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DERMATOLOGY PHARMACOLOGY

KELLIE WILSON, PharmD

Kellie Wilson, is a Doctor of Pharmacy practicing in Anaconda, MT. She specializes in retail pharmacy at an independent pharmacy. She attended the University of Montana in Missoula, MT where she graduated in 2009 with a doctorate in pharmacy. She then when on to work in Boise, ID as a retail pharmacist for one of the big corporations for 2 years. She then moved home to Montana to work at a retail pharmacy that is independently owned. In the 8 years she has worked as an independent retail pharmacist she has become very involved in psychiatric pharmacy for two major behavioral health organizations that are located around all of Montana. Kellie loves working as a retail pharmacist because she enjoys the interaction with her customers. Pharmacy is always changing and keeping up to date with new is very challenging and very rewarding all at the same time and this is why Kellie has chosen a career in pharmacy and is pursuing more towards psychiatric pharmacy.

NOAH CARPENTER, MD

Dr. Noah Carpenter is a Thoracic and Peripheral Vascular Surgeon. He completed a Bachelor of Science in Chemistry and medical school and training at the University of Manitoba. Dr. Carpenter completed surgical residency and fellowship at the University of Edmonton and Affiliated Hospitals in Edmonton, Alberta, and an additional Adult Cardiovascular and Thoracic Surgery fellowship at the University of Edinburgh, Scotland. He has specialized in microsurgical techniques, vascular endoscopy, laser and laparoscopic surgery in Brandon, Manitoba and Vancouver, British Columbia, Canada and in Colorado, Texas, and California. Dr. Carpenter has an Honorary Doctorate of Law from the University of Calgary, and was appointed a Citizen Ambassador to China, and has served as a member of the Native Physicians Association of Canada, the Canadian College of Health Service Executives, the Science Institute of the Northwest Territories, the Canada Science Council, and the International Society of Endovascular Surgeons, among others. He has been an inspiration to youth, motivating them to understand the importance of achieving higher education.

1 NurseCe4Less.com ABSTRACT

Many types of skin diseases can occur in people that range in onset and severity. Health providers need to be informed of the varied skin conditions and pharmacological therapy in order to appropriately inform patients of drug benefits and risks and to deliver comprehensive medical treatment. Dermatological treatment may be directed toward the management of an inflammatory process, comorbid medical conditions, or it may be cosmetic. There are evolving dermatology drug products and market factors that providers will need to guide patients on when addressing their skin health concerns and treatment choices. The effect of certain dermatological agents in special populations, such as during pregnancy can range from inconclusive to a known potential risk. When used in excessive amounts for prolonged periods of time, there are product warnings related to certain drug treatments for skin disease in pediatric, elderly and pregnant women. In pregnant women, for example, topical steroids have been classified as category C drugs, therefore caution must be observed to avoid harm to fetal health. More research is needed to determine the benefits and risks of dermatological agents used as cosmeceuticals and in the prevention and treatment of skin disease.

2 NurseCe4Less.com 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.

Continuing Education Credit Designation This educational activity is credited for 4 hours at completion of the activity. Pharmacology content is 4 hours.

Statement of Learning Need The skin is an important body organ, and health providers need to be informed about dermatology cosmeceuticals and used to treat various skin diseases. Many factors ultimately determine the therapeutic benefit of dermatology pharmaceuticals. A clinical knowledge of the many different types and forms of dermatology medication, an awareness of patient preferences for treatment, and the health benefits and risks of selected skin products, are essential for health clinicians when recommending, initiating and following the progress of skin treatment.

Course Purpose To provide interdisciplinary health professionals who work in dermatology, surgical, and general medicine areas of patient care with a general knowledge of dermatology pharmacology for varied skin conditions and to support clinician efforts to educate patients on appropriate medication use and compliance.

Target Audience Advanced Practice Registered Nurses, Registered Nurses, and other Interdisciplinary Health Team Members.

Disclosures Noah Carpenter, MD, Kellie Wilson, PharmD, William Cook, PhD, Douglas Lawrence, MA, Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures. There is no commercial support.

3 NurseCe4Less.com Self-Assessment of Knowledge Pre-Test:

1. ______is defined as a sudden, acute decrease in response to a drug after the drug is administered.

a. Tapering down b. Rebound effect c. Tachyphylaxis d. Topical nonadherence

2. Skin lesions are classified into two categories:

a. Primary and secondary skin lesions. b. Site involvement and structure affected. c. Congenital and acquired skin lesions. d. Skin lesions caused by an infectious agent or an autoimmune mechanism.

3. ______are at an increased risk of absorbing topical .

a. Infants b. Individuals who are overweight c. Women d. The elderly

4. ______is an antimitotic that reduces and can help treat psoriasis.

a. b. c. d. Anthralin

5. The term ______refers to the inactive part of a topical preparation that brings a drug into contact with the skin.

a. b. vehicle c. prilocaine d. astringent

4 NurseCe4Less.com Introduction

Patients with a dermatological concern may report a condition ranging from a serious diagnosis such as cancer to a cosmetic issue that impacts a person's physical and emotional health. A health provider will need to determine the cause of a skin disorder by evaluating whether there is a genetic abnormality, an , or an autoimmune mechanism that is causing a skin disorder. Identifying the site of involvement, the type of skin disorder, and the structure that is mainly diseased will be needed before determining treatment. Once a patient has been evaluated, there are topical medications, as well as oral or injectable medications that may be used for dermatological treatment. Topical treatments to select from are many and continue to grow in the area of dermatology, which may include , , corticosteroids, retinoids and biologics. Depending on the patient’s condition, an oral or injectable medication may be recommended. The treatment of an infectious or inflammatory will sometimes require the use of an antiviral or immunosuppressive agent. Dermatological treatment is presented in the following sections with a primary focus on the most common medications used. The important role of biologics in treating psoriasis and the FDA-approved biologics used for psoriasis and psoriatic arthritis are discussed.

Skin Disease Classifications and Treatments

Skin diseases are classified in various ways. The classifications and subcategories of a skin condition are briefly listed here but these are evolving.1 It is useful to look at skin conditions by identifying the site of involvement, the cause of the skin condition, and the main structure affected by the disease.2,3

The site of involvement may include facial rashes or lesions on sun- exposed sites. Skin lesions are classified into two categories: 1) Primary skin lesions, which are abnormal skin conditions from birth or that are acquired over a person’s lifetime, and 2) Secondary skin lesions, which are the result of irritated or manipulated primary skin lesions, such as when a person scratches a mole until it bleeds. In such instances, the resulting lesion, a crust,

5 NurseCe4Less.com becomes a secondary skin lesion.4 Pathogenesis may include genetic abnormalities, infectious etiology or autoimmune mechanisms. The main diseased structure may be epidermal disease, abnormalities of melanocytes, and vascular changes.4

Many different medications are used to treat different skin or conditions. There are topical medications as well as oral medications and injectable medications.

Topical Agents

Topical medications use vehicles that are the inactive part of the topical preparation and that help bring the drug into contact with the skin. The vehicles that deliver topical therapies include inactive ingredients such as powders, liquids, oils, or a combination of products. The location of application of the topical medication, the cosmetic effects, and convenience determine the choice of the vehicle. Some common topical treatments for skin conditions include those listed in this section.2,5-10

● Antibacterials: Mupirocin or clindamycin, are often used to treat or prevent infection. ● Anthralin: Anthralin is an antimitotic, is not often used because it can be irritating and can stain, but is used to reduce inflammation and can help treat psoriasis. ● Agents: (Lotrimin), ketoconazole (Nizoral), and (Lamisil AT), are a few examples ● Oral Antifungal Drugs: For the treatment of skin conditions such as ringworm and athlete's foot. ● Benzoyl Peroxide: Creams, gels, washes, and foams containing benzoyl peroxide are used to treat . ● Coal Tar: Available with/without a prescription, ranging from 0.5% to 5% in strength. Coal tar is used to treat conditions including seborrheic (usually in shampoos) or psoriasis. Currently, coal tar is seldom used because it can be slow acting and can cause severe staining of personal clothing and bedding.

6 NurseCe4Less.com ● Corticosteroids: Used to treat skin conditions including eczema, and are available in many different forms including foams, lotions, ointments, and creams. ● Non-steroidal Ointment: The ointment crisaborole (Eucrisa) is used to treat mild to moderate eczema. ● Retinoids: Retin-A and Tazorac are examples, and these are gels, foams or creams derived from vitamin A used to treat conditions including acne. ● : Sold in lotions, gels, soaps, shampoos, washes, and patches. Salicylic acid is the active ingredient in many skin care products for the treatment of acne and warts.

Oral or Injection Treatments

Some common oral or injection treatments used for skin conditions may include those listed here. A more detailed review of these treatments will be included in later sections of this course.2,8-13

● Antibiotics: Oral antibiotics are used to treat many skin conditions. Common antibiotics include dicloxacillin, erythromycin, and . ● Antifungal Agents: Oral antifungal drugs include and . These drugs can be used to treat more severe fungal infections. Terbinafine is an oral antifungal medicine that may be used to treat fungal infections of the nails. ● Antiviral agents: Common antiviral agents include acyclovir (Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex). Antiviral treatments are used for skin conditions including those related to herpes and shingles. ● Corticosteroids: These medications, including prednisone, can be helpful in treating skin conditions linked to autoimmune diseases including vasculitis and inflammatory diseases such as eczema. Dermatologists prefer topical steroids to avoid side effects; however, short-term use of prednisone is sometimes necessary. ● Immunosuppressants: Immunosuppressants, such as azathioprine (Imuran) and methotrexate (Trexall), can be used to treat conditions including severe cases of psoriasis and eczema.

7 NurseCe4Less.com ● Biologics: These new therapies are the latest methods being utilized to treat psoriasis and other conditions. Examples of biologics include adalimumab (Humira), adalimumab-atto (Amjevita), a biosimilar to Humira, brodalumab (Siliq), etanercept (Enbrel), etanercept-szzs (Erelzi), a biosimilar to Enbrel, infliximab (Remicade), ixekizumab (Taltz), secukinumab (Cosentyx), and ustekinumab (Stelara). ● Enzyme Inhibitors: Enzyme inhibitors such as apremilast (Otezla) shuts down an enzyme in the immune system to fight inflammation. Eucrisa is an enzyme inhibitor FDA approved for mild to moderate atopic dermatitis/eczema. ● Retinoids: Acitretin (Soriatane) is specifically used to treat all types of severe psoriasis. It reduces skin cell growth. It causes severe birth defects and should not be used if a woman is planning to become pregnant, is pregnant or is breastfeeding.

Antibacterial Agents and Antibiotics

Topical antibiotics play an important role in the management of many common dermatologic conditions. Some antibiotics may be used as systemic treatments through oral or injectable administration. They are prescribed most often for the management of mild-to-moderate acne vulgaris or as adjunctive treatment with oral agents. For localized superficial infections, such as impetigo, the use of a topical agent (mupirocin or retapamulin) may eliminate the need for oral antibiotics and the accompanying problems of patient compliance, gastrointestinal side effects, and potential drug interactions.2,18-15

Localized impetigo, superficial dirty abrasions, and secondarily infected chronic dermatoses are commonly treated with topical antibiotics. However, widespread impetigo, an infection of the lower extremities or disease occurring in immunocompromised individuals should be treated with systemic antibiotics to reduce the risk of serious complications.2,8-15

Topical antibiotics are used following minor surgical procedures. Petrolatum, commonly called petroleum jelly, may also be used. It acts as an

8 NurseCe4Less.com ointment or moisturizer to prevent dry, rough, scaly skin. When comparing bacitracin and petrolatum in minor surgical procedures bacitracin does not statistically decrease the already low rate of infection. Some patients are allergic to bacitracin. Petrolatum has been found to be of equal efficacy with fewer side effects than bacitracin. When clean wounds are made during minor surgery, there is no need to use antibacterial ointment to aid in healing or prevent infection.2,8-15 Because produce a fertile ground for life- threatening secondary infection, prophylactic topical therapy is often used.2,8- 15 Topical antibiotics, recommended uses and administration are listed next.

