Adverse effects, retinoids

Adverse effects are likely with the use of topical retinoids. Although transient, erythema, irritation, dryness, and peeling at the site of application are all common effects. Photosensitivity can also occur with retinoid use, causing increased skin irritation and redness.14... 

Tetracyclines inhibit P. acnes, reduce the amount of keratin in sebaceous follicles, and have antiinflammatory properties (inhibiting chemotaxis, phagocytosis, complement activation, and cell-mediated immunity). Drawbacks to tetracyclines include hepatotoxicity and predisposition to infections (e.g., vaginal candidiasis). Other adverse effects include GI disturbances, photosensitivity, tooth discoloration in children, and inhibition of skeletal growth in the developing fetus. Tetracyclines must not be combined with systemic retinoids because of an increased risk of intracranial hypertension. / Tetracycline is the least expensive agent in this class and is often... 

Tazarotene (Tazorac) is a synthetic retinoid that is hydrolyzed to its active metabolite, tazarotenic acid, which modulates keratinocyte proliferation and differentiation. It is available as a 0.05% or 0.1% gel and cream and is applied once daily (usually in the evening) for mild to moderate plaque psoriasis. Adverse effects are dose- and frequency related and include mild to moderate pruritus, burning, stinging, and erythema. Application of the gel to eczematous skin or to more than 20% of body surface area is not recommended because this may lead to extensive systemic absorption. Tazarotene is often used with topical corticosteroids to decrease local adverse effects and increase efficacy. 

Adapalene is a napthoic acid derivative with retinoid-like activity used for the topical treatment of acne vulgaris. Adverse effects include erythema, dryness of skin and skin irritation. 

Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate, is quite effective in the treatment of psoriasis, especially pustular forms. It is given orally at a dosage of 25-50 mg/d. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug s prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years. 

As detrimental effects result from deficiency as well as an excess of retinoids and carotenoids, and since both have similar adverse effects in terms of fibrosis, carcinogenesis, and possibly embryotoxicity, therapeutic measures must pay attention to the narrow therapeutic window, especially in drinkers, in whom alcohol narrows the therapeutic window even further by promoting the depletion of retinoids and by potentiating their toxicity (91). 

Vitamin A (retinol) is a key regulator of epithelial ceU proliferation and differentiation. Aberrations in these processes are a feature of many skin diseases, and dermatologists have therefore long taken an interest in vitamin A as a therapeutic agent. However, marginal efficacy and unacceptable adverse effects (Table 1) have minimized the usefulness of vitamin A itself. Therefore, derivatives of vitamin A (retinoids) have been developed. 

Although the various retinoids have similar toxicity profiles, they differ in the extent to which they affect various body systems. Cutaneous and mucous membrane symptoms (up to 70%) are by far the most prominent adverse effects patients who use isotretinoin have a 50% incidence of conjunctivitis and irritation of the eyes. Musculoskeletal symptoms occur in up to 15% of users. Hypersensitivity reactions are rare and consist of occasional drug rashes. The occurrence of sarcomas in patients treated with isotretinoin may well be a chance finding (SEDA-21, 164) retinoids may prevent or even cure certain malignancies (20). All the retinoids are strongly teratogenic (21-23). 

Hypercalcemia has been reported as an adverse effect of systemic retinoid therapy (60). 

The gastrointestinal adverse effects of retinoids include anorexia, nausea, vomiting, weight loss, stomach pain, thirst, splenomegaly, and acute esophagitis (SEDA-21, 162). Proctosigmoiditis has been reported (SEDA-13, 123). 

Table 4 The adverse effects of oral retinoids on the skin and hair...

Patients should be warned of the high probability of adverse effects, which fortunately are only temporary. Tretinoin is more irritant than glycolic acid. The irritation is usually mild, but can take the form of retinoid dermatitis if high concentrations are used or if the skin is delicate. 

