Systemic and topical drugs for aging skin

Journal of Drugs in Dermatology, August, 2003 by Michael Kockaert, Martino Neumann

Abstract

The rejuvenation of aging skin is a common desire for our patients, and several options are available. Although there are some systemic methods, the most commonly used treatments for rejuvenation of the skin are applied topically. The most frequently used topical drugs include retinoids, alpha hydroxy acids (AHAs), vitamin C, beta hydroxy acids, anti-oxidants, and tocopherol. Combination therapy is frequently used; particularly common is the combination of retinoids and AHAs (1). Systemic therapies available include oral retinoids and vitamin C. Other available therapies such as chemical peels, face-lifts, collagen, and botulinum toxin injections are not discussed in this article.

Topical Retinoids

Vitamin A derivatives (retinoids) work by binding to retinoid receptors (RAR), and are the most-studied topical agents used to reverse chronic cutaneous photodamage. Retinoids are considered the gold standard of topical, patient-applied, anti-aging products. The role of vitamin A in keratinocyte proliferation and differentiation has been well recognized since the early 20th century (2,3). However, the positive clinical results obtained from vitamin A were offset by the side effects associated with hypervitaminosis A. Retinoids allow a higher degree of therapeutic effects to be attained with a lower degree of systemic toxicity.

Today, 3 generations of retinoids are clinically used (4,5). The first generation includes vitamin A (retinol, ROL) and its metabolites such as retinaldehyde (RAL), all-trans-retinoic acid (ATRA), and 13-cis-retinoic acid. The second generation includes synthetic analogs like etretinate and acitretin. The third generation is constituted of a group of poly-aromatic analogues and arotinoids such as adapalene. Topical tretinoin has been the best-studied topical remedy for skin aging, in both clinical and laboratory studies.

Compliance with topical retinoids is compromised by retinoid dermatitis, a commonly-seen side effect characterized by erythema, scaling, and pruritus of the skin developing within 3-4 weeks of retinoid therapy. During this period of time, the retinoid effects are limited to the epidermis. After 3 to 4 weeks, however, dermal effects on collagen, elastin, and the extracellular matrix begin to appear. The pro-drugs ROL and RAL and retinoid esters appear to have the therapeutic effects of tretinoin without its side effects. As such, these compounds are being studied more closely for their role in reversing photoaging (6-9).

Clinical studies have demonstrated the beneficial effects of topical retinoids on photodamaged skin. Eight percent of topically applied tretinoin remains on the skin surface. The penetration through the skin is vehicle dependent, with diffusion through the epidermis occurring in minutes followed by a much slower dermal distribution. The percutaneous absorption is 1-2%, and the amount absorbed does not affect the plasma concentration of vitamin A and its metabolites. In contrast to the teratogenic effects of systemic retinoids, a number of studies have demonstrated that topical tretinoin is not associated with congenital abnormalities (1). However, individual case reports have described congenital defects in patients born to mothers who used topical tretinoin during the first trimester of pregnancy (7). Thus, the use of topical retinoids during pregnancy is not recommended.

Tretinoin is transported through the cytoplasm to the nuclear receptors via cellular retinoic acid binding protein-II (CRABP-II). This CRABP is expressed as a receptor on keratinocytes and dermal fibroblasts, with a retinoic acid response element (RARE) on the receptor. This suggests that CRABP regulates the biological availability and the metabolism of retinoids. Topical tretinoin increases the expression of CRABP-II through an unknown mechanism. The retinoids act on two nuclear receptors, RAR and RXR, which are part of the superfamily of the steroid/thyroid ligand dependent transcription factors (5).

Topical tretinoin is most effective for fine facial wrinkles, the rough texture associated with photodamaged skin, and mottled epidermal pigmentation. Softening of the skin is the first improvement to be noted, and is associated with increased production of hyaluronic acid and perhaps other glycosaminoglycans (GAGs) in the dermis, as well as thinning of the stratum corneum. Hyaluronic acid binds 1,000 times its weight in water, adding to the buoyancy of the dermis (7,8). The disappearance of fine wrinkles is seen after 3-4 months of topical application, and the disappearance of mottled hyperpigmentation takes 1 year to become noticeable (9).

Histologically, topical tretinoin causes thinning of the stratum corneum, thickening of the nucleated epidermis, and some spongiosis. There is an evident increase in Alcian blue staining, corresponding to an increase in epidermal GAGs. As tretinoin decreases dermal GAGs, the effects of tretinoin on fine wrinkles are caused by its effects on dermal collagen. Griffith et al. demonstrated that topical tretinoin increases the collagen-I fibers in the dermis by 80%. Woodley et al. demonstrated an increase in anchoring fibrils (collagen-VII) in the dermoepidermal junction. Moreover, tretinoin downregulates the production of matrix-metalloproteinases (MMPs) such as collagenase, gelatinase, and stromelysin, resulting in decreased breakdown of dermal collagen. The inhibitors of the MMPs are not inhibited by tretinoin, so the MMP/TIMP ratio favors inhibition of the MMPs (8,9). Moreover, increased papillary dermal elastic fibers are noted. This was shown in a study of chicken skin fibroblasts which demonstrated increased elastin mRNA and protein expression with topically applied tretinoin.