Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 2 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 3 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 4 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 5 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 6 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 7 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 8 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 10 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 12 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 13 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 14 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 15 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 16 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 17 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 18 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 19 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 20 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 21 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 22 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 23 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 24 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 25 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 26 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 27 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 28 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 29 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 30 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: nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 31 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 32 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 33 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 34 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, nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 35 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 36 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 37 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 38 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 39 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 40 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 41 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 42 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 43 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 44 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 45 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 46 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 47 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 48 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 49 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 50 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 51 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 52 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 53 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 54 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 55 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 56 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 57 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 58 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 59 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 60 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 61 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 62 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 63 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 64 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 65 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 66 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 67 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 68 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 69 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 70 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, nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 71 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 72 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 73 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 74 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 75 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 76 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 77 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 78 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 79 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 80 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 81 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 82 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 83 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 84 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 85 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 86 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 87 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 88 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 89 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 90 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 91 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 92 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 93 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 94 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 95 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 96 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 97 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 98 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 99 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 100 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 101 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 102 (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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 103 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 104 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 105 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, nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 106 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 107 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 108 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 109 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). nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 110 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 111 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 112 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 113 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 114 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 115 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 116 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, nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 117 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 118 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 119 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 120 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 121 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 122 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 123 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 124 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 125 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 126 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 127 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 128 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 129 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 130 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 131 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 132 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 133 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 134 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 135 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 136 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 137 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 138 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 139 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: nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 140 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 141 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 142 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 143 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 144 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 145 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 146 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 147 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 148 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 149 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 150 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 151 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 152 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 153 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 154 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. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 155 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 156 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 157 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 158 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 nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 159 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: nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 160 Correct Answer: Corticosteroids also decrease the release of interleukin-1α. References Section The reference section of in-text citations include published works intended as helpful material for further reading. Unpublished works and personal communications are not included in this section, although may appear within the study text. 1. 2. 3. 4. 5. 6. 7. Buxton PKK, Morris-Jones R. ABC of Dermatology. Buxton PK, MorrisJones R, editors. ABC of Dermatology. 