Retinoids

RETINOIDS

Retinoids are a family of naturally occurring and syn-thetic analogues of vitamin A. The skin of subjects defi-cient in vitamin A becomes hyperplastic and keratotic (phrynoderma, or toad skin). While natural vitamin A is occasionally employed therapeutically, synthetic retinoids are more effective and represent a major ad-vance in dermatological pharmacotherapy. Retinoids have myriad effects on cellular differentiation and pro-liferation; it is likely that nuclear retinoic acid receptors mediate these effects by activating gene expression in a manner analogous to receptors for steroid hormones and thyroid hormones. Despite a common mechanism of action, however, retinoids vary widely in their physi-ological effects.

Retinoid action depends on binding to both cytosolic and nuclear retinoic acid receptors (RARs). RARs have distinct DNA and retinoid-binding domains, and they function as pairs and bind to the retinoic acid receptor element (RARE) to regulate transcriptional activity.

Isotretinoin

Isotretinoin (Accutane) alters keratinization in the acroinfundibulum of sebaceous glands and shrinks them, thereby reducing sebum excretion and comedo-genesis. These features underlie its usefulness in acne vulgaris, since sebum secretion is a hallmark of acne-prone skin. Furthermore, the drug has antiinflammatory activity.

Isotretinoin is rapidly absorbed orally, with peak blood concentrations 3 hours after ingestion. It is not stored in tissue, and the elimination half-life is 10 to 20 hours, either after a single dose or during chronic therapy.

Isotretinoin is most useful for the treatment of se-vere recalcitrant nodular acne vulgaris. It may also be helpful in other disorders of keratinization, but it is not useful for psoriasis. High doses of isotretinoin (2mg/kg/day) are effective as cancer chemoprevention agents to reduce the frequency of cutaneous malignan-cies in patients at increased risk, such as those with xe-roderma pigmentosum, an inherited disorder in which DNA repair is deficient, or in immunosuppressed pa-tients.

The most serious toxicity of isotretinoin is terato-genicity. Pregnant women should never receive the drug, and women should not conceive for at least 1 month after its discontinuation. Other toxicities:

·            Skin complaints, particularly xerosis, conjunc-tivitis, and cheilitis.

·            Hypertriglyceridemia in about a quarter of pa-tients.

·            Elevation of liver function test findings, which is usually reversible.

·            Headache, which rarely may be attributable to pseudotumor cerebri.

·            Arthralgias, including skeletal changes such as hyperostoses, tendinous calcifications, prema-ture epiphysial closure, and pathological frac-tures.

·            Depression and suicidal ideation may occur, but no mechanism of action for these events has been established.

Acitretin

Unlike isotretinoin, acitretin (Soriatane) is not prima-rily sebosuppressive. Rather, it promotes normalization of dysregulated keratinocyte proliferative activity in the epidermis and is also antiinflammatory. Oral absorption is optimal when acitretin is taken with a fatty meal; peak levels are reached approximately 3 hours after inges-tion, while steady-state plasma levels are achieved after approximately 3 weeks of daily dosing. The mean ter-minal elimination half-life of the parent compound is 49 hours. However, when consumed with ethanol, acitretin may be transesterified to form etretinate, a retinoid that is stored in adipose tissue, resulting in a much longer half-life (3–4 months or longer).

Acitretin is most useful for the treatment of severe psoriasis, particularly the pustular and erythrodermic variants. Psoriatic nail changes and arthritis also may re-spond. Combining the drug with ultraviolet light ther-apy (Re-UVB, in the case of ultraviolet B radiation, or Re-PUVA, with psoralen plus ultraviolet A radiation) permits the use of lower doses of both acitretin and ul-traviolet radiation. Other conditions for which the drug may be especially useful include congenital and ac-quired hyperkeratotic disorders, such as the ichthyoses and palmoplantar keratodermas, and severe lichen planus.

Like other systemic retinoids, acitretin is a serious teratogen and should not be prescribed for women of childbearing potential unless no acceptable alternative is available and the patient has acknowledged in writing that she understands the need to use two effective forms of contraception during therapy and for 3 years following discontinuation of therapy. Because of the much longer half-life of etretinate, which may be formed when ethanol is ingested with acitretin, female patients of childbearing potential must also agree not to ingest alcohol during treatment and for 2 months fol-lowing its discontinuation. Other toxicities are similar to those of isotretinoin; they include cutaneous irrita-tion and inflammation, bone and joint pain, hyperlipi-demia, hepatic enzyme elevation, and tendinous and ligamentous calcifications. Alopecia (hair loss) may also occur in some patients.

