Transdermal Xenobiotic Absorption
Although there is no active uptake mechanism for xenobiotics by the skin, many undergo percutaneous absorption by passive diffusion. Lipid solubility, concentration gradient, molecular weight, and certain specific skin characteristics are important determinants of dermal absorption. Absorption is generally considered to occur though intercellular movement, requiring that the xenobiotic dissolve in the ceramides. This accounts for the importance of lipid solubility of the xenobiotic in transdermal absorption. However, excessive lipid solubility limits the partitioning of the xenobiotic from the stratum corneum into the aqueous dermis, a critical requirement since the blood vessels are in this deeper layer.13,14,31,32 The relationship between lipid and water solubility is often described by the octanol-water partition coefficient. Xenobiotics with values between 10 and 1000 have sufficient lipid and water solubility to permit skin permeation.
For example, morphine sulfate, with an octanol water partition coefficient of approximately 1, is not absorbed when applied topically, whereas fentanyl, with a coefficient of approximately 700, is widely used as a transdermally delivered medication. The dermal toxicity of the various organic phosphorus compounds may be predicted based on this coefficient.9 Although metal ions such as Hg+ have limited skin penetration, the addition of a methyl group, to form methylmercury, increases its lipophilicity and its systemic absorption. Dimethylmercury, has even better absorption and may produce life-threatening systemic effects with a minute amount applied to the skin (Chap. 96). Similarly, the nonionized component of the weakly acidic hydrofluoric (HF) acid is able to penetrate deeply through skin and even bone. The proton (H+) and fluoride ion (F−) are unable to penetrate the lipids of the skin individually because of their charged nature; however, once in the dermis, the HF acid may ionize and cause both acid-induced tissue necrosis and fluoride-induced toxicity (Chap. 105).4
Children appear particularly at risk for toxicity from percutaneous absorption because their skin is more penetrable than an adult's and specific anatomic sites, such as the face, often represent larger percentage of body surface areas than in the adult.37 Furthermore, there is enhanced absorption on anatomic parts of the body with thinner skin, such as the mucous membranes, eyelids, and intertriginous areas (axillae, groin, inframammary, and intergluteal). Under certain circumstances, such as with more highly lipophilic xenobiotics, the stratum corneum may serve a depot function leading to slow onset and continued systemic exposure despite apparent removal of the xenobiotic. For example, applied topically in the form of a transdermal device, fentanyl does not result in peak concentration for 24 to 72 hours after initial application. When removed, the serum fentanyl concentrations fall with an average half-life of 17 hours, which is substantially longer than when administered intravenously.18 The vehicle of a xenobiotic may also influence absorption; indeed, transdermal drug-delivery systems are based on their ability to alter the skin partition coefficient through the use of an optimized vehicle. Similarly, through localized dermal occlusion, transdermal systems hydrate the skin and raise its temperature to increase absorption. Despite these techniques to enhance drug delivery, transdermal systems require that large amounts of drug be present externally to maximize the transcutaneous gradient. Much of the drug typically remains in the patch when it is removed following its intended course of therapy, raising concerns for safe disposal, especially for children.13,14,31,32
Transdermal drug delivery has several therapeutic advantages, such as continuous dosing resulting in more stable pharmacokinetics, prolonged drug delivery resulting in a more convenient dosing schedule (eg, weekly device changes), and the avoidance of first pass hepatic metabolism. These delivery devices, familiarly called "patches," are highly developed and crafted to deliver their content at a specified rate. Some variability occurs related to skin thickness, dermal barrier damage (eg, dry skin, rashes), or external factors, such as ambient temperature. As with any route of administration, adverse effects and toxicity caused by excessive absorption following patch application may occur following therapeutic use and misuse. For example, this is reported with nicotine, fentanyl, NSAIDS, and lidocaine transdermal delivery devices. Other xenobiotics, topically applied without a specific delivery device, may be associated with systemic morbidity and mortality, including podophyllin, camphor, phenol, organic phosphorus compounds, ethanol, organochlorines, and nitrates.
Allergic contact dermatitis from plants and dyes such as fragrances and paraphenylenediamine (henna) is increasing in frequency. Miconidin and miconidin methyl ester were isolated from Primula obconica (primrose). Parthenolide is an ingredient in feverfew and can cause an airborne contact dermatitis. Triethanolamine polyethylene glycol-3 (TEA-PEG-3) cocamide sulfate was identified recently to cause allergic reactions in coconut oil.
Exposure to any of a myriad of industrial and environmental xenobiotics can result in dermal "burns." Although the majority of these xenobiotics injure the skin through chemical reactivity rather than thermal damage, the clinical appearances of the two are often identical. Injurious xenobiotics may act as oxidizing or reducing agents, corrosives, protoplasmic poisons, desiccants, or vesicants. Often an injury may initially appear to be mild or superficial with only faint erythema, blanching, or discoloration of the skin. Over the subsequent 24 to 36 hours there may be progression to extensive necrosis of the skin and its underlying tissues.
Acids are water soluble and many readily penetrate into the subcutaneous tissue. The damaged tissue coagulates and forms a thick leathery eschar that limits the spread of the xenobiotic. The histopathologic finding following acid injury is termed coagulative necrosis. Alkali exposures characteristically produce a liquefactive necrosis, which allows continued penetration of the corrosive xenobiotic; consequently, dermal injury following alkali exposure is typically more severe than after an acid exposure of an equivalent magnitude.7
Thermal damage can also be the result of a toxicologic exposure. For example, the exothermic reaction generated by the wetting of elemental phosphorus or sodium may result in a thermal burn. In these circumstances, the products of reactivity, phosphoric acid and sodium hydroxide respectively, may produce secondary chemical injury. Alternatively, skin exposure to a rapidly expanding gas, such as nitrous oxide from a whipped cream cartridge or compressed liquefied nitrogen, or to frozen substances, such as dry ice, can produce a freezing injury, or frostbite.
Hydrocarbon-based solvents are typically liquids that are capable of dissolving non–water-soluble solutes.7 Although the most prominent effect is a dermatitis due to loss of ceramides from the stratum corneum, prolonged exposure can result in deeper dermal irritation and destruction.