Mupirocin

Mupirocin, which was formerly known as pseudomonic acid A, is a topical agent derived from Pseudomonas fluorescens. The drug reversibly binds to isoleucyl-tRNA synthetase and inhibits bacterial protein synthesis.5

The activity of mupirocin is limited to Gram-positive bacteria, especially staphylococci and most streptococci. Its activity is enhanced in an acid pH environment (5.5), which is the normal pH of the skin. Mupirocin is somewhat temperature-sensitive, and thus loses efficacy if exposed to high temperatures.5

Mupirocin ointment 2% is applied three times daily and is principally indicated for the treatment of localized impetigo caused by S. aureus and Streptococcus pyogenes.5 Prolonged use of mupirocin ointment to control methicillin-resistant S. aureus (MRSA) carriage, especially in bedridden patients with decubitus ulcers, led to significant resistance.

Low serum concentrations of mupirocin are achieved after intranasal application, which might explain the selection of mupirocin-resistant strains of S. aureus.6 A small intranasal application of a combination antibiotic ointment containing bacitracin, , and gramicidin can successfully decolonize more than half of MRSA-positive patients who remain clear after an average follow-up of a few months. Mupirocin-sensitive MRSA has a high chance of

9 NurseCe4Less.com being eradicated; however, in cases that are mupirocin-resistant it is much harder to successfully treat S. aureus infection.6

New formulations that involve the use of the calcium salt of mupirocin (the calcium salt aids in chemical stability in the intranasal preparation) are available for intranasal use as a 2% ointment and a 2% topical cream.6

Retapamulin

Retapamulin is approved for the topical treatment of impetigo in patients older than 9 months of age.17 It is a semisynthetic pleuromutilin antibiotic derived from fermentation in Clitopilus paseckerianus with activity against staphylococci. The antibacterial mechanism of action is inhibition of protein synthesis. Allergic contact dermatitis to the active ingredient has been reported.7

Bacitracin

Bacitracin is a topical polypeptide antibiotic originally isolated from the Tracy-I strain of Bacillus subtilis.18 Bacitracin is a cyclic polypeptide with multiple components (A, B, and C). Bacitracin A is the major component of commercial products and is often used as the zinc salt. Bacitracin interferes with bacterial cell wall synthesis by binding to and inhibiting the dephosphorylation of a membrane-bound lipid pyrophosphate.8 It is active against Gram-positive cocci such as staphylococci and streptococci. Most Gram-negative organisms and yeast are resistant to the drug. It is available as bacitracin ointment and as zinc bacitracin, with 400 to 500 units per gram.8

Topical bacitracin is effective for the treatment of superficial bacterial infections of the skin such as impetigo, furunculosis, and pyodermas. It is often combined with polymyxin B and as a triple antibiotic ointment applied several times daily for the treatment of secondarily infected eczematous dermatitis such as atopic dermatitis, nummular dermatitis, or stasis dermatitis.8 Unfortunately, the topical application of bacitracin carries

10 NurseCe4Less.com with it the risk of allergic contact sensitization and, rarely, anaphylactic shock.8

Polymyxin B

Polymyxin B is a topical antibiotic derived from a spore-forming soil aerobe B. polymyxa.8 Polymyxin B is a mixture of polymyxin B1 and B2, which are both cyclic polypeptides. They function as cationic detergents that interact strongly with bacterial cell wall membrane phospholipids, thus disrupting the integrity of the cell membrane.8

Polymyxin B is active against a wide range of Gram-negative organisms, including P. aeruginosa, Enterobacter, and Escherichia coli.18 Polymyxin B is available in ointment form (5,000 to 10,000 units per gram) in combination with bacitracin or as triple antibiotic ointment with bacitracin and neomycin. It should be applied one to three times a day.8

Topical Aminoglycosides (Neomycin and )

The aminoglycosides are an important group of antibiotics used topically and systemically to treat infections caused by Gram-negative bacilli. Aminoglycosides exert their bactericidal effects by binding to the 30S ribosomal subunit and interfering with protein synthesis.9,10

Neomycin sulfate, the aminoglycoside most often used topically, is a fermentation product of Streptomyces fradiae. Commercial neomycin is a mixture of neomycin B and C, whereas framycetin, used in Canada and some European countries, is pure neomycin B.9,10 Neomycin sulfate has activity against aerobic Gram-negative bacteria and is used most commonly for prophylaxis against infection in superficial abrasions, cuts, and burns. It is available in ointment form (3.5 mg/g) and is also packaged in combination with other antibiotics such as bacitracin, polymyxin, and gramicidin.9,10 Many dermatologists do not recommend neomycin because it is responsible for a large number of cases of allergic contact dermatitis.9,10

11 NurseCe4Less.com Other agents, such as lidocaine, pramoxine, or are available in combination with neomycin.9,10 Neomycin sulfate (20%) in petrolatum is used to assess for contact allergy. Gentamicin sulfate is derived from the fermentation of Micromonospora purpurea. It is available as a topical 0.1% cream or ointment.9,10 Gentamicin sulfate is used by some dermatologic surgeons to provide prophylaxis against malignant otitis externa due to P. aeruginosa when operating on the ear, especially on diabetic or other immunocompromised patients. The ophthalmic formulation is useful in caring for operative wounds in the periorbital area.9,10

Sulfonamides (Silver and Mafenide Acetate)

Silver sulfadiazine and mafenide acetate are broad-spectrum antibacterials useful in the treatment of acne vulgaris, acne , and burns.11 Sulfacetamide is available as a 10% lotion and in combination with 5% sulfur in a gel, cream, suspension, cleanser, cloths, and mask.11

Most sulfonamides are structurally similar to PABA and compete with it during the synthesis of folic acid and their antibacterial mechanism of action is to compete with para-aminobenzoic acid (PABA) during the synthesis of folic acid; however, the mechanism of action of mafenide is not the typical mechanism of action since PABA does not antagonize mafenide’s performance.11 The mechanism of action of sulfonamides for topical treatment of rosacea is not understood.

Silver sulfadiazine is thought to release silver slowly. Silver sulfadiazine exerts its effect on the bacterial cell walls and membranes. Mafenide acetate, if used over large areas of skin, has the potential to cause metabolic acidosis, and intense pain on topical administration. Candida superinfection may also be a problem with mafenide cream.11

Nitrofurazone

Nitrofurazone (Furacin) is a derivative used for the treatment of burns.12 The mechanism of action involves the inhibition of bacterial

12 NurseCe4Less.com enzymes involved in aerobic and anaerobic degradation of glucose and pyruvate. Nitrofurazone is available as a 0.2% cream, solution, or soluble , and its spectrum of activity includes staphylococci, streptococci, E. coli, Clostridium perfringens, and Proteus spp.12

Gramicidin

Gramicidin is a topical antibiotic derived from B. brevis.13 The gramicidins are linear peptides that form stationary ion channels in susceptible bacteria. The antibiotic activity of gramicidin is restricted to Gram-positive bacteria.13

Clioquinol

Clioquinol (also known as iodochlorhydroxyquin) is a broad-spectrum antibacterial/antifungal topical that is currently indicated for the treatment of inflammatory skin disorders and tinea pedis and has been used for minor bacterial infections. It is a synthetic hydroxy-quinoline whose mechanism of action is unknown.14

The disadvantages of clioquinol include discoloration of clothing, skin, hair, and nails and the potential to cause irritation. Clioquinol may interfere with thyroid function determination when taken orally and possibly topically if used extensively.14 The iodine moiety interferes with tests that rely on iodine uptake (this effect can last for up to 3 months after application). However, clioquinol does not interfere with testing for T3 or T4.14

Erythromycin

Erythromycin belongs to the group of macrolide antibiotics and is active against both Gram-positive cocci and Gram-negative bacilli. It is used principally as a topical agent in the treatment of acne.15

Erythromycin binds to the bacterial 50S ribosomes and blocks translocation of the peptidyl-transfer RNA (tRNA) molecule from the acceptor

13 NurseCe4Less.com 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.15

Erythromycin is available as a 1.5% to 2.0% solution, gel, pledgets, and ointment as a single agent. It is also available in combination with benzoyl peroxide.15

Clindamycin

Clindamycin is a semisynthetic lincosamide antibiotic that is derived from lincomycin. The mechanism of action is very similar to that of erythromycin, with binding to the 50S ribosome and suppression of bacterial protein synthesis.16 Clindamycin is used topically as a 1% gel, solution, suspension (lotion), and foam primarily for the treatment of acne. It is also available as a combination with benzoyl peroxide, which may slow the development of antibiotic resistance to clindamycin. Pseudomembranous colitis rarely has been reported to occur with the topical use of clindamycin.16

Metronidazole

Metronidazole, a topical nitroimidazole, is currently available as a 0.75% gel, cream, or lotion and as a 1% cream or gel for the topical treatment of rosacea.17 In the lower strength, it is applied twice daily, and in the higher strength, it is used once daily. Orally, metronidazole has broad-spectrum activity against many protozoal organisms and anaerobes.17

Antifungals

Superficial fungal infections, including , candidiasis, and pityriasis versicolor, are most often restricted to the epidermis.18-20 In treating these infections, the clinician must select between topical or systemic management. Factors guiding management may include the 1) extent and severity of the infection, 2) site of involvement, 3) any comorbid conditions

14 NurseCe4Less.com or potential drug interactions, 3) anticipated efficacy of treatment, cost and access to medication, and 4) ease of use.18-20

Patients with limited fungal infections confined to glabrous skin are usually best treated with topical agents. Conversely, those with extensive or recalcitrant disease, or with involvement of terminal hair or nails, may be better suited for systemic management. In some cases, either treatment option may be reasonably chosen.18-20

Treatment with topical antifungal therapy enjoys several advantages over systemic management, including: fewer side effects, fewer drug interactions, localization of treatment, and generally lower cost.18-20 Numerous topical antifungal medications are available. For the most part, specific antifungal agents have replaced nonspecific topical treatments, such as keratolytics (salicylic acid) or (gentian violet or Castellani paint), which were once the first choice for management. The ideal topical antifungal is efficacious, inexpensive, well tolerated, and has low resistance within targeted fungi.18-20

Despite widespread availability, few topical antifungal agents have been directly compared with one another in clinical trials. Studies sponsored by the manufacturer often compare the active agent in the antifungal to the delivery vehicle. Extrapolation between studies is further complicated due to differences in study design, duration of therapy, site of infection, selection methodology, or treatment endpoint. Topical antifungals typically fall into one of three classes: 1) , 2) and , and 3) polyenes.18-20

Imidazoles

Imidazoles represent a broad class of antifungal medications. Certain of these, such as clotrimazole, have been around for decades, while others, such as , have only become available recently.20-22 Imidazoles impede synthesis of a component of the fungal cell wall through inhibition of lanosterol 14α-demethylase, a cytochrome P450-dependent enzyme, which converts

15 NurseCe4Less.com lanosterol to .20-22 Depletion of ergosterol results in membrane instability and hyperpermeability; changes incompatible with growth and survival of the fungus. Imidazoles are considered fungistatic in practical application, with the possible exception of sertaconazole when used to treat some Candida species.20-22 While all imidazoles possess the same mechanism of action, in-vitro studies demonstrate that not all dermatophytes are uniformly susceptible to an at an equivalent concentration, and this may explain some treatment failures.20-22

Topical imidazoles possess anti-inflammatory activity via inhibition of neutrophil chemotaxis, calmodulin activity, synthesis of leukotrienes and prostaglandins, and histamine release from mast cells. Some agents, such as ketoconazole, yield anti-inflammatory effects equivalent to 1% hydrocortisone.20-22 Topical imidazoles also demonstrate limited antibacterial properties, particularly with respect to gram-positive organisms.20-22 All marketed imidazoles demonstrate excellent penetration of the stratum corneum with strong keratinophilic behavior. may be detected in the stratum corneum up to 96 hours after application. Similarly, sertaconazole, the newest of all marketed imidazoles, has a half-life within the stratum corneum of more than 60 hours.20-22

