DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Lamellar
body
Tight
junction
Scale desquamation
1805
SC
SG
Cornified lipid envelope
Lipid bilayers
Cornified cell envelope with
involucrin, foricrin, flaggrin
Keratohyalin granule
SS
Cytokeratin K1/K10
Desmosome
SB
Cytokeratin K5/K14
CHAPTER 65
Figure 65–2. Structure of the epidermis. The epidermis matures progressively from the stratum basale (SB) to the stratum spinosum
(SS), stratum granulosum (SG), and stratum corneum (SC). Important structural and metabolic proteins are produced at specific layers
of the epidermis. (Reproduced with permission from Wolff et al., 2008. Figure 45-2. Copyright © The McGraw-Hill Companies,
Inc. All rights reserved. Available at http://www.accessmedicine.com.)
idealized situation and can only approximate what occurs in normal
or diseased epidermis.
Preferable characteristics of topical drugs include low molecular
mass (600 Da), adequate solubility in both oil and water, and a
high partition coefficient (Barry, 2004) so the drug will selectively
partition from the vehicle to the stratum corneum. Except for very
small particles, water-soluble ions and polar molecules do not
penetrate significantly through intact stratum corneum. Commercial
topical pharmaceuticals are compounded for optimum diffusion and
partition, and the extemporaneous addition of other ingredients
may interfere with the activity or change the absorption of the
primary drug.
Drugs may target enzymes or cells of any of the skin compartments,
including inflammatory cells not normally in that compartment.
The exact amount of drug entering or leaving the skin in
clinical situations usually is not measured; rather, the clinical endpoint
(e.g., reduction in inflammation) usually is the desired effect.
A hydrated stratum corneum allows more percutaneous
absorption and often is achieved through the selection of drugs formulated
in occlusion vehicles such as ointments and the use of plastic
films, wraps, or bags for the hands and feet and shower or bathing
caps for the scalp, or through the use of medications that are impregnated
on patches or tapes. Occlusion may be associated with
increased growth of bacteria with resultant infection (folliculitis) or
maceration and breakdown of the epidermis. Transport of most drugs
is a passive thermodynamic process, and heat generally increases
penetration. Ultrasonic energy or laser-induced vibration also can
be used to increase percutaneous absorption. The latter may function
by the production of lacunae in the stratum corneum.
The epidermis contains a variety of enzyme systems capable of
metabolizing drugs that reach this compartment. Many of these
enzymes have genetically determined variants that may affect drug
activity. Enzymes that have been studied in detail include CYPs, epoxide
hydrolase, transferases such as N-acetyl-transferases, glucuronyl
transferases, and sulfatases (Baron et al., 2001). A specific CYP isoform,
CYP26A1, metabolizes retinoic acid and may control its level
in the skin (Baron et al., 2001). In addition, transporter proteins that
influence influx (OATP) or efflux (MDR, P-glycoprotein) of certain
xenobiotics are present in human keratinocytes (Baron et al., 2001).
Although substrate turnover is considerably less than that for hepatic
CYPs, these enzymes influence concentrations of xenobiotics in the
skin. Genetic variants of enzymes that regulate the cellular influx and
efflux of methotrexate have been associated with toxicity and effectiveness
in patients with psoriasis (Warren et al., 2008).
Pharmacologic Implications of Epidermal Structure.
The healthcare provider must answer a number of questions
when proposing topical application of drugs
(Table 65–1), including consideration of proper dosage
and frequency of application, extent and condition of
DERMATOLOGICAL PHARMACOLOGY