5th ed. Chichester: WileyBlackwell; 2009. p.11. 2009. 11-14,17,24,25 p. Burns T, Breathnach S, Cox N GC. Rook’s Textbook of Dermatology. Dermatology. 2010. p. 47. 37–8. Burgess CM. Cosmetic dermatology. Cosmetic Dermatology. 2005. 1170 p. Dunn J, Koo J. Dermatology Online Journal UC Davis. Dermatol Online J. 2013;19(6):1–19. Merk HF. [Pharmacogenetics: Important aspects for dermatology]. Hautarzt. 2005;56(1):44–7. Lee EH, Nehal KS, Dusza SW, Hale EK, Levine VJ. Procedural dermatology training during dermatology residency: A survey of thirdyear dermatology residents. J Am Acad Dermatol. 2011;64(3):475– 83.e5. Thappa DM. Recent advances in topical therapy in dermatology. Indian J Dermatol. 2010;48(01):1. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 161 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. Iozumi K. Topical antifungal agents. Japanese J Med Mycol. 2013;54(3):269–78. Tan X, Feldman SR, Chang J, Balkrishnan R. Topical drug delivery systems in dermatology: a review of patient adherence issues. Expert Opin Drug Deliv. 2012;9(10):1263–71. Russell JJ. Topical therapy for acne. American Family Physician. 2000. p. 357–66. S K, VK S, K S. Topical immunomodulators in dermatology. J Postgr Med. 2004;54:641–61; quiz 662. Cesur S. Topical antibiotics and clinical use. Top antibiyotikler ve Klin Kullan. 2002;36(3-4):353–61. Palm MD, Altman JS. Topical hemostatic agents: a review. Dermatol Surg. 2008;34(4):431–45. Greenhalgh DG. Topical Antimicrobial Agents for Burn Wounds. Clin Plast Surg. 2009;36(4):597–606. Woo DK, James WD. Topical tacrolimus: a review of its uses in dermatology. Dermat contact, atopic, Occup drug. 2005;16(1):6–21. Seyednejad H, Imani M, Jamieson T, Seifalian a. M. Topical haemostatic agents. Br J Surg. 2008;95:1197–225. Kang S. The mechanism of action of topical retinoids. Cutis. 2005;75(2 Suppl):10–3; discussion 13. Warren RB, Brown BC, Griffiths CEM. Topical treatments for scalp psoriasis. Drugs. 2008;68(16):2293–302. Baumann L, Woolery-Lloyd H, Friedman A. “Natural” ingredients in cosmetic dermatology. J Drugs Dermatol. 2009;8(6 Suppl):s5–9. Aria N, Kauffman CL. Important drug interactions and reactions in dermatology. Dermatol Clin. 2003;21(1):207–15, ix. N. S. Immunobiologic agents in dermatology. Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry. 2007. p. 180–2. C.-C. C. Evidence-based dermatology. Dermatologica Sinica. 2013. p. 2–6. Lipozenčić J, Bukvić-Mokos Z. Corrective dermatology today. Acta Clin Croat. 2010;49(4):519–23. Chandler D, Bewley A. Biologics in dermatology. Pharmaceuticals. 2013. p. 557–8. Lebwohl M. A clinician’s paradigm in the treatment of psoriasis. J Am Acad Dermatol. 2005;53(1 SUPPL.):59–69. James W, Berger T, Elston D. Andrews’ Diseases of the Skin: Clinical Dermatology. Andrews’ Diseases of the Skin: Clinical Dermatology. 2005. p. 2–4. Lio P a., Kaye ET. Topical Antibacterial Agents. Med Clin North Am. 2011;95(4):703–21. Spann CT, Taylor SC, Weinberg JM. Topical antimicrobial agents in dermatology. Dis Mon. 2004;50(7):407–21. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 162 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. Singal A, Thami GP. Topical antibacterial agents in dermatology. J Dermatol. 2003;30:644–8. Pariser DM, Ballard A. Topical therapies in hyperhidrosis care. Dermatol Clin. 2014;32(4):485–90. S. K, J. L. Dermatology. Med Hyg (Geneve). 2002;60(2375):89–96. Puizina-Ivić N, Mirić L, Carija A, Karlica D, Marasović D. Modern approach to topical treatment of aging skin. Coll Antropol. 2010;34(3):1145–53. Hexsel D, Mazzuco R. Update in Cosmetic Dermatology. Cellulite. 2013;21–33. Baldwin HE, Nighland M, Kendall C, Mays DA, Grossman R, Newburger J. 40 years of topical tretinoin use in review. J Drugs Dermatol. 2013;12(6):638–42. Rang H, Dale M, Ritter M, Flower R, Henderson G. Pharmacology. Rang and Dale’s Pharmacology. 2012. 237-245 p. Chowdhury MM. Dermatological pharmacology: topical agents. Medicine (Baltimore). 2004;32(12):16–7. Robertson GS, LaCasse EC, Holcik M. Pharmacology. Pharmacology. 2009. 455-473 p. Micali G, Lacarrubba F, Nasca MR, Schwartz R a. Topical pharmacotherapy for skin cancer: Part I. Pharmacology. J Am Acad Dermatol. 2014;70(6):965.e1–965.e12. Martin. Journal of Investigative Dermatology. J Invest Dermatol. 2008;2014–5. P. V. Innovations in cosmetic dermatology. Ned Tijdschr voor Dermatologie en Venereol. 2008;18:120–1. Kormeili T, Yamauchi PS, Lowe NJ. Topical photodynamic therapy in clinical dermatology. Br J Dermatol. 2004;150(6):1061–9. Junkins-Hopkins JM. Antioxidants and their chemopreventive properties in dermatology. J Am Acad Dermatol. 2010;62(4):663–5. Draelos ZD. Cosmetic Dermatology: Products and Procedures. Cosmetic Dermatology: Products and Procedures. 2010. 548 p. Nijhawan RI, Alexis AF. Practical approaches to medical and cosmetic dermatology in skin of color patients. Expert Rev Dermatol. 2011;6(2):175–87. Elston DM. Topical Antibiotics in Dermatology - Emerging Patterns of Resistance. Dermatologic Clinics. 