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.
9. Is topical tretinoin cream really useful in treating photoinduced wrinkles?
Yes. Several vehicle-controlled studies have clearly demonstrated that topical tretinoin improves the wrinkling and irregular pigmentation of photoaged skin. It does not make the skin normal but it does increase both the thickness of the epidermis and the synthesis of anchoring fibrils and collagen. New blood vessels form, and cutaneous blood flow also increases. Topical tretinoin is not a panacea; prevention of dermatoheliosis by reducing sun exposure and using sunscreens is still preferable.
Kockaert M, Neumann M: Systemic and topical drugs for aging skin, J Drugs Dermatol 2:435–441, 2003.
10. Is there clinical evidence that topical retinoids improve melasma?
Yes. Topical retinoids have been used in the treatment of many pigmentary disorders including melasma, solar lentigines, and postinflammatory hyperpigmentation. An evidence-based review found fair evidence to support the use of topical tretinoin as a monotherapy in the treatment of both melasma and solar lentigines. This study also found evidence to support clinical efficacy of topical tretinoin in a fixed, triple-combination therapy (hydroquinone 4%/tretinoin 0.05%/fluocinolone acetonide 0.01%) for the treatment of melasma.
11. What are the side effects of topical tretinoin?
The most common side effect is an irritant reaction that manifests as erythema and scaling. Severe irritant reactions may require decreasing the concentration or frequency of application. True allergic contact dermatitis to topical tretinoin preparations has been reported but is rare. An unusual potential problem is that the topical tretinoin gels are flammable. At least one dermatologist has reported that it is useful during hunting trips for starting campfires! Patients who are not able to tolerate tretinoin gel or cream may be able to tolerate tretinoin gel with microspheres and adapalene gel, because they are less irritating.
12. Is topical tretinoin safe to use during pregnancy or when nursing?
Topical tretinoin is classified as a pregnancy category C drug, which means that a risk to the fetus cannot be ruled out. Prospective human studies are lacking, but studies on animals using doses up to 320 times those used in humans did not produce teratogenic effects. A retrospective British study on pregnant women who had received topical tretinoin did not demonstrate teratogenic effects. However, because high-dose (1000 times the topical human dose) oral tretinoin has been demonstrated to be teratogenic in rats, many dermatologists do not use this drug in pregnant women to avoid litigation in the event congenital abnormality occurs. Birth defects have been reported in rare patients receiving topical tretinoin or topical adapalene; however, it is unknown whether these birth defects were due to the topical retinoids. Because of the lack of data, it is probably prudent to not use topical retinoids in pregnant patients if possible. It is not known whether topical tretinoin is secreted in human milk, but the manufacturers recommend that caution be exercised when this drug is administered to nursing mothers.
13. What are the clinical indications for tazarotene?
Tazarotene is a recently introduced synthetic retinoid. It is a prodrug that is rapidly converted in vitro by skin esterases to tazarotenic acid. Tazarotenic acid has a high affinity for RAR-γ, which is the primary retinoid receptor in keratinocytes. Tazarotene is approved for the treatment of psoriasis and acne vulgaris. Dermatologists typically use a topical corticosteroid in conjunction with tazarotene when treating psoriasis.
Yamauchi PS, Rizk D, Lowe NJ: Retinoid therapy for psoriasis, Dermatol Clin 22:467–476, 2004.
14. What are the clinical indications for alitretinoin?
Alitretinoin (9-cis-retinoic acid) is a retinoid that binds to all six retinoid receptors. It is indicated for the topical treatment of Kaposi’s sarcoma. It is formulated in a 0.1% gel that is applied to individual lesions. Irritant dermatitis is seen in approximately 75% of patients and severe irritant dermatitis is seen in about 10% of patients. In two different studies, 35% and 36% of patients, respectively, demonstrated significant responses. A recent double-blind, placebo-controlled, multicenter trial has also demonstrated efficacy of oral alitretinoin in the treatment of chronic hand dermatitis that is refractory to standard treatments.