Because of this high affinity for keratin, systemic absorption of imidazoles is low, with urinary excretion usually in the range of 0.3%–1.0% of the applied dose.20-22 Even when applied to inflamed skin, absorption of imidazoles does not usually exceed 4% of the applied dose. Again, sulconazole is unique in that percutaneous absorption in the range of 8%–11% of the applied dose exceeds that of all other imidazoles.20-22

Due to inherent antibacterial activity, some topical imidazoles have demonstrated modest efficacy in treating erythrasma, impetigo, and ecthyma. Because there are more potent antibacterial agents, this is not a preferred indication for imidazole use.20-22 Cure rates for superficial fungal infection treated with imidazoles are variable and often depend upon study design. A thorough review of the literature provides no compelling evidence that significant differences in cure or relapse exist among the various topical

16 NurseCe4Less.com imidazoles; however, other considerations may dictate the selection of a particular imidazole.20-22

Topical imidazoles are available as a cream or lotion. Although lotions are better suited for use over large areas or upon hair-bearing skin, limited studies suggest a cream may be marginally more effective. In studies performed by the manufacturer, cream yielded a clinical and mycologic cure in an approximate half of tinea pedis cases while the lotion yielded the same cure.20-22 Additionally, the potential for irritancy must be considered. Topical clotrimazole for the treatment of has shown erosive reactions in patients while sulconazole did not cause any erosion in the reviews.20-22

Topical imidazoles are available in a multitude of forms. , ketoconazole, and oxiconazole are approved for once-daily dosing but twice- daily dosing is recommended for the remainder. Although twice-daily dosing is recommended for sulconazole, a study comparing once-daily to twice-daily dosing in tinea corporis and tinea cruris reported an identical rate of cure.20- 22 This might have been predicted based upon the 60-hour half-life within the stratum corneum. Application of all topical antifungals, including imidazoles, should include normal skin for a radius of 2 cm beyond the affected area. Duration of treatment with imidazoles has varied. In general, tinea corporis and tinea cruris require treatment for approximately 2 weeks, whereas tinea pedis may require treatment for up to 4 weeks. Treatment should be continued for at least 1 week after all symptoms have abated.20-22

Risks associated with the use of topical imidazoles include those inherent to all topical medications, and consist chiefly of irritant and allergic reactions. Additionally, clotrimazole is marketed in combination with the topical glucocorticoid, dipropionate. It was initially assumed that the addition of the steroid would more rapidly relieve inflammation, scaling, and pruritus.20-22 The combination has been found to be more effective than clotrimazole alone in alleviating symptoms. However, betamethasone dipropionate is a potent topical steroid, and striae and other cutaneous side effects from the steroid component may occur.

17 NurseCe4Less.com It is likely that overuse by non-specialists occurs because of the mistaken assumption either that the steroid agent is mild, or that the combination will be a better choice when the differential diagnosis is unresolved. The U.S. Food and Drug Administration (FDA) has twice revised the product warnings for clotrimazole-betamethasone dipropionate, discouraging use on thin skin, for prolonged periods, or when the diagnosis is in doubt.20-22

Use of topical imidazoles is associated with few complications. Because of low systemic absorption, drug reactions with topical imidazoles are rare.20- 22 Concerns of resistance must also be considered. Resistance of to clotrimazole has been described in human immunodeficiency virus- positive patients with mucocutaneous candidiasis. There has also been documentation of low levels of in-vitro resistance of various Candida species to other topical imidazoles. Often, this resistance is associated with resistance to oral fluconazole.20-22

Allylamines and Benzylamines

Allylamines and benzylamines are closely related compounds. Currently, two topical allylamines and single topical are marketed in the United States. Allylamines and benzylamines impede synthesis of ergosterol through inhibition of squalene epoxidase, an enzyme that converts squalene to squalene oxide.23

Depletion of ergosterol results in membrane instability and hyperpermeability. Allylamines and benzylamines are considered fungicidal because the accumulation of intracellular squalene leads directly to cell death. The clinical significance of this cidal action is unclear.23 Unlike imidazoles, the activity of allylamines and benzylamines is independent of the cytochrome P450 enzyme system. When compared to , terbinafine demonstrates a 10- to 100-fold increased potency in vitro, although this does not appear to be relevant in clinical use.23

18 NurseCe4Less.com Like imidazoles, allylamines, and benzylamines demonstrate anti- inflammatory activity. Naftifine inhibits adhesion of polymorphonuclear cells to endothelium, interrupts chemotaxis, and inhibits the 5-lipoxygenase proinflammatory pathway.23,24 It is assumed that terbinafine and yield anti-inflammatory effects through similar mechanisms. Allylamines and benzylamines also demonstrate limited antibacterial properties.23

Allylamines and benzylamines are highly lipid soluble and efficiently penetrate the stratum corneum, where they may persist for extended durations.23,24 Butenafine has been detected within the stratum corneum at minimum inhibitory concentration for at least 72 hours after application, and terbinafine may persist at a similar level for up to 7 days after application. Systemic absorption of these agents is quite low, with typical urinary excretion in the range of 3%–5% of the applied dose.23,24

Despite antibacterial properties, terbinafine has proven inferior to mupirocin for treatment of impetigo, and a traditional antibacterial agent should be used. Similarly, although allylamines and benzylamines do demonstrate activity against fungi involved in systemic infection, such as Sporothrix schenckii, Blastomyces dermatitidis, and Histoplasmosis capsulatum, topical therapy is inappropriate.23,24

Limited evidence suggests that topical allylamines or benzylamines may be preferred over topical imidazoles for certain dermatophyte infections. In cases of tinea pedis one week of topical terbinafine may be as effective as four weeks of topical imidazoles, with a high rate of cure.23,24 Use of this abbreviated treatment with terbinafine has been confirmed in trials using the active agent versus vehicle alone.

In some instances, resolution of tinea pedis using terbinafine has occurred with as few as three doses.23,24 Generic terbinafine 1% cream is more expensive than an equivalent amount of clotrimazole 1%, but considering the frequency of application, the amount of medication required, the likelihood of patient compliance and ease of use, and the rapidity of results, some experts recommend topical terbinafine over topical imidazoles for tinea pedis.23,24

19 NurseCe4Less.com 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 the use of topical allylamines and benzylamines are those inherent to all topical medications.23,24 A possible interaction between topical terbinafine and acenocoumarol may exist, however complications arising from the use of topical allylamines or benzylamines are few.23,24

Polyenes

Polyenes were among the first agents discovered to possess specific antifungal properties. The two major topical polyene antifungals are and .25 Only topical nystatin is actively marketed in the United States. Like all polyenes, nystatin binds irreversibly to membrane sterols present in susceptible species of Candida.25 The polyene molecules demonstrate a higher affinity for fungal sterols, including ergosterol, than for human sterols, yielding imperfect selective toxicity. This irreversible binding alters membrane permeability, causing leakage of essential intracellular components and fungal death. In low concentrations, nystatin is fungistatic, but, at high concentrations, it may be fungicidal.25

Nystatin is insoluble in water and is not absorbed from intact skin, the gastrointestinal tract, or the vagina. Topical nystatin is used to treat mucocutaneous candidiasis caused by C. albicans, and other susceptible species such as C. parapsilosis, C. krusei, and C. tropicalis.25,36 Repeated studies have demonstrated that topical imidazoles are more effective than nystatin in treating vulvovaginal candidiasis, and use of nystatin for this indication has diminished in recent years. Nystatin is not effective against dermatophytes or Pityrosporum; and, hence, it is not indicated for treatment of tinea or pityriasis versicolor.25,26

Nystatin is available as a powder, cream, ointment, suspension, and pastille. To treat oral candidiasis (thrush), the suspension or pastille is used four to five times daily, usually for 2 weeks.26 To treat cutaneous infection,

20 NurseCe4Less.com the powder, cream, and ointment are used twice daily for approximately two weeks. Risks associated with the use of topical nystatin are those inherent to all topical medications. A significant number of cases of allergic contact dermatitis attributed to nystatin alone have been reported. These reactions have been reported with topical and oral use. Anaphylaxis has been described with the use of nystatin-containing vaginal suppositories but the reaction was attributed to ingredients other than nystatin.26

A combination agent consisting of nystatin and triamcinolone acetonide is widely marketed.27 The addition of triamcinolone may provide additional benefit over nystatin alone during the first few days of treatment when inflammation is maximal.27 After this initial period, the manufacturer recommends a transition to nystatin alone or to other topical antifungal agents. Although triamcinolone acetonide is only a mid-potency agent, cutaneous sequelae, including striae, skin atrophy, and steroid-induced acne, has been reported. Because candidiasis often involves thin and fragile skin, such as that of the intertriginous areas, the risk of damage is likely potentiated. Many of the combined formulations contained, or may still contain, ethylenediamine, a sensitizer that may cause allergic contact dermatitis. As with clotrimazole-betamethasone dipropionate, the combination agent of nystatin triamcinolone acetonide is more often prescribed by non-dermatologists.27

Complications with topical polyenes are few. Nystatin resistance may be encountered in some Candida. This resistance may either be seen in wild strains (primary type) or it may be induced during therapy (secondary type).24 Although C. albicans maintains a low rate of spontaneous resistance to nystatin, particularly in comparison to resistance to imidazoles, other species, such as C. tropicalis, C. guilliermondii, C. krusei, and C. stellatoidea, rapidly acquire resistance upon exposure to nystatin.24

Ciclopirox Olamine

Ciclopirox olamine is a hydroxypyridone antifungal agent with a unique structure and mode of action. Unlike most other topical antifungals, ciclopirox

21 NurseCe4Less.com olamine does not interfere with sterol synthesis.28-30 Instead, it interrupts active membrane transport of essential cellular precursors, particularly trivalent cations. Ultimately, this disrupts cellular function, leading to the demise of the fungus. If concentrations of the drug are high enough, the membrane integrity of the fungus may actually be impaired.28-30

Ciclopirox olamine also has inherent anti-inflammatory activity exerted through inhibition of prostaglandin and leukotriene synthesis within polymorphonuclear cells. Broad-spectrum antibacterial properties have also been attributed to ciclopirox olamine. In one study, topical ciclopirox olamine had broader coverage against Gram-positive and Gram-negative organisms than did topical imidazoles or topical allylamines.28-30

When applied to the skin, ciclopirox olamine remains in high concentration within the epidermis and upper dermis. Ciclopirox Olamine penetrates keratin easily, with cadaveric skin demonstrating concentrations in the epidermis that were 10–15 times the minimum inhibitory concentration for a sensitive species.28-30 This ability to penetrate keratin recommends use for , as the drug is also capable of penetrating the nail plate material. Studies of drug metabolism have demonstrated that, with typical use, approximately 10% of the administered dose is excreted in the urine.28- 30

Ciclopirox olamine is indicated for the treatment of dermatophytoses and onychomycosis, candidiasis, pityriasis versicolor, seborrheic dermatitis, and even cutaneous infections with unusual saprophytes. In tinea pedis, a mycologic cure rate of up to 85% has been observed, and in seborrheic dermatitis, a significantly larger percentage of users had >75% improvement within 2 weeks of use than those using the shampoo vehicle alone.28-30 Although treatment with ciclopirox olamine for tinea pedis and seborrheic dermatitis has yielded results on par with other modalities, use in onychomycosis has met with more modest success.28-30

Often, an assessment of efficacy depends upon whether a mycologic cure (culture-negative) or clinical cure (a disease-free nail) defines success.

