Either the vehicle or its active ingredients may cause local toxicity to the applied site. Local adverse effects are usually minor and reversible. Major cutaneous side effects include irritation, allergenicity, atrophy, comedogenicity, formation of telangiectases, pruritus, stinging, and pain. The mechanism of toxicity may be as simple as the desiccation of the stratum corneum (the removal of sebum and oils by the preparation's emulsifiers, for example), or involve a more complex effect on either the cells of the epidermis or dermis and the structures these cells comprise (i.e., epidermis, adnexae). Local damage may occur either directly at, or within close proximity to, the treated site. Further, irritation and damage may appear even after a drug has been discontinued. Often the therapeutic effects of the active ingredient mask or immediately treat the toxic effects of the formulation so that acutely toxic effects are transient.18 For example, an allergic contact dermatitis to a preservative in a topical steroid may be masked by the effects of the steroid itself.
Irritant Contact Dermatitis
Irritation is driven less by drug penetration and more by drug concentration. Thus, lowering the concentration of an irritating drug may lower the risk of side effects. However, a change in formulation may reduce the preparation's efficacy. Nevertheless, often using a less concentrated preparation over a greater period of time is as therapeutically efficacious while minimizing adverse effects; for example, the use of benzoyl peroxide 2% to 5% preparations in contrast to 10% preparations.18 In some instances, though, skin irritancy might be central to drug efficacy. For example, although not conclusively shown, the power of immunomodulating agents such as imiquimod might rely on an increased innate (inflammatory or irritant) immune response.
Subjective or Sensory Irritant Contact Dermatitis
Patients may detect burning or stinging sensations without any signs of cutaneous irritation after applying a topical medication.19,20 Several compounds may induce sensory irritant contact dermatitis in predisposed individuals, such as tacrolimus,21 sorbic acid, propylene glycol, benzoyl peroxide hydroxy acids, mequinol, ethanol, lactic acid, azelaic acid, benzoic acid, and tretinoin.19,20
Allergic Contact Dermatitis
In contrast to local irritation, contact allergy development depends on local penetration. Allergy, of course, is driven by antigen recognition and presentation, and thus, percutaneous absorption of the drug must be at a level that guarantees interaction with the immune effector cells of the skin. Therefore, the contact allergenicity of a drug relates most significantly to percutaneous absorption. In some instances, cutaneous allergy may be therapeutic, for example, the treatment of patients with cutaneous T-cell lymphoma with topical nitrogen mustard. The shift in malignant T cells from T helper (Th) 2 to Th1-type cytokine expression is believed to lead to apoptosis of the malignant T cells and tumor regression.22
Rarely, topical therapy may result in neoplasia. For example, the risk of secondary malignancies, such as keratoacanthomas, basal and squamous cell carcinomas, lentigo maligna and primary melanoma have been reported with the long-term use of nitrogen mustard.22
The application of topical corticosteroids to the periorbital skin has been reported both to induce cataracts and increase in intraocular pressure.5
One should be aware of the potential systemic toxicities of topical drugs. Although generally safer than the other routes of administration, topical application can result in systemic toxicities ranging from end-organ toxicity (central nervous system, cardiac, renal, etc.), teratogenicity, and carcinogenicity to drug interactions. These outcomes may relate to the drug itself, its metabolites, or even a component of the vehicle.
The kinetics of topically applied drugs differ significantly from those administered by other routes. One important consideration is the lack of hepatic first-pass metabolism of a topical drug. This is especially relevant to drugs such as salicylic acid that are relatively innocuous when given enterally, but may manifest central nervous system toxicity when applied topically. Additionally, acting as a reservoir, the stratum corneum may store large amounts of a topical drug, and a subsequently long diffusion period of many days may ensue, delivering a steady supply of drug to the systemic circulation.
Percutaneous toxicity directly relates to percutaneous absorption. Therefore, factors that modulate absorption also influence toxicity: the concentration of the drug, its vehicle, the use of occlusion, the body site and area treated, frequency of use, the duration of therapy, and the nature of the diseased skin. For example, 6% salicylic acid in Eucerin used for 11 days in the treatment of psoriasis has been associated with epistaxis and deafness, while the same concentration of salicylic acid in hydrophilic cream under occlusion for 4 days for the treatment of dermatitis (involving the same amount of body surface area) may result in hallucination.18 Similar to their effect on systemically administered drugs, renal and hepatic diseases, by influencing drug clearance, also contribute to an increased potential for drug toxicity.
