Retinoids include natural compounds and synthetic derivatives of retinol that exhibit vitamin A activity. First-generation retinoids include retinol, tretinoin (all-trans-retinoic acid), isotretinoin (13-cis-retinoic acid), and alitretinoin (9-cis-retinoic acid). Second-generation retinoids, also known as aromatic retinoids, were created by alteration of the cyclic end group and include acitretin. Third-generation retinoids contain further modifications and are called arotinoids. Members of this generation include tazarotene and bexarotene. Adapalene, a derivative of naphthoic acid with retinoid-like properties, does not fit precisely into any of the three generations.
Retinoic acid (RA) exerts its effects on gene expression by activating two families of receptors—retinoic acid receptors (RARs) and the retinoid X receptors (RXRs)—that are members of the nuclear receptor superfamily. Retinoids (ligands) bind transcription factors (nuclear receptors), and the ligand-receptor complex then binds to the promoter regions of target genes to regulate their expression. The gene products formed contribute to the desirable pharmacological effects of these drugs and their unwanted side effects. Additional complexity arises because each receptor has three isoforms (a, b, and g) that form homo- and heterodimers. Retinoid-responsive tissues express one or more RAR and RXR subtypes in various combinations that determine activity locally. Human skin contains mainly RARa and RARb.
First- and second-generation retinoids can bind to several retinoid receptors because of the flexibility imparted by their alternating single and double bonds. This relative lack of receptor specificity may lead to greater side effects. The structures of third-generation retinoids are much less flexible than those of earlier-generation retinoids and therefore are more selective.
Acute retinoid toxicity is similar to vitamin A intoxication. Side effects of retinoids include dry skin, nosebleeds from dry mucous membranes, conjunctivitis, and hair loss. Less frequently, musculoskeletal pain, pseudotumor cerebri, and mood alterations occur. Oral retinoids are potent teratogens and cause severe fetal malformations. Because of this, systemic retinoids should be used with great caution in females of childbearing potential.
Retinoids are used in the treatment of diverse diseases and are effective in the treatment of inflammatory skin disorders, skin malignancies, hyperproliferative disorders, photoaging, and many other disorders. Topical retinoids can normalize disordered keratinization in sebaceous follicles and reduce inflammation, and they may enhance the penetration of other topical medications.
Tretinoin (retin-a, others) is used to reduce the hyperkeratinization that leads to microcomedone formation, the initial lesion in acne. Follicular corneocytes become less cohesive as a result of shedding of desmosomes, decreasing tonofilaments, and increasing keratinocyte autolysis and intracel-lular deposition of glycogen.
In addition to treating acne, tretinoin improves photodamaged human skin. Ultraviolet radiation activates growth factor and cytokine receptors on epidermal keratinocytes and dermal cells. These receptors stimulate MAP kinases, which, in turn, induce c-Jun expression. This transcription factor heterodimerizes with c-Fos to form activated AP-1 complexes that induce the transcription of met-alloproteinases that degrade dermal collagens and other proteins. Epidermal effects of tretinoin include increased epidermal and granular layer thickness, decreased melanocytic activity, and increased secretion of a glycosaminoglycan-like substance into the intercellular space. In the dermis, blood vessel vasodilation and angiogenesis and increased papillary dermal collagen synthesis have been documented. Clinically, this translates to modest attenuation of fine and coarse wrinkling, smoother texture, increased pinkness, and diminished hyperpigmentation.
Tretinoin is approved for the treatment of acne vulgaris and as an adjunctive agent for treating photoaging. Topical preparations contain from 0.01% to 0.1% tretinoin in cream, gel, and solution formulations. Initiation of therapy with lower-strength preparations and progression to higher strengths may be useful because individual sensitivity is unpredictable. Tretinoin formulations with a cream base are indicated for dry skin, whereas gel-based formulations are indicated for oily skin. The medication is applied once daily before bedtime to minimize photodegradation. Maximum clinical response in acne may require several months, and maintenance therapy is necessary. A formulation of tretinoin with active drug incorporated into microsponges (retin-a micro) decreases irritation by slowing the release of the medication and enhances efficacy by targeting delivery to the sebaceous follicle.