22 NurseCe4Less.com Although a disease-free nail is often the patient’s true goal, ciclopirox olamine achieved such a response in just 5.5%–8.5% of those treated with a standard 48-week course.28-30 Use of oral terbinafine in combination with topical ciclopirox olamine is more effective as compared to treatment with oral terbinafine alone.28-30

Debate regarding the use of ciclopirox olamine as an independent or adjunct treatment for onychomycosis is ongoing. Ciclopirox Olamine is available in a wide range of forms.28-30 Cutaneous candidiasis, dermatophytosis, and pityriasis versicolor should be treated twice daily for 2 weeks to 1 month, but treatment for tinea pedis should continue 1 month or longer.28-30 When using ciclopirox shampoo for seborrheic dermatitis, treatment may continue twice weekly for an indefinite duration. Improvement is generally noted in 2–4 weeks. Finally, in treating onychomycosis, nail lacquer is applied daily to the nail and hyponychium for 48 weeks and excess medication is removed weekly with alcohol.28-30

Risks associated with the use of topical ciclopirox olamine are those inherent to all topical medicaments. Allergic contact dermatitis has been reported only rarely, and ciclopirox olamine is considered a weak sensitizer. In patients with an allergic reaction to ciclopirox, imidazoles may be used with relative safety because of a markedly different chemical structure. Serious complications with topical ciclopirox olamine are few.28-30

Tolnaftate

Tolnaftate is a thiocarbamate is contained in over-the-counter antifungal remedies. The precise mechanism of action of tolnaftate is unknown.32 It is thought to impair ergosterol synthesis via inhibition of squalene epoxidase but in a different manner than that of allylamines and benzylamines. Tolnaftate may be fungistatic or fungicidal, depending upon the concentration. No antibacterial properties have been attributed to tolnaftate. Little data exists regarding the pharmacokinetics of tolnaftate.32

23 NurseCe4Less.com 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.32 Although direct comparisons are lacking, topical tolnaftate is widely considered less effective than topical imidazoles, allylamines, and benzylamines. Tolnaftate is ineffective for candidiasis.32

Tolnaftate is available in a variety of formulations. Twice-daily use for at least 2 to 4 weeks, and up to 6 weeks on hyperkeratotic skin, is recommended. To diminish the incidence of recurrence, others simply recommend treatment be continued 2 weeks beyond apparent resolution.32 Risks associated with the use of topical tolnaftate are those inherent to all topical medicaments. Allergic contact dermatitis has been reported on occasion. Serious complications with the use of topical tolnaftate are few.32

Undecylenic Acid

The mechanism of action for undecylenic acid is largely unknown. It appears that the organic acid interacts with components in the fungal cell wall. In C. albicans, the inhibition of germ tube formation has been recently identified, and a similar effect has been noted in conidia formation in Trichophyton rubrum.33

Undecylenic acid is available as zinc, calcium, or copper salt. As tissue pH rises, this salt fails to dissociate, and antifungal properties of the medication diminish. The acid is practically insoluble in water, but is miscible in ethanol, water, or ether. With topical use, systemic absorption is negligible.33 The zinc contained in the zinc undecylenate form, the most common in clinical use, provides some astringent action that may aid in reducing rawness and irritation. Topical undecylenic acid is used for the treatment of dermatophytosis and candidiasis.33

24 NurseCe4Less.com 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 , clotrimazole, or tolnaftate in the treatment of tinea pedis.33 A trial of topical undecylenic acid for herpes labialis demonstrated a decreased incidence and duration of viral shedding, with a decrease in pain and tenderness. The antiviral effect was of short duration and most pronounced when acid was applied during the prodrome.33

Other long chain enjoy specific approval for abbreviation of herpes labialis and appear more effective. Undecylenic acid and its salts are available as a powder, aerosol, cream, and solution. Standard dosing for children and adults is twice-daily for 4 weeks of use.33 Risks associated with the use of topical undecylenic acid are those inherent to all topical medicaments. Allergic contact dermatitis has been recently reported, and a protocol for patch testing exists if such an allergy is suspected.33

Topical forms of undecylenic acid may yield an unpleasant “fishy smell” that discourages use. Complications with topical undecylenic acid are few. Because undecylenic acid is widely accepted to be less effective than imidazoles, clinical monitoring for treatment failure is indicated.33

Corticosteroids

Topical corticosteroids are used to relieve inflammation and pruritus of contact dermatitis, insect bites, minor burns, seborrheic dermatitis, psoriasis, and eczema.34 These medications contain a drying agent or conversely an emollient and are usually found in creams, ointments, lotions, and gels to facilitate absorption at the site of action. Absorption is high in areas of thin skin, but penetration is poor with thick skin. These preparations vary widely in strength, with those available over the counter (OTC) being of low potency.34

Systemic toxicity may be a side effect with long-term therapy using high-potency topical preparations. Site of application influences the

25 NurseCe4Less.com 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.34

Corticosteroids have specific and nonspecific effects that are related to different mechanisms of action, including anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.34 Most of their actions are mediated by an intracellular receptor called the glucocorticoid receptor. The glucocorticoid receptor α-isoform is located in the cytosol, binds glucocorticoids, and translocates to a region of the nuclear DNA known as the responsive element, where it is then able to stimulate or inhibit transcription of the adjacent genes, thus regulating the inflammatory process.34

The glucocorticoid receptor β-isoform does not bind glucocorticoids, but is able to bind the antiglucocorticoid/antiprogestin compound RU-486 to regulate gene expression. The glucocorticoid receptor β can attenuate the ligand-mediated transactivation of hormone-sensitive genes by the α-isoform and may be an important marker of steroid insensitivity.34

Anti-Inflammatory Effects

Corticosteroids are thought to exert their potent anti-inflammatory effects by inhibiting the release of phospholipase A2, an enzyme responsible for the formation of prostaglandins, leukotrienes, and other derivatives of arachidonic acid pathway.35 Corticosteroids also inhibit transcription factors, such as activator protein 1 and nuclear factor κβ, which are involved in the activation of proinflammatory genes. Genes known to be upregulated by corticosteroids and that play a role in the resolution of inflammation include lipocortin and p11/calpactin-binding proteins, both involved in the release of arachidonic acid.35

Lipocortin I inhibits phospholipase A2, reducing the release of arachidonic acid from phospholipids. Corticosteroids also decrease the release

26 NurseCe4Less.com 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.35

Immunosuppressive Effects

The effectiveness of corticosteroids is, in part, also due to their immunosuppressive properties. Corticosteroids suppress the production and effects of humoral factors involved in the inflammatory response, inhibit leukocyte migration to sites of inflammation, and interfere with the function of endothelial cells, granulocytes, mast cells, and fibroblasts.35-37 Several studies have shown that corticosteroids can cause mast cell depletion in the skin. Experiments have also shown that topical corticosteroids cause local inhibition of chemotaxis of neutrophils in vitro, and decrease the number of Ia+ Langerhans cells in vivo.35-37

Corticosteroids reduce eosinophilia in patients with asthma. They also reduce T-cell proliferation and induce T-cell apoptosis, in part from inhibition of the T-cell growth factor IL-2. In addition, several cytokines are directly affected by corticosteroids, including IL-1, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, and IL-8. These effects may also be a result of steroid action on antigen presenting cells.35-37

Antiproliferative Effects

The antiproliferative effect of topical corticosteroids is mediated by inhibition of DNA synthesis and mitosis, partly explaining the therapeutic action of these drugs in scaling dermatoses. They are known to reduce the keratinocyte size and proliferation. Fibroblast activity and collagen formation are also inhibited by topical corticosteroids.35-37

27 NurseCe4Less.com 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.35-37 The ability of a given corticosteroid agent to cause vasoconstriction usually correlates with its anti-inflammatory potency and, thus, vasoconstriction assays are often used to predict the clinical activity of an agent. These assays, in combination with double blind clinical trials, have been used to separate the topical corticosteroids into seven classes based on potency. Class 1 includes the most potent, while class 7 contains the least potent.35-37

Modifications of Cortisol and Preparation Choice

Modifications of cortisol, by addition or alteration of functional groups, have led to the development of compounds with variable anti-inflammatory potency, glucocorticosteroid versus mineralocorticoid activity, and adverse effects.35-37 Before choosing a topical glucocorticoid preparation, patient- related and drug-related factors that can affect its systemic absorption should be taken into account. This would include the age of the patient, the extent and location of the body surface area to be treated and the presence or absence of skin inflammation, which greatly affect the activity of the topical agent.35-37

Penetration of the glucocorticoid varies according to the skin site, which, in turn, is related to the thickness of the stratum corneum and the vascular supply to the area.35-37 For example, penetration of topical steroids through the eyelids and scrotum is four times greater than for the forehead and 36 times greater than for the palms and soles. Inflamed, moist, and denuded skin also shows increased penetration.35-37

Areas of the body where the skin is inherently thin allow for increased penetration of the drug and are also more susceptible to developing side

28 NurseCe4Less.com 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.35-37 The concentration of the therapeutic agent used, the duration of the application, the use of occlusive dressings, the elected vehicle, and the intrinsic characteristics of the chosen molecule, can also affect the absorption and the degree of adverse effects.35-37

The target site for topical corticosteroids is the viable epidermis or dermis, and clinical response to a formulation is directly proportional to the concentration of corticosteroid achieved at the target site.35-37 A comparison study of skin concentrations after topical versus oral corticosteroid treatment found that most topical corticosteroids have the potential to achieve greater effective drug levels in the superficial layers of the skin than those achieved with standard doses of oral prednisone. Therefore, the apparently greater efficacy of oral corticosteroid therapy may be due in part to poor patient compliance with topical therapy.35-37

Topical corticosteroids are compounded in several formulations and with varying strengths. Recent research has emphasized the importance of treatment adherence in the management of skin conditions. As such, newer formulations including spray, foam, lotion, hydrogel, and shampoo formulations have been developed to improve patient convenience and acceptance, without sacrificing the efficacy, safety and tolerability of the traditional ointment and cream formulations.35-37 A recent systematic review of the literature found that while there are few direct comparison studies between clobetasol propionate, a class 1 steroid, in different vehicles, the efficacy rates for more recent formulations is roughly comparable to that of clobetasol ointment in the treatment of psoriasis. The most common adverse effect was mild and transient stinging or burning at the lesion site, which may be due to the alcohol content found in these formulations. None of the clinical trials directly compared these formulations with one another.35-37

Increasing hydration of the stratum corneum can enhance absorption of topical corticosteroids by four to five times.35-37 Absorption is also enhanced by ten times with occlusion. A retrospective study of wet dressings used with

29 NurseCe4Less.com 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.35-37

Topical corticosteroids are recommended for their anti-inflammatory activity in inflammatory skin diseases, but they can also be used for their antimitotic effects and capacity to decrease the synthesis of connective tissue molecules. Certain variables must be considered when treating skin disorders with topical glucocorticoids.35-37 For example, the responsiveness of diseases to topical glucocorticoids varies depending on whether the disease state is highly responsive, moderately responsive, or least responsive.

Corticosteroids have been used with success for atopic dermatitis for several decades. Placebo-controlled trials have found them effective in more than half or more of patients with atopic dermatitis when compared with fewer than 30% of placebo-treated patients.35-37 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.35-37

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.35-37

Infants and Children

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.24,38 However, children and, in particular, infants,

30 NurseCe4Less.com 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.24,38

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.24,38

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 with cosyntropin is more accurate. If suppression is present, the child should be slowly weaned from the steroids to prevent these complications.38,39

Hemangiomas of infancy show a good or partial response to treatment with ultrapotent topical glucocorticoids in a majority of infants where there was 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.24,38,39 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.24,38-40

31 NurseCe4Less.com Elderly

Elderly patients similarly can have thin skin, which allows for increased penetration of topical glucocorticoids.24 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.24

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.41 The safety of topical corticosteroids in pregnancy performed according to 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.41

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.41 Most of the previous studies only assessed the risk of 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 risk.41

32 NurseCe4Less.com It is currently unknown whether topical glucocorticoids are excreted in breast milk. It is recommended that they should be used with caution in breastfeeding mothers and never used on the breasts before breastfeeding.41

Corticosteroids Dosing Regimen

The frequency of topical application of corticosteroids was developed in an empirical manner, with most textbooks and physicians recommending twice-daily use. For super potent corticosteroids, once-daily application is considered as beneficial as twice-daily application.24,42 Likewise, there is at best a slight difference with once versus twice daily application of potent or moderately potent corticosteroids.