2009. p. 25–31. Baeck M, Goossens a. Systemic contact dermatitis to corticosteroids. Allergy Eur J Allergy Clin Immunol. 2012;67(12):1580–5. Del Rosso JQ, Kim GK. Topical antibiotics: therapeutic value or ecologic mischief? Dermatol Ther. 2009;22(5):398–406. Lolis M, Dunbar SW, Goldberg DJ, Hansen TJ, MacFarlane DF. Patient safety in procedural dermatology: Part II. Safety related to cosmetic procedures. J Am Acad Dermatol. 2015;73(1):15–24. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 163 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. Lee I a., Maibach HI. Pharmionics in dermatology: A review of topical medication adherence. Am J Clin Dermatol. 2006;7(4):231–6. Rotta I, Sanchez a., Gonçalves PR, Otuki MF, Correr CJ. Efficacy and safety of topical antifungals in the treatment of dermatomycosis: A systematic review. Br J Dermatol. 2012;166(5):927–33. List of Antibiotics - eMedExpert.com [Internet]. [cited 2014 Feb 28]. Available from: http://www.emedexpert.com/lists/antibiotics.shtml Antibiotic Classification & Mechanism - Basic Science - Orthobullets.com [Internet]. [cited 2014 Mar 1]. Available from: http://www.orthobullets.com/basic-science/9059/antibioticclassification-and-mechanism Gelmetti C. Local antibiotics in dermatology. Dermatol Ther. 2008;21(3):187–95. Sulfonamides [Internet]. [cited 2014 Mar 7]. Available from: http://www.nlm.nih.gov/cgi/mesh/2004/MB_cgi?field=entry&term=Sulf onamides Gamble R, Dunn J, Dawson A, Petersen B, McLaughlin L, Small A, et al. Topical antimicrobial treatment of acne vulgaris: an evidence-based review. Am J Clin Dermatol. 2012;13(3):141–52. Antibiotic medications - sulfa drugs | University of Maryland Medical Center [Internet]. [cited 2014 Mar 7]. Available from: http://umm.edu/health/medical/altmed/depletion/antibioticmedications-sulfa-drugs Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracyclines in the treatment of acne vulgaris: a review. Br J Dermatol. 2008;158:208–16. Tadicherla S, Ross K, Shenefelt PD, Fenske NA. Topical corticosteroids in dermatology. J Drugs Dermatol. 2009;8(12):1093–105. Ference JD, Last AR. Choosing topical corticosteroids. Am Fam Physician. 2009;79(2):135–40. Barnes PJ. Corticosteroids: The drugs to beat. Eur J Pharmacol. 2006;533(1-3):2–14. Brazzini B, Pimpinelli N. New and established topical corticosteroids in dermatology: clinical pharmacology and therapeutic use. Am J Clin Dermatol. 2002;3(1):47–58. Maibach HI. Topical Corticosteroids : Unapproved Uses , Dosages , or Indications Dosage. Clin Dermatol. 2002;(02):490–2. Burkholder B. Topical Corticosteroids : An Update. Curr Probl Dermatol. 2000;12(5):222–5. Carlos G, Uribe P, Fernández-Peñas P. Rational use of topical corticosteroids. Aust Prescr. 2013;36(5):158–61. Bartok V. Topical corticosteroids: 10 must-know facts. Pharm Times. 2014;80(5). F. C. The use of topical corticosteroids in atopic dermatitis in children. Ann Dermatol Venereol. 2005;132(SPEC. ISS. 1):1S64–1S67. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 164 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. Radley K. NICE guidance on use of topical corticosteroids in atopic eczema. Nurs Times. 2004;100(38):26–7. Stenner M, Vent J, Hüttenbrink K-B, Hummel T, Damm M. Topical therapy in anosmia: relevance of steroid-responsiveness. Laryngoscope. 2008;118(9):1681–6. Bewley a. Expert consensus: Time for a change in the way we advise our patients to use topical corticosteroids. Br J Dermatol. 2008;158(5):917–20. Chi CC, Kirtschig G, Aberer W, Gabbud JP, Lipozencic J, Karpati S, et al. Evidence-based (S3) guideline on topical corticosteroids in pregnancy. British Journal of Dermatology. 2011. p. 943–52. Chi C-C, Wang S-H, Kirtschig G, Wojnarowska F. Systematic review of the safety of topical corticosteroids in pregnancy. J Am Acad Dermatol. 2010;62(4):694–705. Alabdulrazzaq F, Koren G. Topical corticosteroid use during pregnancy. Can Fam Physician. 2012;58(6):643–4. Chi CC, Lee CW, Wojnarowska F, Kirtschig G. Safety of topical corticosteroids in pregnancy. Cochrane Database Syst Rev. 2009;(3):CD007346. Uva L, Miguel D, Pinheiro C, Antunes J, Cruz D, Ferreira J, et al. Mechanisms of action of topical corticosteroids in psoriasis. Int J Endocrinol. 2012;2012(iv):16. Mentzelopoulos SD, Zakynthinos SG, Tzoufi M, Katsios N, Papastylianou A, Gkisioti S, et al. Vasopressin, epinephrine, and corticosteroids for inhospital cardiac arrest. Arch Intern Med. 2009;169:15–24. Poetker DM, Reh DD. A comprehensive review of the adverse effects of systemic corticosteroids. Otolaryngol Clin North Am. 2010;43(4):753– 68. Senyiğit T, Padula C, Ozer O, Santi P. Different approaches for improving skin accumulation of topical corticosteroids. Int J Pharm. 2009;380(1-2):155–60. Dhar S, Seth J, Parikh D. Systemic side-effects of topical corticosteroids. Indian J Dermatol. 2014;59(5):460–4. Vatti RR, Ali F, Teuber S, Chang C, Gershwin ME. Hypersensitivity Reactions to Corticosteroids. Clin Rev Allergy Immunol. 