A 0.5% emollient cream formulation of tretinoin (renova) is approved for treatment of pho-toaged skin. Nightly application produces maximum response within 1 year, and application 1-3 times weekly is said to maintain improvement. Treatment must be combined with a rigorous program of photoprotection, including sunscreens, sun avoidance, and photoprotective clothing.
Adapalene (differin), a derivative of naphthoic acid, is a synthetic retinoid-like compound that is available in solution, cream, and gel formulations for topical use. In addition to displaying typical retinoid effects, it also has anti-inflammatory properties. Adapalene has similar efficacy to tretinoin, but unlike tretinoin, it is stable in sunlight and tends to be less irritating.
Tazarotene (tazorac) is a third-generation retinoid approved for the treatment of psoriasis and acne vulgaris. This retinoid binds to all three RARs.
Tazarotene gel, applied once daily to dry skin, may be used as monotherapy or in combination with other medications, such as topical corticosteroids, for the treatment of localized plaque psoriasis. This is the first topical retinoid approved by the FDA for the treatment of psoriasis. Side effects of burning, itching, and skin irritation are relatively common, and patients should avoid sun exposure.
Alitretinoin (panretin) is a retinoid that binds all types of retinoid receptors and is approved only for treatment of the skin manifestations of Kaposi's sarcoma. Approximately 50% of patients in an open-label trial responded positively to topical application of this drug.
toxicity and monitoring Adverse effects of all topical retinoids include erythema, desquamation, burning, and stinging. These effects often decrease spontaneously with time and are lessened by concomitant use of emollients. Photosensitivity can occur as a result of epidermal thinning, with a resulting greater potential for phototoxic reactions such as sunburn. Although there is little systemic absorption of tretinoin and no alteration in plasma vitamin A levels with its use as a topical agent, most physicians do not prescribe tretinoin during pregnancy and it is category X for pregnant women.
Oral isotretinoin (accutane) is approved for the treatment of severe nodulocystic acne vulgaris. The drug has remarkable efficacy in severe acne and may induce prolonged remissions after a single course of therapy. It normalizes keratinization in the sebaceous follicle, reduces sebocyte number with decreased sebum synthesis, and reduces Propionibacterium acnes, the organism that produces inflammation in acne.
therapeutic uses Isotretinoin is administered orally. The recommended dose is 0.5-2 mg/kg/day for 15-20 weeks. Lower doses are effective but are associated with shorter remissions. The cumulative dose also is important, so smaller doses for longer periods can be used to achieve a total dose in the range of 120 mg/kg. Approximately 40% of patients will relapse, usually within 3 years of therapy, and may require retreatment. Preteens and patients with acne con-globata or androgen excess are at increased risk of relapse. However, mild relapses may respond to conventional management with topical and systemic antiacne agents.
Isotretinoin is prescribed for severe, recalcitrant nodular acne, moderate acne unresponsive to oral antibiotics, and acne that produces scarring. It also is used commonly for other related disorders, such as gram-negative folliculitis, acne rosacea, and hidradenitis suppurativa.
toxicity and monitoring Dose-dependent adverse effects on the skin and mucous membranes are observed most commonly, including cheilitis, mucous membrane dryness, epistaxis, dry eyes, blepharoconjunctivitis, erythematous eruptions, and xerosis. Alteration of epidermal surfaces may facilitate Staphylococcus aureus colonization and, rarely, subsequent infection. Hair loss, exuberant granulation tissue formation, photosensitivity, and decreased night vision are rarer occurrences.
Systemic side effects generally are less significant with short-term therapy. Transitory elevations in serum transaminases occur rarely. Hyperlipidemia is frequent, with 25% of patients developing increased triglyceride levels and, less frequently, increased cholesterol and low-density lipoproteins, and decreased high-density lipoproteins. Myalgias and arthralgias are common complaints. Headaches occur and rarely are a symptom of pseudotumor cerebri. Use of isotretinoin con-comitantly with tetracycline antibiotics may increase the risk of pseudotumor cerebri.
