Sensible topical drug therapy involves not only the selection of an appropriate agent, but also a thoughtful consideration of the areas of the body affected, the state of the diseased skin, the concentration of the drug, the type of vehicle (e.g., ointment, cream, lotion), the method of application, and a defined duration of use that both maximizes efficacy and minimizes adverse side effects. Behind each of these considerations are basic principles that help guide the practitioner toward a rational plan of therapy.

The therapeutic efficacy of a topical drug relates to both its inherent potency and the ability of that drug to penetrate the skin.1 In fact, many potent agents, such as hydrocortisone and fluocinolone acetonide, are quite poorly absorbed after topical application. Conversely, many well-absorbed agents with weak potency have negligible therapeutic use. Percutaneous absorption necessitates passage through the stratum corneum, epidermis, papillary dermis, and into the bloodstream. (See Chapter 215 for information on the pharmacokinetics of topical therapy.)

In contrast to many orally administered drugs that are nearly completely absorbed within a few hours, topical medicines generally have a poor total absorption and a very slow rate of absorption. For example, less than 2% of a topically applied corticosteroid such as hydrocortisone is absorbed after a single application left on the skin for more than 1 day. Furthermore, peak rates of absorption are reached up to 12–24 hours after application. Fortunately, low absorption does not necessarily translate into low efficacy. Drugs such as topical corticosteroids are effective because of their inherent potency and can exert clinically significant effects in spite of low absorption. In this light, absorption represents only one of many facets of efficacy.

Stratum Corneum

The stratum corneum is the rate-limiting barrier to percutaneous drug delivery. This cornified layer is composed of ceramides, free fatty acids, and cholesterol in a 1:1:1 molar ratio. By weight, the stratum corneum consists of 50% ceramides (acylceramides being the most abundant), 35% cholesterol, and 15% free fatty acids. The stratum corneum thickness and, thus, drug penetration will vary depending on body site.2 Box 214-1 lists varying body sites and their relative resistance to percutaneous absorption.

There are two main routes for permeation through the stratum corneum: (1) the transepidermal and (2) the transappendageal pathways. The transappendageal, or shunt route, involves the flow of molecules through the eccrine glands and hair follicles via the associated sebaceous glands.3 In the transepidermal route, molecules pass between the corneocytes via the intercellular micropathway, or through the cytoplasm of dead keratinocytes and intercellular lipids, defined as the transcellular micropathway.3,4 The intercellular pathway is considered the most important route for cutaneous drug delivery.

An important consideration in topical therapy is that diseased skin may have an altered (increased, decreased, or absent) stratum corneum, thus changing the body site’s barrier function. Abraded or eczematized skin presents less of a barrier. Solvents, surfactants, and alcohols can denature the cornified layer and increase penetration; as a result, topical medications with these components may enhance absorption. Importantly, simple hydration of the stratum corneum enhances the absorption of topically applied steroids by four to five times.5

Occlusion

Occlusion via closed, airtight dressings or greasy ointment bases increases the hydration and temperature of the stratum corneum, limits rub-off/wash-off of the drug and, consequently, enhances drug penetration. Occlusion techniques range from application under an airtight dressing such as vinyl gloves, plastic wrap, and hydrocolloid dressings to occlusion with cotton gloves or socks at night for treatment of hands and feet, to application of a medication already impregnated into an airtight dressing, as seen in flurandrenolide tape. To derive the greatest benefit from occlusion, the patient should hydrate the skin by immersion in water for approximately 5 minutes before the application of a cream or ointment. Clinically, this may correspond to application immediately after bathing and before drying completely. With many drugs, occlusion increases drug delivery by 10–100 times the amount of drug delivered when not occluded.6 This approach can lead to more rapid onset times and increased efficacy when compared with topical application alone. On the other hand, occlusion may also lead to a more rapid appearance of the drug’s adverse effects, such as the ability of topical corticosteroids to induce local skin atrophy or suppression of the hypothalamus–pituitary–adrenal axis. Occlusion may promote infection, folliculitis, or miliaria. In the case of topical anesthetics such as lidocaine and prilocaine, occlusion hastens absorption into both the skin and the bloodstream, which has led in rare cases to cardiac complications from lidocaine toxicity or methemoglobinemia from prilocaine toxicity.

Frequency of Application

The frequency of drug application likely has little effect on increasing a topical drug’s overall efficacy.6,7 One daily application is enough for most topical glucocorticoids, for example, but the nonspecific emollient or protective effect of creams and ointments are likely enhanced by more frequent applications. Regardless, increasing the contact time for a topical drug augments its total absorption.