2014;(2014):1–12. Principles of Topical Dermatologic Therapy - Dermatologic Disorders Merck Manuals Professional Edition [Internet]. [cited 2015 Oct 10]. Available from: http://www.merckmanuals.com/professional/dermatologicdisorders/principles-of-topical-dermatologic-therapy/principles-oftopical-dermatologic-therapy Drucker CR. Update on topical antibiotics in dermatology. Dermatol Ther. 2012;25(1):6–11. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 165 82. Fernandez-Obregon AC, Rohrback J, Reichel MA, Willis C. Current use of anti-infectives in dermatology. Expert Rev Anti Infect Ther. 2005;3(4):557–91. 83. Simonart T, Dramaix M. Treatment of acne with topical antibiotics: Lessons from clinical studies. Br J Dermatol. 2005;153:395–403. 84. Rolewski SL. Clinical review: topical retinoids. Dermatol Nurs. 2003;15(5):447–50, 459–65. 85. Zaenglein AL. Topical Retinoids in the Treatment of Acne Vulgaris. Semin Cutan Med Surg. 2008;27:177–82. 86. Thielitz A, Abdel-Naser MB, Fluhr JW, Zouboulis CC, Gollnick H. [Topical retinoids in acne--an evidence-based overview]. J Dtsch Dermatol Ges. 2010;8 Suppl 1(12):S15–23. 87. Sorg O, Antille C, Kaya G, Saurat J-H. Retinoids in cosmeceuticals. Dermatol Ther. 2006;19(5):289–96. 88. Wolf JE. Potential anti-inflammatory effects of topical retinoids and retinoid analogues. Adv Ther. 2002;19(3):109–18. 89. Hubbard B a, Unger JG, Rohrich RJ. Reversal of skin aging with topical retinoids. Plast Reconstr Surg. 2014;133(4):481e – 90e. 90. Boswell CB. Skincare science: update on topical retinoids. Aesthet Surg J. 2006;26(2):233–9. 91. Thielitz A, Gollnick H. Topical retinoids in acne vulgaris: update on efficacy and safety. Am J Clin Dermatol. 2008;9(6):369–81. 92. Dawson MI, Abraham DJ. Retinoids. Burger’s Medicinal Chemistry and Drug Discovery. 2003. p. 500–63. 93. Yentzer BA, McClain RW, Feldman SR. Do topical retinoids cause acne to “flare”? J Drugs Dermatol. 2009;8(9):799–801. 94. Weinberg JM. Topical therapy for actinic keratoses: current and evolving therapies. Rev Recent Clin Trials. 2006;1(1):53–60. 95. Ianhez M, Fleury LFF, Miot HA, Bagatin E. Retinoids for prevention and treatment of actinic keratosis. An Bras Dermatol. 2013;88(4):585–93. 96. Millikan LE. The rationale for using a topical retinoid for inflammatory acne. Am J Clin Dermatol. 2003;4(2):75–80. 97. Tang X-H, Gudas LJ. Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol. 2011;6:345–64. 98. Brun PJ, Yang KJZ, Lee SA, Yuen JJ, Blaner WS. Retinoids: Potent regulators of metabolism. BioFactors. 2013;39(2):151–63. 99. Okokon EO, Verbeek JH, Ruotsalainen JH, Ojo OA, Bakhoya VN. Topical antifungals for seborrhoeic dermatitis. Cochrane database Syst Rev. 2015;5:CD008138. 100. Andes D. Pharmacokinetics and Pharmacodynamics of Antifungals. Infect Dis Clin North Am. 2006;20(3):679–97. 101. Black D. History of Antifungal Drug Development. Therapy Using Antifungals. 2003. p. 91–5. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 166 102. Xi N, Huang Q, Liu L. Imidazoles. Compr Heterocycl Chem III. 2008;4:143–364. 103. Grimmett MR. Product class 3: imidazoles. Sci Synth. 2002;12:325– 528. 104. Yamagishi M, Okazaki J, Nishigai K, Hata T, Urabe H. Additive-free nucleophilic addition of imidazolines and imidazoles to haloacetylenes. Org Lett. 2012;14(1):34–7. 105. Sheets MR, Li A, Bower E a., Weigel AR, Abbott MP, Gallo RM, et al. Superelectrophilic chemistry of imidazoles. J Org Chem. 2009;74(6):2502–7. 106. Robert MEM, Kalia YN. New developments in topical antifungal therapy. American Journal of Drug Delivery. 2006. 107. Chen SC a, Sorrell TC. Antifungal agents. Med J Aust. 2007;187(7):404–9. 108. Gupta AK, Cooper E a. Update in antifungal therapy of dermatophytosis. Mycopathologia. 2008;166(5-6):353–67. 109. Birnbaum JE. Pharmacology of the allylamines. J Am Acad Dermatol. 1990;23(4 Pt 2):782–5. 110. Gant TG, Sarshar S. Preparation and utility of substituted allylamines. PCT Int. Appl. 2008. p. 94pp. 111. Miura M, Feng CG, Ma S, Yu JQ. Pd(II)-catalyzed orthotrifluoromethylation of benzylamines. Org Lett. 2013;15(II):5258–61. 112. Musiol R, Serda M, Hensel-Bielowka S, Polanski J. Quinoline-based antifungals. Curr Med Chem. 2010;17(18):1960–73. 113. Wang JW, Huang J, Li HG, Zhang SH. Synthesis of 11 monobactams and their antibacterial activity. Chinese J Antibiot. 2003;28:459–62. 114. Lai J, Maibach HI. Experimental models in predicting topical antifungal efficacy: practical aspects and challenges. Skin Pharmacol Physiol. 2009;22(5):231–9. 115. Bryskier A. Antimicrobial agents: Antibacterials and antifungals. ASM Press. 2005;42–3. 116. Chu G, Li C. Convenient and clean synthesis of imines from primary benzylamines. Org Biomol Chem. 2010;8(20):4716–9. 117. Moses JE, Baldwin JE, Brückner S, Eade SJ, Adlington RM. Biomimetic studies on polyenes. Org Biomol Chem. 2003;1(21):3670–84. 118. Bourcier T, Chaumeil C. [How to prescribe local antifungal and antiamoebicide topical drugs]. J Fr Ophtalmol. 2007;30(4):431–5. 119. Schmidt M, Tavan P. Electronic excitations in long polyenes revisited. J Chem Phys. 2012;136(12):124309. 