This chapter reviews topical therapies not covered elsewhere in the text that are used to treat dermatologic diseases. The topic headings are those of the drug designation of the US Pharmacopeia and at times reflect clinical usage rather than specific pharmacologic mechanisms. All topicals when applied to large areas of skin, particularly in the presence of skin disease or to infants and children, have the potential for systemic side effects.

Capsaicin

Capsaicin is the molecule that confers the “hotness” to hot peppers of the genus Capsicum, including cayenne, jalapeno, and Tabasco peppers.1 Initial topical application results in itching, pricking, and burning as nociceptor activate. Repeated applications, however, are hypothesized to lead to degeneration of epidermal nerve fibers and nociceptor desensitization, thereby producing hypalgesia.1

Topical capsaicin has been used to treat postherpetic neuralgia, diabetic neuropathy, reflex sympathetic dystrophy, Raynaud phenomenon, nostalgia paresthetica, arthralgias, plantar warts, diabetic neuralgia, and hemodialysis-related pruritus.1 A recent placebo-controlled trial of a high-concentration capsaicin dermal patch showed that the patch significantly reduced postherpetic neuralgia pain with transient application site pain reactions managed effectively with analgesics.2 Other therapies for postherpetic neuralgia should also be considered.3

Topical Anesthetics

Numerous topical anesthetics are available.4 Eutectic mixture of local anesthetics (EMLA) cream contains the sodium-channel-blocking amide anesthetics lidocaine 2.5% and prilocaine 2.5%. Application under occlusion to intact skin or genital mucous membranes for at least 1 hour before performance of a painful procedure, including debridement of venous leg ulcers,5 can provide local anesthesia that may persist for up to 2 hours. The cream may cause transient local blanching followed by transient local erythema. Like all products containing lidocaine, it should not be used in patients with hypersensitivity to amide anesthetics. Additionally, the prilocaine component has been linked to cases of methemoglobinemia in patients for whom applications exceeded the recommended dose, application area, or application time.6 Those particularly susceptible to methemoglobinemia include patients who are very young, those with glucose-6-phosphate dehydrogenase deficiency, and those taking oxidizing drugs such as sulfonamides and antimalarials.

Caution regarding dosing should also be used in patients susceptible to systemic effects of lidocaine or prilocaine, including acutely ill, debilitated, and elderly patients. Finally, as EMLA is ototoxic, it should not be used if there is a concern that it could penetrate or migrate beyond the tympanic membrane to the middle ear.

Various topical anesthetic products contain only lidocaine, typically at concentrations of 4% or 5%, which may be applied with or without occlusion. Systemic toxicity from topical lidocaine prepared in a 30% concentration has been reported.7 In 2007, FDA reported that two women, aged 22 and 25, experienced seizure, coma, and death after using compounded topical formulations of lidocaine and tetracaine, under occlusion, prior to laser hair removal procedures. Cases of arrhythmia and apnea were also reported. Those adverse events prompted FDA to warn the public about potential hazards of use of topical numbing products for cosmetic procedures,8 and pharmacies against violating regulations in compounding such products.9

Coal Tar

Coal tar has been used to treat inflammatory dermatoses for up to 2 millennia, although currently it is used primarily to treat psoriasis.10 Coal tar has been shown to inhibit DNA synthesis and mitosis in epidermal cells, an effect potentiated by ultraviolet A exposure.11 Coal tar also has anti-infective, antipruritic, photosensitizing, and vasoconstrictive effects and, with repeated applications, causes epidermal atrophy. The precise mechanism by which it treats inflammatory skin diseases has not been fully described.

In 1925, Goekerman pioneered the concomitant use of coal tar and ultraviolet B therapy for psoriasis.

Coal tar has historically been messy to use, has an unpleasant odor, and can stain clothing, making its use challenging for some. Newer formulations, however, might be better tolerated.12,13 Systemic adverse effects are uncommon, whereas local adverse effects can include tar folliculitis, acneiform eruptions, irritant dermatitis, burning, and stinging, allergic contact dermatitis, atrophy, telangiectases, pigmentation, exfoliative dermatitis, and keratoacanthomas.10 Although occupational exposure to coal tar has been associated with increased risk of developing skin cancer, epidemiologic studies of coal tar-treated psoriasis have not demonstrated an increased risk of skin cancer due to coal tar.14

Wood Tar

Produced by distillation of wood under controlled conditions, wood tar can be added to arachis oil (peanut oil) or other bases. The preparation is then typically used to treat scalp psoriasis. Most commonly derived from juniper (oil of cade), wood tar may also be derived from beech, birch, and pine. Contact sensitivity to wood tar has been reported.15

Shale Oil

Shale oil (also referred to as ammonium bituminosulphonate, ichthyol, ichthammol, or black salve) is derived from oil shale, a sulfur-rich sedimentary rock. Further processing of extracted shale oil yields light- and dark-colored components. The light component is also referred to as pale sulfonated shale oil (PSSO) or ichthyol pale.16 Shale oil decreases inflammation by inhibiting lipoxygenase.17 A recent trial of PSSO cream for atopic dermatitis showed that it was more effective than vehicle in treating atopic dermatitis.18 A study of PSSO to treat venous leg ulcers showed that the size of ulcers treated with PSSO gel, compared with vehicle, significantly decreased, although there was no difference in complete epithelialization of granulation of ulcers.19 PSSO has also been used to treat acne, psoriasis, seborrhea, eczema, rosacea, and pruritus.16,20