15. Do retinoids have any role in the treatment or prevention of cancer?
Oral isotretinoin, etretinate, acitretin, and bexarotene have all been used as monotherapy or in combination with other drugs for a variety of cutaneous and internal malignancies. Oral retinoids have been used in experimental studies for the treatment of myelocytic leukemias, head and neck squamous cell carcinoma, breast carcinoma, cervical intraepithelial dysplasia, cervical cancer, and renal cell carcinoma. Bexarotene, which is a highly selective retinoid-X receptor retinoid, induces apoptosis of malignant cells in mycosis fungoides and has received FDA approval for use in this disease. Retinoids, particularly acitretin, have also achieved modest success in preventing squamous cell carcinomas in solid organ transplant patients.
16. What are the clinical indications for oral isotretinoin?
Oral isotretinoin is FDA-approved for the treatment of severe recalcitrant cystic or nodular acne vulgaris and disorders of keratinization. It is the most effective form of therapy for acne vulgaris; however, it is not a first-line drug and should be reserved for patients with cystic acne who are not responsive to conventional therapies such as oral antibiotics. Isotretinoin produces wide-ranging biologic effects and is used in many other diseases. Many authorities consider it to be the drug of choice for pityriasis rubra pilaris, severe lichen planus, Darier’s disease, and the ichthyoses. A partial list of clinical indications is presented in Table 56-3.
17. What is the mechanism of action of oral isotretinoin in acne vulgaris?
Like tretinoin, the mechanism of action has not been precisely determined. Isotretinoin is the most effective known inhibitor of sebum production (up to 90% inhibition). Because clinical improvement in acne vulgaris appears to correlate with a reduction of sebum production, this is believed to be the most important mechanism of action. Isotretinoin also markedly affects keratinization and probably exerts an effect on the cohesiveness of the follicular keratinocytes, thus reducing microcomedone formation. Less important actions include antiinflammatory effects, antibacterial effects, and inhibition of microbial enzyme activity.
18. Are there any contraindications to the use of oral isotretinoin?
Isotretinoin is classified as a pregnancy category X drug, which means that it is absolutely contraindicated for patients who are pregnant. Between 1982 and 1989, the manufacturer received 151 reports of patients who carried their fetuses to term. In 47% there were significant congenital malformations, with most being cardiovascular, craniofacial, or central nervous system in nature.
| FDA-APPROVED INDICATIONS | SELECTED NONAPPROVED APPLICATIONS |
|---|---|
19. How is oral isotretinoin administered for the treatment of acne vulgaris?
Patients should initially have comprehensive counseling about the potential side effects of this drug. Under the iPledge program, they must register online and answer a series of questions regarding their menstrual periods, method of birth control, and other mandatory information before they can enter the program. At a minimum, all patients should have pretreatment blood lipid and liver function studies. Some dermatologists also obtain complete blood counts. An initial pregnancy test is required to enter the iPledge program, followed by a second pregnancy test at an approved laboratory before actually receiving the drug.
20. What are the side effects of oral retinoid therapy?
More than 50 different acute and chronic adverse reactions of oral retinoid therapy have been documented in the literature (Table 56-4). More than 90% of patients receiving oral isotretinoin at therapeutic levels demonstrate cheilitis or xerosis to some degree. A very controversial side effect is the association of inflammatory bowel disease (Crohn’s disease, ulcerative colitis) with oral isotretinoin. There are numerous recent law suits and pending litigation regarding this alleged and controversial association. While one recent study concluded that isotretinoin is not associated with the induction of inflammatory bowel disease, a second study found a weak link between isotretinoin use and the development of ulcerative colitis.
