolonging the anticipated effect.165
Combined Therapies
The superiority of Botox-A when used with other cosmetic procedures has
been documented in a number of studies. When administered one week prior
to the treatment with filling agents, Botox-A prevents the distortion of the
fillers and prolongs the effects of augmentation by reducing the muscular
activity associated with rhytide formation. Botox-A therapy works
synergistically with resurfacing techniques to provide an optimal
improvement of dynamic rhytides and in some cases enhance overall skin
tone and texture. One study indicated that CO2 ablative laser resurfacing
combined with Botox-A provided a stronger and longer-lasting effect.164,166
Within many cosmetic practices, Botox-A is now a part of the standard
resurfacing protocol. The synergistic effects of Botox-A and other
rejuvenation procedures can extend to intense pulsed light protocols. In one
study, the combined effect of intense pulsed light and Botox-A produced a
more pronounced global aesthetic improvement in reducing crow’s feet,
telangiectasia, pore size, and lentigines, as well as ameliorating facial skin
texture as compared with the use of intense pulsed light alone.130
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Risks and Complications
Resistance to Botulinum Toxin:
This section addresses the development of antibodies during Botox therapy.
Botulinum neurotoxins may be immunogenic, and antibodies may inactivate
the molecule. The Botox molecule is composed of a light chain and a heavy
chain. The toxin is embedded in a protein complex that protects the toxin’s
binding site until the desired pH is reached and the toxin is released.
Antibodies to this critical binding site on the heavy chain of the Botox
molecule will prevent binding of the toxin to its receptor, thereby crippling
the actions of the toxin. “Neutralizing antibodies” have been reported in
patients treated with high doses of Botox for neurologic disorders such as
cerebral palsy. It is important to understand that there are many types of
antibodies that can interact with Botox; however, the only antibodies that
can affect the efficacy of the toxin are neutralizing antibodies.
Antibodies may develop to Botox that are inconsequential to the patient, yet
the antibodies that are capable of neutralizing the toxin are a concern as
they have the potential to decrease the efficacy of the toxin. By definition,
antibodies that neutralize Botox-A would not neutralize Botox-B and vice
versa. Patients who develop antibodies to Botox-A can still enjoy the benefits
of Botox-B. For this reason, it is recommended that practitioners have
several different Botox serotypes available on the market.
The incidence of antibody-mediated resistance to Botox, as determined by
the mouse lethality assay, is reported between 3% and 9.5% and is
accepted generally to be approximately 5%. The only apparent symptom of
the development of antibodies is lack of response to further injections. The
use of other serotypes (F or B) may benefit those who have developed
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antibody resistance. There are two types of therapy resistance to Botox,
primary and secondary. A patient who does not respond to the first injection
of Botox-A is referred to as a “primary nonresponder,” but reasons for
nonresponse can include inappropriate site of injection, poor technique,
and/or insufficient dose.
Immunogenicity should be suspected in a patient who no longer responds to
Botox-A (“secondary nonresponder”) following a successful course of earlier
injections. Antibody formation could be targeted against the neurotoxin
component of Botox or against its nontoxic protein component. The
recommended approach is to inject 20 U Botox into the hypothenar or
forehead muscles. If the patient responds to Botox, then transient weakness
will develop in the muscle 1 to 2 weeks after injection. An alternative is to
take blood for an antibody assay that is rarely used. In secondary
nonresponders, the problem can be further overcome by using a different
Botox serotype, for example, Botox-B if resistance develops to Botox-A.
Risk factors for the development of antibodies include higher doses, shorter
intervals between injections, booster doses, and young age.
Recommendations to help prevent development of antibodies include the
following: (1) use of the smallest possible dose to achieve relief, (2) an
interval between injections of at least 1 month (the preferred interval is 3
months), and (3) “touch-up injection” avoidance.
Many researchers have postulated that the risk of antibody formation is due
in part to the quantity of protein or the “protein load” of the toxin, the type
of protein present in the toxin, and to other factors. Manufacturers of Botox
have attempted to minimize each of these factors in order to create a less
immunogenic product. For example, the original Botox that was used until
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December 1997 contained a higher level of protein than the Botox currently
in use; therefore, it should lead to a lower incidence of antibody formation.
Merz Pharmaceuticals, the manufacturer of the new Botox product Xeomin,
claims that its product contains a negligible amount of bacterial proteins
(0.6 ng) with lower immune response. In spite of the concerns regarding
immunogenicity, there are no known or published reports of antibody
production in patients treated with doses of any of the available Botox
products for cosmetic indications, which may be explained by the lower
doses used in comparison with neurologic and cervical dystonia indications
where reports of resistance are centered.
Side Effects:
Complications from the use of Botox injections occur infrequently and are
transient and reversible. Bruising at the injection site(s) is one of the most
common adverse events and avoiding aspirin, NSAIDs, green tea, vitamin E,
and other anticoagulants for 10 days prior to treatment can lessen the
incidence. Anecdotal reports reveal that application of ice packs to the area
prior to injection reduces the pain of the procedure and the incidence of
bruising. Some studies have shown an association with flu-like symptoms
(Botox and Myobloc) and dry mouth (Myobloc) after injection of these
products in larger doses used for neurologic indications.
The most serious side effects of Botox treatment in the upper face are ptosis
and, very rarely, diplopia or ectropion. Proper placement of the toxin with
good injection technique will drastically reduce the incidence of these
temporary side effects. In fact, many experts anecdotally state that
physicians just learning to perform Botox injections in the upper face have
approximately a 4% incidence of inducing ptosis, which, with practice, falls
to 0.5% incidence. Adverse effects from injection into the platysma can
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include bruising, drooling, down-turning of the corner of the mouth,
weakness in the neck muscles, and dysphagia. Lip ptosis or mouth
asymmetry may result from injections in this area. Treatment of the palms
and soles for hyperhidrosis can induce temporary muscle weakness. One
should exercise caution when treating patients that require a strong grip
(i.e., tennis players) and manual dexterity (i.e., piano players) and these
patients should be aware of the risks of treatment of the palms.
The use of Botox has been reported, in one patient, to unmask underlying
myasthenia gravis; therefore, its use is contraindicated in patients with
myasthenia gravis, systemic lupus, and other autoimmune disorders
associated with a preexisting neuromuscular condition. Dysport is the only
brand of Botox that contains lactose. Its use has been blamed for a fixed
drug eruption in one patient. Care should be taken to label all syringes
containing Botox to avoid inadvertent administration of the
toxin.48,147,151,167,162,168-174
The injection of the C. botulinum A exotoxin is a safe; fast, and
nontraumatic approach to correcting wrinkles, raising eyebrows, and
improving hyperhidrosis. A significant number of physicians worldwide
perform this procedure for cosmetic purposes. There are many new forms
and brands of Botox entering the market. It is certain that much more
research will be seen that examines this interesting agent in the near future.
Pain Control
With the expanding use of botulinum toxins in cosmetic practice, pain
alleviation remains an important aspect of the injection. Pain sensation is
dependent on many factors, most importantly the concentration of the
neuropeptides (substance P) at the site of injection, the tissue density
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(higher tissue density implies more pain), and the density of the nociceptor
distribution at the site of injection. Other factors include the volume injected,
the bore of the needle used, the layer of skin within which the toxin is
injected, the rate of the fluid injection, and, of course, the provider’s level of
experience.171
Differences in pain perception among patients treated with the commercially
available toxin preparations have not been studied extensively; however,
results from the only comparative study of three available preparations of
the toxin showed that the pain induced by Neurobloc (Botox-B) was found to
be significantly higher than that induced by Botox and Dysport (Botox-A),
between which no significant difference was found. The study concluded that
the different chemical properties and pharmaceutical adjuvants in toxins A
and B likely affect the pain sensation and speculated that the pH difference
of Neurobloc (pH 5.6) and Botox/Dysport (pH 6.8) influences pain
perception.129
Pain sensation during toxin injections is usually fleeting, and simple
measures can improve patient comfort. For facial wrinkles, anesthesia is not
necessary unless the patient prefers it. The 30-gauge needles that are used
to inject the medication are the same size as acupuncture needles and cause
minimal pain in a calm patient. Allowing the Botox to come to room
temperature may decrease the level of pain otherwise felt by the patient.
When the provider approaches the patient in a calm and reassuring manner,
not allowing the patient to see the needles prior to and during the injections,
the patient’s anxiety is significantly reduced as is the perception of pain.
Topical anesthetic creams such as EMLATM or LMXTM can be applied prior to
injection to decrease the sensation of pain. Botox should not be mixed with
local anesthetics because they can alter the pH of the preparation and cause
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the toxin to lose potency. Ice packs can be applied prior to injections, which
may decrease the pain and encourage vasoconstriction, resulting in less
bruising.131
For hyperhidrosis, pain control is a necessity, especially for the palms and
soles. Although some physicians perform nerve blocks, many recommend
the following method: at least 1 hour prior to treating for hyperhidrosis, the
topical anesthetic ElaMax™ or EMLA (eutectic mixture of local anesthetic) is
applied to the area to be treated. Next, these areas are occluded with plastic
bags or gloves when treating hands and feet or with tape when treating
axillae.
Many attempts have been made to decrease the pain associated with the
use of Botox for palmar hyperhidrosis. These have included topical
anesthetics, intravenous regional anesthesia, nerve blocks, ice, Frigiderm
spray, and others. The use of nitrous oxide (“laughing gas”) requires office
training and can induce an anxiolytic rather than a pain-diminishing effect.
Ongoing trials to assess the effects of different anesthetics for an optimal
injection with minimal pain are needed to establish the full potential of the
different approaches of pain reduction with Botox injections.155
Dermal Fillers
The dermal filler market is rapidly growing worldwide. According to the
American Academy of Aesthetic Plastic Surgeons, 1,448,716 people received
hyaluronic acid (HA) injections by plastic surgeons in 2007. The actual
number is likely much higher when factoring in procedures performed by
dermatologists and other aesthetically oriented physicians and physician
extenders. Although collagen products (Zyplast and Zyderm) were the first
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dermal fillers to become widely available, collagen fillers have largely been
replaced by HA fillers.175
The ultimate goal of dermal fillers is to smooth out wrinkles and folds, even
out scars, volumize furrows and sunken valleys, contour unevenness and
laxity, and sculpt skin into a 360-degree, rejuvenated look. Over the last
quarter century, several kinds of products suitable for soft tissue
augmentation have become available, with intense industry research yielding
more and more filler options with increasing regularity. Different regulatory
mechanisms usually leave the U.S. a few months or years behind other
developed countries in making the latest products available to patients.176
In the U.S., dermal fillers are regulated as medical devices. In order to
obtain FDA approval, the company applying for approval for a dermal filler
must satisfy the intense safety and efficacy criteria including
nonteratogenicity, nonmigration, noncarcinogenesis, biocompatibility, and
optimal purity, as well as reproducible and durable efficacy in correcting skin
defects. Unfortunately, some physicians and physician extenders choose to
use dermal filling substances that have not yet received FDA approval for
any indication. This is not advisable for several reasons including the fact
that it is illegal and that the safety of these products has not been
established. With the multitude of safe, efficacious, and durable fillers on the
market, there is no need or justifiable reason to use unapproved dermal
fillers in the U.S.177
Patient Evaluation and Consultation
When embarking on soft tissue augmentation, proper preparations are
essential. An initial consultation should include distant and close evaluation
of the patient’s facial structure and discussion of the cosmetic treatment
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options. The patient’s history is taken to assess contraindications including
allergy to filler components, herpes facialis, pregnancy/lactation, keloid
predisposition, and autoimmune diseases. In addition, use of medications
that inhibit clotting such as aspirin and ibuprofen should be examined. The
ideal cosmetic outcome is achieved through a combination of various
cosmetic procedures in order to attain an even tone, smooth texture, and
adequate facial volume and shape.
