Chapter 56 Retinoids
1. What are retinoids?
Retinoids are structural analogs of vitamin A (retinol). Vitamin A is a fat-soluble vitamin that was first extracted from egg yolk in 1909. It can be obtained directly from the diet (e.g., liver) or produced from carotenoids, a pigmented precursor that is found in abundance in yellow vegetables such as carrots. Beta-carotene, the primary carotenoid found in carrots, is particularly efficient in its ability to be converted to vitamin A. The physiologic effects of vitamin A are broad, but the most important functions include tissue differentiation (especially epithelial tissues), general growth, visual function, and reproduction. Retinoids may be produced naturally during vitamin A metabolism, but most retinoids used in the treatment of skin diseases are synthetic. Synthetic retinoids are produced by changing either the polar end group, polyene side chain, or cyclic group of vitamin A. More than 1500 retinoids have been synthesized and tested for their biologic properties since 1968.
2. How do vitamin A and retinoids exert their effect at a molecular level?
Vitamin A exerts its effect on cells by a mechanism similar to that of corticosteroids; some authorities have suggested that it should be classified as a hormone. Vitamin A acts on cells by binding to nuclear retinoic acid receptors (RAR) and/or other retinoid X receptors (RXR) that are closely related to the steroid and thyroid hormone receptors. Each of these receptors demonstrates three distinct receptor subtypes, which have been named α, β, and γ. Retinoids vary in their affinity for these six receptors, which partially accounts for the different pharmacologic effects produced by different retinoids. Another important factor is that different tissues appear to vary in the expression of receptor subtypes. In human keratinocytes, RAR-γ is the major retinoid receptor expressed. Tissues appear to regulate their requirement for vitamin A and retinoids by changing the concentration of the binding proteins.
3. Which retinoids are prescribed for the treatment of skin diseases?
Retinoids may be used topically or orally. Topical retinoids approved for use in the United States include tretinoin (all-trans retinoic acid), a naturally occurring metabolite of vitamin A; tazarotene, a synthetic retinoid; and alitretinoin (9-cis-retinoic acid). Adapalene is a retinoid-like drug that is also available topically. The three oral synthetic retinoids available in the United States are isotretinoin, acitretin, and bexarotene. Etretinate was formerly available, but it has been pulled from the market and replaced by acitretin. Prescription retinoids are summarized in Table 56-1.
4. Are there any retinoids found in topical over-the-counter (OTC) products?
Yes. Numerous OTC topical products, especially antiwrinkle and skin rejunvenation products, contain retinol or, less commonly, retinyl palmitate or retinaldehyde. These OTC retinoids do not bind to retinoid receptors and do not exert a biologic effect until they have been enzymatically converted in the skin into the active form, retinoic acid. Retinyl palmitate is first converted to retinol, which is then converted to retinaldehyde before being finally converted to the biologically active retinoic acid. Because the conversion is incomplete, and these topical retinoids are easily oxidized and degraded, they are less effective than prescription retinoids.
6. What is the mechanism of action of tretinoin in acne vulgaris?
The precise mechanism of action is not proved, but tretinoin is believed to exert its therapeutic effect by decreasing the cohesiveness of follicular epithelial cells that are responsible for producing microcomedones. Microcomedones are the earliest recognizable abnormality in acne vulgaris. Tretinoin also stimulates mitotic activity of follicular keratinocytes, promotes extrusion of comedones by rapid cell turnover, and decreases the production of sebum, although this effect is minimal.
| TOPICAL PREPARATIONS | ORAL PREPARATIONS |
|---|---|
| Tretinoin (all-trans retinoic acid) Retin-A (0.025%, 0.05%, 0.1% cream; 0.025% gel; 0.05% liquid) Retin-A Micro (0.04%, 0.1% gel microsphere) Renova (0.02%, 0.05% emollient cream) Avita (0.025% cream and gel) Atralin (0.05% gel) Refissa (0.05% cream) Tazarotene Avage (0.1% cream) Tazorac (0.05%, 0.1% gel) Alitretinoin (9-cis-retinoic acid) Panretin (0.1% gel) Adapalene (retinoid-like drug) Differin (0.1% gel, solution, cream, pledgets) Epiduo (also contains benzoyl peroxide) |
Isotretinoin (13-cis-retinoic acid) Multiple brands (10-, 20-, 30-, and 40-mg capsules) Acitretin Soriatane (10- and 25-mg capsules) Bexarotene Targretin (75-mg capsules) |
Generic drugs appear as bold terms in the list.
Table 56-2. Therapeutic Applications of Topical Tretinoin
| FDA-APPROVED INDICATIONS | SELECTED NONAPPROVED APPLICATIONS |
|---|---|
7. How should topical tretinoin be used to treat acne vulgaris?
Tretinoin is applied once per day to affected areas. It should be applied in the evening to minimize photodegradation. The strength and formulation depend on the severity of the acne and the tolerance of the individual patient. After washing the face, the patient should wait 20 to 30 minutes before applying the medication, or use a hair dryer to blow-dry the face before application. The periocular skin, mouth, and angles of the nose should be avoided, because these are more susceptible to irritant reactions. The medication should be applied sparingly to dry skin. Care should be taken when using other topical preparations, such as benzoyl peroxide or antibiotics in conjunction with tretinoin, because the irritant effect of these medications is additive.
8. After starting topical tretinoin for acne vulgaris, the patient reports that her acne is worse. Should she immediately discontinue the drug?
No. While many textbooks state that acne vulgaris may flare during initiation of topical treatment; current evidence suggests that this most likely represents normal fluctuation in the intensity of disease. Patients should not discontinue therapy and should understand that beneficial effects may not be seen for 6 weeks. Maximum improvement may take up to 6 months or more with continued therapy. The most common reasons for tretinoin failures are failure of the health care provider to instruct patients thoroughly about proper application and failure to provide an accurate assessment about expected results. Patients often discontinue therapy after failing to see improvement during the first month.
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