Tretinoin

Topical tretinoin (Retin-A, Renova, Avita), like iso-tretinoin, alters keratinization in the acroinfundibulum. In addition, it reverses certain premalignant and other histological changes associated with the photoaging changes that accompany chronic exposure to ultraviolet radiation. Topically applied tretinoin is indicated in comedogenic and papulopustular acne vulgaris, and its mild exfoliative effects make it sometimes useful in mol-luscum contagiosum, flat warts, and some ichthyotic dis-orders. It is often prescribed to lessen the clinical signs of photoaging (wrinkling and hyperpigmented macules).

The major toxic effect of tretinoin is erythema and irritation of the skin to which it is applied, especially if the skin is moist. This toxicity often decreases with con-tinued therapy.

Adapalene

Adapalene (Differin) is a polyaromatic retinoidlike compound that binds to specific retinoic acid nuclear re-ceptors and is thought to normalize the differentiation of keratinocytes in the sebaceous acroinfundibulum. Adapelene is indicated for topical treatment of acne. Minor local irritation is a common, usually tolerable side effect. In contrast to other drugs of the retinoid group, adapalene has not been shown to be teratogenic in rodents. However, since adequate human studies are lacking, its use in pregnant women should be discour-aged until further information is available.

Tazarotene

Like other retinoids, tazarotene (Tazorac) acts by bind-ing to RARs and altering gene expression. Tazarotene appears to be particularly selective for the retinoid re-ceptors RAR- and RAR- , but the clinical significance of this observation is unknown.

In the United States, tazarotene has been approved for topical treatment of psoriasis (involving up to 20% body surface area) and mild to moderate facial acne. Application site burning, stinging, and desquamation are common side effects, especially with acne. Tazarotene is contraindicated in women who are pregnant.

Bexarotene

Bexarotene (Targretin) belongs to a subclass of retinoids that selectively bind to and activates retinoid X receptors (RXRs), which have biological properties distinct from those of RARs. In vitro, bexarotene exerts antiproliferative effects on some tumor lines of hematopoietic and squamous cell origin.

Bexarotene is available in oral and topical formula-tions. Peak plasma levels are achieved within 2 hours of oral administration, although higher levels are obtained when the drug is ingested with a fatty meal. It is thought to be metabolized primarily by the hepatobiliary sys-tem, with a terminal half-life of approximately 7 hours.

Topical and oral bexarotene are approved for early-stage (patch and plaque) cutaneous T-cell lymphoma that is refractory to at least one other therapy. Oral bexarotene is also approved for refractory cases of ad-vanced disease; however, the best response has been noted in early disease.

Local irritation, such as burning, pruritus, and irritant contact dermatitis, is common following topical applica-tion. Major side effects seen after systemic administra-tion include dyslipidemia, leukopenia, liver function test abnormalities, and possibly development of cataracts. Unlike other systemic retinoids, oral bexarotene causes thyroid abnormalities in approximately half of patients, which may necessitate treatment for hypothyroidism. Bexarotene is teratogenic and should not be prescribed in topical or oral form to women of childbearing poten-tial unless a negative serum pregnancy test has been ob-tained and the patient agrees in writing to use two effec-tive forms of contraception from 1 month before to 1 month after treatment.

Alitretinoin

Alitretinoin (Panretin) is a naturally occurring endoge-nous retinoid that binds to and activates all known retinoid receptors (both RARs and RXRs). It is ap-proved for the topical treatment of cutaneous lesions of Kaposi’s sarcoma. Most patients have local irritation while using alitretinoin gel; however, the irritation rarely necessitates discontinuation of therapy.

β-Carotene

This naturally occurring retinoid (Solatene), a dimer of vitamin A, reduces free radical formation induced by photosensitizing porphyrins and light. Its major use in dermatology is for decreasing skin photosensitivity in patients with erythropoietic protoporphyria. Its major side effect is a yellow-orange discoloration of skin.