120. Canuto MM, Rodero FG. Antifungal drug resistance to azoles and polyenes. Lancet Infect Dis. 2002;2(September):550–63. 121. Joseph W, Pollak R, Vlahovic T, Caldwell B, Jennings M, Ashton S, et al. Onychomycosis and the Role of Topical Antifungals. Pod Today. 2013;(November). nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 167 122. Gupte M, Kulkarni P, Ganguli BN. Antifungal antibiotics. Appl Microbiol Biotechnol. 2002;58:46–57. 123. Watanabe S, Harada T, Hiruma M, Naoe S. Guidelines for clinical evaluation of topical antifungal agents. Japanese J Med Mycol. 2003;44(2):115–20. 124. Chandrasekar P. Management of invasive fungal infections: a role for polyenes. J Antimicrob Chemother. 2011;66(3):457–65. 125. Elewski BE, Jones T, Zaias N. Comparison of an antifungal agent used alone with an antifungal used with a topical steroid in inflammatory tinea pedis. Cutis. 1996;58:305–7. 126. Horowitz BZ. Botulinum Toxin. Crit Care Clin. 2005;21(4):825–39. 127. P.S. F. Clinical uses of botulinum toxin. Advanced Studies in Medicine. 2005. p. 176–82. 128. Benecke R. Clinical Relevance of Botulinum Toxin Immunogenicity. Biodrugs. 2012;26(2):1–9. 129. Nigam PK, Nigam A. Botulinum toxin. Indian J Dermatol. 2010;55:8– 14. 130. Kelly PE. Injectable success: from fillers to Botox. FacialPlastSurg. 2007;23(0736-6825 (Print)):7–18. 131. Brin MF. Basic and clinical aspects of BOTOX. Toxicon. 2009;54(5):676–82. 132. Dhaked RK, Singh MK, Singh P, Gupta P. Botulinum toxin: Bioweapon & magic drug. Indian J Med Res. 2010;132(11):489–503. 133. Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol. 2004;44:167–93. 134. Shah MD, Johns MM. Office-Based Botulinum Toxin Injections. Otolaryngol Clin North Am. 2013;46(1):53–61. 135. Dastoor SF, Misch CE, Wang H. Botulinum toxin (Botox) to enhance facial macroesthetics: a literature review. J Oral Implantol. 2007;XXXIII(3):164–71. 136. A. A, E. B, R. S, P. S, D. M, P. S, et al. A new facial expression to botox. American Journal of Gastroenterology. 2013. p. S194. 137. Wu WTL. Botox Facial Slimming/Facial Sculpting: The Role of Botulinum Toxin-A in the Treatment of Hypertrophic Masseteric Muscle and Parotid Enlargement to Narrow the Lower Facial Width. Facial Plast Surg Clin North Am. 2010;18(1):133–40. 138. Khanna S, Jain S. Botox: the poison that heals. Int Dent J. 2006;56(6):356–8. 139. Markey AC. Botulinum A exotoxin in cosmetic dermatology. Clin Exp Dermatol. 2000;25(3):173–5. 140. Huang W, Foster J a, Rogachefsky a S. Pharmacology of botulinum toxin. J Am Acad Dermatol. 2000;43(2 Pt 1):249–59. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 168 141. Flynn TC, Carruthers J a., Carruthers JA, Clark RE, Alam M. Botulinum A toxin (BOTOX) in the lower eyelid: Dose-finding study. Dermatologic Surg. 2003;29(9):943–51. 142. M.F. B. Basic and clinical aspects of BOTOX. Toxicon. 2009. p. 676–82. 143. Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry. 2004;75(7):951–7. 144. Small R. Botulinum Toxin Injection for Facial Wrinkles. Am Fam Physician. 2014;90(3):168–75. 145. Carruthers J, Carruthers A. Botox: beyond wrinkles. Clin Dermatol. 2003;22(1):89–93. 146. Carruthers J, Carruthers A. BOTOX use in the mid and lower face and neck. Semin Cutan Med Surg. 2001;20(2):85–92. 147. Francisco GE. Botulinum toxin: dosing and dilution. Am J Phys Med Rehabil. 2004;83(10 Suppl):S30–7. 148. Gordon RW. BOTOX cosmetic for lip and perioral enhancement. DentToday. 2009;28(8750-2186 (Print)):94–7. 149. Kane MAC. Botox injections for lower facial rejuvenation. Oral Maxillofac Surg Clin North Am. 2005;17(1):41–9, vi. 150. Bhidayasiri R, Truong DD. Expanding use of botulinum toxin. J Neurol Sci. 2005;235:1–9. 151. Dressler D, Saberi FA, Barbosa ER. Botulinum toxin: mechanisms of action. Arq Neuropsiquiatr. 2005;63(1):180–5. 152. Kazim N a, Black EH. Botox: shaken, not stirred. Ophthal Plast Reconstr Surg. 2008;24(1):10–2. 153. Brin MF. Basic and clinical aspects of BOTOX?? Toxicon. 2009;54(5):676–82. 154. Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry. 2004;75(7):951–7. 155. Doft M a, Hardy KL, Ascherman J a. Treatment of hyperhidrosis with botulinum toxin. Aesthet Surg J. 2012;32(2):238–44. 156. Baumann LS, Halem ML. Botulinum toxin-B and the management of hyperhidrosis. Clin Dermatol. 2004;22(1):60–5. 157. Wollina U, Karamfilov T. Botulinum toxin A for palmar hyperhidrosis. JEurAcadDermatolVenereol. 2001;15(0926-9959 (Print)):555–8. 158. Hexsel DM, Dal’forno T, Hexsel CL. Inguinal, or Hexsel’s hyperhidrosis. Clin Dermatol. 2003;22(1):53–9. 159. Jost WH. Other indications of botulinum toxin therapy. Eur J Neurol. 2006;13(supplement 1):65–9. 160. Saunders D, Smith F, Brown E, Harrison B. Individualizing client goals in the clinical setting: beyond beauty with Botox. J Multicult Nurs Heal. 2005;11(3):70–1. 161. Carruthers J, Carruthers A. Botulinum toxin (botox) chemodenervation for facial rejuvenation. Facial Plast Surg Clin North Am. 2001;9(2):197–204, vii. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 169 162. Flynn TC. Update on botulinum toxin. Semin Cutan Med Surg. 2006;25(3):115–21. 