Young children have a greater surface area–volume ratio, and thus are at greater risk of percutaneous toxicity than adults. This phenomenon necessitates alternative drugs, formulations, and dosing schedules for children with widespread cutaneous disease. Patients with acute flares of cutaneous illness (for example, psoriasis or atopic dermatitis) may require the treatment of a larger body surface area in a relatively abbreviated period of time. These patients may also increase their dose and frequency of application during such flares. Coupled with the likely increased percutaneous absorption of the diseased skin, these scenarios exponentially increase the possibility of systemic toxicity, and patient education is vital to prevent adverse outcomes.12 To reduce the risk of toxicity from topical drugs and to increase treatment efficacy, many practitioners will rationally advocate systemic approaches (i.e., methotrexate, cyclosporine, injectable or infusable biologics, or ultraviolet radiotherapy) to patients whose disease involves an extensive body surface area.
Type I Hypersensitivity Reactions
In rare instances, anaphylactic shock can be precipitated by topical drug application. For example, when applied to diseased or abraded skin, bacitracin ointment can induce an immediate-type (type I) hypersensitivity reaction in susceptible individuals. Such reactions might be represented by a local and then subsequently generalized pruritus leading to cardiopulmonary arrest.12 Nonimmunologic acute toxicity results from substances such as pesticides and chemical warfare agents that rapidly diffuse through the skin and reach target organs.
Systemic calcineurin inhibitors have been associated with increased risk of lymphoma and nonmelanoma skin cancer. But the topical use of such drugs does not appear to be related to cancer.23,24 In fact, the risk for lymphoma with the use of topical calcineurin inhibitors was assessed in animal studies that demonstrated an increased risk only when blood levels were 30 times higher than those measured after topical application in human subjects.24 Numerous studies have demonstrated the efficacy and safety of topical calcineurin inhibitors. More than 50 cases of lymphoma have been reported, although the topical calcineurin inhibitor use may be coincidental. Nevertheless, there is a clear need for additional follow-up information to establish the long-term safety profile of this class of drugs. Two long-term trials currently being conducted might help address these concerns.24
Topical corticosteroids can rarely cause hypothalamic–pituitary–adrenal axis suppression, growth retardation, hyperglycemia, iatrogenic Cushing syndrome and femoral head osteonecrosis.5 Factors that enhance drug absorption are directly related to an increase in these side effects; therefore, carefully monitoring must be ensured when prescribing usage in large surfaces areas, prolonged use of potent corticosteroids, usage under occlusion, high potency corticosteroids, or use for the pediatric age group (due to their increased surface to body mass ratio).
Transdermal drug delivery, in contrast to topical drug delivery, uses topical application of therapeutic drug as a delivery system for systemic therapy. Transdermal patches have been approved by the US Food and Drug Administration since 1981 (scopolamine being the first) for the delivery of 13 different medications, with more seeking approval. The most commonly used patches are for nitroglycerin and fentanyl. Advantages of this approach include controlled release, a steady blood-level profile with zero-order kinetics, lack of a plasma peak, and, in some cases, improved patient compliance. These patches remain on the skin for 12 hours to 1 week. A patch consists of a plastic backing, a reservoir of medication, either a rate-controlling membrane or a polymer matrix system for controlled diffusion, followed by an adhesive facing the skin. The most common adhesives used are acrylates, silicones, and polyisobutylenes. These patches have been tested and are approved for use on the thighs, buttocks, lower abdomen, upper arms, and chest; application to other sites can lead to either sub- or supratherapeutic blood levels. Adverse effects of patches include local irritation and allergic contact dermatitis to either an adhesive or to the drug itself and may necessitate discontinuation. Topical therapies are a mainstay of treatment for the dermatologist. An understanding of the interactions between a drug's concentration, penetration, availability, and treatment of diseased skin allows physicians to maximize both efficacy and tolerability of topical therapy. An understanding of local and systemic toxicities allows selection of appropriate, safe therapy for patients and minimizes unwanted effects. Appropriate selection of topical agents and patient education on proper use can optimize therapeutic outcomes.