The discussion of the sequence and description of each proposed procedure,
alternatives, risks and benefits, financial cost, and recovery period prepares
the patient for realistic expectations and informed decision-making. After the
treatment procedures are selected and informed consent is signed and
witnessed, the patient should undergo pretreatment photography for the
purpose of documentation; posttreatment photography is scheduled
immediately after and on the follow-up visits. For novice patients, it is better
to start the soft tissue intervention with the temporary and predictable fillers
(i.e., collagen and hyaluronic acid), and then gradually advance with more
lasting fillers (i.e., Sculptra and Radiesse) based on their comfort level and
desire.178-180
The best approach to minimizing the side effects of soft tissue augmentation
is, first, to prevent them. To reduce bruising, patients should avoid
anticoagulant medications or supplements (i.e., aspirin, vitamin E, etc.) for
10 days prior and several days after the procedure. The utility of Arnica
montana oral tablets or topical gel or post-procedure oral bromelain
supplements to decrease ecchymoses is anecdotal but these are often used
in the primary author’s practice. The pain associated with injection can be
diminished with topical (i.e., lidocaine cream, ice), regional (i.e., infraorbital,
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dental nerve block), or intraprocedural anesthesia (i.e., fillers that contain
lidocaine).181-183
Patients prone to regional herpes outbreaks should obtain antiviral
prophylaxis with systemic medications (i.e., valcyclovir 1 g twice daily for 3
days, starting a day before the procedure). The procedure should be
conducted in a clean, safe, well-lit, and soothing environment that is
prepared to address any potential complications. Vasovagal responses are
not uncommon; therefore, orange juice should be available in the event that
the patient feels dizzy or faint. Topical steroids may be needed in case of a
contact allergy to lidocaine cream. Most importantly, nitropaste should be
immediately available in case a purple duskiness is seen on injection,
warning of a possible arterial occlusion. Some physicians suggest keeping
hyaluronidase on hand in case an arterial occlusion occurs with hyaluronic
acid.178,184
Types of Dermal Fillers
Dermal fillers can be classified based on various criteria: depth of
implantation (superficial upper and mid-dermis, deep dermis, and
subcutaneous levels); longevity of correction (temporary, semi-permanent,
and permanent); allergenicity (whether pre-procedure allergic testing is
required); composition of the agent (xenografts, allografts, or autologous,
semi/fully synthetic); and stimulatory behavior (capacity to drive physiologic
processes of endogenous tissue proliferation) versus replacement fillers
(space-replacing effect). The FDA requires safety and efficacy studies of the
available fillers; however, studies looking at the durability of the filler are not
required and, therefore, subject to disagreement and frequent citing of
anecdotal evidence. The lasting effect of the filler is dependent on the
composition, amount used, depth injected, and carrier of the agent. The
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discussion of fillers to follow will proceed by dividing them according to
composition: collagen fillers will be discussed first, followed by hyaluronic
acid (HA) fillers, and then other agents.185
Temporary Fillers (Collagen and Hyaluronic Acid)
Injectable fillers such as collagen and hyaluronic acid are biodegradable and
last from 4 to 9 months. These fillers commonly serve an important role as
the initial step for new patients interested in soft tissue augmentation.
Because of their transient effect, the potential patient dissatisfaction and
side effects are also short-lived. Therefore, temporary fillers should always
be the first line of therapy, saving the longer-lasting fillers for future patient
visits.
Collagen
The major structural component of the dermis, collagen is the most
abundant protein in the human organism as well as, in particular, the skin.
Collagen confers strength and support to the skin. It is also one of the
strongest natural proteins, imparting durability and resilience to the skin,
and comprising 70% of dry skin mass. Collagen is actually a meshwork of
scaffolding-like structures composed of a complex family of over 18 types,
11 of which are found in the dermis. Type I collagen (80%–85%) and type
III collagen (10%–15%) are the primary collagen constituents in the dermal
matrix of adult human skin. Dermal fibroblasts produce a precursor form of
collagen, procollagens, which in turn produce both collagen types I and III,
each of which is composed of three collagen chains.
Skin fragility and wrinkles result from the loss of collagen, which occurs with
aging as well as solar exposure and other insults. UV light, free radicals, and
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other factors cause the body to produce collagenase, an enzyme that breaks
down collagen. The injection of various forms of collagen into the skin helps
it regain a youthful appearance, but such results are temporary. The range
of collagen products has increased in recent years as manufacturers have
worked to extend the duration of product effects.186,187 The table below lists
the types of collagen products and describes the properties, method of
administration and action of each.178,183,184,188-190
Bovine Collagen
With a record of safety and efficacy spanning over two decades,
bovine collagen was the traditional dermal filler agent used to
ameliorate undesirable signs of cutaneous facial aging. In 1977,
Zyderm I was introduced as the first injectable bovine collagen
implant; it was approved by the FDA in 1981 for fine lines and
shallow acne scars. Zyderm II and Zyplast were introduced and
approved, respectively, in 1983 for moderate lines and deeper
acne scars and 1985 for deep dermal folds and lines.
Although these products were the standard for years to which
newer implants were compared, because of better safety
profiles, human-derived collagen and HA products have become
more widely used. Zyderm I is 96% type I collagen and 4%
type III collagen derived from the bovine skin of U.S. enclosed
cattle herds.
Zyderm I and II differ only by collagen concentration. Zyderm I
contains 35 mg/cc, while Zyderm II contains 65 mg/cc. The
difference in concentration is significant insofar as it renders
Zyderm II thicker and stiffer than Zyderm I. Like Zyderm I,
Zyplast contains 35 mg/cc of collagen, but this collagen is crosslinked with glutaraldehyde, which makes it last longer via
resistance to degradation. Consequently, Zyplast is more
viscous and less immunogenic than Zyderm. Zyderm and
Zyplast are white substances prepackaged in 0.5-, 1-, and 2-mL
syringes and injected with a 30-gauge, 0.5-inch needle. The
product should be stored in the refrigerator ideally at 4 C.
While Zyderm I is properly injected into superficial dermis at
20- to 30-degree angles with the expectation of temporary skin
blanching, Zyderm II can be injected slightly deeper at 35- to
45-degree angles with less anticipated blanching and minimal
overcorrection. Since Zyderm is diluted with phosphate-buffered
sterile saline, which is rapidly reabsorbed in skin, to achieve the
optimal effect, overcorrecting implantation is necessary. Zyplast
is implanted into even deeper dermis at 45- to 90-degree angles
with minimal delayed blanching and without overcorrection.
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Bovine-derived collagen dermal filling agents effectively reduce
wrinkles and scars. Zyplast is appropriate for shaping the
vermilion border of the lips and treating moderate and deep
wrinkles, such as nasolabial folds and atrophic scars. Zyderm I
is well suited for treating superficial rhytides (i.e., horizontal
forehead wrinkles, crow’s feet, fine perioral wrinkles, and scars)
or for use over Zyplast in deeper wrinkles. The higher
concentration of collagen in Zyderm II renders this product
more appropriate for acne scar revision, but Zyplast lasts longer
because it is cross-linked. Collagenase ultimately succeeds in
degrading these products, returning the skin to its appearance
prior to injection. Zyplast is the most commonly used bovine
collagen product and lasts approximately 4 months, just slightly
longer than Zyderm I and II.
Bovine collagen can be safely reinjected 3 to 4 times per year if
needed. Zyderm and Zyplast are the least expensive dermal
fillers on the market and typically engender less bruising than
products that contain HA.
All the bovine collagen products contain 0.3% lidocaine to
reduce the pain associated with the procedure. Two skin tests, 6
and 2 weeks before the scheduled treatment, are required
before the use of bovine collagen agents to reduce the risk of
inducing hypersensitive or allergic reactions.
A positive skin response can occur as early as 6 hours after the
test, but are more likely to emerge 48 hours or 4 weeks after
the test. A positive skin test disqualifies a patient for treatment
with bovine collagen. Approximately 3% of the general
population is thought to be sensitive to bovine collagen.
Although a patient is unlikely to react to bovine collagen
implants after two negative skin tests, the risk is never
completely eliminated.
The risk of hypersensitive reaction is 1.3% to 6.2% after one
negative test and 0.5% after two negative tests. Patients should
be advised that should such a reaction occur, it can be expected
to spontaneously resolve within 4 to 24 months.
Allergic reactions also arise, albeit rarely, following multiple
treatments. Topical, intralesional, or a brief course of systemic
corticosteroids can be effective to treat these reactions. Oral
cyclosporine and topical tacrolimus have also reportedly been
used for the successful treatment of recalcitrant hypersensitive
reactions to bovine collagen. Patients with lidocaine
hypersensitivity are contraindicated for obtaining these
injections because the fillers contain lidocaine.
Nonhypersensitive reactions to bovine collagen fillers can also
infrequently occur (i.e., abscesses, bacterial infections, beading,
cyst and granuloma formation, ecchymoses, and local necrosis).
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Several previously discussed preventative steps can be taken to
reduce the likelihood of such outcomes. Because of its viscosity,
Zyplast should not be injected into the glabellar region, as there
have been reports of local necrosis and retinal artery occlusion
leading to visual loss. However, Zyderm I or II can be injected
into the glabellar area very slowly and with extreme caution.
Vascular occlusion or compression manifests as prominent
immediate blanching and pain.
Warm compresses, topical nitroglycerin, and meticulous wound
care are necessary treatments. Prior to 1990, beads and cysts
were reported at the injection site in 0.04% of patients treated
with Zyderm or Zyplast, most likely caused by injections that
were too superficial. Injections should be made only into the
dermis to avoid such reactions.
Abscesses should be treated with incision and drainage and a
combination of antibiotics and corticosteroids to reduce
secondary scarring. More than a decade ago, there was some
speculation that autoimmune diseases, namely, polymyositis
and dermatomyositis, might be induced by the injection of
bovine collagen, but studies have demonstrated that antibodies
to bovine collagen do not cross-react with human collagen.
Therefore, the FDA has agreed that it is unlikely that bovine
collagen causes connective tissue disease in humans. A study by
Hanke et al. showed that the incident rate of polymyositis or
dermatomyositis in patients receiving bovine collagen was not
higher than the control-matched population.
Despite the studies cited above, experts recommend avoiding
the use of bovine collagen containing fillers in patients with a
history of autoimmune disease. Another major downside to
using bovine collagen is the minimal durability of about 3 to 4
months.
Bioengineered
Human Collagen
Over the last 10 years, several companies, motivated by the
drawbacks of bovine-derived collagen, have developed humanderived soft tissue fillers. Unlike earlier cadaver-derived collagen
(i.e., Cymetra) and, more recently, autologous collagen (i.e.,
Isolagen), bioengineered human collagen is pregenerated to
ensure ease of accessibility.
The manufacturing process begins with the harvesting of dermal
fibroblasts from bioengineered human skin and placement into a
three-dimensional mesh. The fibroblasts are then cultured in a
bioreactor that simulates the conditions of the human body.
Then, the fibroblasts synthesize collagen and extracellular
matrix proteins. The derived collagen is purified to enhance
safety. Human- bioengineered collagen implants include
CosmoDerm I, CosmoDerm II, and CosmoPlast (Allergan
Corporation, Irvine, CA), which contain human collagen types I
and III, and were approved by the FDA in March 2003.
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CosmoDerm I is composed of 35 mg/cc human-bioengineered
collagen distributed in a phosphate-based saline solution and
0.3% lidocaine. CosmoDerm II contains twice the collagen
concentration of CosmoDerm I. CosmoPlast contains the same
ingredients as CosmoDerm I, but is cross-linked by
glutaraldehyde, yielding a product more resistant to
degradation, thus lasting longer, and more appropriate for use
in treating deeper furrows. While
CosmoDerm is indicated for superficial wrinkles and shallow
scars, CosmoPlast, which exhibits a stiff consistency (even more
so than products containing HA), is well suited to treating the
vermilion border of the lips, as well as raising the corners of the
mouth. In addition, it is a good choice to correct deformities of
the bridge of the nose or to raise the nasal tip.
CosmoPlast is typically used in combination, usually with an HA
agent, to treat medium and deep wrinkles, with the collagen
product injected first to create a volume-filling base and the HA
filler injected more superficially into the same location. Similar
to bovine collagens, CosmoDerm and CosmoPlast are white
substances prepackaged in 1-mL syringes and injected via 30gauge 0.5-inch needles.
Although some anecdotal reports indicate better rheology of
human collagen fillers, their technique of injection, cosmetic
outcome, and durability are comparable to bovine collagen
fillers. Furthermore, like bovine collagen, CosmoDerm and
CosmoPlast must be kept refrigerated when stored. For humanderived collagen devices, on average, one syringe is used for
patients in their twenties, two syringes for patients in their
thirties, three syringes for patients in their forties, and as
needed for older patients to correct age-related lines and folds.
Given the absence of allergy risk associated with these agents,
no skin testing is required. This allows for patients to be treated
in their initial visit to the physician. The cosmetic effects of
CosmoDerm and CosmoPlast are immediate, lasting about 3
months for the former and about 4 months for the latter, and
are typically associated with less bruising than the effects of
procedures using agents containing HA.
Also similar to the bovine-derived fillers, CosmoDerm and
CosmoPlast contain lidocaine to mitigate the pain of injection
and lower the risk of edema and ecchymoses by inhibiting the
activation of eosinophils.