Some physicians have proposed a causal relationship with mood changes and depression in a limited number of patients. These uncontrolled clinical observations have not been examined in a rigorous, prospective manner. In addition, there is a paucity of data on the effect of retinoids on adult brain function. Long-term therapy may produce skeletal side effects, including diffuse idio-pathic skeletal hyperostoses, extraskeletal ossification (particularly at tendinous insertions), and premature epiphyseal closure in children.
Teratogenicity is a major problem; it occurs if the drug is given within the first 3 weeks of gestation and is not dose-related. Teratogenic effects include CNS, cardiac, thymus, and craniofacial abnormalities. Spontaneous abortion occurs in one-third of patients. Pregnancy is an absolute contraindication to the use of isotretinoin. Two forms of birth control (one of which must be surgical or hormonal) must be practiced during therapy and for 1 month both before beginning therapy and after completion of therapy; pregnancy tests should be repeated monthly. Patients should not donate blood for transfusion during treatment and for 1 month after treatment.
Other laboratory evaluations should include a complete blood count, liver function tests, and fasting lipid determination before initiating therapy. Testing should be repeated after 1 month of therapy and thereafter only as abnormalities indicate.
Acitretin (soriatane) is the major metabolite of etretinate, an aromatic retinoid that formerly was approved for psoriasis but withdrawn from the market because of its undesirable pharmacokinetics. Acitretin has an elimination t1/2 of 2-3 days.
Acitretin is readily esterified in vivo to produce etretinate, especially in the presence of ethanol. The optimal dosing range for acitretin in adults is 25-50 mg/day, providing efficacy with an acceptable level of side effects. Improvement of plaque psoriasis requires up to 3-6 months for optimal results. As monotherapy, acitretin has an overall rate of complete remission of <50%; response rates are higher when the drug is combined with other modalities. At doses of 10-25 mg/day, both pustular and erythrodermic psoriasis usually respond more rapidly than common plaque psoriasis. Excellent control of these conditions usually can be achieved with acitretin. Common side effects include dry skin and mucous membranes, xerophthalmia, and hair thinning. Less frequently, arthralgias and decreased night vision have been noted. Serious side effects (e.g., hepatotoxicity or pseudotumor cerebri) are rare. Acitretin is a potent teratogen and should not be used by females who intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy. The same precautions regarding blood donation described earlier for isotretinoin should be followed. Laboratory monitoring should include a baseline pregnancy test in all female patients and a complete blood count, lipid profile, and hepatic profile in all patients. Serial follow-up of laboratory tests should be conducted every 1-2 weeks until stable and thereafter as clinically indicated.
Bexarotene (targretin) is a retinoid that selectively binds RXRs. Bexarotene has been used in patients with cutaneous T-cell lymphoma with a suggested dose of 300 mg/m2/day. Inhibitors of CYP3A4 (e.g., imidazole antifungals and macrolide antibiotics) will increase and inducers of the CYP3A4 system will decrease plasma levels of bexarotene. Side effects include lipid abnormalities, hypothyroidism secondary to a reversible RXR-mediated suppression of TSH gene expression, pancreatitis, leukopenia, and GI symptoms. Blood lipids and thyroid function should be measured before initiating therapy and periodically thereafter.
cancer chemoprevention with retinoids Systemic and topical retinoids have been used successfully to treat premalignant skin conditions and may have a role in chemo-prevention of skin malignancies. High-dose isotretinoin (2 mg/kg/day) has suppressed skin cancers in patients with increased risk of skin malignancy from congenital disorders such as xeroderma pigmentosa and nevoid basal cell carcinoma syndrome. To achieve an anticancer effect, toxic doses of retinoids generally are required. Acitretin at a dose of 25 mg/day or more appears to reduce the risk of skin cancer by ~25% among patients with psoriasis who are at high risk for squamous cell carcinoma. Isotretinoin also is effective for oral leukoplakia. Topical tazarotene has shown efficacy in some basal cell carcinomas. Cutaneous T-cell lymphoma has been shown to respond to several types of topical and systemic retinoids, including bexarotene. The benefits of long-term retinoid use in malignant lymphomas such as cutaneous T-cell lymphoma are balanced by appreciation of retinoid toxicity and the chronicity of the disease.
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