Systemic and topical drugs for aging skin

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

The AHAs can be divided into 3 groups (21):

1. Creams with a low concentration, below 10%. These are used in topical cosmetic preparations. Preparations with a pH < 3.5 (ideally pH = 2) have the best efficacy, but most topicals have a higher pH (22).

2. A concentration of 20% to 30%. These are neutralized after timed application, used in light chemical peels.

3. High concentrations, 70% glycolic acid. These are not neutralized, used for resurfacing.

The action of AHAs is pH dependent. Most AHAs have a pH of 3. When applied frequently, they provoke skin irritation. The pH of the skin is naturally between 4.2 and 5.7, and this physiologic pH is altered by the application of AHAs. To avoid this side effect, the acid can be partially or completely neutralized, but this is associated with decreased efficacy of the AHA.

One of the characteristics of sun damaged skin is hyperkeratosis, with increased cohesion of keratinocytes resulting in a thickened stratum corneum. AHAs have keratolytic activity resulting in reduced adhesion of keratinocytes and an increased turnover of the stratum corneum. Because of these effects, the skin appears smoother. Moreover, AHAs enhance the hydration of the skin.

One study showed an increase in hyaluronic acid after application of glycolic acid (23). Another study suggested that improvements in photodamage are mediated by increased expression of factor XIII transglutaminase and degranulation of mast cells. Moreover, TNF release may stimulate fibroblast proliferation and activity (24). Another study of topically applied 25% lotions of glycolic, lactic, or citric acids demonstrated a thickening of the epidermis, an increase in dermal collagen fibers, and improved elastin quality. However, these acids do not have the same effects on expression of collagen I and II mRNA and inhibition of collagenase activity that tretinoin does.

The effects of AHAs are interesting and promising, but their underlying mechanisms in reversing photodamage are unclear today. Their low pH could be responsible for the detachment of the desmosomes mediating keratinocyte attachment (25). Moreover, a pH < 5 is thought to stimulate TGF-beta growth factor production. It is also unclear if the alpha position of the hydroxy group is essential for these effects or if the cutaneous pH alterations are sufficient.

Beta Hydroxy Acids

Salicylic acid, an organic carboxylic acid with a hydroxy group in the beta position, is the only beta hydroxy acid (BHA) used clinically. This phenolic compound is hydrophobic and lipophilic, allowing it to enter the pilosebaceous unit (26). In concentrations up to 50%, it can be used for chemical peelings. In concentrations from 3-5%, it can enhance the penetration of topical preparations. Application of salicylic acid in concentrations as low as 1-2% results in increased epidermal turnover (27).

A possible side effect of salicylic acid is toxicity and hepatic injury. It should be applied only to small surface areas and for limited periods of time, as is commonly done during chemical peeling. A double-blind, placebo-controlled study investigated the combination of 0.025% tretinoin, 5% salicylic acid, and placebo (28). Both tretinoin and salicylic acid induced epidermal proliferation and activated factor XIII and TNF alpha. These effects were, however, most prominent in the tretinoin group (29).