Dermatology

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Chapter 13 Dermatology

Retinoids

Description

Retinoids activate retinoic acid receptors (RARs).

Prototype and Common Drugs

Topical

image Adapalene, tazarotene

Oral

image First-generation agents: tretinoin (also called all-trans retinoic acid [ATRA]), isotretinoin
image Second-generation agent: acitretin
image Third-generation agent: bexarotene

Moa (Mechanism of Action)

image A retinoid is a molecule (or a metabolite of a molecule) that binds to and activates RARs. There are also retinoid X receptors (RXRs), which also play a role in transducing retinoid signaling (Figure 13-1).
image Retinoid receptors are intranuclear and act as transcription factors; they bind to regulatory regions in DNA called hormone response elements and activate gene transcription.
image Increased growth factors are then released, which results in epidermal hyperplasia and thickened skin, caused by the increased proliferation of basal keratinocytes.
image As a consequence of the hyperplasia, subsequent desquamation and peeling of the skin occur.
image

Figure 13-1

Acne

image Isotretinoin decreases sebum secretion and sebaceous gland size, the main contributors to the oily characteristic of the skin of patients with severe acne.
image Isotretinoin reduces the abnormal follicular epithelial differentiation and desquamation that play an important role in the pathogenesis of acne.
image Isotretinoin reduces comedogenesis (a comedone is a blackhead that occurs when excess oils accumulate in sebaceous glands).
image Isotretinoin reduces colonization with Propionibacterium acnes, a bacterium implicated in acne.

Photoaged Skin

image Partial restoration of markedly reduced levels of collagen in sun-exposed skin is one of the mechanisms of benefit for patients with photoaged skin.

Cutaneous T-Cell Lymphoma

image Bexarotene is 100 times more potent for RXR than for the RAR. This results in the following:

image Blocking of cell cycle progression
image Induction of apoptosis and differentiation
image Prevention of multidrug resistance
image Inhibition of angiogenesis and metastasis

Pharmacokinetics

image Oral retinoids are lipophilic, and their absorption is increased when they are taken with fatty foods.
image Adapalene and tazarotene are not taken orally; they are topically applied.
image Topically applied retinoids do not demonstrate appreciable systemic absorption; however, because the skin lesions treated with retinoids are not life-threatening, it is strongly recommended that topical retinoid application be delayed in pregnant patients until after the pregnancy is complete.
image All retinoids are metabolized by the liver.
image Acitretin has a half-life of 2 days, but etretinate, a related drug, has a half-life of 120 days because of storage in adipose tissue (as it is highly lipophilic). If taken with alcohol, acitretin is converted to etretinate. Therefore pregnancy must be avoided for 2 years (3 years in the United States) after acitretin is discontinued, according to a manufacturer’s warning.

Indications

Isotretinoin, Adapalene, Tazarotene

image Acne
image Photoaged (sun damaged) skin

Acitretin

image Psoriasis
image Other keratinizing disorders

Bexarotene

image Cutaneous T-cell lymphoma, but not as first-line treatment

Contraindications

image Pregnancy: Retinoids are teratogens. Acne treatment commonly occurs in patients during teenage years. Special attention to pregnancy avoidance must be discussed with patients at higher risk for unplanned pregnancy.
image Tetracycline coadministration: there is a risk of increased intracranial hypertension. Note that tetracycline also is often used to treat acne.

Side Effects

Common

image Mucocutaneous side effects:

image Cheilitis: dry, cracked, chapped lips
image Xeroderma: dry skin; also called xerosis
image Skin peeling
image Sicca (dry eyes) resulting in conjunctivitis
image Epistaxis (nose bleeds) from dry mucosa in the nasal passages

image Myalgias (back pain and joint pain)

image Occur in up to 50% of patients; usually not severe but are worse with exercise

image Hyperostosis (excessive bone growth)

image After 5 years of treatment, hyperostosis occurs in most patients but is usually asymptomatic. Younger patients who are still growing have a very small risk of premature growth plate closure (leading to short stature).