163. Carruthers J, Fagien S, Matarasso SL. Consensus recommendations on the use of botulinum toxin type a in facial aesthetics. Plast Reconstr Surg. 2004;114(6 Suppl):1S – 22S. 164. Truong DD, Jost WH. Botulinum toxin: clinical use. Parkinsonism Relat Disord. 2006;12(6):331–55. 165. Aoki KR. Pharmacology and immunology of botulinum toxin type A. Clin Dermatol. 2003;21(6):476–80. 166. Coleman KR, Carruthers J. Combination therapy with BOTOX??? and fillers: The new rejuvnation paradigm. Dermatol Ther. 2006;19:177– 88. 167. Lam SM. The basic science of botulinum toxin. Facial Plast Surg Clin North Am. 2003;11(4):431–8. 168. Ramirez-Castaneda J, Jankovic J, Comella C, Dashtipour K, Fernandez HH, Mari Z. Diffusion, spread, and migration of botulinum toxin. Mov Disord. 2013;28(13):1775–83. 169. P. K. Long-term effects of botulinum toxin treatment. Annales de Dermatologie et de Venereologie. 2009. p. S86–8. 170. Niamtu J. Complications in fillers and Botox. Oral Maxillofac Surg Clin North Am. 2009;21(1):13–21, v. 171. Davis JI, Senghas A, Brandt F, Ochsner KN. The effects of BOTOX injections on emotional experience. Emotion. 2010;10:433–40. 172. Hamdy RC, Montpetit K, Ruck-Gibis J, Thorstad K, Raney E, Aiona M, et al. Safety and efficacy of botox injection in alleviating post-operative pain and improving quality of life in lower extremity limb lengthening and deformity correction. Trials. 2007;8:27. 173. Breikaa RM, Mosli HA, Nagy AA, Abdel-Naim AB. Adverse testicular effects of Botox® in mature rats. Toxicol Appl Pharmacol. 2014;275(2):182–8. 174. Vartanian a J, Dayan SH. Complications of botulinum toxin A use in facial rejuvenation. Facial Plast Surg Clin North Am. 2005;13(1):1–10. 175. Baumann L. Dermal fillers. J Cosmet Dermatol. 2004;3(4):249–50. 176. Candelas D. Dermal Fillers: Types, Indications, and Complications. Actas Dermosifiliogr. 2010;101(5):381–93. 177. Goldberg DJ. Breakthroughs in US dermal fillers for facial soft-tissue augmentation. J Cosmet Laser Ther. 2009;11(4):240–7. 178. Tezel A, Fredrickson GH. The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther. 2008;10(1):35–42. 179. Engelman DE, Bloom B, Goldberg DJ. Dermal fillers: complications and informed consent. J Cosmet Laser Ther. 2005;7(1):29–32. 180. Dayan SH, Bassichis BA. Facial Dermal Fillers: Selection of Appropriate Products and Techniques. Aesthetic Surg J. 2008;28(3):335–47. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 170 181. Vedamurthy M, Vedamurthy A. Dermal fillers: tips to achieve successful outcomes. J Cutan Aesthet Surg. 2008;1(2):64–7. 182. Lowe NJ, Maxwell CA, Patnaik R. Adverse reactions to dermal fillers: review. Dermatol Surg. 2005;31(August):1616–25. 183. Buck DW, Alam M, Kim JYS. Injectable fillers for facial rejuvenation: a review. J Plast Reconstr Aesthetic Surg. 2009;62(1):11–8. 184. Cockerham K, Hsu VJ. Collagen-based dermal fillers: past, present, future. Facial Plast Surg. 2009;25(2):106–13. 185. Vedamurthy M, Vedamurthy A, Nischal K. Dermal Fillers: Do’s and Dont's. J Cutan Aesthet Surg. 2010;3(1):11–5. 186. Rohrich RJ. Temporary Dermal and Soft-Tissue Fillers Supplement. Plast Reconstr Surg. 2007;120(Supplement):1S – 2S. 187. Breithaupt A, Custis T, Beddingfield F. Next-Generation Dermal Fillers and Volumizers. Cosmet Dermatology. 2012;25:184–91. 188. Shin JH, Park S. Fillers for Soft Tissue Augmentation: A Materials Perspective. Tissue Eng Regen Med. 2011;8(1):A1–8. 189. Dayan SH, Arkins JP, Brindise R. Soft Tissue Fillers and Biofilms. FACIAL Plast Surg. 2011;27(1):23–8. 190. Beasley KL, Weiss M a., Weiss R a. Hyaluronic acid fillers: A comprehensive review. Facial Plast Surg. 2009;25(2):86–94. 191. Lupo MP. Hyaluronic Acid Fillers in Facial Rejuvenation. Semin Cutan Med Surg. 2006;25(3):122–6. 192. Baumann LS, Shamban AT, Lupo MP, Monheit GD, Thomas J a., Murphy DK, et al. Comparison of smooth-gel hyaluronic acid dermal fillers with cross-linked bovine collagen: A multicenter, double-masked, randomized, within-subject study. Dermatologic Surg. 2007;33(SUPPL. 2):128–35. 193. Sudha PN, Rose MH. Beneficial effects of hyaluronic acid. Adv Food Nutr Res. 2014;72:137–76. 194. Kablik J, Monheit GD, Yu L, Chang G, Gershkovich J. Comparative physical properties of hyaluronic acid dermal fillers. Dermatologic Surg. 2009;35(SUPPL. 1):302–12. 195. Price RD, Berry MG, Navsaria H a. Hyaluronic acid: the scientific and clinical evidence. J Plast Reconstr Aesthetic Surg. 2007;60(10):1110–9. 196. Monheit G, Coleman K. Hyaluronic acid fillers. Dermatol Ther. 2006;19(3):141–50. 197. Gold MH. Use of hyaluronic acid fillers for the treatment of the aging face. Clin Interv Aging. 2007;2(3):369–76. 198. Borrell M, Leslie DB, Tezel A. Lift capabilities of hyaluronic acid fillers. J Cosmet Laser Ther. 2011;13(December 2010):21–7. 199. Necas J, Bartosikova L, Brauner P, Kolar J. Hyaluronic acid (hyaluronan): A review. Vet Med (Praha). 2008;53:397–411. 