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

1806
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Table 65–1
Important Considerations When a Drug Is Applied
to the Skin
What are the absorption pathways of intact and diseased
skin?
How does the chemistry of the drug affect the
penetration?
How does the vehicle affect the penetration?
How much of the drug penetrates the skin?
What are the intended pharmacological targets?
What host and genetic factors influence drug function in
the skin?
the permeability barrier, patient age and weight, physical
form of the preparation to be applied, and whether
intralesional or systemic administration should be used.
Dosage. Covering the entire skin of an adult with a topical preparation
requires ~30 g of spreadable material. Underapplication of drug
because of cost considerations often occurs when large amounts of
skin are treated for a long time.
Regional Anatomical Variation. Permeability generally is inversely
proportional to the thickness of the stratum corneum. Drug penetration
is higher on the face, intertriginous areas, and perineum due to
stratum corneum thickness. Skin sites that are naturally occluded by
apposing surfaces, such as the axillae, groin, and inframammary
areas, are vulnerable to drug-related atrophy from potent topical
glucocorticoids.
Altered Barrier Function in Disease. In many dermatological diseases,
the stratum corneum is abnormal and barrier function is compromised.
In these settings, increased percutaneous absorption of potential
topical steroids can cause systemic toxicity, such as
hypothalamic–pituitary–adrenal (HPA) axis suppression.
Vehicle. Drug vehicles are summarized in Table 65–2. Newer vehicles
include liposomes and microgel formulations. Liposomes are
concentric spherical shells of phospholipids in an aqueous medium
intended to enhance percutaneous absorption in normal and abnormal
stratum corneum. Variations in size, charge, and lipid content
can influence liposome function substantially. Transfersomes are a
drug-delivery technology based on highly deformable, ultraflexible
lipid vesicles that penetrate the skin when applied nonocclusively
(Barry, 2004). Microgels are polymers intended to enhance solubilization
of certain drugs, thereby enhancing topical penetration and
diminishing irritancy.
Age. Children have a greater ratio of surface area to mass than adults
do, so the same amount of topical drug can result in a greater systemic
exposure. Based on transepidermal water loss and percutaneous
absorption studies, term infants seem to possess a stratum
corneum with barrier properties comparable to adults. Preterm
infants have markedly impaired barrier function until the epidermis
keratinizes completely.
Application Frequency. Topical agents often are applied twice daily.
For certain drugs, once-daily application of a larger dose may be
equally effective as more frequent applications of smaller doses. For
some drugs, the stratum corneum may act as a drug reservoir that
allows gradual penetration into the viable skin layers over a prolonged
period. Intermittent pulse therapy—treatment for several days or
weeks alternating with treatment-free periods—may prevent development
of tachyphylaxis (loss of clinical effectiveness associated with
drugs such as topical glucocorticoids). The mechanism of loss of effectiveness
may be related to the corticosteroid binding and response of
nuclear receptors rather than absorption.
Intralesional Administration. Intralesional drug administration is
used mainly for inflammatory lesions but also can be used for treatment
of warts and selected neoplasms. Medications injected intralesionally
have the advantages of direct contact with the underlying
pathological process, no first-pass metabolism, and the opportunity
for a slowly absorbed depot of drug. In considering the use of intralesional
glucocorticoids, it is important to be cognizant of the possibility
of complete systemic absorption and suppression of the HPA.
Systemic Administration. Systemic administration of medication in
dermatology involves several routes of administration: oral, intramuscular
(e.g., methotrexate, glucocorticoids), intravenous (e.g.,
immunoglobulin, alefacept), or subcutaneous (e.g., efalizumab,
etanercept).
GLUCOCORTICOIDS
Glucocorticoids are prescribed frequently for their
immunosuppressive and anti-inflammatory properties.
They are administered locally, through topical and
intralesional routes, and systemically, through intramuscular,
intravenous, and oral routes. Mechanisms of
glucocorticoid action are numerous, as discussed in
Chapter 42. These include apoptosis of lymphocytes,
inhibitory effects on the arachidonic acid cascade,
depression of production of many cytokines, and myriad
effects on inflammatory cells.
Topical Glucocorticoids
Topical glucocorticoids have been grouped into seven
classes in order of decreasing potency (Table 65–3);
many of the more potent drugs have a fluorinated
hydrocortisone backbone. Potency traditionally is
measured using a vasoconstrictor assay in which an
agent is applied to skin under occlusion, and the area of
skin blanching is assessed. Other assays of glucocorticoid
potency involve suppression of erythema and
edema after experimentally induced inflammation and
the psoriasis bioassay, in which the effect of steroid on
psoriatic lesions is quantified.
Therapeutic Uses. Many inflammatory skin diseases
respond to topical or intralesional administration of