Chapter 30: Retinoids

INTRODUCTION

Retinoids are a family of compounds derived from vitamin A that includes beta-carotene and other carotenoids, retinol, tretinoin, tazarotene, and adapalene. For many years, retinoids have been used topically and systemically for the treatment of dermatologic diseases, particularly acne. The potential benefits of retinoids for the treatment and prevention of photoaging have also been explored through the last two decades. This research has led to a greater understanding of the etiology of skin aging. Concurrent but unrelated research has also recently demonstrated that doses of ultraviolet (UV) light too low to cause visible skin reddening are still capable of activating the enzymatic machinery that leads to photoaging.¹

The first anecdotal evidence that retinoids could improve aged skin was seen in female patients being treated for acne. These patients reported that their skin felt smoother and less wrinkled after treatment.² This observation was followed by a clinical trial that showed that patients treated with tretinoin demonstrated improvement of sunlight-induced epidermal atrophy, dysplasia, keratosis, and dyspigmentation.³ A plethora of clinical trials have confirmed such early observations. The data were submitted to the U.S. Food and Drug Administration (FDA), which later approved tretinoin (brand name Renova™) for use against photodamage. Although there are many different topical retinoids on the market today that are also useful against photodamage, Renova and Avage are the only topical agents approved specifically for this purpose. Retinol, the metabolic precursor of tretinoin, is often added to over-the-counter (OTC) cosmetic formulations that are touted as “antiwrinkle” creams. This chapter will focus on the antiaging activity of topical retinoids. It should be noted, though, that oral retinoids are also being used to treat photodamage.

MECHANISM OF ACTION

Chemical Structure

In 1931, the Nobel Prize was awarded to Karrer et al. for determining the structure of retinol.⁴ Twelve years later, retinol was successfully synthesized and soon became commercially available. Since that time, the retinoid field has proliferated with compounds, now numbering more than 2500 products.⁵ In fact, many generic forms of tretinoin are currently available in the United States and retinoids are even combined with medications such as antibiotics, as in Ziana, and hydroquinone, as in Tri-Luma. Initially, a retinoid was defined as a compound the structure and action of which resembled the parent compound retinol. Through the last several decades, chemists have made extensive modifications to the naturally-occurring molecule that have resulted in the development of three generations of retinoids (Fig. 30-1). The latest retinoids bear little structural resemblance to retinol but still qualify as retinoids because they can exert their biologic action through the same nuclear receptors modulated by the active natural metabolite of vitamin A, retinoic acid.