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

Dermatological Pharmacology
Craig Burkhart, Dean Morrell,
and Lowell Goldsmith
Drugs can be applied to skin for two purposes: to
directly treat disorders of the skin and to deliver drugs
to other tissues (Figure 65–1). The optimization of cutaneous
therapies requires detailed physiological knowledge
of the skin as reviewed extensively elsewhere
(Wolff et al., 2008). This chapter emphasizes the basis
of common skin therapies. Therapies that are used primarily
for skin diseases are discussed in detail; other
therapies that are applicable for skin disease are summarized
and the reader referred to the appropriate portion
of this book for their detailed pharmacology and
toxicology.
Many skin diseases can be treated with active
pharmacological agents topically; understanding the
principles for percutaneous drug absorption and metabolism
are essential for their effective and safe use.
Non-pharmacological therapy for skin diseases includes the
entire electromagnetic spectrum applied by many sources, such as
lasers, X-rays, visible light, and infrared light. These approaches
may be used alone or to enhance the penetration or alter the nature
of drugs and prodrugs. Freezing and ultrasound are other physical
therapies that alter epidermal structure for direct treatment or to
enhance percutaneous absorption of drugs. Chemicals are used to
decrease the effect of various wavelengths of ultraviolet (UV) light
and ionizing radiation.
Effective and safe use of topical agents requires
appreciation of the physical and physiological variables
that influence the interactions of drugs and the skin,
impacting absorption and transport. The skin is a multifunctional
and multicompartment organ affected in numerous
ways by diseases and their treatments. Figure 65–1
outlines general features of skin structure and percutaneous
absorption pathways. The bulk of percutaneous
absorption for most agents is through the stratum corneum,
which covers almost the entire skin surface. Epidermal
structure and the role of hair follicles and sweat glands as
pathways for absorption are reviewed below.
Stratum Corneum. The stratum corneum (outer 5-600 μm)
is the major barrier to percutaneous absorption of drugs
and to the loss of water from the body. It is made of
“dead” epidermal cells that cannot reproduce and have
lost their nuclei and mitochondria. It possesses multiple
proteins and lipids that may reversibly or irreversibly
bind drugs. Many chemicals and physical treatments to
enhance percutaneous absorption work within the stratum
corneum. Many drugs may partition into the stratum
corneum and can function as a reservoir for drugs
that will diffuse into the rest of skin even after topical
application of the drug has ceased.
The stratum corneum differs in thickness, with the
palm and sole being the thickest (400-600 μm) followed
by the general body stratum corneum (10-16 μm), and the
scrotum (5 μm). Facial and post-auricular regions have
the thinnest stratum corneum. Thickness is only one variable
in determining regional differences in drug penetration.
Cellular arrangement has a significant role as well.
Living Epidermis. The living layers of the epidermis with
metabolically active cells comprise a layer ~100 μm thick
(Figure 65–2). The lowest layer (basal layer, or stratum
basale) is responsible for the bulk of cell division. Several
cell layers in the spinous layer (stratum spinosum) contain
cells that actively synthesize most epidermal proteins,
especially keratins, a large family of intracellular
fibrous molecules that form the bulk of the epidermal
mass. The uppermost living layer, the granular layer
(stratum granulosum), is where extracellular lipids are
extruded from the epidermis, forming extracellular lipids
that are an important transport pathway; where the cell
envelope, resistant to most proteolysis and alkali, is
formed; and where extracellular lipids are covalently
bound. The granular layer is also the site of synthesis of
filaggrin, an intracelluar molecule that enhances keratin
packing. Filaggrin is proteolyzed at the granular/stratum
corneum junction, and its amino acids contribute to a