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

DRUGS FOR HYPERKERATOTIC
DISORDERS
Keratolytic agents are substances that reduce hyperkeratosis
through a variety of mechanisms (e.g., breaking of
intercellular junctions, increasing stratum corneum
water content, increasing desquamation). Common disorders
treated with keratolytics include psoriasis, seborrheic
dermatitis, xerosis, ichthyoses, and verrucae.
-Hydroxy acids are organic acids in which a hydroxyl group
is attached to the first carbon ( carbon) following its carboxyl acid
group. Various -hydroxy acids include glycolic, lactic, malic, citric,
hydroxycaprylic, hydroxycapric, and mandelic. They reduce the
thickness of the stratum corneum by solubilizing components of the
desmosome, activating endogenous hydrolytic enzymes, and drawing
water into the stratum corneum, allowing cell separation to occur.
They also appear to increase glycosaminoglycans, collagen, and
elastic fibers in the dermis and are used in various formulations to
reverse photoaging. The FDA requires that cosmetics containing -
hydroxy acids be labeled with a sunburn alert warning that the product
may increase sensitivity to the sun and reminding users to wear
protective clothing, use sunscreen, and limit sun exposure.
Salicylic acid functions through solubilization of intercellular
cement, reducing corneocyte adhesion, and softening the stratum
corneum. Salicylism may occur with widespread and prolonged use,
especially in children and patients with renal or hepatic impairment,
and use should be limited to <2 g to the skin surface in a 24-hour
period. Salicylic acid, while chemically not a true a -hydroxy acid,
often is listed as such on cosmetic labels. Other -hydroxy acids
ingredients in cosmetics include -hydroxybutanoic acid, tropic
acid, and trethocanic acid. As with -hydroxy acids, sun protection
should accompany the application of skin products containing
-hydroxy acids.
At low concentrations, urea increases skin absorption and
retention of water, leading to increased flexibility and softness of the
skin (Hessel et al., 2007). At high concentrations (>40%), urea denatures
and dissolves proteins and is used to dissolve calluses or avulse
dystrophic nails.
Sulfur is anti-septic, anti-parasitic, anti-seborrheic, and keratolytic,
accounting for its myriad uses in dermatology. It is believed
to exert its keratolytic effect by reacting with cysteine within keratinocytes,
producing cystine and hydrogen sulfide. Hydrogen sulfide
breaks down keratin, causing dissolution of the stratum corneum
(Hessel et al., 2007).
Often used in conjunction with plastic occlusion, propylene
glycol (as 60-100% solutions in water) increases the water content
of the stratum corneum and enhances desquamation. It is most effective
in disorders with retention hyperkeratosis, in which the thickened
stratum corneum is slowly reformed.
DRUGS FOR ANDROGENETIC ALOPECIA
Androgenetic alopecia, commonly known as male and
female pattern baldness, is the most common cause of
hair loss in adults >40 years of age. Up to 50% of men
and women are affected. Androgenetic alopecia is a
genetically inherited trait with variable expression. In
susceptible hair follicles, dihydrotestosterone binds to
the androgen receptor, and the hormone-receptor complex
activates the genes responsible for the gradual
transformation of large terminal follicles into miniaturized
vellus follicles. Treatment of androgenetic alopecia
is aimed at reducing hair loss and maintaining
existing hair. The capacity to stimulate substantial
regrowth of human hair remains a formidable pharmacological
challenge.
Minoxidil. Minoxidil (ROGAINE, others) was first developed as an antihypertensive
agent (see Chapter 27) and was noted to be associated
with hypertrichosis in some patients. A topical formulation of
minoxidil then was developed to exploit this side effect. The structure
of minoxidil is:
Topical minoxidil is available as a 2% or 5% solution.
Minoxidil enhances follicular size, resulting in thicker hair shafts, and
stimulates and prolongs the anagen phase of the hair cycle, resulting
in longer and increased numbers of hairs. Treatment must be continued,
or any drug-induced hair growth will be lost. Allergic and irritant
contact dermatitis can occur, and care should be taken in applying the
drug because hair growth may emerge in undesirable locations. This
is reversible on stopping the drug. Patients should be instructed to
wash their hands after applying minoxidil.
Finasteride. Finasteride (PROPECIA, other) inhibits the type II isozyme
of 5-reductase, the enzyme that converts testosterone to dihydrotestosterone
(see Chapter 41). The structure of finasteride is:
The type II 5-reductase is found in hair follicles. Balding
areas of the scalp are associated with increased dihydrotesterone
levels and smaller hair follicles than nonbalding areas. Orally
administered finasteride (1 mg/day) has been shown to variably
increase hair growth in men over a 2-year period, increasing hair
counts in the vertex and the frontal scalp (Leyden et al., 1999).
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CHAPTER 65
DERMATOLOGICAL PHARMACOLOGY