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

to reserve this method for allergic contact dermatitis to
plants (e.g., poison ivy) and for life-threatening vesiculobullous
dermatoses such as pemphigus vulgaris and
bullous pemphigoid. Chronic administration of oral glucocorticoids
is problematic, given the side effects associated
with their long-term use (see Chapter 42).
Daily morning dosing with prednisone generally is preferred,
although divided doses occasionally are used to enhance
efficacy. Fewer side effects are seen with alternate-day dosing, and
if chronic therapy is required, prednisone usually is tapered to
every other day as soon as it is practical. Pulse therapy using large
intravenous doses of methylprednisolone sodium succinate (SOLU-
MEDROL, others) is an option for severe resistant pyoderma gangrenosum,
pemphigus vulgaris, systemic lupus erythematosus with
multi-system disease, and dermatomyositis. The dose usually is
0.5-1 g given over 2-3 hours. More rapid infusion has been associated
with increased rates of hypotension, electrolyte shifts, and
cardiac arrhythmias.
Toxicity and Monitoring. Oral glucocorticoids have numerous systemic
effects, as discussed in Chapter 42. Most side effects are dose
dependent. Long-term use is associated with a number of complications,
including psychiatric problems, cataracts, myopathy, osteoporosis,
avascular bone necrosis, glucose intolerance or overt
diabetes mellitus, and hypertension. In addition, psoriatic patients
treated with parenteral or topical glucocorticoids may have a pustular
flare, particularly if the steroid is tapered rapidly.
RETINOIDS
Retinoids are defined as natural and synthetic compounds
that exhibit vitamin A–like biological activity
or bind to nuclear receptors for retinoids. Retinoids
have many important functions throughout the body,
including roles in vision, regulation of cell proliferation
and differentiation and bone growth, immune
defense, and tumor suppression (Vahlquist et al., 2008).
Early use of systemic retinoids to treat acne and disorders
of keratinization was limited by the toxic side
effects of first-generation retinoids. This was largely
solved through molecular modifications that yielded
new generations of compounds with vastly improved
margins of safety. First-generation retinoids include
retinol (vitamin A), tretinoin (all-trans-retinoic acid;
vitamin A acid), isotretinoin (13-cis-retinoic acid), and
alitretinoin (9-cis-retinoic acid). Second-generation
retinoids, also known as aromatic retinoids, were created
by aromatization of the cyclic end group and
include acitretin and methoxsalen (also known as etretinate;
not marketed in the U.S.). Third-generation
retinoids were created after the discovery of specific
retinoid receptors and have diverse structures designed
to optimize receptor-selective binding. Members of this
generation include tazarotene, bexarotene, and adapalene.
Characteristics of topical and systemic retinoids are
summarized in Tables 65–4 and 65–5.
Retinoids exert their effects on gene expression by activating
two families of receptors—retinoic acid receptors (RARs) and
retinoid X receptors (RXRs)—that are members of the steroid receptor
superfamily (Winterfield et al., 2003). Both retinoid receptor families
have three isoforms (, , and ), which are expressed in unique
combinations in individual tissues and cells. The human epidermis,
for example, expresses RAR-, RAR-, RXR-, and RXR- (Kang
and Voorhees, 2008). Upon binding to a retinoid, RARs and RXRs
form heterodimers (RAR-RXR), which subsequently bind specific
DNA sequences called retinoic acid–responsive elements (RAREs)
that activate transcription of genes whose products produce the desirable
pharmacological effects of these drugs and their unwanted side
effects (Bastien and Rochette-Egly, 2004).
Unique therapeutic effects can be produced by targeting specific
retinoid receptors. For example, retinoids that target RARs predominantly
affect cellular differentiation and proliferation, whereas
retinoids that target RXRs predominantly induce apoptosis (Germain
et al., 2006a; Germain et al., 2006b). Hence, tretinoin, adapalene,
and tazarotene, which target RARs, are used in acne, psoriasis, and
photoaging (disorders of differentiation and proliferation), whereas
bexarotene and alitretinoin, which target RXRs, are used in mycosis
fungoides and Kaposi sarcoma (to induce apoptosis of malignant
cells). Acute retinoid toxicity is similar to vitamin A intoxication.
Side effects of systemic retinoids include dry skin, nosebleeds from
dry mucous membranes, conjunctivitis, reduced night vision, hair
loss, alterations in serum lipids and transaminases, hypothyroidism,
inflammatory bowel disease flare, musculoskeletal pain, pseudotumor
cerebri, and mood alterations. RAR-selective retinoids are more
associated with mucocutaneous and musculoskeletal symptoms,
whereas RXR-selective retinoids induce more physiochemical
changes (Germain et al., 2006a; Germain et al., 2006b). Because all
oral retinoids are potent teratogens, they should be used carefully in
females of childbearing potential and not in pregnant patients or
patients who are trying to conceive. Suicide or suicide attempts have
been associated with the use of isotretinoin. Thus, all patients treated
with isotretinoin should be observed closely for symptoms of depression
or suicidal thoughts.
Topical Retinoids
Acne is believed to result from a combination of sebaceous
gland hyperplasia, follicular hyperkeratosis,
Propionibacterium acnes colonization, and inflammation.
Through incompletely understood mechanisms,
topical retinoids correct abnormal follicular kerati -
nization, reduce P. acnes counts, and reduce inflammation,
thereby making them the cornerstone of acne
therapy. Topical retinoids are first-line agents for
non-inflammatory (comedonal) acne and often are
combined with other agents in the management of
inflammatory acne.
Fine wrinkles and dyspigmentation, two important
features of photoaging, also are improved with
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CHAPTER 65
DERMATOLOGICAL PHARMACOLOGY