CosmoPlast can create the beautiful “Snow White line” and
“Cupid’s bow” shape of the lip borders as well as upturn the tip
of the nose to create a poised appearance. Although HA fillers
are favored because they last longer and are softer,
CosmoDerm I can be used to plump the body of the lip.
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CosmoDerm I can be layered over CosmoPlast for the purpose
of ideal contouring of deep lines, such as nasolabial folds and
marionette lines. In addition, to treat medium and deep
wrinkles, HA fillers can be superimposed on top of CosmoPlast
or injected in the same plane as CosmoPlast.
Although fillers should be used rarely and with great caution in
the glabellarrhytides because of the potential risk of tissue
necrosis, CosmoDerm I can be used with great care in this
region. At the time of publication of this text, there were no HA
fillers geared for superficial placement, although Prevelle,
Juvéderm, and Restylane may have superficial fillers soon.
Therefore, CosmoDerm I, although it lasts only about 3 months,
is the filler of choice for periorbital wrinkles and smoker’s lines
above the top lip. CosmoDerm II is most often used for acne
scars. Bioengineered human-derived collagen is expensive to
produce, rendering these agents somewhat costly.
Further, the cosmetic effects from these products do not last, on
average, any longer than the bovine-derived products. The
duration is thought to be around 4 months. However, these
products are associated with less bruising, erythema, and pain
than other filling agents and, consequently, remain desirable
options for those who cannot afford to have downtime.
Excluding the reduction in immunogenic potential, human
collagen fillers have similar side effect profiles to bovine
collagen fillers. Likewise, patients with lidocaine allergies should
avoid these agents.
Cadaveric Collagen
Approved by the FDA in 2000 for soft tissue augmentation,
Cymetra® (LifeCell Corp., Palo Alto, CA) is a micronized
collagen derived from processed human cadaver skin. A similar
product, Fascian (Fascia Biosystems, Beverly Hills, CA), is
obtained from cadaver fascia, and has a heavier consistency.
Cymetra is packaged as a 330-mg white powder in a 5-cc
syringe, stored at room temperature and reconstituted with 1
mL of 1% lidocaine to create a thick paste.
Tunneling and threading injection methods are accomplished
through a 26-gauge syringe into a subcutaneous plane, avoiding
overcorrection. This acellular and purified filler negates a
potential sensitivity reaction and pretesting is, therefore,
unnecessary. The cadaver collagen has somewhat longer
durability versus other collagen products, lasting from 3 to 9
months, although durability is controversial.
Cymetra is indicated for use in deep rhytides (i.e., nasolabial
folds), depressed scars, and volumizing of the lips.
Reconstitution with lidocaine yields reduction in intraprocedural
pain. Based on the composition of the product, Cymetra is
contraindicated in patients with gentamicin allergies.
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The product is very viscous, which makes it difficult to operate,
generating more local tissue discomfort and trauma as well as
leading to longer recovery time for patients. Fascian is an even
thicker and stiffer product, which translates to more side effects
and difficulty in administration. The implantation of cadaver
products into superficial and mobile wrinkles can induce
migration and, therefore, is discouraged. The major issues with
employing these agents are the cumbersome preparations and
deficit of adequate clinical trials demonstrating their long-term
efficacy and safety.
Hyaluronic Acid
In the last few years, hyaluronic acid filler substances have become the new
gold standard, far outpacing in usage the other soft tissue augmentation
agents. Hyaluronic acid, or hyaluronan, is a nonsulfated glycosaminoglycan
(GAG) that occurs naturally in the skin and other tissues (specifically,
connective, epithelial, and neural tissues) as space-occupiers of the
extracellular matrix. It is also ubiquitous across animal species, which makes
HA nonimmunogenic. This polysaccharide has the capacity to bind water up
to 1000 times its mass. The biologic behavior of HA is predictable; it creates
lubrication and volume with an aqueous and pliable framework that
suspends and adheres to collagen, elastin, and cells.178
With age, the concentration of HA in skin decreases, translating to more lax,
sallow, and dull skin. The viscoelastic qualities of HA serve to plump up the
skin, yielding a more youthful appearance. Naturally occurring, unmodified,
or uncross-linked HA has a half-life of about 24 hours. For this reason, HA is
cross-linked when formulated into a dermal filler product. Higher
concentrations and moderate cross-linking of the HA in a product impart
greater longevity. There exists a certain threshold where beyond that value
additional cross-linking can cause biocompatibility issues. In effect, crosslinking has to be in the right balance to maintain duration and
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biocompatibility of the HA filler. Hyaluronic acid is readily metabolized by the
liver and yields by-products, water, and carbon dioxide. In the skin, HA is
broken down by hyaluronidase, mechanical degradation caused by facial
movement, and by free radicals. Supplementation with oral antioxidants
theoretically will increase the duration of HA fillers, but this has not been
proven.191-193
There are two main categories of HA fillers: animal derived (i.e., Hylaform)
and bacteria derived (i.e., Restylane, Captique, Juvéderm, etc.). Medicis, the
company that sells Restylane, trademarked the name “nonanimal derived
synthetic hyaluronic acid (NASHA)” to show that their products, Restylane
and Perlane, are not animal based. Because of the expense of animalderived products, the vast majority of HA products are bacterial derived.
Until recently, no HA products on the market contained lidocaine and,
therefore, were more painful than fillers that contain lidocaine. However,
lidocaine-containing injectables, such as Prevelle Silk, have recently entered
the market. Because of their nonallergenic nature and manufacturing, HA
fillers do not require prior testing and can be stored at room temperature.
Their advantages over collagen products are longer duration (6–12 months),
better pliability, and less immunogenic and allergic side effects. On the
whole, side effects of various HA fillers are similar, mild, and rare; these
include bruising, temporary swelling, lumps, acneiform eruptions, and,
rarely, acute hypersensitivity. In addition, arterial occlusion, thought to be
due to swelling of the HA implant, causing vascular compromise, can rarely
occur.130,177,193
A major advantage of HA fillers is that if skin nodules do arise, these
reactions can be easily dissolved with intralesional hyaluronidase. The
disadvantages of the currently available HA fillers are increased pain on
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injection and post-procedure edema, erythema, and ecchymoses as
compared to CosmoPlast injections.191 HA fillers do not require skin testing
and the risk of allergy with all products that are FDA approved is minimal.
Cost, availability, duration of correction, and size of the required needle for
injection all play a role in product selection and manufacturers all strive to
create an affordable, long-lasting product that can be injected with a 30gauge or smaller needle. However, there are other, less obvious, scientific
considerations to be taken into account when choosing a filler. The stiffness
or G* (G prime) of a product is one of the most important considerations. G*
is a measurement of gel hardness. It is obtained when a gel is placed on a
plate. A second plate is placed over the gel and a lateral force is applied. The
measurement of resistance to deformation is known as the elastic modulus
or the G*. Together with the cohesivity of the product, G* values could be
used to determine the appropriate placement of an HA dermal filler. For
example, more robust products (higher G* values and higher cohesivities)
such as Juvéderm Ultra Plus and Perlane, in the primary author’s opinion,
should be used in deeper lines, such as nasolabial folds and marionette lines,
as well as to lift the lateral brow, to correct the nasal bridge, to give the ear
lobe youthful volume, to evert the nipples, and to raise the nasal tip. More
fluid products such as Juvéderm Ultra and Restylane are better suited to be
used over large areas such as the cheekbones and cheeks. Low G* products
such as Hylaform and Juvéderm Ultra are necessary in areas that require a
softer agent, such as the body of the lip or the tear trough. As new products
reach the market, knowing the G* will help practitioners match fillers with
indications.194-197
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The concentration of HA in a product is important to consider as well. Many
authorities believe that the higher the concentration of HA, the stiffer the
product and the longer its duration. This is true in general when comparing
products within a brand, for example, when comparing Juvéderm 18 to
Juvéderm 24. However, this does not hold true across brands because not all
of the HA in the dermal fillers is cross-linked. Many HA fillers contain
uncross-linked HA and lightly cross-linked chains and fragments. The
uncross-linked HA, fragments of HA, and lightly cross-linked HA are included
in the overall concentration measurement but only remain in the skin for a
limited time and should minimally contribute to the longevity of the filler.
The uncross-linked HA does help decrease extrusion force and make
injection easier, which is the main reason it is included. Therefore, the fact
that Restylane contains 20 mg of HA/cc and Juvéderm contains 24 mg of
HA/cc does not give a provider enough information to decide which filler will
have longer duration. It is actually the amount of modified HA that plays the
primary role in duration.198-200
The type of modification (cross-linking) and the cross-linking agent used is
also important. Cross-linking can be best visualized by imagining a ladder.
Each side of the ladder is an HA chain. The rungs of the ladder are the crosslinks. When the “rungs” of the ladder attach to both sides of the ladder, the
agent is considered completely modified. However, the cross-linking agent
used may incompletely cross-link the chains of HA, leaving the sides of the
rungs unattached and resulting in incomplete modification. Such a product
might not be as durable as a completely modified product. In addition, there
are two types of rungs in the HA ladder. One is called an ether linkage and
the other is called an ester linkage. Ether linkages are formed by 1,4butanediol diglycidyl ether (BDDE, the cross-linking agent in Restylane and
Juvéderm) and divinyl sulfone (DVS, the agent used in Prevelle Silk,
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Captique, and Hylaform). The cross-linking agent used in Prevelle Dura,
1,2,7,8 diepoxyoctane (DEO), forms both ether and ester linkages (known
as “double cross-linking”). It is unknown at this time what advantages, if
any, ether linkages impart to a dermal filler.191,195,201,202
The hydration status of the filler once it is packaged in the syringe also
affects filler performance. HA is well known to bind up to 1000 times its
weight in water. The amount of water bound to the HA prior to its packaging
in the syringe determines how much more water the filler can absorb once it
is injected into the skin. In other words, fillers that are completely hydrated
in the syringe will bind less water on injection and the volume will expand
less upon injection as compared to fillers that are not completely hydrated in
the syringe. Fillers that are not completely hydrated in the syringe will swell
somewhat within 24 hours after correction; therefore, it is prudent to slightly
under-correct with these substances. In addition, patients can be told that
they will “look even better” 24 hours after the injection. Restylane and
Juvéderm are not completely hydrated in the syringe while Captique and
Hylaform are close to being fully hydrated.198,203,204
Another process that may affect the performance of the filler is referred to
as “sizing technology.” This term is used by Allergan to differentiate
Juvéderm from the other HA fillers. When an HA filler is cross-linked, the
chains of modified sugars form a gel. In the process of manufacturing
Restylane, Restylane Fine Line, Restylane Lip, Restylane Touch, Perlane, and
Restylane Sub-Q, this gel is extruded through a screen. This produces
various sizes of the gel that are considered “sized.” The large pieces become
Perlane or Restylane Sub-Q, while the small pieces are marketed as
Restylane Fine Line or Restylane Lip. The medium-sized pieces are
Restylane. The larger pieces yield products that are best used in the mid to
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lower dermis while the small pieces such as Restylane Fine Line can be used
more superficially. The Juvéderm family of products is not sized. In other
words, Juvéderm is not pushed through a screen and broken into sized
pieces and, therefore, it consists of randomly sized and shaped pieces. It is
unknown at this time what role sizing technology plays, if any, in the
performance of a filler.205,206
There are many factors that must be understood in order to make the most
suitable choice of HA filler. There are no peer-reviewed publications that
review the above mentioned properties so it is difficult at this point to know
how important these various characteristics are in choosing a filler. More
data needs to be collected to properly ascertain if, for example, sizing
technology makes a difference or if ester bonds last longer than ether bonds.
These distinctions will become clearer and more important as more HA fillers
are introduced onto the market and more data are collected. The table below
lists and discusses the individual HA brands in terms of their properties,
indications, methods of administration, potential risks and
benefits.130,166,189,195,196,198,205-210
Restylane
Restylane (Medicis, Scottsdale, AZ) was the first nonanimal HA
product approved in the US. It is a NASHA gel formulated through
fermentation, with sugar present, in bacterial cultures of equine
streptococci. Restylane has a higher concentration of HA compared
to Hylaform and Captique and the highest G´of the fillers currently
on the market, denoting that it is a slightly stiffer product. It is the
most popular of the HA fillers in the U.S.
Restylane is popular to use because of its safety profile, brand
recognition, and ease of injection. It is composed of approximately
100,000 particles/mL (approximately 250 m on average) and
contains 20 mg/mL of HA. Restylane is indicated for middermal
wrinkle reduction and was the first HA filler approved in the U.S. in
2003. The FDA more recently approved Perlane, another product in
the Restylane family, to use for significantly deeper folds and
furrows.