Quantity of Application

The quantity of the drug applied likely has a negligible effect on drug absorption. Obviously enough drug must be dispensed and spread to cover the affected areas. Further, the quantity of drug applied might affect patient adherence to the prescribed regimen. For example, too much applied drug might negatively alter the subjective experience of having a medication on the skin, i.e., the drug may feel “wrong” (greasy, caked, chalky, etc.) or is cosmetically unattractive (shiny, white color). Regardless, the amount prescribed must be adequate to treat the affected body surface area for the necessary length of time. In this regard, patient education is critical to prevent wasteful overuse or ineffective underuse of the medication. The amounts of topical medications to dispense, based on the estimated body surface area, frequency of application, and duration of therapy, are presented in Table 214-1. For topical medications like sunscreens that are used over large areas, underapplication is a problemfor most patients. However, for smaller areas, patients may apply a large amount of an ointment, for example, leading to complaints of greasiness or rubbing off on clothing, which can be minimized by using an appropriate amount.

Adherence

Topical medication adherence is a critical although often overlooked aspect of medication efficacy. Generally, adherence to a treatment regimen is associated with female gender, employment, being married, and low prescription costs. Lower adherence is seen for patients with extensive disease, and paradoxically, disease on the face.8 One 8-week survey using electronic monitoring showed that adherence to treatment for a twice-daily topical prescription decreased from 84% the first week to 51% during the eighth week, with topical nonadherence being especially notable on weekends.9 Furthermore, adherence is negatively affected by depression, which is common in people with chronic skin conditions and found in up to 20% of patients with psoriasis.10

Tachyphylaxis

Defined as the decrease in drug response when used over a prolonged period of time, tachyphylaxis is commonly observed during corticosteroid topical therapy. It is now thought that adherence may be a contributing factor, rather than loss of corticosteroid receptor function.5,11 Increase in adherence may be achieved by asking patients to use it only on weekends (weekend therapy) or specific days of the week (pulse therapy).5

Rebound Effect

Worsening of preexisting dermatoses can occur in patients who have been using topical potent corticosteroids for prolonged regimens.5 Either tapering down the corticosteroid strength to moderate- or low-potency corticosteroids or increasing the duration of time between applications of the topical drug might prevent the rebound effect.

Miscellaneous Factors

Vigorous rubbing or massaging of the drug into the skin not only increases the surface area of skin covered, but also increases blood supply to the area locally, augmenting systemic absorption. It may cause a local exfoliative effect that will also enhance penetration. The presence of hair follicles on a particular body site also enhances drug delivery, with the scalp and beard areas presenting less of a barrier when compared with the relatively hairless body sites. Although having a thinner stratum corneum, the skin of older individuals is poorly hydrated, with fewer hair follicles and, therefore, may impede drug delivery.

Reducing the particle size of the active ingredient increases its surface area–volume ratio, allowing for a greater solubility of the drug in its vehicle. This forms the basis for the increased absorption of certain micronized drugs.12

The vehicle is the inactive part of a topical preparation that brings a drug into contact with the skin. Before the mid-1970s pharmaceutical companies performed limited testing of the impact of the vehicle on the potency of a given formulation. The lack of a scientific analysis of the vehicle led to the marketing of topical drugs that, while having different concentrations of the same active ingredient, nevertheless exhibited similar bioavailability and potency. For example, older preparations of triamcinolone acetonide showed no real differences in potency among the 0.025%, 0.1%, and 0.5% concentrations. By contrast, modern drug development attempts to maximize drug bioavailability by optimizing vehicle formulation. Additionally, during the current drug development process, dose-response studies determine the maximal effective concentration within a given vehicle, above which any further increase in concentration serves no therapeutic benefit.

The vehicle of a topical formulation often has beneficial nonspecific effects by possessing cooling, protective, emollient, occlusive, or astringent properties. Rational topical therapy matches an appropriate vehicle that contains an effective concentration of the drug. The vehicle functions optimally when it is stable both chemically and physically and does not inactivate the drug. The vehicle also should be nonirritating, nonallergenic, cosmetically acceptable, and easy to use. Additionally, the vehicle must release the drug into the pharmacologically important compartment of the skin. Finally, the patient must accept using the vehicle or else compliance will be poor. For example, although ointments are often pharmacodynamically more effective than creams, patients generally prefer creams to ointments, and thus, it is no surprise that more prescriptions are written for cream-based formulations. Box 214-2 lists many commonly used ingredients in topical preparations. Many of these compounds may serve more than one function in a particular formulation.