Less Common

image Reversible increase in liver enzyme test values
image Hypothyroidism (bexarotene only)
image Elevated cholesterol
image Loss of color or night vision

Uncommon

image Pseudotumor cerebri (benign intracranial hypertension): Diagnosed as new onset of headache and visual changes. This is more common when retinoids are coadministered with tetracycline (an antibiotic also used to treat acne); therefore they should not be coadministered with tetracycline.
image Depression and psychosis: There is an increased risk of psychiatric disturbances.
image Inflammatory bowel disease: Retinoids might be associated with an increased risk of inflammatory bowel disease.

Important Notes

image Liver enzyme measurements need to be performed at baseline, before the patient starts taking isotretinoin, and again 1 to 2 months after the patient has started to take the medication, to look for an elevation in enzymes.
image Photoaged skin demonstrates increased wrinkles and pigmentation. Treatment for several weeks with isotretinoin or tazarotene has demonstrated improvement.
image Cheilitis occurs in virtually all patients taking isotretinoin, and if it does not occur, it should be considered an indication of treatment failure or noncompliance.

Advanced

image Ultraviolet irradiation results in functional impairment of receptor-dependent retinoid responsiveness in human skin. Thus stimulation of these receptors is the basis from which to counter the aging process that occurs from sun damage.

Evidence

Photoaged Skin

image A Cochrane review in 2005 (eight studies, N = 460) showed that topical tretinoin cream in concentrations of 0.02% or higher was superior to placebo for participants with mild to severe photodamage on the face and forearms. The relative risk of improvement for 0.05% tretinoin cream compared with placebo (three studies) at 24 weeks was 1.73. This effect was not seen for 0.001% (one study) or 0.01% (three studies) topical tretinoin. A dose-response relationship was evident for both effectiveness and skin irritation.

Acne

image A systematic review of topical retinoids found evidence to support the following:

image Retinoids are superior to placebo.
image 0.1% tazarotene was more effective than 0.025% tretinoin, 0.1% tretinoin microsphere gel, and 0.1% adapalene.
image 0.1% adapalene showed fewer side effects than 0.025 to 0.05% tretinoin creams or gels.

FYI

Nomenclature

image Xero– is from the Greek, meaning dry. Xerostomia means dry mouth. Xerophagia means eating dry foods, something that might be difficult if you already had xerostomia.
image The company Xerox got its name from xerography, which means dry writing.
image Sjögren’s syndrome is an autoimmune condition that results in a dry mouth and dry eyes.
image Retinoids have biologic activity that is similar to that of vitamin A. Tretinoin is in fact the acid form of vitamin A. Remember that vitamin A is important for vision, so visual problems are a rare risk of retinoids.
image Alitretinoin is a retinoid that has not yet received U.S. Food and Drug Administration (FDA) approval but has been studied as a treatment for chronic refractory eczema and Kaposi’s sarcoma. Kaposi’s sarcoma is a cancer that is seen most commonly in patients with acquired immunodeficiency syndrome (AIDS).
image RARs have a lot of similarity to hormone and steroid receptors.

Steroids, Topical

Description

Topical steroids are corticosteroids that are used on the skin.

Common Drugs

Organized by nomenclature for easier recall:

image Hydrocortisone, betamethasone, dexamethasone, fluticasone, flumethasone, mometasone, diflorasone, desoximetasone
image Triamcinolone, prednisolone, methylprednisolone
image Desonide, budesonide, halcinonide, fluocinonide, amcinonide, flurandrenolide
image Halobetasol, clobetasol

Moa (Mechanism of Action)

image As topical agents, steroids are used for their antiinflammatory properties, which are exerted through the following mechanisms:

image Inhibition of the release of phospholipase A2, which is the principle enzyme for the formation of arachidonic acid–based inflammatory mediators prostaglandins and leukotrienes.
image Inhibition of transcription factors that are involved in the activation of proinflammatory genes. Transcription factors increase or decrease gene expression; two examples are activator protein 1 and nuclear factor kappa B (NF-κB).

• Another example: lipocortin I is up-regulated by steroids. It inhibits phospholipase A2.

image Decrease in the release of interleukin-1 (IL-1) (a proinflammatory cytokine) from keratinocytes.
image Inhibition of phagocytosis and stabilization of lysosomal membranes of phagocytizing cells.
image This property benefits inflammatory skin lesions.

image The second benefit topical steroids provide to skin is immunosuppression,

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