Clinical observations of treatment outcomes suggest that a once-daily application of topical corticosteroids may be as effective as twice daily, while decreasing the risk of side effects, such as tachyphylaxis (a sudden, acute decrease in response to a drug after the drug is administered to a patient). A once-daily application also reduces the cost of therapy, and has better patient compliance.24,42

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.24,42

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, chemistry panel, and a baseline morning cortisol level should be performed. In a patient with

33 NurseCe4Less.com confirmed HPA suppression, gradual reduction of potency and amount of topical steroid, and possibly the simultaneous institution of oral steroid supplementation, are needed.24

Risks and Precautions

Local as well as systemic side effects have been documented with the use of topical corticosteroids. Under normal conditions, almost all of the applied topical corticosteroid (up to 99%) is cleared from the skin, and is minimally therapeutically active.24 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.24 Considerations for prescribing topical corticosteroids to prevent side effects should be followed.

Complications

Local adverse effects caused by topical corticosteroid use are more prevalent than systemic reactions. These effects are mostly due to the tendency of these agents to inhibit cell growth.24

Atrophic Changes

The most conspicuous adverse effect to the skin is skin atrophy. It involves both the epidermis and dermis. Dermal atrophy develops from the antiproliferative effects directly caused by topical corticosteroids on fibroblasts, which inhibits the synthesis of collagen and mucopolysaccharide. This results in a loss of dermal support.24

Reduction of glycosaminoglycan production has also been described. Levels of hyaluronan, the major glycosaminoglycan in the skin, are also rapidly decreased after short-term glucocorticoid treatment, because of decreased hyaluronan synthesis.24 There is fragmentation and thinning of elastic fibers in the upper layers that develops; however, the deeper fibers form a compact and dense network. These atrophic changes reportedly lead to “vascular

34 NurseCe4Less.com dilatation, telangiectasias, purpura, easy bruising, stellate pseudoscars (purpuric, irregularly shaped, and hypopigmented atrophic scars), and ulceration.”24 While somewhat reversible, the formation of striae (visible linear scars) that develop in areas of dermal damage believed to occur during mechanical stress are permanent.24

Acneiform Reactions

The development or exacerbation of dermatoses of the face, including steroid rosacea, acne, and , 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.24,43 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.24,43

Prolonged corticosteroid treatment can also result in “,” 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 change after withdrawal of high-potency, topical corticosteroid therapy to an extensive surface area for a prolonged period of time.24,43

Hypertrichosis

Hypertrichosis occurs rarely in women and children who apply potent corticosteroids to the face. The mechanism is still unknown.24,43

Pigmentary Changes

Decreased pigmentation is a common side effect of topical steroid use. The pigment generally returns after discontinuation of therapy.24,43

35 NurseCe4Less.com 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 estimated to be less than half of all cases. Tinea versicolor, disseminated Alternaria infection, and dermatophytosis, including tinea incognito (masked dermatophyte infection), can develop.24,43 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.24,43

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.24,43 The prevalence of topical corticosteroid sensitization ranges but has been reported to be less than 10%, and increases with prolonged exposure and selection of certain drugs.24,43

A classification has been created to determine cross-reactivity among the various available preparations.24,43 This classification has four groups on the basis of structure and cross-reactivity 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.24,43 Patch-test reactions to class A steroids are most common, whereas patch-test reactions to class C steroids are extremely rare.24,43 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. Desoximetasone

36 NurseCe4Less.com 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.24,43 There are seven vehicle ingredients that are commonly used in topical corticosteroid preparations and are well known allergens; these included propylene glycol, sorbitan sesquioleate, formaldehyde-releasing preservatives (imidazolidinyl and diazolidinyl urea), parabens, methylchloroisothiazolinone/methylisothiazolinone, lanolin, and fragrance. Of all topical corticosteroids (including all creams) most of them 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.24,43

Topical corticosteroid potency depends on drug characteristics, concentration and base used. Class I is the most potent. Class VII is the least potent. 24,43-45

RELATIVE POTENCY OF TOPICAL CORTICOSTEROIDS24,43-45 CLASS I DRUGS Betamethasone dipropionate 0.05% ointment Clobetasol propionate 0.05% cream or ointment Diflorasone diacetate 0.05% ointment Halobetasol propionate 0.05% cream or ointment CLASS II DRUGS 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 Mometasone furoate 0.1% ointment

37 NurseCe4Less.com CLASS III DRUGS 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 CLASS IV DRUGS 0.025% ointment Flurandrenolide 0.05% ointment Mometasone furoate 0.1% cream or lotion Triamcinolone acetonide 0.1% cream or ointment CLASS V DRUGS 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 CLASS VI DRUGS 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 Triamcinolone acetonide 0.1% cream Triamcinolone acetonide 0.025% cream or lotion CLASS VII DRUGS Hydrocortisone 1% or 2.5% cream, 1% or 2.5% lotion, 1% or 2.5% ointment

38 NurseCe4Less.com Topical Retinoids

Retinoids are widely used in topical preparations as cosmeceuticals and prescription drugs. Retinoids may contain naturally occurring compounds or they may be made using 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, photoaged skin, and melasma.24 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 the management of cutaneous T-cell 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.24,46-48

Of the different classes of anti acne 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 anti acne regimens. A potential for aggravating inflammation exists in treating inflammatory acne (papules and pustules) with topical retinoids, but when properly administered, this type of acne also responds well to retinoids.24,46-48

Fine wrinkles and dis-pigmentation are two features of photoaged 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.48

The ability of tretinoin to improve photo-aging is 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-

39 NurseCe4Less.com aging; however, a recent study indicates that it also holds promise in ameliorating the clinical features of photo-damage.49

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.48

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 dermatologic conditions seen in pregnancy that may respond to topical retinoids (i.e., acne, melasma, stretch marks) is life-threatening to the mother or the fetus, it seems prudent to delay the treatment until after delivery.24 Early inflammatory stretch marks have been reported to improve 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.24,48

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 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.46-48

Tretinoin 0.05%/hydroquinone 4%/fluocinolone 0.1% is a topical combination approved for the treatment of melisma (a common condition of grey-brown patches on the face).48 Different formulations allow some

40 NurseCe4Less.com 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.46-48

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 not been supported by subsequent reports in which 0.025% and 0.1% tretinoin were shown to be equally effective, but the former was significantly less irritating than the latter.24,48 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 once-daily regimen. This method of individualizing topical therapy minimizes unwanted acute retinoid dermatitis.24,48

Under the nonprescription category, there are countless “natural retinoid” preparations with various claims (mostly anti-aging) being sold throughout the world. Most of these contain retinyl , 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.24 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.24

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.24

41 NurseCe4Less.com 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 fine wrinkles associated with atrophic, naturally aged skin of the elderly.24

Risks and Precautions

The most common adverse effect associated with topical retinoid use is local skin irritation. It is characterized by erythema, peeling, dryness, tightness, and a burning sensation. This response is temporary but many patients find it mildly distressing. This skin irritation tends to peak within the first month of treatment and diminishes thereafter.24 It responds to a temporary reduction in the frequency or amount of retinoid application and to liberal use of emollients.24

This signaling pathway in the hyperplastic response of the epidermis to topical retinoids has been reportedly demonstrated with the use of pharmacologic agents that blocked retinoid-induced epidermal thickening in human skin organ culture and in vivo.24 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.24

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-to- moderate with a small number of patients requiring treatment withdrawal in clinical trials.24 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.46-48,50

42 NurseCe4Less.com 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 one month.24 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.24 Indeed, a large, population-based study demonstrated no excess risk of birth defects in offspring born to mothers who were exposed to topical tretinoin during pregnancy. Therefore, no evidence exists for teratogenicity of topical tretinoin in humans.24,48

“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.48 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).48-50

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.24 Specifically, the traditional rodent models significantly overestimate the human carcinogenic potential of tested agents.

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

43 NurseCe4Less.com nonmelanoma skin cancer, systemic retinoids have provided effective protection.24,50

Clinically observed anticarcinogenic activities of retinoids have been 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.24

Drug Interaction and Compatibilities

Retinoids, in general, are photo-labile and therefore can be photo- inactivated. 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.24 Ketoconazole and liarozole are effective inhibitors of CYP26 and, therefore, are RAMBAs. Concurrent use of these and topical tretinoin can increase the amount and prolong the half-life of tretinoin locally in the skin, thereby aggravating local side effect.24

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. Topical retinoids can positively influence vitamin D pharmacology in human skin.24

Antiviral and Immunosuppressant Agents

The treatment of infectious or inflammatory skin conditions will sometimes require the use of antiviral or immunosuppressive agents. The most common medications used are discussed here.

44 NurseCe4Less.com Antivirals

Antiviral medications prevent the varicella virus (shingles and herpes) from multiplying, speed healing of skin lesions, and reduce the severity and duration of pain.24,51 Antivirals are most effective when given within 72 hours of the first appearance of a rash. Patients who do not begin treatment with an antiviral drug within 72 hours, may still benefit from taking one.24,51

There are three antiviral drugs for treating shingles: Zovirax (acyclovir), Famvir (famciclovir), and Valtrex (valacyclovir).51-53 People with compromised immune systems (such as organ donors and those with advanced infection with human immunodeficiency virus, or HIV) may require intravenous acyclovir. Acyclovir tends to be the least expensive of these but it must be taken more frequently than the other drugs.51-53

Immunosuppressants

It is important to understand that immunosuppressant drugs used to treat severe eczema were originally developed to prevent skin graft rejection in transplant patients. Currently immunosuppressant drugs are used to treat many conditions, including skin diseases, as a means of reducing oral steroid use. Azathioprine and methotrexate, available for 40 years, and mycophenolate mofetil for 20 years, are three drugs that are not approved for use in atopic eczema and are prescribed ‘off-licence’ only by dermatologists.51- 55 Cyclosporine, however, is approved for severe atopic eczema when systemic therapy is required.55

Azathioprine

Azathioprine is generally used for cases of severe, persistent atopic eczema that are unresponsive to topical treatment, or that require frequent courses of oral steroids.53 The drug interferes with the proliferation of certain types of white blood cells (lymphocytes) that are involved in generating the inflammation associated with eczema. Azathioprine is available as 25-mg and 50-mg tablets, which are taken once or twice a day with or after food.53

45 NurseCe4Less.com Azathioprine is less suitable for acute flares because it takes a little longer to take effect than ciclosporin and the benefits generally are not seen until after 4–5 weeks.53

Side effects of azathioprine can include nausea, diarrhoea and loss of appetite. Azathioprine can also increase a person’s susceptibility to infections.53 Those on the drug who are exposed to chickenpox or shingles should seek preventative treatment. Hair loss is typically a mild issue, and the hair should grow back once azathioprine is stopped. Drug hypersensitivity syndrome may develop with flu-like symptoms, such as aches and fever. Long-term treatment is believed to possibly predispose people to certain types of malignancy, but this has not been proven.53

Azathioprine can cause photosensitivity, so sun exposure should be avoided and sunscreen and protective clothing used when out in the sun.53 The treatment risk providers should explain to patients before starting azathioprine is the possible development of bone-marrow suppression, severe anaemia and the risk of infection. A blood test is now available to determine which patients are most at risk of developing this side effect.53

Approximately one in 200 people have low levels of an enzyme called thiopurine methyltransferase (TPMT) that make them unable to break down azathioprine normally and who are at high risk of dangerous bone-marrow suppression.53 Such individuals should not receive azathioprine.53 Onset of an infection, unusual bruising or bleeding should be reported by the patient to their medical provider, as it may be a sign that the bone marrow is being affected.

Methotrexate

Methotrexate was originally introduced as an anti-cancer drug (used especially to treat leukemia and similar cancers).54 It was soon discovered to be effective in the treatment of psoriasis and psoriatic arthropathy, and more recently it has been shown to be helpful in controlling severe eczema.

46 NurseCe4Less.com The drug is usually taken in a single weekly dose.54 Folic acid is commonly used to supplement treatment on the non-methotrexate days as it helps to reduce side effects.54 Typically, a dermatologist experienced in monitoring methotrexate therapy should initiate and monitor this treatment.