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Restylane is made of medium-sized particles of HA gel, while
Perlane is composed of larger HA gel particles (approximately
1000 m), but with the same HA concentration.
The Restylane family of products also includes Restylane Fine Line,
Restylane Touch, Restylane Lip, and Restylane Sub-Q, which are not
currently approved for use in the US. These products have the same
formulation as Restylane and differ only in their particle size.
Restylane and Perlane are packaged as transparent gels, with a
shelf life of 18 months, and stored at room temperature. Restylane
is enclosed in 0.4- and 1-mL syringes while Perlane is packaged in a
0.7-mL syringe; both are injected via a 27-gauge needle. Restylane
is implanted using linear threading anterograde or retrograde
techniques. It is important to avoid injecting at withdrawal of the
needle, which can result in superficial injection, creating bluecolored nodules.
A fanning threading technique can also be employed with Restylane
at the nasolabial fold or lip commissures. The stiffness of Restylane
renders it well suited for moderate to deep wrinkles and it is this
quality among other factors that is thought to impart greater
longevity in human tissue as compared to Hylaform and Captique.
The cosmetic effects of Restylane are thought to last over 6
months; Perlane delivers a durability of 6 to 9 months. Product
stiffness makes Restylane and Perlane more suitable for moderate
and deep wrinkles than for use in the body of the lips or the tear
trough.
Restylane is ideal to fill nasolabial and marionette lines, chin and
jowl depressions, nasal deformities, and for nasal tip-lift as well as
acne scars and other defects. Bruising is associated with all HA
fillers. However, the stiffness is a downside if a poorly skilled
physician uses the product, with bumps and blue blebs possibly
arising from improper injection technique. Injection into the tear
trough may result in visible blebs. Slower injection of any HA filler
will limit the risk of inflammation.
Restylane can be used in the vermilion border to augment the shape
of the lip. Restylane and Perlane may be a poor choice for the body
of the lips. However, outside the U.S., Restylane Lip is available and
is a better choice for use in this area. As with other fillers that do
not contain an anesthetic, the injection of Restylane can be painful.
The use of topical anesthetics and/or dental nerve blocks is
recommended to reduce the pain on injection. Restylane tends to
sting less after injection when compared to Juvéderm. It is unknown
why this occurs as they are both the same pH of approximately 7.0.
Juvéderm
Juvéderm (Allergan, Irvine, CA), is manufactured by a bacterial
fermentation process similar to that used for other stabilized
bacterial-based HA filler and was approved by the FDA in late 2006.
There are many products in the Juvéderm line (Juvéderm 18,
Juvéderm 24, Juvéderm 24 HV, Juvéderm 30, and Juvéderm 30
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HV), but only Juvéderm 24 HV (also known as Juvéderm Ultra) and
Juvéderm 30 HV (also known as Juvéderm Ultra Plus) are currently
approved by the FDA and sold in the U.S.
All the products in the line vary by the amount of HA concentration,
the amount of cross-linking, and the regularity of the cross-linking.
Both Juvéderm Ultra and Ultra Plus consist of 24 mg/cc of HA, but
Juvéderm Ultra Plus has a higher degree of cross-linking than
Juvéderm Ultra, which makes Ultra Plus more suitable for the
deepest facial grooves and furrows. Unlike Restylane, which consists
of stiff and a fairly narrow range of particle sizes, Juvéderm is a
smooth consistency gel composed of a broad range of particles of
various sizes and shapes (referred to as “Hyalacross technology”).
Juvéderm products are packaged as a clear gel in 0.8-mL syringes.
They are stored at room temperature.
Juvéderm Ultra is injected into the middermis via a 30-gauge needle
while Juvéderm Ultra Plus is implanted deeper via a 27- gauge
needle. The needles must be tightly attached to the Luer-lock
syringe to prevent detachment during injections. Various techniques
of injection can be used with Juvéderm, including serial puncture
and tunneling. Juvéderm Ultra and Ultra Plus are in the medium
range of stiffness; therefore, they can be used in any wrinkles,
moderate or deep, and to correct scars.
Juvéderm Ultra is easily placed in the vermilion border or the body
of the lips. The high concentration of HA in Juvéderm Ultra and Ultra
Plus and the high degree of cross-linking results in longer-lasting
aesthetic effects as compared to products such as Hylaform. As
other HA products, these agents have an overall low, mild, and
transient adverse-event profile. Juvéderm is not completely
hydrated in the syringe, so it will slightly expand after injection as it
absorbs more water. This is important to remember when injecting
the body of the lips, which should be slightly undercorrected to
allow for the expansion.
Similar to Restylane, the longevity of Juvéderm Ultra is about 6 to 9
months and Ultra Plus may last up to 12 months. All HA products
can cause erythema, swelling, and bruising after implantation. Pain
during injection caused by lack of anesthetic can be alleviated with
the use of topical or regional anesthesia. Juvéderm can be placed
with care in the tear trough area, but the proximity to the eye is
unnerving with the risk of the needle popping off, so injections
should be very slow with only moderate extrusion force.
The needle is more likely to pop off when the syringe is almost
empty; therefore, the tear trough area should be injected with a
new syringe and the last part of the syringe can be saved for less
dangerous areas such as the nasolabial folds. As with all fillers, the
skill and experience of the physician is crucial for optimal outcome.
If Juvéderm is injected too superficially, it can create a bluish hue.
Caution should be taken in overinjecting the vermilion border and
creating an unnatural “duck bill” appearance. In addition, superficial
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placement of Juvéderm in the tear trough defects can result in blue
nodules. Blue nodules and unwanted bulges can be corrected with
the use of hyaluronidase.
Prevelle Silk
Prevelle Silk is sold by the Mentor Corp. (Santa Barbara, CA). This
bacterial-derived product is similar to the Captique formulation with
moderate softness illustrated by its G´ in the middle of the
spectrum. This product is softer than Restylane and is similar in
softness to Juvéderm. Prevelle Silk has a higher degree of crosslinking density than Hylaform and therefore is slightly stiffer than
Hylaform. The gel contains 5.5 mg/mL of cross-linked HA with an
average particle size of 300 m. Prevelle is suitable for treating
shallow to moderate wrinkles, lips, and scars.
The longevity of the product is unknown but reported to be about 4
months. Prevelle Silk contains 0.3% lidocaine. It was approved in
the United States in 2008. This product is suitable for use in the lips
since it generates less pain during injections. Side effects, which are
rare and relatively mild, include redness, swelling, and pruritus. This
product is softer than other products on the market since Hylaform
and Captique were discontinued. It can be used in any moderate to
deep facial wrinkles, the body of the lip, and periorbital areas.
Prevelle Silk is the first lidocaine-containing HA in the United States.
Longevity of the correction is not known but thought to be 4-6
months.
Prevelle Dura
Prevelle Dura (Mentor Corp.) is another bacterial-derived filler
approved for the US market in 2008. It is composed of 220-μm HA
particles cross-linked with DEO. As mentioned previously, DEO
cross-linking results in both ether bonds and ester bonds, known as
double cross-linking. These ester bonds may confer better stability
and longer duration but this has not yet been proven. Prevelle Dura
is touted for suitability in any dermal layer to correct middermal and
deep rhytides.
The G* (stiffness) of this product is 900 Da, which renders it slightly
stiffer than Restylane. Preliminary studies demonstrate the safety of
this product; however, more trials need to be performed to establish
its strengths and weaknesses. Based on double cross-linking
technology, the company claims that this device may last longer
than previous HA fillers; however, this has not been proven. The
role of the double cross-linking technology in terms of duration of
the filler has not been ascertained. Prevelle Dura is slightly more
viscous and, therefore, requires more pressure on injection.
Hyaluronidase
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Hyaluronidase is a soluble enzyme that hydrolyzes HA, other GAGs, and
other connective tissue components in the skin and vitreous humor of the
eye. The FDA has approved Vitrase and Amphadase for enhancement of
injectable drug absorption and resorption of radiopaque agents. However,
effective off-label uses include wound care and postsurgical flap care among
other uses.175,178
Several reports have indicated the usefulness of hyaluronidase to dissolve
HA filler overcorrection for symmetric contouring, as well as to manage
impending tissue necrosis because of HA skin injections. Specifically, there
were two cases of imminent tissue necrosis caused by intra-arterial injection
of HA and surrounding tissue compression of vital vessel, which resolved
with employment of hyaluronidase. After using other appropriate techniques
to manage impending tissue necrosis including systemic aspirin, Nitro BID
under occlusion, and hot compresses (with massage) without significant
response, the authors injected 30 units of hyaluronidase into deep dermal
tissue and subcutis using a serial puncture method along the distribution of
affected arteries, which led to the resolution of symptoms within a day.
Although early reports have recommended the utility of hyaluronidase only
within 16 minutes of the critical event, studies reported successful responses
after several days. Furthermore, the effectiveness of hyaluronidase for bluish
(Tyndall) manifestations and asymmetric lumpiness from HA overcorrection
has also been reported at various concentrations. Because of the described
benefits of hyaluronidase for the treatment of complications of the popular
HA fillers, it has been recommended as a necessary agent to keep in an
aesthetic physician’s office.211-213
Hyaluronidase is a clear liquid that is stored in the refrigerator and
reconstituted with 1 mL of normal saline to generate 150 units. Very rare
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adverse acute and delayed-type hypersensitivity reactions to hyaluronidase
have been reported, so it may be prudent to perform a skin test prior to the
use of this agent. Injection of hyaluronidase into patients with an allergy to
hymenoptera stings and thimerosal is contraindicated.214
Semi-permanent Fillers
Fat, Radiesse, and Sculptra are considered semitransitory because they are
partly biostimulatory and partially biodegradable; this balance allows them
to last approximately 1 to 3 years. The adverse events associated with semipermanent fillers include rare granuloma formations. The aesthetic effects of
these fillers are best preserved with annual touch-up sessions. These are
outlined in the table below.175, 176, 215, 181, 180, 184, 185, 200, 216, 217
Autologous
Fat
Originating in the 1890s, transplantation of fat from a patient’s excess
adipose areas to other skin defects is the oldest soft tissue
augmentation method. Fat injection filling has gained recognition for
several reasons. Naturally, the patient’s own cells are unlikely to
cause sensitivity or inflammation and are therefore considered
supremely biocompatible. Furthermore, the technique of fat
implantation has undergone remarkable polishing over many years,
especially with the advent of harvesting subcutis through liposuction.
The procedure is a multistep process, whereby the fat cells are
obtained from the buttock, thigh, and abdominal regions, then
segregated, stored (refrigerated up to 18 months), and injected back
into the patient’s subcutis on the face, hands, and any other areas
requiring volume enhancement.
As anticipated, this process is more invasive, time-consuming, both
for the clinician to prepare and perform as well as the patient to
recover from, as well as more costly. In effect, the optimal efficacy
with minimal adverse effects is mainly achieved in the hands of a
qualified dermasurgeon. Approximately 0.1 cc aliquots of fat are
inserted into subcutis through a 17- to 18-gauge needle via a
tunneling technique, without overcorrection. Postprocedure massage is
recommended for proper shaping of contours.
Because of its autologous character, lipotransfer is unlikely to cause
sensitivity and reactivity of the tissue, minimizing potential long-term
side effects and obviating prior testing. Nasolabial folds, sunken
cheeks, tear troughs, marionette lines, scars, and lips are the most
appropriate areas of correction with fat. Furthermore, fat transfer
provides a reported duration of about 12 months; although the
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concrete duration is controversial.
The injectable material used is the patient’s own tissue, so its use
decreases the amount of money spent on the actual filler. The
procedure also has an attractive double-gain, where two cosmetic
areas can be simultaneously addressed, lipoexcess and lipodystrophy.
Stem cells have been isolated from fat cells. It is believed that the
stem cells found in fat lead to increased skin rejuvenation. When
performed by a skilled physician, the results of lipotransfer are
remarkable. Fat injections require prophylactic local or regional
anesthesia.
Because of the fact that the procedure is more surgically invasive,
more complex preparations and settings are required with longer and
more frequent office visits. Although the harvesting portion can cause
a longer recovery time and an increased risk of side effects (i.e.,
infection, scarring), the actual injection has a similar adverse event
profile to the other fillers (i.e., edema, redness, bruising, and
discomfort lasting a few days).
