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CASE STUDY
A 43-year-old woman presents with a complaint of worsening rosacea. She initially responded to once-daily topical metronidazole 0.75% gel with excellent clearing of the papulopustular component of her acne rosacea. Recently, she has noted increasing persistent facial erythema. What therapeutic options are available?
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Diseases of the skin offer special opportunities to the clinician. In particular, the topical administration route is especially appropriate for skin diseases, although some dermatologic diseases respond as well or better to drugs administered systemically.
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The general pharmacokinetic principles governing the use of drugs applied to the skin are similar to those involved in other routes of administration (see Chapters 1 and 3). However, human skin is a complex series of diffusion barriers (Figure 61–1). At least 20 factors affect percutaneous flux. Quantitation of the flux of drugs and drug vehicles through these barriers is the basis for pharmacokinetic analysis of dermatologic therapy, and techniques for making such measurements are rapidly increasing in number and sensitivity.
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Major factors that determine pharmacologic response to drugs applied to the skin include the following:
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Physicochemical properties of the drug: A drug’s particle size/molecular weight (MW), lipophilicity, volatility, pH, pKa, and partition coefficients (oil:water and formulation:skin) may all play a role in drug penetration through skin. For example, most topical drugs are less than or around 500 Da in size/MW with a few exceptions such as calcineurin inhibitors (tacrolimus MW 822 Da and pimecrolimus MW 810 Da). Drugs with larger particle sizes will have difficulty penetrating through skin effectively.
Regional variation in drug penetration: For example, the scrotum, face, axilla, and scalp are far more permeable than the forearm and may require less drug (or a less potent drug) for equivalent effect. For example, lower-potency corticosteroids are used on face and skin folds whereas high potency corticosteroids may be needed for palms and soles.
Concentration gradient: Increasing the concentration gradient increases the mass of drug transferred per unit time, just as in the case of diffusion across other barriers (see Chapter 1). Thus, lack of efficacy of topical corticosteroids can sometimes be overcome by use of higher concentrations of drug.
Dosing schedule: Because of its physical properties, skin acts as a reservoir for many drugs. As a result, the “local half-life” may be long enough to permit once-daily application of drugs with short systemic half-lives. For example, once-daily application of corticosteroids appears to be just as effective as multiple applications in many conditions.
Vehicles and occlusion: An appropriate vehicle maximizes the ability of the drug to penetrate the outer layers of the skin. In addition, through their physical properties (moistening or drying effects), vehicles may themselves ...