Methotrexate can cause quite marked nausea. Although it suppresses the immune system, generally there are fewer problems with the risk of infection than with azathioprine or cyclosporine. However, infection and anemia can occur as a result of methotrexate causing bone-marrow suppression. It can also cause liver inflammation leading to fibrosis and lung fibrosis.54

Cyclosporine

The reasons for prescribing cyclosporine are similar to those for prescribing azathioprine. Cyclosporine will start to work rapidly (within 1–2 weeks).55 Further improvements can occur up to 12–16 weeks after the start of treatment. Many patients find this drug to be very effective, including a marked improvement in the itching and appearance of their skin.55

Cyclosporine comes in four strengths and is taken in capsule or liquid form, twice daily.55 Although it is currently licensed only for short-term treatment (8 weeks) for patients with severe atopic eczema for whom conventional therapy is ineffective or inappropriate, the drug may be prescribed for a longer maintenance course for adults.55

The main side effects of cyclosporine are hypertension (high blood pressure) and reduced efficiency of the kidneys (renal toxicity). Side effects are more likely to occur with higher doses.55 There is a potential increase in the likelihood of developing certain types of cancer with long-term treatment due to the effect of cyclosporine on the immune system. For this reason, females taking cyclosporine should have a cervical smear, and regularly check their breasts for lumps.55

47 NurseCe4Less.com Since cyclosporine suppresses the immune system, the risk of bacterial, fungal and viral infection is greater when a person is taking this medication. Other, less serious but troublesome side effects include increased hair growth - a relatively common problem and can be distressing, particularly for women.55 Swelling and enlargement of the gums may occur, although this usually only happens with higher doses. Nausea, diarrhea, tiredness, tremor and altered sensation, such as a feeling of pins and needles can also occur.55

Mycophenolate Mofetil

Mycophenolate mofetil was developed as an immunosuppressive drug for transplant patients. It acts by decreasing the activity of white cells in the body, thus suppressing the immune system.56 It has been used for quite a wide variety of skin problems, including psoriasis, eczema and other inflammatory skin disorders. The use of mycophenolate mofetil in eczema is off-licence and treatment should be introduced and monitored under the supervision of a dermatology service.56

Most patients tolerate mycophenolate mofetil well. Although the risk of infection is less than with azathioprine or cyclosporine, the patient still needs to go for regular blood tests to check for infection and anemia. Like azathioprine, mycophenolate may cause some photosensitivity.56 Patients should therefore take extra precautions when in the sun on this medication.

Biologics

Biologics have revolutionized the treatment of psoriasis, changing the lives of people with severe disease. Alefacept (Amevive), the first biologic approved by the FDA in 2003 for the treatment of moderate-to-severe chronic plaque psoriasis, was stopped by the manufacturer by 2011. Currently, there are five other FDA-approved biologics for psoriasis and psoriatic arthritis; these include adalimumab (Humira®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®) and ustekinumab (Stelara®). Each biologic has a unique mechanism of action, dosing schedule and route of administration.24,57,58

48 NurseCe4Less.com Methotrexate, cyclosporine, acitretin and mycophenolate mofetil were used in the past for psoriasis that was too extensive or refractory to topical therapy and phototherapy. These medications suppress the entire immune function, and require routine laboratory monitoring because of the increased potential for liver and renal toxicity, hematological conditions (anemia, pancytopenia) and myelosuppression. In pregnancy and nursing mothers and individuals with liver or kidney disease, systemic therapies are contraindicated.24

Safety and Efficacy

Biologics have changed the treatment and progression of psoriasis, and they target specific parts of the immune system. Drug efficacy has been studied relative to symptom improvement for patients diagnosed with psoriasis. The efficacy and tolerability is more favorable than systemic therapies, providing clinicians with an effective and safe treatment alternative for patients with psoriasis and psoriatic arthritis. Biologics are not associated with renal toxicity, hepatotoxicity and other side effects associated with non- biologic systemic treatments.24,57,58

In terms of safety, biologics have a better safety profile compared with some systemic agents. The commonly reported adverse events with biologics were mild and discontinuation of therapy was not indicated. Adverse events include injection site reactions, respiratory infections and flu-like symptoms. Severe, less common adverse events include exacerbation of new-onset congestive heart failure, certain types of cancer, multiple sclerosis, blood disorders, tuberculosis and opportunistic infections.57,58 A potential drawback to biologic therapy is that it has to be given either by injection or intravenous infusion. Infusion can last 2 hours per session. Patients who have not experienced injection therapy tend to prefer a pill.57,58

The efficacy of specific biologics and their courses of treatment are briefly reviewed for the remainder of this section.

49 NurseCe4Less.com Adalimumab

In the recently published open-label extension of the REVEAL trial, patients received adalimumab for 3 years. Patients maintained their improvement after both 100 and 160 weeks of continuous therapy.59

Infliximab

The Phase III EXPRESS (European Infliximab for Psoriasis [Remicade®] Efficacy and Safety Study) trial assessed the efficacy and safety of continuous treatment with infliximab in patients with moderate-to-severe plaque psoriasis who received infusions of infliximab 5 mg/kg at weeks 0, 2 and 6, then every 8 weeks up to week 46. The results showed that infliximab-treated patients had a high rate of improvement in symptoms by week 50, as compared to placebo.60,61

Etanercept

Both continuous and intermittent etanercept treatment regimens improved quality of life. Patients with moderate-to-severe plaque psoriasis showed significant improvement from baseline to week 54 in their symptoms.62

Golimumab

Golimumab 50 mg or golimumab 100 mg every 4 weeks through week 20 has been shown to lead to improvement by week 14 in study trials, as compared with placebo.63

Ustekinumab

Ustekinumab 45 mg or 90 mg at weeks 0 and 4 were administered to patients, and continued every 12 weeks, then assessed at week 28. The results showed more partial responders at week 28 who received ustekinumab

50 NurseCe4Less.com 90 mg every 8 weeks than those who continued to receive the same dose every 12 weeks, as compared to placebo.64

Case Study: Tattoo-associated Skin Eruptions

The following case study was obtained from a PubMed search where the authors reported on a 36-year-old man who presented with a 6-month history of skin-colored flat-topped papules within a black colored tattoo.65 The tattoos over the arms and forearms were applied over 20 years prior by a professional tattoo artist and there was no previous history of cutaneous eruptions within the tattoos.

The skin-colored papules appeared suddenly with no associated symptoms. The number of papules within the tattoo had been increasing from the initial time of onset. Hundreds of papules were present at the time the patient was evaluated.

The patient reportedly had no other medical conditions and was not taking any prescription medications. There was a dermatologic history of atopic dermatitis for which topical corticosteroids were used for occasional flares. There was no history of cigarette smoking or intravenous drug use. Full skin examination did not reveal the presence of these papules anywhere on the body apart from the tattooed areas of the right forearm and arm. All laboratory investigations were normal including negative tests for human immunodeficiency virus (HIV) and hepatitis. The differential diagnosis included other inflammatory skin conditions (i.e., papular eczema, papular sarcoidosis, lichen planus and verrucae planae).

Histopathology study included a biopsy of the right forearm that revealed keratinocytes with human papillomavirus (HPV)-induced changes and the patient was diagnosed with verrucae planae (warts). Stained slide studies revealed an epidermis with abnormal findings, including hypergranulosis. The black tattoo ink was identified in the dermis below the verrucae.

51 NurseCe4Less.com Initial treatment was described as one cycle of light liquid nitrogen cryotherapy directed at two test areas. Unfortunately, this did not result in clinical improvement and a slight scale developed in the treated areas. Topical treatments such as 5% 5-fluorouracil or 5% imiquimod were offered as the next option while informing the patient that these treatments may affect the integrity of the tattoo color. The patient reportedly did not return for follow- up and no further treatments were provided.

Discussion65

The authors reported that the prevalence of tattoos in the general population is estimated at 15% to 25% with a higher prevalence among younger men and women. They stated that “as the population of tattooed men and women grow, there have been a growing number of reports of complications associated with tattoos. By far the most common reactions to tattoos are the inflammatory reactions.”65 Inflammatory reactions seen in people with tattoos will range from existing inflammatory conditions to allergic reactions involving tattoo ink or components.

Relative to the risk of infection, tattoos are reportedly associated with the transmission of HIV, hepatitis B, hepatitis C, syphilis, tuberculosis, leprosy and other mycobacteria infections. Also, HPV infections associated with tattoos have been found in several reports. In particular, black tattoo ink has “a higher risk of verrucae development and HPV infection.”65

Tattoo-associated verrucae planae or flat warts was presented in this case study, which reportedly had developed over 20 years from the time of initial tattooing. The authors reported that “verrucae planae are usually caused by HPV-3, -10, -28 and -49 and have a predilection for the face, larynx and hands. They normally present as white/pink to skin-coloured flat-topped papules. The mechanism by which HPV localizes to the tattoo may involve either traumatic implantation of HPV during the tattoo process or the contamination of the tattoo inks or instruments or by localized immunosuppression that occurs secondary to the tattoo ink.”65 The longest

52 NurseCe4Less.com latency period reported prior to this case (between tattooing and the development of HPV infection) was reported to be 10 years.

Clinicians should be aware that typically a long latency period exists between tattooing and the manifestations of HPV infection; average latency is estimated to be 5 years. While the immune system can control the infection, it is believed that with tattooing there is some immune system deviation leading to a clinical disease. Exposure to sunlight has been implicated in the development of verrucae within two and a half years after tattooing.

Primary treatment for verrucae planae in this case included topical 5% 5-fluorouracil or 5% imiquimod. The authors noted that the treatment success in tattoo-associated verrucae possibly was possibly limited to the deeper virus implantation. Other topical treatments included 10% salicylic acid, 10%–30% glycolic acid and 0.025%–0.05% tretinoin. Some topical treatments, particularly imiquimod, may affect the esthetics of the tattoo. Ablative laser, curettage or surgical excision were also reported options but were reported to likely damage to the tattoo and lead to scarring. Liquid nitrogen cryotherapy in this case did not provide significant clinical improvement.

The long-term infectious risk of tattooing needs to be explained to patients considering tattoos, including the limits of treatment options. Esthetic tattooing “involves the implantation of pigment into the upper and middle dermis to create pictures, words, geometric patterns and other aesthetically desirable designs. Historically, tattoo-associated infection rates were much higher with common transmission and implantation of Staphylococcus and Streptococcus bacteria resulting in erysipelas, cellulitis, gangrene and sepsis.”65 While there are advances in sterile technique that reduce infectious risks from tattooing, reports of transmission of hepatitis B, hepatitis C and human immunodeficiency virus has been reported in several cases.

Summary

Pharmacological agents can be a useful treatment option for dermatological issues, such as those involving the hair, nails, and skin. There

53 NurseCe4Less.com are a wide variety of pharmacological agents that may be used to treat 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 condition 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 treatment. 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.

The process of esthetic tattooing was discussed with a focus on tattoo- associated infection rates, which were reportedly much higher with the common transmission of Staphylococcus and Streptococcus bacteria causing cellulitis, gangrene and sepsis. Advances in sterile technique have reduced the infectious risks associated with tattooing; however, there have been reports of transmission of hepatitis B, hepatitis C and human immunodeficiency virus (HIV) most recently. Several cases of human papilloma virus (HPV) infections associated with tattoos have also been reported. It is believed that HPV infection in tattoos is attributable either to the tattooing process or tattoo inks. The case study that was presented gave an example of a tattoo-associated HPV infection and serves as a reminder of the risks of tattooing even with advanced sterile technique.

54 NurseCe4Less.com Self-Assessment of Knowledge Post-Test:

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 a sudden, acute decrease in response to a drug after the drug is administered.

a. Tapering down b. Rebound effect c. Tachyphylaxis d. Topical nonadherence

2. Skin lesions are classified into two categories:

a. Primary and secondary skin lesions. b. Site involvement and structure affected. c. Congenital and acquired skin lesions. d. Skin lesions caused by an infectious agent or an autoimmune mechanism.

