Applying a xenobiotic to the skin to treat a systemic medical condition is not new. Ointments and other salves have been applied topically for thousands of years for the treatment of local and systemic diseases. During World War I, dynamite workers used nitroglycerin applied to their hatbands to prevent angina when they were away from work and no longer exposed to organic nitrates.31 Mustard seed plaster for chest congestion, releasing allyl isothiocyanate, and topical elemental mercurials for syphilis are other examples from the early 20th century.24 Over the past 30 years, an increasing number of medications have been formulated in transdermal delivery systems or patches to allow for systemic delivery of a xenobiotic. The first commercially available patch delivered scopolamine for motion sickness (1979), which was followed by nitroglycerin for chronic angina (1981) and then fentanyl for chronic pain management (1990). In the United States, the nicotine patch remains the most widely used transdermal delivery system both because of the high need for smoking cessation and its nonprescription availability. Certain medicinal xenobiotics, such as testosterone, can be administered topically without a patch as a spray or gel.18 Furthermore, nonmedicinals can be absorbed transdermally, as occurs with nicotine after direct exposure to moist tobacco leaf in patient with "green tobacco sickness" or with organic phosphorus pesticides.3
The skin is the largest organ in the body, although it is not generally used as a route for intentional xenobiotic delivery. However, there are several benefits of transdermal delivery of systemic medication. This route provides a noninvasive means to discreetly administer medications. Patches result in steady serum concentrations that reduce side effects particularly for xenobiotics with short half-lives. The patches can be left in place for long periods of time, which improves compliance. Importantly, the avoidance of first-pass metabolism permits a means to effectively deliver poorly orally bioavailable xenobiotics. However, because all absorption through the skin is passive, there is a large degree of variability among both patients and xenobiotics.
This chapter does not cover xenobiotics applied to the skin to produce an effect locally. These xenobiotics can be available in patch formulation (eg, lidocaine and capsaicin) or as a directly applied preparation, such as a variety of antibiotics or acne creams. Locally acting formulations (eg, lidocaine) typically provides only trivial amounts of systemic xenobiotic;6 with tretinoin, despite devastating fetal complication when taken orally, these same effects do not occur when applied topically.16
TRANSDERMAL ADMINISTRATION PHARMACOLOGY
The same hydrophobic property that allows the skin to prevent water loss hinders the ability to administer a water-soluble xenobiotic transdermally. To reach the systemic circulation, a xenobiotic applied to the stratum corneum (horny layer) (Fig. 18–1) must initially pass through about a dozen layers of keratinized epidermal cells and then into the dermis. This keratinaceous horny layer is highly ...