The objectives of this chapter are to describe (l)retinoids that are currently in clinical use, including the adverse effects associated with the therapeutic use of these compounds (2) retinoid biosynthesis and metabolism (3) the basis of action of retinoids in molecular, cellular, and organismal contexts including vision and (4) new agents on the horizon of retinoid biology. 

Adverse effects of retinoids in current use are generally severe and limit the clinical use-... 

Non-teratogenic, adverse effects of retinoids are also severe and are dependent on route of administration and the nature of the disease being treated. Untoward effects of retinoid compounds administered by mouth are similar to those of hypervitaminosis A and include cheilitis and pronounced lipid disturbances such as hypertriglyceridemia, hypercholesterolemia, and reduction in high density lipoprotein levels, pancreatitis, vasculitis, con-... 

Adverse effects of tetracyclines include resistant bacteria, folliculitis, candidiasis, gastrointestinal upset, and phototoxic effects. Tetracyclines must not be combined with systemic retinoids because of the increased probability for development of intracranial hypertension. Tetracycline is used in the treatment of moderate to severe acne vulgaris. It is the least expensive of the tetracyclines and therefore often prescribed for initial therapy. A common initial approach includes tetracycline 1 g daily (500 mg twice daily), 1 hour before meals after 1 or 2 months, when marked improvement of inflammatory lesions is observed, the dose may be decreased to 500 mg every day, for another 1 or 2 months. Drawbacks to the use of tetracycline include also a drug-food interaction with dairy prodncts. 

Acitretin, an oral retinoid, is the active metabolite of etretinate and has demonstrated clinical effects similar to etretinate, but with fewer adverse effects. Acitretin is indicated for the treatment of severe psoriasis, including erythrodermic and generalized pustular types, but is more useful as an adjunct in the treatment of plaque psoriasis. In contrast to the fast-acting cyclosporine and methotrexate, acitretin resolves psoriatic lesions more slowly. 

Several studies have reported that retinoids are effective for animal models of autoimmune diseases. Lupus nephritis is a major cause of mortality among systemic lupus erythematosus patients. ATRA inhibits IFN-y cytokine production from Thl and production and deposition to the kidneys of anti-DNA antibody IgG2a, and suppresses proteinuria and renal involvement in NZB/WFl mice, which are used as a lupus nephritis model (Nozaki et al. 2005). In an open clinical trial, seven patients with active lupus nephritis were treated with ATRA. As a result, four patients showed improvements in clinical symptoms and laboratory findings, including proteinuria and anti-dsDNA antibody levels. There were no adverse effects of ATRA therapy in any patient (Kinoshita et al. 2009). 

Although a major adverse effect of the retinoids is an increase in serum alkaline phosphatase, an association of this effect with fractures has not been unequivocally established. There have been no studies demonstrating that the increase in the activity of the serum enzyme is due to an increase in bone isozyme and there has been no clear-cut association between the incidence of fractures and serum alkaline phosphatase activity. 

The current leading hypothesis is that nuclear RAR and RXR play a direct role in this process. The retinoid receptors can be activated by physicochemical binding of free retinoic acid to RAR and RXR. Alternatively, covalent forms, such as retinoyl derivatives of RAR and RXR, might also exist. Interestingly, retinyl and retinoyl p-glucuronide stimulate the differentiations of HL-60 cells well without evident conversion to retinol and retinoic acid, respectively. Retinoic acid has also been implicated as a morphogen in embryonic development (18). The adverse effects of vitamin A deficiency on reproduction, growth, and the immune response, in all likelihood, are an expression of perturbations in the process of cellular differentiation. 

The frequency and severity of adverse reactions are also specific for the various retinoids (Table IX). For example, cheilitis, facial dermatitis, and conjunctivitis are frequently occurring side effects of isotretinoin therapy whereas telogen effluvium, palmar-plantar desquamation, skin fragility, paronychia, arthralgias, and pruritus are more commonly observed in patients receiving etretinate. 

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