3. ______are at an increased risk of absorbing topical corticosteroids because they have a higher ratio of skin surface area to body weight.

a. Infants b. Individuals who are overweight c. Women d. The elderly

4. ______is an antimitotic that reduces inflammation and can help treat psoriasis.

a. Mupirocin b. Clindamycin c. Ketoconazole d. Anthralin

55 NurseCe4Less.com 5. The term ______refers to the inactive part of a topical preparation that brings a drug into contact with the skin.

a. lidocaine b. vehicle c. prilocaine d. astringent

6. Vehicle selection for topical dermatologic treatment is guided by

a. location of application. b. cosmetic effects. c. convenience. d. All of the above

7. True or False: Under normal conditions, up to 99% of the applied topical corticosteroid is cleared from the skin, and only about 1% is therapeutically active.

a. True b. False

8. The most important element in retinoid, topical therapy is

a. the retinoid preparation. b. the patient’s age. c. educating the patient/guardian about skin irritation. d. the patient’s gender.

9. ______is usually used in shampoos to treat seborrheic dermatitis.

a. Terbinafine b. Salicylic acid c. Benzoyl peroxide d. Coal tar

10. Topical steroids cause capillaries in the superficial dermis to

a. constrict, thus reducing erythema. b. expand, thus increasing erythema. c. constrict, thus increasing erythema. d. expand vascular supply to the area.

56 NurseCe4Less.com 11. Topical corticosteroids are recommended for their

a. ability to aid cellular division and growth. b. anti-inflammatory activity. c. capacity to increase the synthesis of connective tissue molecules. d. All of the above

12. True or False: Results from large-scale surveys show that patients or caregivers overestimate the risks associated with using topical corticosteroids.

a. True b. False

13. Women who are or who may become pregnant should know that

a. acitretin (a retinoid) is not excreted in breast milk and is safe to use when breastfeeding. b. acitretin causes severe birth defects and should not be used. c. topical glucocorticoids are excreted in breast milk. d. pregnant women should not use topical corticosteroids.

14. Crisaborole is a/an ______ointment that is used to treat mild to moderate eczema.

a. retinoid b. antimitotic c. glucocorticoid d. non-steroidal

15. ______is an oral antifungal medicine that may be used to treat fungal infections of the nails.

a. Dicloxacillin b. Erythromycin c. Tetracycline d. Terbinafine

57 NurseCe4Less.com 16. True or False: A once-daily application of topical corticosteroids is significantly less effective than a twice-daily use, regardless of the potency of the corticosteroid.

a. True b. False

17. ______is an immunosuppressant that can be used to treat conditions including severe cases of psoriasis and eczema.

a. Prednisone b. Terbinafine c. Erythromycin d. Azathioprine

18. Which of the following side effects may result from the use of topical corticosteroids?

a. Vasodilation b. Seborrhoea c. Perioral dermatitis d. All of the above

19. Gels are most suitable for use on ______areas of the skin.

a. hairy b. dry or scaly c. unprotected d. weepy

20. Clindamycin is a semisynthetic lincosamide ______that is derived from lincomycin.

a. antibiotic b. steroid c. antifungal d. antimitotic

58 NurseCe4Less.com 21. Dermal atrophy develops from the ______effects directly caused by topical corticosteroids on fibroblasts.

a. vasodilative b. mitotic c. antiproliferative d. enhanced phospholipase A2

22. The following is/are true about the penetration of topical steroids:

a. side effects are less likely where the skin is thin. b. penetration of topical steroids through the forehead is 4 times greater than for the eyelids. c. increased penetration of the drug occurs where the skin is thin. d. All of the above

23. 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.

24. True or False: Corticosteroids are thought to exert their potent anti-inflammatory effects by inhibiting the release of phospholipase A2.

a. True b. False

25. Increasing hydration of the stratum corneum can enhance absorption of topical corticosteroids by

a. 98%. b. ten times. c. four to five times. d. 50%.

59 NurseCe4Less.com 26. A serious consequence of ceasing topical steroid therapy after an extended treatment period can result in

a. an Addisonian crisis. b. seborrhoea. c. hemangiomas. d. dry skin.

27. Mupirocin is temperature-sensitive and ______if exposed to high temperatures.

a. is enhanced b. synthesizes c. penetrates the skin d. loses efficacy

28. Hemangiomas of infancy show a good or partial response to treatment with

a. sulfacetamide. b. topical glucocorticoids. c. metronidazole. d. nitroimidazole.

29. Sulfacetamide is a topical sulfonamide used in the treatment of

a. psoriasis. b. eczema. c. hemangiomas. d. rosacea and acne.

30. 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.

60 NurseCe4Less.com 31. True or False: Pseudomembranous colitis is a common side effect that occurs with the topical use of clindamycin.

a. True b. False

32. Clioquinol may interfere with

a. testing for T3 or T4. b. the synthesis of folic acid. c. the release of interleukin-1α. d. thyroid function determination.

33. The most common adverse effect associated with topical retinoid use is

a. inflammation of the skin. b. local skin irritation. c. a discoloration of the skin. d. perioral dermatitis.

34. Most adverse effects caused by topical corticosteroid use are

a. systemic in nature. b. caused by the mitotic activity of these agents. c. due to the tendency of these agents to inhibit cell growth. d. caused by the agents vasodilative effects.

35. Deaths from Addisonian crisis have been reported with the use of topical steroids, and the risk of this occurring is greater in

a. women. b. men. c. children. d. the elderly.

36. True or False: Continued use of topical corticosteroids may lead to tachyphylaxis.

a. True b. False

61 NurseCe4Less.com 37. Mupirocin reversibly binds to isoleucyl-tRNA synthetase and

a. its activity is limited to Gram-negative bacteria. b. inhibits bacterial protein synthesis. c. acts through fermentation of Gram-negative bacteria. d. All of the above

38. Mupirocin ointment 2% is principally indicated for the treatment of localized

a. tachyphylaxis. b. impetigo. c. perioral dermatitis. d. rosacea and acne.

39. Which of the following topical imidazoles is approved for twice- daily dosing?

a. Econazole b. Ketoconazole c. Oxiconazole d. Sulconazole

40. True or False: Erythromycin is active against both Gram- positive cocci and Gram-negative bacilli.

a. True b. False

41. ______penetrates keratin easily.

a. Generic terbinafine b. Ciclopirox Olamine c. Ketoconazole d. Sulconazole

42. Undecylenic acid and its salts are widely considered less effective than ______in the treatment of tinea pedis.

a. miconazole b. clotrimazole c. tolnaftate d. All of the above

62 NurseCe4Less.com 43. True or False: At this time, biologics are not as safe as a treatment option when compared to other systemic agents.

a. True b. False

44. Adverse events commonly reported with biologics include

a. respiratory infections. b. certain types of cancer. c. multiple sclerosis. d. tuberculosis.

45. A potential drawback to biologic therapy is that it has to be administered

a. in a pill form. b. by injection or intravenous infusion. c. in conjunction with other systemic treatments. d. All of the above

63 NurseCe4Less.com CORRECT ANSWERS:

1. ______is defined as a sudden, acute decrease in response to a drug after the drug is administered. c. Tachyphylaxis

“...tachyphylaxis (a sudden, acute decrease in response to a drug after the drug is administered to a patient)....”

2. Skin lesions are classified into two categories: a. Primary and secondary skin lesions.

“Skin lesions are classified into two categories: 1) Primary skin lesions, which are abnormal skin conditions from birth or that are acquired over a person’s lifetime; and, 2) Secondary skin lesions, which are the result of irritated or manipulated primary skin lesions, such as when a person scratches a mole until it bleeds.”

3. ______are at an increased risk of absorbing topical corticosteroids. a. Infants

“However, children and, in particular, infants, are at an increased risk of absorbing topical corticosteroids for several reasons.”

4. ______is an antimitotic that reduces inflammation and can help treat psoriasis. d. Anthralin

“Anthralin: An antimitotic, is not often used because it can be irritating and can stain, but is used to reduce inflammation and can help treat psoriasis.”

5. The term ______refers to the inactive part of a topical preparation that brings a drug into contact with the skin. b. vehicle

“Topical medications use ‘vehicles’ that are the inactive part of the topical preparation. The vehicle helps bring the drug into contact with the skin.”

64 NurseCe4Less.com 6. Vehicle selection for topical dermatologic treatment is guided by a. location of application. b. cosmetic effects. c. convenience. d. All of the above [correct answer]

“The location of application of the topical medication, the cosmetic effects, and convenience determine the choice of the vehicle.”

7. True or False: Under normal conditions, up to 99% of the applied topical corticosteroid is cleared from the skin, and only about 1% is therapeutically active. a. True

“Under normal conditions, almost all of the applied topical corticosteroid (up to 99%) is cleared from the skin, and is minimally therapeutically active.”

8. The most important element in retinoid, topical therapy is c. educating the patient/guardian about skin irritation.

“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.”

9. ______is usually used in shampoos to treat seborrheic dermatitis. d. Coal tar

“Coal tar is used to treat conditions including seborrheic dermatitis (usually in shampoos) or psoriasis. Currently, coal tar is seldom used because it can be slow acting and can cause severe staining of personal clothing and bedding.”

10. Topical steroids cause capillaries in the superficial dermis to a. constrict, thus reducing erythema.

“Topical steroids cause capillaries in the superficial dermis to constrict, thus reducing erythema.”

65 NurseCe4Less.com 11. Topical corticosteroids are recommended for their b. anti-inflammatory activity.

“Topical corticosteroids are recommended for their anti-inflammatory activity in inflammatory skin diseases, but they can also be used for their antimitotic effects and capacity to decrease the synthesis of connective tissue molecules.”

12. True or False: Results from large-scale surveys show that patients or caregivers overestimate the risks associated with using topical corticosteroids. a. True

“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.”

13. Women who are or who may become pregnant should know that b. acitretin causes severe birth defects and should not be used.

“Retinoids: Acitretin (Soriatane) is specifically used to treat all types of severe psoriasis. It reduces skin cell growth. It causes severe birth defects and should not be used if a woman is planning to become pregnant, is pregnant or is breastfeeding…. 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.”

14. Crisaborole is a/an ______ointment that is used to treat mild to moderate eczema. d. non-steroidal

“Non-steroidal Ointment: The ointment crisaborole (Eucrisa) is used to treat mild to moderate eczema.”

66 NurseCe4Less.com 15. ______is an oral antifungal medicine that may be used to treat fungal infections of the nails. d. Terbinafine

“Terbinafine is an oral antifungal medicine that may be used to treat fungal infections of the nails.”

16. True or False: A once-daily application of topical corticosteroids is significantly less effective than a twice-daily use, regardless of the potency of the corticosteroid. b. False

“For super potent 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 a once-daily application of topical corticosteroids may be as effective as twice daily, while decreasing the risk of side effects, such as tachyphylaxis (a sudden, acute decrease in response to a drug after the drug is administered to a patient).”

17. ______is an immunosuppressant that can be used to treat conditions including severe cases of psoriasis and eczema. d. Azathioprine

“Immunosuppressants, such as azathioprine (Imuran) and methotrexate (Trexall), can be used to treat conditions including severe cases of psoriasis and eczema.”

18. Which of the following side effects may result from the use of topical corticosteroids? c. Perioral dermatitis

“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.”

67 NurseCe4Less.com 19. Gels are most suitable for use on ______areas of the skin. a. hairy

“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.”

20. Clindamycin is a semisynthetic lincosamide ______that is derived from lincomycin. a. antibiotic

“Clindamycin is a semisynthetic lincosamide antibiotic that is derived from lincomycin.”

21. Dermal atrophy develops from the ______effects directly caused by topical corticosteroids on fibroblasts. c. antiproliferative

“The most conspicuous adverse effect to the skin is skin atrophy. It involves both the epidermis and dermis. Dermal atrophy develops from the antiproliferative effects directly caused by topical corticosteroids on fibroblasts, which inhibits the synthesis of collagen and mucopolysaccharide. This results in a loss of dermal support.”

22. The following is/are true about the penetration of topical steroids: c. increased penetration of the drug occurs where the skin is thin.

“Topical corticosteroids are used to relieve inflammation and pruritus of contact dermatitis, insect bites, minor burns, seborrheic dermatitis, psoriasis, and eczema…. Absorption is high in areas of thin skin, but penetration is poor with thick skin ... 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.”

68 NurseCe4Less.com 23. Elderly patients may have thin skin, which c. allows for increased penetration of topical glucocorticoids.

“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.”