Another variable to consider when selecting candidates for this
procedure is to ensure that the patient has a sufficient graft supply. In
some patients, the fat injections last several years and in other
patients the injections last merely months. Many tricks are employed
to try and increase longevity, but at this time there are no guarantees.
Radiesse
Radiesse (BioForm Medical, San Mateo, CA) was approved by the FDA
in 2006 for the correction of moderate to severe folds and wrinkles
along with HIV-associated lipoatrophy. It is composed of 30% calcium
hydroxylapatite (CaHA) microspheres (25–45 μm) suspended in an
aqueous gel carrier (1.3% sodium carboxymethyl cellulose, 6.4%
glycerin, and 36.6% sterile water). As the gel carrier of this filler
dissipates in several months, the microspheres stimulate cutaneous
cells to generate focal foreign body reaction and neocollagenesis. This
leads to envelopment of the microspheres by fibrin, collagen, and
fibroblasts, and slows the degradation by macrophages and
metabolism into calcium and phosphate ions. Because of a similar
mineral constitution as human bones, and no foreign antigenic
properties, CaHA is particularly biocompatible.
It is critical for patients to be aware that Radiesse is a radioopaque
material that can be visualized and misinterpreted on facial
radiographs, but importantly, it does not radiographically mask
surrounding tissues. Radiesse is a white material packaged in a 1-mL
syringe and injected via a 25- to 27-gauge and 11/4-inch needle into
the deep dermis or subcutis without overcorrection. The product
should be stored at room temperature. A reasonable injection method
for Radiesse is tunneling or crisscross threading techniques.
A placement of Radiesse in the supraperiosteal plane yields better
control and ability to contour skin with this stiffer filler. Since Radiesse
is immunologically inert, it does not require skin testing. With more
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than 20 years of use as implantable devices for otolaryngology and
orthopedic specialties, CaHA possesses an excellent safety record.
The average duration of Radiesse is 9 to 18 months. The proper
locations of injection include the nasolabial folds, marionette lines,
prejowl sulcus, and cheek depressions.
Unlike Sculptra, where time is necessary to build up new collagen,
Radiesse offers the advantage of immediate wrinkle ablation.
Interestingly, although Radiesse induces foreign body reaction, it is
not known to cause granuloma formation. In its gel form, the device is
also quite pliable, permitting timely manipulation and appropriate
modification. In addition, it can be combined with other fillers, such as
Sculptra, HA, and collagen.
The main drawback of Radiesse is that it is not reversible like HAs.
Radiesse also does not contain an anesthetic and because of its high
viscosity, requires administration through a high-bore needle.
However, Radiesse can be combined with lidocaine in the syringe to
decrease pain on injection. Hence, the use of topical or regional
anesthesia is recommended. Minimal side effects such as ecchymoses,
edema, and erythema appear soon after Radiesse injection and are
transitory. Rare nodules have also been associated with Radiesse and
can be managed with intralesional steroids or excision.
Similar to Sculptra, an implantation of Radiesse in the superficial and
mobile wrinkles (i.e., lips and periorbital area) and the body of the lips
is discouraged because of the palpable and visible white papules that
can develop (also known as “popcorn lips”). Radiesse should not be
performed in the nose of a patient anticipating rhinoplasty. Several
facial plastic surgeons have given anecdotal reports in lectures
suggesting that this complicates rhinoplasty surgery. An HA or
collagen filler would be a more appropriate choice in preoperative
rhinoplasty patients.
Sculptra
Sculptra is a synthetic, biodegradable, biocompatible, immunologically
inert peptide polymer (also known as NewFill). Sculptra (Dermik
Laboratories, Sanofi-Aventis, Bridgewater, NJ) is composed of poly-Llactic acid (PLLA) microspheres, sodium carboxymethylcellulose, and
nonpyrogenic mannitol and is manufactured from powdered,
absorbable suture material (i.e., Vycryl). This agent is not a true
dermal filler because it does not fill the dermis the way collagen and
HA do but, rather, it promotes the production of new and organized
collagen in the dermis. Many physicians refer to it as a “dermal
stimulator.”
Sculptra is thought to foster neocollagenesis by stimulating fibroblasts
and gradually restoring facial volume. However, Sculptra is eventually
cleared from the skin via phagocytic digestion. In the U.S., the FDA
approved Sculptra in 2004 for the treatment of HIV-associated facial
lipoatrophy, but it has been used off-label for cosmesis, and Dermik is
currently applying for approval for its use in facial rejuvenation.
NewFill has been used in Europe and Asia for many years.
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When it was first introduced, NewFill was diluted with a lower amount
of saline and many granules and nodules were reported. This led to
new recommendations to dilute one bottle with 5 to 10 cc of sterile
water and massage after application. With the new recommendations,
adverse events have been minimal.
Freeze-dried Sculptra powder is stored at room temperature and
reconstituted approximately 2 to 4 hours prior to injection. The
package label states that the product should be used within 72 hours.
In our practice, we prefer using Sculptra that has been reconstituted
for at least 2 days because the solution is easy to work with and
results in less needle clogging.
Sculptra is reconstituted and kept in the refrigerator for 2 days to 2
weeks. Although the package label recommends that the formulation
be reconstituted with 5 cc of sterile water, many physicians
reconstitute with 4 mL of sterile water and 1 mL of 2% lidocaine with
epinephrine. The lidocaine decreases pain while the epinephrine
reduces bruising.
Strong agitation of the filed syringes is recommended directly before
injection to homogenize the white suspension. (Sculptra tends to
settle in the bottom of the syringe.) By means of tunneling and
threading techniques, a 25- or 26-gauge needle is utilized to implant
Sculptra into overlapping deep dermal and subcutaneous layers of the
skin.
The mechanism of action and proper technique of injecting Sculptra
require practitioners to restore volume to a selected treatment plane
rather than a specific wrinkle. Indeed, injecting Sculptra is more
similar to fat injection procedures than collagen or HA injections,
because it serves to sculpt the prominent hollows and deep grooves
associated with loss of deep soft tissue. In addition, specialized
training to use Sculptra is required prior to injections.
Small and exact aliquots of Sculptra are injected in the correct tissue
plane without overcorrection. In general, 2 to 3 cc of the product are
used for patients in their thirties, 4 cc for patients in their forties, and
5 cc or more for older patients. The cost is approximately $230 per
syringe. Once Sculptra is injected, there is a transient period lasting
about 1 hour during which the patient can see a slight effect because
of the volume of fluid injected. Once this resolves, results are not seen
until about 4 weeks after treatment when results may begin to
appear. Injections are performed on a monthly basis until desired
results have been obtained.
The number of injection sessions required varies greatly from person
to person and it is difficult to predict the total number of sessions
needed. Injections are performed 3 to 6 weeks apart. Anecdotal
reports state that premenopausal women and postmenopausal women
on hormone replacement therapy (HRT) require fewer sessions than
postmenopausal women not on HRT. Postmenopausal women not on
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HRT may require up to eight sessions.
Men tend to correct more quickly than women for unknown reasons.
After the procedure, the patient’s skin is strenuously massaged with
topical arnica (for its anticoagulant properties) for about 5 minutes to
reduce bruising, pain, and nodule formation.
Patients should be told to massage the treated area for 5 minutes
every night for five nights. Sculptra treatments can be combined with
other fillers for instant gratification. In this case, Sculptra is injected
first, the massage with arnica is performed, and then the HA or
collagen filler is applied in the treatment area. Sculptra is often used
in the cheeks and cheekbone area while an HA filler is used in the
nasolabial folds, marionette lines, and the lips. Alternatively, a course
of three to four Sculptra treatments is used and then an HA filler is
used after Sculptra at the last visit. Sculptra should always be used
first, then massaged, before the HA is injected so that the lidocaine
and epinephrine in the Sculptra will reduce the pain and bruising of
the HA injection, and the massaging will not affect the placement of
the HA filler. Sculptra does not require prior skin testing. It is ideal for
treating volume loss in the cheeks, nasolabial folds, and the malar
area.
Once the desired result is achieved, results last about 18 to 24
months. The correction is very natural looking. Having been used
successfully in various medical devices for more than 30 years, PLLA
has an established safety record. Moreover, new product guidelines
and injection techniques (i.e., using a more dilute product, avoiding
overcorrection, not injecting too superficially, and postinjection
massage) have reduced the incidence of side effects (i.e., formation of
granulomas and nodules) as compared to when the product was
originally packaged as NewFill.
Sculptra injection results are not immediate and multiple courses are
required to achieve the optimal cosmetic effect, with the number of
treatments depending on volume of the defect being treated.
Preinjection reconstitution can contribute to scheduling limitations
because it must be made at least 2 hours in advance. Injecting
suspension can be slightly difficult because of recurrent clogging of the
needles, which leads to frequent needle changes. Adverse events are
rare, but PLLA can cause postinjection site pain, bruising, and
swelling, as compared to other products, partly because of the larger
needle used. Adding lidocaine to the diluent mitigates injection pain.
Ecchymoses can be reduced by mixing epinephrine into the PLLA
suspension and taking bromelain supplements (500 mg twice daily)
after injection.
Hyperkinetic areas (i.e., crow’s feet and the corner of the mouth) and
regions with thin skin (i.e., around the eyes, smoker’s lines above the
lips) should not be treated with Sculptra because of irregular papules
that can emerge. Most lumps that do arise are from superficial
administration of Sculptra and are not visible, although they are
palpable by the patient. Reassuring patients that these lumps are
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transient in nature is important. Nodule and hematoma formation are
the other rare adverse effects that have been reported, but are less
likely if the new injection guidelines are followed. Sculptra injection
technique is very different than that of HA fillers and the learning
curve is higher. In addition, there is lack of reversibility as with HA
fillers. Specialized training is required by the manufacturers of
Sculptra before they will sell the product to a physician.
Permanent Fillers
Although the current momentum in the cosmetic market is toward the less
invasive procedures, which are safer, permanent fillers are very popular
outside the U.S. because of the lower cost. Many of these products are used
by unskilled practitioners and lead to disfiguring results. If practitioners are
to use a permanent filler, they should be skilled in the technique and certain
of the patient’s expectations. In the primary author’s opinion, it is best to
use a temporary filler first, to make sure that a patient is pleased, before
proceeding to a permanent or semi-permanent option.
Newer fillers (i.e., Artefill) as well as older fillers (i.e., silicone) are being
used for this purpose. These nonbiodegradable fillers stay enclosed by the
skin for an indeterminate and lasting period of time. However, these fillers
are not to be used for and by the lighthearted. They are associated with
rare, significant side effects such as granulomas, migration, and asymmetry
and are best implanted into a patient experienced with prior soft tissue
augmentations and by a proficient provider.
Remember, as with anything enduring, if one is not pleased with the results,
one has to live with long-term consequences. The following table outlines
the list of fillers.176,192,208,209,216,218-221
Artefill
In October 2006, the FDA approved the novel permanent filler Artefill
(Artes Medical, Inc., San Diego, CA) for the correction of nasolabial
folds. Artefill is constituted with 20% homogenous
polymethylmethacrylate (PMMA) suspended in equilibrium with partly
denatured 3.5% bovine collagen (from enclosed US cattle herds) and
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0.3% lidocaine.
As opposed to the original European product, Artecoll, which contained
different size microspheres of PMMA that potentially contributed to a
higher risk of granulomas, Artefill is composed of uniform size PMMA
microspheres (30–50 m) that are less likely to result in the formation
of granulomas.
Small size, uniformity, and smoothness are refined characteristics of
Artefill that promote biocompatibility and resistance tphagocytic
degradation and migration as well as ensure encapsulation by patients’
collagen leading to lasting nonimmunogenic results.
Artefill is packaged in a kit of three 0.8-mL and two 0.4-mL syringes
that are injected through a 26-gauge needle into subdermal and
subcutaneous space via a tunneling technique without overcorrection.
After injection, gentle massage is recommended to evenly distribute
material in the skin and prevent clumping. Artefill must be stored via
refrigeration (2 C–10 C) and warmed before use. In order to achieve
optimal correction of rhytides, two to three treatment sessions, a few
months apart, are suggested.
Like Sculptra, specific injection training for Artefill is required. Artefill
offers the dual action of immediate wrinkle correction from collagen
(lasting about 1–3 months) and permanent deep-fold ablation from
PMMA (lasting for more than 5 years).
The long-term efficacy is believed to be because of the stimulatory
influence of PMMA on the surrounding skin, causing fibroblast and
collagen proliferation around the material starting at 1 month.