(Table 222-1)

Chlorhexidine

Chlorhexidine gluconate is a bisbiguanide that binds to the stratum corneum, providing sustained bactericidal and fungicidal activity for over 6 hours, even when wiped from the field. Although it does not kill bacterial spores or mycobacteria, it does inhibit their growth. Because it does not lose its effectiveness in the presence of organic material, such as whole blood, it is an important antiseptic, disinfectant, antibacterial dental rinse, and preservative. Due to ototoxicity and the risk of conjunctivitis and corneal ulceration, chlorhexidine is not recommended for preoperative preparation of the face or head.

Dyes

Dyes are useful topical treatments because they are inexpensive and chemically and physically stable. The topical antiseptic dyes used in dermatology, gentian violet (methylrosaniline chloride), brilliant green (p-diethylamine triphenylmethanol), malachite green, and fuchsine, are all derivatives of triphenylmethane. The dyes are effective against Candida species and several aerobic Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Gentian violet is a known contact sensitizer and may cause skin necrosis in concentrations greater than 2% aqueous solution or when used undiluted in skin folds.21

Hydrogen Peroxide

Hydrogen peroxide has been used for a number of years as a cleansing agent and for the removal of debris. It has antibacterial properties against both Gram-positive and -negative bacteria, and its effervescent quality helps débride wounds.

Iodinated Compounds

Iodine solution is bactericidal, sporicidal, and viricidal. Iodophors are complexes of iodine with a carrier that slowly liberates inorganic iodine on contact with reducing substances. This preserves the antimicrobial activities of iodine without the irritant effects of the free tincture. Iodophors must be applied to dry skin as they are inactivated by contact with blood, serum proteins, and sputum.

Povidone-Iodine

Povidone iodine has a wide spectrum of in-vitro activity against Gram-negative and -positive bacteria, fungi, and viruses. Systemic absorption can occur with resultant renal and thyroid dysfunction if large or prolonged quantities are used.

Clioquinol

Clioquinol, 5-chloro-8-hydroxy-7-iodoquinolinol, is weakly antifungal and antibacterial. It is effective alone or combined with a topical steroid to treat inflammatory dermatoses, especially in intertriginous areas. Adverse reactions include a yellowish discoloration on clothing or skin, delayed contact hypersensitivity, and contact dermatitis. In the early 1970s, it was linked to subacute myelo-optic neuropathy in Japan22 and was banned in many countries, including the United States. This link was questioned by subsequent epidemiologic studies,23 but product labeling still warns of possible irreversible optic atrophy and peripheral neuromuscular disease.

Metronidazole

Metronidazole is an imidazole with activity against anaerobic bacteria and protozoa that is most often used in dermatology for rosacea. In addition to its antibiotic properties, its mode of action in rosacea may involve the impedance of leukocyte chemotaxis and selective suppression of cellular immunity.

Mupirocin

Mupirocin, also known as pseudomonic acid, is bactericidal at the concentration achieved with topical application to the skin and mucous membranes. As mupirocin has a unique mechanism of action, in which it prevents the incorporation of isoleucine into proteins by inhibiting bacterial isoleucyl-t-RNA synthetase, there is no cross-resistance with other antimicrobials.25 It has activity against staphylococci, streptococci, and certain Gram-negative bacteria, but is inactive against much of the normal skin flora. It is the treatment of choice for nonbullous impetigo and the most effective topical antibiotic for the elimination of S. aureus nasal colonization.24

Retapamulin

Retapamulin is a member of the pleuromatilin class of antibiotics prescribed as a 1% topical ointment. It is bacteriostatic and inhibits the elongation phase of protein synthesis through selective binding to the 50S subunit of prokaryotic ribosomes. It is FDA approved for treatment of methicillin sensitive S. aureus and Streptococcus pyogenes, but is effective in vitro against isolates resistant to B-lactams, macrolides, quinolones, fusidic acid, and mupirocin.25

Azelaic Acid

Azelaic acid is a naturally occurring aliphatic dicarboxylic acid that is a competitive inhibitor of tyrosinase. Azelaic acid is a reversible inhibitor of cytochrome P450 reductase and 5α-reductase in microsomes and a reversible inhibitor of some enzymes in the respiratory chain. In-vitro azelaic acid has antimicrobial affects against Propionibacterium acnes and Staphylococcus epidermidis. Its efficacy against acne and rosacea is attributed to activity against P. acnes, normalization of keratinization, and a direct anti-inflammatory effect.26

Benzoyl Peroxide

Benzoyl peroxide is a nonspecific bactericidal agent that derives its biologic function through decomposition into benzoyloxy and phenyl radicals that react with numerous constituents of microbial cells. This effect may be enhanced by the addition of antibiotics or other molecules containing tertiary amines or transitional metals. As a topical therapy, benzoyl peroxide is mainly used for acne, although it is also occasionally used to speed healing of chronic wounds. When used for acne, it is frequently combined with topical antibiotics, as such combination therapy may reduce the development of antibiotic resistance by P. acnes.27

(See Chapter 208; Table 222-2)