200. Johl SS, Burgett R a. Dermal filler agents: a practical review. Curr Opin Ophthalmol. 2006;17(5):471–9. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 171 201. Edwards PC, Fantasia JE. Review of long-term adverse effects associated with the use of chemically-modified animal and nonanimal source hyaluronic acid dermal fillers. Clin Interv Aging. 2007;2(4):509– 19. 202. Edsman K, Nord LI, Öhrlund Å, Lärkner H, Kenne AH. Gel properties of hyaluronic acid dermal fillers. Dermatologic Surg. 2012;38(7 PART 2):1170–9. 203. Brandt FS, Cazzaniga A. Hyaluronic acid gel fillers in the management of facial aging. Clin Interv Aging. 2008;3(1):153–9. 204. Kakehi K, Kinoshita M, Yasueda SI. Hyaluronic acid: Separation and biological implications. J Chromatogr B Anal Technol Biomed Life Sci. 2003;797(1-2):347–55. 205. Brandt FS, Cazzaniga A. Hyaluronic acid fillers: Restylane and Perlane. Facial Plast Surg Clin North Am. 2007;15(1):63–76, vii. 206. Tan SW, Johns MR, Greenfield PF. Hyaluronic acid--a versatile biopolymer. Aust J Biotechnol. 1990;4(1):38–43. 207. Monheit GD, Prather CL. Juvéderm: a hyaluronic acid dermal filler. J Drugs Dermatol. 2007;6(11):1091–5. 208. Bray D, Hopkins C, Roberts DN. A review of dermal fillers in facial plastic surgery. Curr Opin Otolaryngol Head Neck Surg. 2010;18(4):295–302. 209. Ellis D a F, Segall L. Review of non-FDA-approved fillers. Facial Plast Surg Clin North Am. 2007;15(2):239–46, vii. 210. Hedén P, Sellman G, von Wachenfeldt M, Olenius M, Fagrell D. Body shaping and volume restoration: the role of hyaluronic acid. Aesthetic Plast Surg. 2009;33(3):274–82. 211. Lee A, Grummer SE, Kriegel D, Marmur E. Hyaluronidase. Dermatologic Surg. 2010;36:1071–7. 212. Kemparaju K, Girish KS. Snake venom hyaluronidase: A therapeutic target. Cell Biochem Funct. 2006;24(1):7–12. 213. Menzel E., Farr C. Hyaluronidase and its substrate hyaluronan: biochemistry, biological activities and therapeutic uses. Cancer Lett. 1998;131(1):3–11. 214. Sumantran VN, Kulkarni A a., Harsulkar A, Wele A, Koppikar SJ, Chandwaskar R, et al. Hyaluronidase and collagenase inhibitory activities of the herbal formulation Triphala guggulu. J Biosci. 2007;32(4):755–61. 215. Sturm LP, Cooter RD, Mutimer KL, Graham JC, Maddern GJ. A systematic review of dermal fillers for age-related lines and wrinkles. ANZ J Surg. 2011;81(1-2):9–17. 216. Dastoor SF, Misch CE, Wang H-L. Dermal fillers for facial soft tissue augmentation. J Oral Implantol. 2007;33(4):191–204. 217. Rubin MG. Treatment of nasolabial folds with fillers. Aesthet Surg J. 2004;24(5):489–93. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 172 218. Berbos ZJ, Lipham WJ. Update on botulinum toxin and dermal fillers. Curr Opin Ophthalmol. 2010;21(5):387–95. 219. Sadick NS, Karcher C, Palmisano L. Cosmetic dermatology of the aging face. Clin Dermatol. 2009;27(3):S3–12. 220. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview of adverse events and treatment approaches. Clin Cosmet Investig Dermatol. 2013;6:295–316. 221. Luebberding S, Alexiades-Armenakas M. Safety of dermal fillers. J Drugs Dermatol. 2012;11(9):1053–8. 222. Wollina U, Goldman A. Dermal fillers: Facts and controversies. Clin Dermatol. 2013;31(6):731–6. 223. Beer K, Lupo MP. Making the right choices: attaining predictable aesthetic results with dermal fillers. J Drugs Dermatol. 2010;9(5):458– 65. 224. Smith JM, Davies BW, Hink EM, Durairaj VD. Complications of dermal fillers. J Dermatol Nurses Assoc. 2013;5(5):270–2. 225. Tisi P V, Beverley C, Rees A. Injection sclerotherapy for varicose veins. Cochrane Database Syst Rev. 2006;(4):CD001732. 226. Albanese G, Kondo KL. Pharmacology of sclerotherapy. Semin Intervent Radiol. 2010;27(4):391–9. 227. Worthington-Kirsch RL. Injection sclerotherapy. Semin Intervent Radiol. 2005;22(3):209–17. The information presented in this course is intended solely for the use of healthcare professionals taking this course, for credit, from NurseCe4Less.com. The information is designed to assist healthcare professionals, including nurses, in addressing issues associated with healthcare. The information provided in this course is general in nature, and is not designed to address any specific situation. This publication in no way absolves facilities of their responsibility for the appropriate orientation of healthcare professionals. Hospitals or other organizations using this publication as a part of their own orientation processes should review the contents of this publication to ensure accuracy and compliance before using this publication. Hospitals and facilities that use this publication agree to defend and indemnify, and shall hold NurseCe4Less.com, including its parent(s), subsidiaries, affiliates, officers/directors, and employees from liability resulting from the use of this publication. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 173 The contents of this publication may not be reproduced without written permission from NurseCe4Less.com. nursece4less.com nursece4less.com nursece4less.com nursece4less.com nursece4less.com 174