Although approved only for nasolabial folds, PMMA has also been
successfully used in other deeper defects (e.g., the cheek and malar
regions). Lidocaine content eliminates the necessity for alternative
anesthesia and alleviates intrainjection discomfort. As compared to the
standard of bovine collagen, PMMA filler has been found to be superior
in efficacy with a comparable safety profile. Widely used in implantable
medical devices for more than 50 years, PMMA has a long safety
record.
Artefill contains bovine collagen; therefore, skin testing prior to
injections is strongly advised to reduce the incidence of
hypersensitivity. This means that patients cannot be treated on the
initial office visit. Furthermore, because of Artefill’s higher viscosity,
more administration pressure is required by the clinician, and the
product is more difficult to inject than collagen and HA fillers.
Although the majority of side effects caused by Artefill are mild and
transient (i.e., swelling, redness, hyper sensitivity, and temporary
lumpiness, which is amenable to massage), rare moderate-to-severe
effects have been reported (i.e., granuloma and inflamed nodule
formation, manageable with intralesional steroids or excision). Because
of the reported lumpiness with this product, it is currently discouraged
for lip augmentation or any superficial wrinkle correction.
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Having to inject through a larger bore needle may induce more
posttreatment edema and ecchymoses, which require slightly longer
downtime. The disadvantage of implanting permanent fillers such as
Artefill is the inability to foretell the long-term appearance of the
patient; since the skin changes with age, the natural look may be
altered. Time will tell the exact risk-to-benefit ratio of this filler.
Silicone
Silicone is composed of dimethylsiloxane chains linked by oxygen with
varied viscosity based on the length of the polymer. Used in patients
since the 1940s, the liquid form of this product is one of the oldest soft
tissue augmentation materials.
The use of this injectable filler is fraught with controversy because the
initial unpurified product was associated with long-term disfiguring side
effects, including migration and granuloma formation. It was illegal to
perform silicone injections in the U.S. in some states until recently.
However, because of the purification of liquid silicone and honing of the
injection technique, this soft tissue filler has returned and is very
popular in Brazil.
At the turn of the 21st century, the FDA approved two forms of
medical-grade silicone oils: ADATO (or Silol 5000, Bausch & Lomb
Surgical, Inc., San Dimas, CA) with 5000 centistoke (cs) viscosity and
Silikon 1000 (Alcon Laboratories, Inc., Fort Worth, TX) with 1000 cs
viscosity. These are both indicated for the ophthalmologic uses of
retinal temponade and detachment. Although neither of these products
have been approved by the FDA as skin injectables, they are used offlabel. Furthermore, there are ongoing studies in the U.S. assessing the
safety and efficacy of SilSkin (a 1000 cs, highly purified
polydimethylsiloxane, OFAS Therapeutic Silicone Technologies, Inc.,
New York, NY) for the correction of nasolabial folds and HIV-associated
lipoatrophy. Pilot studies in patients with HIV-lipoatrophy have
revealed satisfactory results with minimal side effects.
Similar to PMMA and PLLA, silicone oil biostimulates the surrounding
skin to slowly generate a focal fibro-granulomatous reaction that leads
to a permanent volumizing. Zappi et al., analyzed the microscopic
biologic behavior of liquid silicone and concluded that it was an
effective, durable (up to 23 years), and immunologically compatible
filler Silikon 1000 is the preferred injectable filler over ADATO because
of its lower viscosity and therefore easier injectability. It is stored at
room temperature and packaged as clear oil. The proficiency in the
injection technique is the crucial variable in achieving successful soft
tissue augmentation with silicone. The favored technique is a serial
puncture of micro droplets and subdermal implantation of 0.01 to 0.02
mL silicone aliquots at 2- to 4-mm intervals using a glass syringe with
a 30-mL needle.3 2, 5 2 The key is not to overcorrect. Instead,
patients should anticipate steady changes with multiple treatment
sessions, 1 to 2 months apart, in order to achieve the most natural and
safe outcome in several months. Since it is immunologically inert, no
prior skin testing is required.
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Practitioners with experience in using Silikon have reported its value in
correcting wrinkles and scars, augmenting lips, and panfacial
contouring of deeper folds and valleys. Its low cost and longevity are
obvious benefits. As with any temporary filler, potential long-term
consequences should be broached when discussing this treatment
option with patients.
Most side effects associated with medical-grade silicone injectables are
minimal and include anticipated temporary pain, edema, bruising, and
redness. The pain is likely because of the absence of anesthetic as part
of the product formulation, so appropriate pre-procedure anesthesia
should be provided. However, it is important to keep in mind that rare
reports of appropriately injected, purified silicone causing significant
nodules, granulomas, cellulitis, and ulceration also exist.
The skill of the physician is crucial as this is a permanent filler. The
primary author has seen myriad unhappy patients who have lumps and
asymmetry after treatment by other physicians. In addition, many
patients who are treated by nonphysicians are treated with impure
silicone. This results in disfiguring edema and long-term complications.
In some clinics, an attempt is made to treat complications of silicone
injections by non-physicians with injectable steroids, tacrolimus,
cyclosporine, and Aldara with minimal and short-term improvement.
Surgical excision has remained the only effective long-term treatment.
Polytetrafluor
oethylene
Approved by the FDA in the 1990s for the purpose of soft tissue
augmentation, several forms of expanded polytetrafluoroethylene
(PTFE) are currently on the market: Gore-Tex strings or strands (Gore
Advanced Technologies Worldwide, Newark, DE); Soft-Form and
UltraSoft tubes (Tissue Technologies, Inc., San Francisco, CA); and
newer dual porous, soft, varied-shape Advanta (Atrium Medical
Corporation, Hudson, NH).
PTFE is a synthetic material used in medical devices since the 1970s
with a good safety record. These are spongy products that provide
significant volume enhancement and stimulate local tissue fibrosis and
integration, which relays permanence and stability. PTFE is
biocompatible with rare instances of inflammatory reactions. The
extended PTFE subdermal implants require a more invasive procedure
via surgical implantation, which translates to higher procedural risks
and the necessity for a more specialized setting and training. Because
of these complex features and generally lower physician satisfaction,
the use of these devices by cosmetic dermatologists is not popular.
Benefits PTFE fillers have been shown to impart an enduring correction
of the nasolabial folds, marionette lines, malar and mandibular deficits,
and enhancement of the lips.
Additionally, these products do not require prior testing because of
immunologic inertness. Although the implants are considered
permanent, if patients are dissatisfied with their image alterations, the
products can be removed in bulk within 3 months. The side effects of
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bleeding, bruising, redness, postoperative pain, scarring, palpability,
and secondary infection occur more frequently with PTFE fillers as
compared to HA fillers and the recovery time is longer. These products
have high displacement and extrusion rates and an unnaturally stiff
appearance. In addition, they can shrink with time leading to an
asymmetric correction.
Advancements in Fillers
As noninvasive cosmetic interventions have become more prominent, the
manufacturing market has responded by developing newer products. In fact,
there are so many products to consider, it has become ever more
challenging for regulatory organizations, physicians, and patients to discern
their differences. While some clinicians opt to jump on the bandwagon and
use novel filling agents by interpreting newer as better, others await
satisfactory clinical evidence before integrating these fillers into their
practices. It is crucial to appreciate the fact that the products once
proclaimed innovative have either stood the test of time, with manufacturers
reaping the rewards, or they have been superseded. The following table
provides an overview of the up and coming soft tissue augmentation
devices.176,187,202,218,222,223
Evolence
Evolence (Colbar LifeScience Ltd., Herzliya, Israel) is cross-linked
porcine-derived collagen (30 mg/mL concentration). Because of the
greater biologic similarity between pig and human skin versus bovine
and human skin, this filler has potentially lower immunogenicity than
bovine collagen fillers, with no pre-procedure sensitivity testing required.
It is currently only approved in Europe and Israel as two products,
Evolence and Evolence Breeze (finer version), for soft tissue
augmentation.
Evolence is injected through a 25- to 27-gauge 1.25- to 1.5-inch needle
into mid-depth dermal space using tunneling and cross-hatching
techniques, while Evolence Breeze is injected in 0.1-mL aliquots via a 31gauge needle using a serial puncture technique into the superficial
dermis; overcorrection is to be avoided. Postimplantation massage is
advised to enhance molding. Without prior allergy testing needed, these
products can be injected on the first visit. Special cross-linking
technology, Glymatrix, yields a more stable collagen product that creates
immediate effects potentially lasting for up to 1 year. Evolence products
may be used in combination with other agents such as HA fillers. This
collagen filler is stored at room temperature.
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A recent study comparing the safety and efficacy of Evolence and
Restylane showed that Evolence performed similarly to Restylane.
Evolence does not contain lidocaine as other collagen fillers do. It is more
difficult to inject than Restylane and Juvéderm. Needle jamming has
been noted on occasion, which makes injections a bit awkward.
Religious beliefs have to be considered prior to implantation because this
product contains porcine collagen, which may be rejected on religious
grounds by Jewish and Muslim patients. The FDA had not yet approved
this product at the time of publication, but approval is expected shortly.
Although postprocedure side effects of porcine collagen fillers are
comparable to HA fillers (i.e., transient edema, erythema, pain,
ecchymoses), the development of infrequent lumps and nodules that last
several months has also been noted. These papules can be treated with
massage and intralesional corticosteroids. Because of these side effects,
injecting Evolence into thin skin areas should be avoided.
This filler is new and does not have the years of experience associated
with other collagen and HA fillers. Its use should be approached with
caution.
Isolagen
Although presently approved in the UK, Isolagen (Isolagen Inc., Exton,
PA) is undergoing clinical studies in the US to obtain FDA approval.
Utilizing the patient’s skin, fibroblasts are cultured and stimulated to
generate injectable material for aesthetic augmentation. The appeal of
Isolagen is that it uses a minimally invasive harvesting technique,
employing very little tissue (a 3-mm skin punch biopsy from a noncosmetic area), to produce an individual, immunologically inert supply of
volume-enhancing product. About 2 months after harvesting, a 1 to 2 cm
3 amount of product is created and injected at about 2-week intervals in
several sessions to provide longer-lasting results.
This product may contain fibroblasts that could confer long-term benefits
not found with other fillers. The crucial benefits of Isolagen are
biocompatibility and safety. This product contains the donor’s own
fibroblasts, which may provide ameliorative effects by increasing the
production of desired cytokines and growth factors, stimulating collagen
and elastin production. Correction is believed, but not proven, to last
about 6 to 12 months. As other collagen fillers, it is injected at superficial
and moderate dermal depth to treat rhytides and nasolabial folds as well
as the lips. This product is particularly expensive because of the specific
engineering technique of cultured autologous fibroblasts and collagen.
There is a waiting period of 2 months and the product derived from the
biopsy is relatively sparse. However, this product can be used in
conjunction with other fillers to make up the volume difference. Special
product shipping, handling and storage, as well as a narrow time-frame
of implantation (within 24 h of Isolagen delivery) are limitations. The
side effects of the product have not been clarified, but are likely similar
to other fillers on the market.
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Laresse
Laresse is a novel dermal filler composed of two polymers in solution,
carboxymethyl cellulose (CMC) and polyethylene oxide (PEO), both of
which are hydrophilic. The product is a viscoelastic gel that is injected
into the dermis as a space-filling substance. Although the clinical data
are limited, it has been available in the UK since mid- 2006 and has
become a competitor to cross-linked HA products.
Since Laresse is not cross-linked, it is smoother to inject than HA fillers
and imparts a soft contour to the dermis. Skin testing is not required
with this product. The components have been used in numerous
injectable therapeutics and medical devices and are known to be
immunologically inert. Laresse is easily injected and is reported to
produce less pain on injection than other fillers.
The product is particularly smooth and natural feeling in the skin and it
has been used in nasolabial folds and other superficial wrinkles. Because
of its ability to stabilize and compact in higher concentrations without a
need for cross-linking, it is hypothesized that Laresse will have longer
durability than HA fillers.
However, no studies have been published in the US to support these
claims. Although studies have shown that Laresse lasts 6 months in
some patients, limited clinical studies have been performed so its
duration will become evident as it becomes available in the marketplace.
The extent of its potential applications in facial augmentation is unclear
as the product has been used clinically only since 2007 and its use in the
hands of practitioners is still being evaluated. Laresse does not contain
lidocaine and, therefore, preprocedure anesthesia is usually topical or a
nerve block, similar to HA fillers. Side effects are analogous to the HA
fillers and consist mainly of transient swelling, bruising, and redness.
Other adverse events are yet to be revealed as the FDA is investigating
Laresse.