| ACUTE ADVERSE REACTIONS | CHRONIC ADVERSE REACTIONS |
|---|---|
| Mucocutaneous Alopecia (<10%) Cheilitis (>90%) Dermatitis (50%) Pruritus (<20%) Pyogenic granuloma-like lesions in acne vulgaris (rare) Xerosis (>50%) Laboratory Elevated liver function tests (<10%) Hyperlipidemia (25%) Leukopenia (<10%) Systemic Arthralgias (16%) Impaired night vision Mental depression (uncommon) Pancreatitis (rare) Pseudotumor cerebri (rare) Spontaneous abortion Teratogenicity (cardiac, head and neck, CNS) |
Mucocutaneous Alopecia, persistent (rare) Dry eyes (rare) Systemic Osteoporosis Premature epiphyseal closure Skeletal hyperostosis |
21. Are there any strategies or treatments that reduce the dry skin and lips associated with retinoid therapy?
Yes. The most common adjunctive treatment is lip balm for the lips and moisturizers for the skin. Preliminary reports suggested that taking 800 IU of vitamin E (α-tocopherol) was effective in reducing the cheilitis and, to a lesser extent, the dry skin. A subsequent investigator-blinded, randomized study could not demonstrate any benefit of vitamin E in ameliorating the side effects of isotretinoin.
22. Are the clinical indications for acitretin the same as for isotretinoin?
No. While both drugs are orally administered retinoids, and they have many of the same therapeutic effects, they also demonstrate significant differences. As a general rule, isotretinoin is more effective in follicular disorders (e.g., acne vulgaris, rosacea, gram-negative folliculitis), and acitretin is more effective in pustular psoriasis and chronic pustular eruptions of the palms and soles. They appear to be of equal efficacy in disorders of keratinization, such as the ichthyoses and pityriasis rubra pilaris, although good comparative studies are lacking.
Acitretin is FDA-approved only for the treatment of severe recalcitrant psoriasis. It is especially effective for pustular and erythrodermic psoriasis. It is often used as monotherapy in these variants but also may be used in conjunction with other forms of therapy such as psoralen plus ultraviolet light, type A (PUVA) in plaque-type psoriasis. Like isotretinoin, acitretin has been used in many other cutaneous diseases (Table 56-5).
23. What is the mechanism of action of acitretin?
As with the other retinoids, the mechanism of action is not known. Acitretin’s clinical and histologic effect on psoriasis and disorders of keratinization suggests normalization of keratinization. The therapeutic response of pustular psoriasis, pustular eruptions of the palms and soles, and subcorneal pustular dermatosis, suggest that this drug also modifies neutrophil function.
24. How is acitretin administered for the treatment of psoriasis?
After appropriate counseling and laboratory tests (liver function tests, serum lipid tests, pregnancy tests), oral acitretin is initially taken with food twice per day in a dosage range of 25 to 50 mg/day. Studies have shown that higher doses are only marginally more effective, but the dose-related side effects are much more common and severe. After the initial response to therapy, which usually takes 8 to 16 weeks, the maintenance dose can often be lowered to 25 mg/day or every other day.
| FDA-APPROVED INDICATION | SELECTED NONAPPROVED APPLICATIONS |
|---|---|
| Severe recalcitrant psoriasis | Granuloma annulare, generalized Ichthyoses (e.g., ichthyosis vulgaris) Keratosis follicularis (Darier’s disease) Mycosis fungoides (cutaneous T-cell lymphoma) Palmar/plantar pustulosis Pityriasis rubra pilaris Porokeratosis Subcorneal pustular dermatosis |
Key Points: Retinoids
2. The physiologic effects of vitamin A and retinoids are broad, but the most important functions include tissue differentiation (especially epithelial tissues), general growth, visual function, and reproduction.
25. What are the contraindications for using oral acitretin?
The contraindications are the same as for oral isotretinoin (previously discussed). As for isotretinoin, acitretin is a pregnancy category X drug and is absolutely contraindicated in pregnant patients. In contrast to isotretinoin, which has a terminal elimination half-life of 10 to 20 hours, acitretin has a longer half-life of 2 to 4 days. Acitretin should not be taken with alcohol, because the alcohol induces esterification of acitretin to etretinate, which has a terminal half-life of 120 days. Women of childbearing age should begin effective contraception for at least 1 month before starting therapy and continue for at least 3 years after discontinuation of therapy.