24. True or False: Corticosteroids are thought to exert their potent anti-inflammatory effects by inhibiting the release of phospholipase A2. a. True

“Corticosteroids are thought to exert their potent anti-inflammatory effects by inhibiting the release of phospholipase A2, an enzyme responsible for the formation of prostaglandins, leukotrienes, and other derivatives of arachidonic acid pathway.”

25. Increasing hydration of the stratum corneum can enhance absorption of topical corticosteroids by c. four to five times.

“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.”

26. A serious consequence of ceasing topical steroid therapy after an extended treatment period can result in a. an Addisonian crisis.

“Consequently, subsequent cessation of topical steroid therapy after an extended treatment period can, albeit rarely, result in an Addisonian crisis.”

69 NurseCe4Less.com 27. Hemangiomas of infancy show a good or partial response to treatment with b. topical glucocorticoids.

“Hemangiomas of infancy show a good or partial response to treatment with ultrapotent topical glucocorticoids in a majority of infants where there was accelerated cessation of growth.”

28. Sulfacetamide is a topical sulfonamide used in the treatment of d. rosacea and acne.

“Silver sulfadiazine and mafenide acetate are broad-spectrum antibacterials useful in the treatment of acne vulgaris, acne rosacea, and burns.”

29. Mechanisms for the anti-inflammatory effects of corticosteroids include c. corticosteroids also decrease the release of interleukin-1α.

“Corticosteroids also decrease the release of interleukin-1α (IL-1α), an important proinflammatory cytokine, from keratinocytes.”

30. True or False: Pseudomembranous colitis is a common side effect that occurs with the topical use of clindamycin. b. False

“Pseudomembranous colitis rarely has been reported to occur with the topical use of clindamycin.”

31. Clioquinol may interfere with d. thyroid function determination.

“Clioquinol may interfere with thyroid function determination when taken orally and possibly topically if used extensively…. However, clioquinol does not interfere with testing for T3 or T4.”

70 NurseCe4Less.com 32. The most common adverse effect associated with topical retinoid use is b. local skin irritation.

“The most common adverse effect associated with topical retinoid use is local skin irritation.”

33. Most adverse effects caused by topical corticosteroid use are c. due to the tendency of these agents to inhibit cell growth.

“Local adverse effects caused by topical corticosteroid use are more prevalent than systemic reactions. These effects are mostly due to the tendency of these agents to inhibit cell growth.”

34. Deaths from Addisonian crisis have been reported with the use of topical steroids, and the risk of this occurring is greater in c. children.

“Deaths from Addisonian crisis have been reported with the use of topical steroids, and the risk of this occurring is greater in children.”

35. True or False: Continued use of topical corticosteroids may lead to tachyphylaxis. a. True

“Continued use of topical corticosteroids may also lead to tachyphylaxis.”

36. Mupirocin reversibly binds to isoleucyl-tRNA synthetase and b. inhibits bacterial protein synthesis.

“Mupirocin, which was formerly known as pseudomonic acid A, is a topical antibiotic agent derived from Pseudomonas fluorescens. The drug reversibly binds to isoleucyl-tRNA synthetase and inhibits bacterial protein synthesis.”

71 NurseCe4Less.com 37. Mupirocin is temperature-sensitive and ______if exposed to high temperatures. d. loses efficacy

“Mupirocin is somewhat temperature-sensitive, and thus loses efficacy if exposed to high temperatures.”

38. Mupirocin ointment 2% is principally indicated for the treatment of localized b. impetigo.

“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.”

39. Which of the following topical imidazoles is approved for twice- daily dosing? d. Sulconazole

“Topical imidazoles are available in a multitude of forms. Econazole, ketoconazole, and oxiconazole are approved for once-daily dosing but twice- daily dosing is recommended for the remainder. Although twice-daily dosing is recommended for sulconazole, a study comparing once-daily to twice-daily dosing in tinea corporis and tinea cruris reported an identical rate of cure.”

40. True or False: Erythromycin is active against both Gram- positive cocci and Gram-negative bacilli. a. True

“Erythromycin belongs to the group of macrolide antibiotics and is active against both Gram-positive cocci and Gram-negative bacilli.”

41. ______penetrates keratin easily. b. Ciclopirox Olamine

“Ciclopirox Olamine penetrates keratin easily….”

72 NurseCe4Less.com 42. Undecylenic acid and its salts are widely considered less effective than ______in the treatment of tinea pedis. a. miconazole b. clotrimazole c. tolnaftate d. All of the above [correct answer]

“Undecylenic acid and its salts are widely considered less effective than miconazole, clotrimazole, or tolnaftate in the treatment of tinea pedis.”

43. True or False: At this time, biologics are not as safe as a treatment option when compared to other systemic agents. b. False

“In terms of safety, biologics have a better safety profile compared with some systemic agents.”

44. Adverse events commonly reported with biologics include a. respiratory infections.

“The commonly reported adverse events with biologics were mild and discontinuation of therapy was not indicated. Adverse events include injection site reactions, respiratory infections and flu-like symptoms. Severe, less common adverse events include exacerbation of new-onset congestive heart failure, certain types of cancer, multiple sclerosis, blood disorders, tuberculosis and opportunistic infections.”

45. A potential drawback to biologic therapy is that it has to be administered b. by injection or intravenous infusion.

“A potential drawback to biologic therapy is that it has to be given either by injection or intravenous infusion. Infusion can last 2 hours per session. Patients who have not experienced injection therapy tend to prefer a pill.”

73 NurseCe4Less.com Reference Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. Wei, L, Gan, Q, Ji, T. Skin Disease Recognition Method Based on Image Color and Texture Features. Computational and Mathematical Methods in Medicine. Volume 2018, Article ID 8145713. 2. Aruna, M, Amruthavalli, GV, Gayathri, R. Use of cosmetic products for treating certain diseases – Know the science. Ed. Gold, M. Cosmetic Dermatology. 2019. Volume 18, Issue 4. Pages: 221-225. 3. Dunn J, Koo J. Dermatology Online Journal UC Davis. Dermatol Online J. 2013; 19(6):1–19. 4. Goldstein, B, Goldstein, A. Overview of benign lesions of the skin. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/overview-of-benign-lesions-of- the- skin?search=classification%20of%20skin%20conditions&source=searc h_result&selectedTitle=9~150&usage_type=default&display_rank=9 5. Lexicomp. Mupirocin: Drug information. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/mupirocin-drug- information?search=mupirocin&source=panel_search_result&selectedT itle=1~74&usage_type=panel&kp_tab=drug_general&display_rank=1 6. Anderson, M, David, M, Scholz, M, Bull, S, Morse, D, Hulse-Stevens, M, Peterson, M. Efficacy of Skin and Nasal Povidone-Iodine Preparation against Mupirocin-Resistant Methicillin-Resistant Staphylococcus aureus and S. aureus within the Anterior Nares corresponding. Antimicrob Agents Chemother. 2015; 59(5): 2765–2773. 7. Lexicomp. Retapamulin: Drug information. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/retapamulin-drug- information?search=Retapamulin&source=panel_search_result&selecte dTitle=1~7&usage_type=panel&kp_tab=drug_general&display_rank= 1 8. Lexicomp. Bacitracin, neomycin, and polymyxin B (topical): Drug information. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/bacitracin-neomycin-and- polymyxin-b-topical-drug- information?search=bacitracin&source=search_result&selectedTitle=3 ~90&usage_type=default&display_rank=2 9. Drew, R. Aminoglycosides. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/aminoglycosides

74 NurseCe4Less.com 10. Germovsek E, Barker C, Sharland M. What do I need to know about aminoglycoside antibiotics? Arch Dis Child Educ Pract Ed. 2017 Apr; 102(2):89-93. 11. Lexicomp. Sulfanilamide: Drug information. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/sulfanilamide- drug- information?search=Sulfonamides&source=search_result&selectedTitle =2~150&usage_type=default&display_rank=2 12. Drugs.com. Furacin Topical Cream. 2019. Retrieved from https://www.drugs.com/mmx/furacin-topical-cream.html 13. Lexicomp. Neomycin, polymyxin B, and gramicidin: Drug information UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/neomycin-polymyxin-b-and- gramicidin-drug- information?search=Gramicidin&source=search_result&selectedTitle=1 ~9&usage_type=default&display_rank=1 14. Lexicomp. Clioquinol and hydrocortisone: Drug information. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/clioquinol- and-hydrocortisone-drug- information?search=Clioquinol&source=search_result&selectedTitle=1 ~7&usage_type=default&display_rank=1 15. PubChem. Erythromycin. US National Library of Medicine. n.d. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/Erythromycin 16. Johnson, M. Clindamycin: An overview. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/clindamycin-an- overview?search=Clindamycin&source=search_result&selectedTitle=2 ~145&usage_type=default&display_rank=1 17. Johnson, M. Metronidazole: An overview. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/metronidazole-an- overview?search=Metronidazole&source=search_result&selectedTitle= 2~145&usage_type=default&display_rank=1 18. Werth, B. Sulfonamides. Merck Manual Professional Version. 2019. Retrieved from https://www.merckmanuals.com/professional/infectious- diseases/bacteria-and-antibacterial- drugs/sulfonamides?query=Sulfonamides 19. Revankar, S. Antifungal Drugs. Merck Manual Professional Version. 2019. Retrieved from https://www.merckmanuals.com/professional/infectious- diseases/fungi/antifungal-drugs?query=Antifungals 20. Mazu, TK, Bricker, BA, Flores-Rozas, H, Ablordeppey, SY. The Mechanistic Targets of Antifungal Agents: An Overview. Mini Rev Med Chem. 2017.555–578.

75 NurseCe4Less.com 21. Dodds, AE, Perfect, JR. Pharmacology of azoles. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/pharmacology-of- azoles?search=Imidazoles&source=search_result&selectedTitle=1~64 &usage_type=default&display_rank=1 22. Sharma, A, Kumar, V, Kharb, R, Kumar S, Sharma, PC, Pathak, DP. Imidazole Derivatives as Potential Therapeutic Agents. Curr Pharm Des. 2016; 22(21):3265-301. 23. Brodell, R, Dolohanty, L. Intertrigo. UpToDate. 2018. Retrieved from https://www.uptodate.com/contents/intertrigo?search=Allylamines%2 0and%20Benzylamines&source=search_result&selectedTitle=1~2&usa ge_type=default&display_rank=1 24. Goldsmith, L, Katz, S, Gilchrest, B, Paller, A, Leffell, D, Wolff, K. Fitzpatrick's Dermatology in General Medicine, 8th Edition. 2012. McGraw-Hill. 25. Kauffman, C. Management of candidemia and candidiasis in adults. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/management-of-candidemia-and- invasive-candidiasis-in- adults?search=polyenes&source=search_result&selectedTitle=4~5&us age_type=default&display_rank=4 26. PubChem. Nilstat. US National Library of Medicine. n.d. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/6433272 27. Prescriber’s Digital Reference. Nystatin/triamcinolone acetonide - Drug Summary. 2019. PDR. Retrieved from https://www.pdr.net/drug- summary/Nystatin-and-Triamcinolone-Acetonide-nystatin- triamcinolone-acetonide-1578 28. Goldstein, B. and Goldstein, A. Tinea versicolor (Pityriasis versicolor). UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/tinea-versicolor-pityriasis- versicolor?search=Ciclopirox%20Olamine&source=search_result&selec tedTitle=4~11&usage_type=default&display_rank=3 29. Prescriber’s Digital Reference. Drug Information: Ciclopirox Olamine Cream. PDR. Retrieved from https://www.pdr.net/drug- information/ciclopirox-olamine-cream?druglabelid=3124 30. PubChem. Ciclopirox Olamine. US National Library of Medicine. n.d. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/38911 31. Goldstein, A and Goldstein, B. Dermatophyte (tinea) infections. UpToDate. 2019. Retrieved from https://www.uptodate.com/contents/dermatophyte-tinea- infections?search=Tolnaftate&source=search_result&selectedTitle=2~ 2&usage_type=default&display_rank=1 32. PubChem. Tolnaftate. US National Library of Medicine. n.d. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/Tolnaftate

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