Aquamid
A novel permanent filler, Aquamid (Ferrosan A/S-Contura International
SA, Cophenhagen, Denmark) has been approved and used in Europe,
South America, and the Middle East for the past few years. Aquamid is
composed of 97.5% pyrogenic water linked to 2.5% cross-linked
polyacrylamide polymer. When it is introduced into skin tissue,
acrylamide stimulates fibrotic and localized foreign-body reactions.
The gel is packaged in a 1-mL syringe and stored at room temperature.
It is injected through a 27-gauge needle using a threading technique
without overcorrection. The material is inert, obviating prior sensitivity
testing. Aquamid is biocompatible and nonabsorbable, which yields an
inert and durable device that can last indefinitely. Aquamid has shown
efficacy in lip augmentation, correction of nasolabial folds, depressed
mouth commissures, as well as glabellar and perioral rhytides.
Lacking lidocaine content, Aquamid requires local or regional anesthesia
prior to the procedure. Although postimplantation side effects are similar
to those of HA fillers (e.g., temporary erythema, edema, redness), rare
long-term and more severe adverse effects are more prominent with
Aquamid. The primary author has seen several patients treated in South
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America with prolonged swelling and edema. The exact duration of
Aquamid in the skin is still unclear, with most recent studies
demonstrating about 2-year durability. Rare hematomas, lumps,
granulomas, and indurations do occur with the use of Aquamid. Use of
this filler should be discouraged until more safety data are gathered.
Determining Which Filler to Use
There are many filler options available, so deciding on which filler to use is
difficult. The A, B, C, D approach can help. “A” stands for assess the patient.
Determine which areas can be treated with the greatest potential for
improvement. Look at the entire face and decide where to get the “best
bang for the buck.” For example, if the patient has prominent nasolabial
folds, there are two main options: treating the nasolabial folds, or treating
the cheek or cheekbone area to add volume that will improve the fold by
pulling the skin back. A patient with large round cheeks would do better to
have the nasolabial fold treated, while a patient with thin cheeks and facial
volume loss would have a better result if the cheeks were treated. As a
practitioner, it is important to form your own impression first before the
patient tells you their thoughts. In some cases you may notice factors that
the patient does not even realize are contributing to an aged appearance.
These observational skills are developed with experience.194
Once you have an idea of what areas would make the most significant
impact if treated, then move to the “B” section, which is budget. It is crucial
to determine how much money the patient is willing to spend. It is often the
case that the budget is lower than what is necessary, so the physician must
determine what areas to treat to achieve the best cosmetic effect possible
within the patient’s budget. In addition, the practitioner must consider the
patient’s time budget or schedule. For example, if a patient is visiting from
another country and planning to leave the following day, a course of
Sculptra injections is not an option.194,202
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Once the time and financial budget have been determined, the practitioner
should talk to the patient about other considerations. The most important
question is what bothers them about their face. It is often different than
what the physician sees. Patient happiness is contingent on improving what
they see as the problems on their face, not what bothers the medical
provider. The following or similar questions may be appropriate to frame
such a discussion, then, in the attempt to identify the most suitable filler for
a patient: What have you tried before? Were you satisfied with the results?
Why or why not? What concerns do you have? Are you a frequent bruiser?
Are you worried that your lips will look too big? Do you hate it when your
lipstick bleeds up into the lines on the top lip? Do you have any religious
restrictions? Do you have any events coming up? What amount of downtime
can you tolerate? These are all critical issues in determining the most
appropriate filler. Once all this information has been gathered, the physician
must choose a filling device that meets all the criteria. It is a relatively easy
choice after the preceding questions have been answered. In addition, the
physician should have many filler choices on hand to give the patient the
best result.178,222,224
Injection Technique
Injection technique varies from filler to filler. Most physicians use either an
anterograde, retrograde, or serial puncture technique. Most collagen and HA
fillers are injected at a 45-degree angle. It is important to be individually
trained on the injection techniques of each filler. Fillers can be used in
combination with botulinum toxins and other cosmetic procedures. Fillers
can also be injected in other areas of the body such as the hands. Many
injection techniques can be used. However, it is difficult to teach various
techniques without video and live demonstrations.181
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Sclerotherapy
Sclerotherapy is successfully used to treat both functional and cosmetic vein
disorders. When it performs as expected, the sclerosant significantly
damages the endothelial lining of the vessel wall being treated and results in
inflammation, fibrosis, and in the eventual obliteration of the vessel.
Hyperosmotic agents, such as hypertonic saline, produce endothelial damage
through dehydration. Detergents, such as sodium tetradecyl sulfate, sodium
morrhuate, ethanolamine oleate, and polidocanol, cause vascular injury by
altering the surface tension around endothelial cells, diminishing their ability
to adhere to one another.225
Foamed sclerosants (either sodium tetradecyl sulfate or polidocanol mixed
with air) are mainly used to treat functional vein disorders, such as chronic
venous insufficiency and venous ulceration under duplex-guided ultrasound.
This approach has been very successful for the medical sclerotherapy
patient. The most common sclerosing agent used in dermatology is
hypertonic saline, although it is approved as an abortifacient rather than a
sclerotherapy agent.226
It is important to know the risk profiles of commonly used sclerosants.
Hypertonic saline is associated with burning and cramping upon injection
and an increased risk of ulcerative necrosis secondary to extravasation.
Sodium tetradecyl sulfate has also been associated with hyperpigmentation,
pain upon extravasation, and skin necrosis. Rarely, sodium tetradecyl sulfate
and, even more rarely, polidocanol have been associated with allergic
hypersensitivity reactions. The optimal concentration of sclerosant may vary
with the diameter of the vessel being treated, with a greater concentration
of sclerosant being required for vessels of larger diameter. If the sclerosant
is too weak, insufficient damage to the endothelium results and a thrombus
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may form that eventually recanalizes. If the sclerosant is too strong, then
ulceration and hyperpigmentation can occur because of extravasation of the
sclerosant.227
Shelf Life Of Pharmacological Agents
The longevity of a pharmacologic agent
is governed by its shelf life. Shelf life of a
drug is the duration from the time the
product is manufactured till the potency
of the drug has been reduced by 10%.
This limit is usually considered
acceptable in practice; more stringent
standard is required if the degradation
products are more toxic or irritative than
the parent drugs.2
The shelf life of pharmacological agents will vary depending on a number of
factors. Each preparation will include detailed information regarding the
expected shelf life, with recommendations for storage and proper use.
Products with a shelf life of more than 3 years are considered to be 'stable'
as these are expected to sold and used within his period. Products with a
shorter half-life should be labeled with expiration date.1
As a guide to good pharmaceutical practice it is suggested that mixtures
recommended to be 'freshly prepared' should be prepared not more than 24
hours before issue to the patient. Mixtures recommended to be 'recently
prepared' should be stored in unopened bottles in the dispensary for not
more than 3 months. Should there be any doubt, the pharmacist should be
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consulted.4 There are a number of environmental factors that can affect the
shelf life of a drug. These are briefly outlined below.5

pH: the pH affects rate of chemical reaction and hence longevity of a
drug.

Temperature: An increase in temperature usually increases the rate of
chemical reaction. Storage of a medicine in a cool place (below 15 C)
will prolong the shelf life. Refrigeration may prolong shelf life of a
medicament that is unstable in room temperature but solid particles
may grow and precipitate in a suspension. The temperatures suitable
for storage of topical drugs lie in the range of 15-25 C.

Oxygen: Many drugs show slow oxidation in the presence of
atmospheric oxygen. If the rate of degradation is significant, the
addition of an antioxidant may be needed.

Light: Can induce photochemical degradation. This can be reduced by
the use of light-resistant containers or, more effectively, by storage in
the dark.

Humidity: Low humidity may be responsible for the powdering of
granular solids containing effervescent salts and for the 'drying out' of
creams. High humidity brings about the deterioration of effervescent
tablets and solid preparations that contain hygroscopic materials. The
adverse effects of humidity can be avoided by the use of moistureproof containers.

Pharmaceutical containers:
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o The basic requirement for a container is that it should not
interact with the formulation. Glass, plastics are commonly used
components of containers. Glass containers have some
disadvantages, i.e., leaching of alkali and insoluble flakes into
the formulation; these can be offset by the choice of an
appropriate glass material.
Plastic containers are convenient to handle but the major
disadvantage is the two-way permeation or 'breathing' through
the container walls. Volatile oils, perfumes and flavoring agents
can permeate through plastics to some extent. Components of
emulsions and creams have been reported to migrate through
the walls of some plastics causing either a deleterious change in
the formulation or collapse of the container. Loss of moisture
from a formulation is also common.
o Closure must form an effective seal for the container. It must
not react chemically or physically with the formulation. Rubber is
a common component of stoppers, cap liners, and parts of
dropper assemblies. Absorption of the active ingredients,
preservatives into the rubber and the extraction of one or more
components of rubber into the formulation is a common
problem.
o The application of an epoxy lining to the rubber closure reduces
the amount of leached extractives but has no effect on the
absorption of the preservative from the solution. Teflon-coated
rubber stoppers may prevent most of the leaching and
absorption.
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Summary
In the course of a day, dermatologists see a wide variety of patients with
concerns ranging from serious medical conditions like cancer to cosmetic
issues that impact the patient's physical and emotional health. As with most
other specialties, pharmacological agents can be a useful resource for
treating dermatological concerns involving the hair, nails, and skin. There
are a wide variety of pharmacological agents that can be utilized in treating
dermatological issues, and they are typically delivered either topically or
percutaneously. As with any medical treatment, the purpose of these
pharmacological agents is to provide relief for the patient's issue with a
minimal amount of pain and other side effects.
The mechanisms of potential toxicity of skin products and the depth of injury
are important for health providers to understand and to educate patients
about during their course of care. Dermatology drug treatments may also
require follow up by the health provider since irritation and damage can
appear even after a drug has been discontinued.
Initial consultation, discussion of the treatment options, and, importantly,
the patient’s history helps to determine the best dermatology treatment and
prevention of potential contraindications to treatment. Evolving marketplace
influences and an overlap of dermatology specialties influence patient care
outcomes. The practice of dermatology is continuously evolving with many
new products and therapies that pose both health benefits and risks for
which health professionals must be continuously informed.
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Please take time to help NurseCe4Less.com course planners evaluate
the nursing knowledge needs met by completing the self-assessment
of Knowledge Questions after reading the article, and providing
feedback in the online course evaluation.
Completing the study questions is optional and is NOT a course
requirement.
1. _____________ is defined as the decrease in drug response due to the
use of a drug over a prolonged period of time.
a) Tapering down
b) Rebound effect
c) Tachyphylaxis
d) Topical nonadherence
2. There are two fields in dermatology:
a) medical and cosmetic dermatology.
b) surgical and cosmetic dermatology.
c) dermatology and general medicine.
d) dermatology and surgery.
3. ____________ are at an increased risk of absorbing topical
corticosteroids.
a) Infants
b) Individuals who are underweight
c) Women
d) The elderly
4. True/False: Cosmetic dermatologists are required to fulfill residency
requirements before they may offer cosmetic procedures.
a) True
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b) False
5. Which of the following is a topical dermatologic treatment:
a) Oil
b) Liquids
c) Anti-infective agents
d) Powders
6. 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) astringents
7. Vehicle selection for topical dermatologic treatment is guided by
a) location of application
b) cosmetic effects
c) convenience
d) all of the above
8. Most powders contain zinc oxide for its
a) lubricating and drying properties
b) improved adherence to the skin
c) composition of magnesium silicate
d) antiseptic and covering properties
9. A poultice, also referred to as a ______________, is a wet solid mass of
particles, sometimes heated, that is applied to diseased skin.
a) talc
b) cataplasm
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c) calamine
d) magnesium silicate
10. In pharmaceutical terms, oil-in-water emulsion bases are
a) creams.
b) poultices.
c) specifically used for conditions on the palms and soles. p. 4
d) composed of magnesium silicate.
11. True/False: Under normal conditions, up to 99% of the applied topical
corticosteroid is cleared from the skin, and only 1% is therapeutically active.
a) True
b) False
12. The most important element in topical therapy is
a) the retinoid preparation.
b) the patient’s age.
c) educating the patient about skin irritation.
d) the patient’s gender.
13. Which of the following is/are not a stabilizer (nontherapeutic ingredient):
a) preservatives
b) antioxidants
c) chelating agents
d) corticosteroids
14. _________________ is the principal solvent for cleansing.
a) Soap
b) Water
c) Isotonic saline
d) Aluminum chloride
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15. True/False: When applying a topical treatment, the patient should avoid
vigorous rubbing or massaging of the drug into the skin.
a) True
b) False
16. Irritant contact dermatitis, caused by a topical drug may be reduced by
a) lessening the drugs penetration properties.
b) using a less concentrated preparation over a greater period of time.
c) cessation of the drug’s use.
d) None of the above.
17. True/False: In some instances, though, skin irritancy might be central
to drug efficacy.
a) True
b) False
18. Topical steroids cause capillaries in the superficial dermis to
a) constrict, thus reducing erythema.
b) expand, thus increasing erythema.
c) enlarge the thickness of the stratum corneum.
d) expand vascular supply to the area.
19. ______________ are triphasic liquids composed of oil, organic solvents
and water.
a) Shake lotions
b) Foams
c) Suspensions (lotions)
d) Aqueous solutions
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20. Topical corticosteroids are recommended for
a) their anti-inflammatory activity in inflammatory skin diseases.
b) their antimitotic effects.
c) their capacity to decrease the synthesis of connective tissue
molecules.
d) All of the above.
21. True/False: Results from large-scale surveys show that patients or
caregivers overestimate the actual risks of topical corticosteroids leading to
treatment noncompliance.
a) True
b) False
22. Liniments have many uses but they do not include:
a) use as a counterirritant.
b) use as an antipruritics.
c) use as a drying agent.
d) use as an analgesics.
23. The current evidence shows that
a) pregnant women should not use topical corticosteroids.
b) topical glucocorticoids are excreted in breast milk.
c) topical glucocorticoids should be used with caution in breastfeeding
mothers.
d) topical glucocorticoids may be used on the breasts before
breastfeeding.
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24. True/False: With respect to dosage regimes in the application of potent
or moderately potent corticosteroids, there is a significant difference with
once versus twice daily dosages.
a) True
b) False
25. Which of the following side effects may result from the use of topical
corticosteroids:
a) steroid rosacea
b) acne
c) perioral dermatitis
d) All of the above
26. An oil-in-water emulsion
a) contains greater than 31% water.
b) contains less than 25% water.
c) is the one most commonly chosen to deliver a dermatologic drug.
d) a) and c)
27. ______________ formulations require no preservative additives.
a) Oil-in-water emulsion
b) Water-soluble bases
c) Paraben
d) Gel
28. True/False: There is no difference between “oil-in-water” and “water-inoil” emulsions; these names are interchangeable and describe the same
thing.
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a) True
b) False
29. _______________ are nonstaining, greaseless, and easily washes off of
the skin.
a) Water-soluble bases
b) Water-in-oil emulsions
c) Hydrophilic (polar) compounds
d) Pastes
30. ______________ are simply the incorporation of high concentrations of
powders (up to 50%) into an ointment.
a) Nonaqueous gels
b) Solubilized therapeutics
c) Pastes
d) Cellulose derivatives
31. Gels are suitable for facial or hairy areas because
a) after application little residue is left behind.
b) they have protective or emollient properties.
c) they may be combined with high concentrations of propylene glycol.
d) they do not require preservatives.
32. Newer gel formulations may contain the viscoelastic _______________,
which can mitigate dermal irritation.
a) propylene glycol
b) glycerin
c) preservatives
d) polysaccharide hyaluronic acid
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33. A hydroalcoholic solution with a concentration of alcohol of
approximately 50% is called a ____________.
a) Burow solution
b) collodion
c) tincture
d) liniment
34. Emollients containing urea or lactic acid are an example of a
a) suspension that is preferred for its uniform application.
b) suspension that requires shaking of the lotion before application.
c) Burow solution.
d) None of the above.
35. True/False: Flexible collodions have added castor oil and camphor and
are used, for example, to deliver 10% salicylic acid as a keratolytic agent.
a) True
b) False
36. Shake lotions are lotions to which
a) a powder is added to hydrate and warm dry skin.
b) triphasic liquids are added for their hydrating effect.
c) organic solvents are added for their hydrating effect.
d) a powder is added to increase the surface area of evaporation.
37. The following is/are true about the penetration of topical steroids:
a) side effects are less likely where the skin is thin.
b) increased penetration of the drug occurs where the skin is thin.
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c) penetration of topical steroids through the palms is 36 times greater
than for the soles.
d) All of the above.
38. Elderly patients may have thin skin, which
a) allows for decreased penetration of topical glucocorticoids.
b) means they are less likely to have preexisting skin atrophy.
c) allows for increased penetration of topical glucocorticoids.
d) means that topical glucocorticoids should not be used.
39. Previous studies have demonstrated that foam vehicles, when compared
to other vehicles,
a) deliver active drug at a decreased rate.
b) act as an added barrier for the stratum corneum.
c) are not effective for drug delivery through the intercellular route.
d) are highly effective in delivering greater amount of active drug.
40. True/False: Foams have been associated with adverse side effects,
especially for localized conditions affecting the scalp.
a) True
b) False
41. Topical aerosols may be used to deliver drugs formulated as
a) solutions.
b) powders.
c) semisolids.
d) All of the above.
42. When applied to abraded or eczematized skin, which of the following
delivery forms is least irritating when applied?
a) aerosols
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b) liniments
c) pastes
d) ointments
43. One of the drawbacks to aerosols is
a) low patient satisfaction.
b) excessive waste when dispensed.
c) the cost.
d) poor application, especially to hair-bearing areas.
44. True/False: Corticosteroids are thought to exert their potent antiinflammatory effects by inhibiting the release of phospholipase A2.
a) True
b) False
45. Increasing hydration of the stratum corneum can enhance absorption of
topical corticosteroids by
a) 98%.
b) four to five times.
c) ten times.
d) 50%.
46. A serious consequence of ceasing topical steroid therapy after an
extended treatment period can result in
a) an Addisonian crisis.
b) a placebo affect.
c) hemangiomas.
d) dry skin.
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47. Hemangiomas of infancy show a good or partial response to treatment
with
a) sulfacetamide.
b) topical glucocorticoids.
c) metronidazole.
d) nitroimidazole.
48. Sulfacetamide is a topical sulfonamide used in the treatment of
a) psoriasis
b) eczema
c) hemangiomas.
d) rosacea and acne.
49. Which of the following is true of topical 5% dapsone gel?
a) It is not approved by the FDA for the treatment of acne.
b) If benzoyl peroxide is applied after it, a temporary orange/yellow
discoloration of skin and facial hair may occur.
c) It awaits FDA approval once the mechanism of action is understood.
d) It is used to treat skin disorders but not acne vulgaris.
50. Mechanisms for the anti-inflammatory effects of corticosteroids include:
a) blocking the release of arachidonic acid.
b) increasing the release of arachidonic acid from phospholipids.
c) Corticosteroids also decrease the release of interleukin-1α.
d) Encouraging the release of inflammatory cytokine, from keratinocytes.
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Correct Answers:
1. _____________ is defined as the decrease in drug response due to the
use of a drug over a prolonged period of time.
Correct Answer: Tachyphylaxis
2. There are two fields in dermatology:
Correct Answer: medical and cosmetic dermatology
3. ____________ are at an increased risk of absorbing topical
corticosteroids.
Correct Answer: Infants
4. True/False: Cosmetic dermatologists are required to fulfill residency
requirements before they may offer cosmetic procedures.
Correct Answer: False
5. Which of the following is a topical dermatologic treatment:
Correct Answer: Anti-infective agents
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6. The term ___________ refers to the inactive part of a topical preparation
that brings a drug into contact with the skin.
Correct Answer: vehicle
7. Vehicle selection for topical dermatologic treatment is guided by
Correct Answer: all of the above
8. Most powders contain zinc oxide for its
Correct Answer: antiseptic and covering properties
9. A poultice, also referred to as a ______________, is a wet solid mass of
particles, sometimes heated, that is applied to diseased skin.
Correct Answer: cataplasm
10. In pharmaceutical terms, oil-in-water emulsion bases are
Correct Answer: specifically used for conditions on the palms and
soles.
11. True/False: Under normal conditions, up to 99% of the applied topical
corticosteroid is cleared from the skin, and only 1% is therapeutically active.
Correct Answer: True
12. The most important element in topical therapy is
Correct Answer: educating the patient about skin irritation.
13. Which of the following is/are not a stabilizer (nontherapeutic ingredient):
Correct Answer: corticosteroids
14. _________________ is the principal solvent for cleansing.
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Correct Answer: Water
15. True/False: When applying a topical treatment, the patient should avoid
vigorous rubbing or massaging of the drug into the skin.
Correct Answer: False
16. Irritant contact dermatitis, caused by a topical drug may be reduced by:
Correct Answer: using a less concentrated preparation over a greater
period of time.
17. True/False: In some instances, though, skin irritancy might be central to
drug efficacy.
Correct Answer: True
18. Topical steroids cause capillaries in the superficial dermis to
Correct Answer: constrict, thus reducing erythema.
19. ______________ are triphasic liquids composed of oil, organic solvents
and water.
Correct Answer: Foams
20. Topical corticosteroids are recommended for
Correct Answer: All of the above.
21. True/False: Results from large-scale surveys show that patients or
caregivers overestimate the actual risks of topical corticosteroids leading to
treatment noncompliance.
Correct Answer: True
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22. Liniments have many uses but they do not include:
Correct Answer: use as a drying agent.
23. The current evidence shows that
Correct Answer: topical glucocorticoids should be used with caution in
breastfeeding mothers.
24. True/False: With respect to dosage regimes in the application of potent
or moderately potent corticosteroids, there is a significant difference with
once versus twice daily dosages.
Correct Answer: False
25. Which of the following side effects may result from the use of topical
corticosteroids:
Correct Answer: All of the above
26. An oil-in-water emulsion
Correct Answer: a) and c)
27. ______________ formulations require no preservative additives.
Correct Answer: Water-soluble bases
28. True/False: There is no difference between “oil-in-water” and “water-inoil” emulsions; these names are interchangeable and describe the same
thing.
Correct Answer: False
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29. _______________ are nonstaining, greaseless, and easily washes off of
the skin.
Correct Answer: Water-soluble bases
30. ______________ are simply the incorporation of high concentrations of
powders (up to 50%) into an ointment.
Correct Answer: Pastes
31. Gels are suitable for facial or hairy areas because
Correct Answer: after application little residue is left behind.
32. Newer gel formulations may contain the viscoelastic _______________,
which can mitigate dermal irritation.
Correct Answer: polysaccharide hyaluronic acid
33. A hydroalcoholic solution with a concentration of alcohol of
approximately 50% is called a ____________.
Correct Answer: tincture
34. Emollients containing urea or lactic acid are an example of a
Correct Answer: suspension that requires shaking of the lotion before
application.
35. True/False: Flexible collodions have added castor oil and camphor and
are used, for example, to deliver 10% salicylic acid as a keratolytic agent.
Correct Answer: True
36. Shake lotions are lotions to which
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Correct Answer: a powder is added to increase the surface area of
evaporation.
37. The following is/are true about the penetration of topical steroids:
Correct Answer: increased penetration of the drug occurs where the
skin is thin.
38. Elderly patients may have thin skin, which
Correct Answer: allows for increased penetration of topical
glucocorticoids.
39. Previous studies have demonstrated that foam vehicles, when compared
to other vehicles,
Correct Answer: are highly effective in delivering greater amount of
active drug.
40. True/False: Foams have been associated with adverse side effects,
especially for localized conditions affecting the scalp.
Correct Answer: False
41. Topical aerosols may be used to deliver drugs formulated as
Correct Answer: All of the above.
42. When applied to abraded or eczematized skin, which of the following
delivery forms is least irritating when applied?
Correct Answer: aerosols
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43. One of the drawbacks to aerosols is
Correct Answer: the cost.
44. True/False: Corticosteroids are thought to exert their potent antiinflammatory effects by inhibiting the release of phospholipase A2.
Correct Answer: True
45. Increasing hydration of the stratum corneum can enhance absorption of
topical corticosteroids by
Correct Answer: ten times.
46. A serious consequence of ceasing topical steroid therapy after an
extended treatment period can result in
Correct Answer: an Addisonian crisis.
47. Hemangiomas of infancy show a good or partial response to treatment
with
Correct Answer: topical glucocorticoids.
48. Sulfacetamide is a topical sulfonamide used in the treatment of
Correct Answer: rosacea and acne.
49. Which of the following is true of topical 5% dapsone gel?
Correct Answer: If benzoyl peroxide is applied after it, a temporary
orange/yellow discoloration of skin and facial hair may occur.
50. Mechanisms for the anti-inflammatory effects of corticosteroids include:
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Correct Answer: Corticosteroids also decrease the release of
interleukin-1α.
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