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, which is mediated through the following:

image Suppressing the production and effects of mediators involved in the inflammatory response, including tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor, IL-1, and IL-8.
image Inhibiting leukocyte migration and chemotaxis to sites of inflammation.
image Interfering with the function of endothelial cells, granulocytes, mast cells, and fibroblasts.
image Depleting mast cells in the skin.
image This property also benefits inflammatory skin lesions.

image The third benefit of topical steroids is antimitotic, or antiproliferative, mediated through the following:

image Inhibition of DNA synthesis and mitosis.
image Inhibition of fibroblast activity and collagen formation.
image This property benefits conditions that demonstrate abnormally high proliferation, such as scaling lesions, but is also the mechanism responsible for the side effect of thin skin.

image The fourth benefit of topical steroids is as a vasoconstrictor:

image The mechanism is unclear, but inhibition of vasodilating inflammatory mediators could be responsible for part of this effect.
image The potency of topical steroids is quantified by the degree of vasoconstriction caused in a vasoconstriction bioassay.
image Vasoconstriction could be of benefit in that it results in less redness of the skin (cosmetic effect only) and reduces blood flood, resulting in less swelling.

Pharmacokinetics

Absorption

image Corticosteroids are only minimally absorbed after application to normal skin—for example, approximately 1% of a dose of hydrocortisone solution is absorbed.
image Occlusion of drug with an impermeable film such as plastic wrap increases absorption by a factor of 10.
image Absorption depends on the body part to which the medication is applied. Relative to the arm, absorption ratios are as follows: plantar foot, 0.14; palm, 0.83; scalp, 3.5; forehead, 6; vulva, 9; scrotum, 42. Also:

image Inflamed skin results in increased absorption.
image Exfoliative skin results in decreased absorption.

Potency

image Topical steroids are graded on a scale from 1 to 7 for potency, with class 1 being the most potent.
image The delivery vehicle can exert a large influence on the potency of a topical steroid. Combinations of powders, oils, and water-based liquids comprise the vehicles. Combinations of ingredients in these three forms in varying proportions make up the most commonly used and are vehicles:

image Ointments are water suspended in oil and are the most potent because of their occlusive effect, but are greasy and not useful on hairy areas. Ointments should be applied two or three times per day, particularly after the skin has been moistened. They are useful for dry lesions because they form a water barrier.
image Creams are semisolid emulsions of oil in 20% to 50% water and are not greasy. Creams are less potent than ointments.
image Lotions are powder in water formulations and are the least potent. They are useful for hairy areas and when large areas have to be treated. Lotions evaporate, providing a cooling and drying effect, making them useful for treating moist lesions.
image Gels are an oil-in-water emulsion with alcohol in the base but are not greasy. They liquefy on contact with skin and are useful for hair-covered areas.
image Foams are pressurized collections of gaseous bubbles in a liquid film. Foam preparations spread readily and are easier to apply.

image The salt (ester derivative) to which the steroid is bound also influences potency. Topical steroids are named according to the ester to which they are bound. For example, betamethasone exists as betamethasone valerate, betamethasone dipropionate, and betamethasone benzoate, each with a different potency. Furthermore, each chemical can be delivered in a different vehicle (cream versus ointment and therefore a range of potencies can be produced using the same original steroid chemical).

image Common examples of ester derivatives include acetate, aceponate, acetonide, benzoate, butyrate, diacetate, dipropionate, furoate, probutate, propionate, and valerate.

image Concentration of the topical steroid (expressed as a percentage) also influences potency. Higher concentrations are more potent.
image One of the highest-potency agents (clobetasol propionate ointment) is approximately 1000 times more potent than one of the lowest potency agents (1% hydrocortisone).

List of Topical Steroid Potencies

Class 1—Superpotent

image Betamethasone dipropionate 0.05% optimized vehicle
image Clobetasol propionate 0.05%
image Diflorasone diacetate 0.05%
image Fluocinonide 0.1% optimized vehicle
image Flurandrenolide, 4 mg/cm2
image Halobetasol propionate 0.05%

Class 2—Potent

image Amcinonide 0.1%
image Betamethasone dipropionate 0.05%
image Desoximetasone 0.25% to 0.5%
image Diflorasone diacetate 0.05%
image Fluocinonide 0.05%
image Halcinonide 0.1%
image Mometasone furoate 0.1%

Class 3—Potent, Upper Midstrength

image Amcinonide 0.1%
image Betamethasone valerate 0.1%
image Diflorasone diacetate 0.05%
image Fluocinonide 0.05%
image Fluticasone propionate 0.005%

Class 4—Midstrength

image Betamethasone valerate 0.12%
image Desoximetasone 0.05%
image Fluocinolone acetonide 0.025%
image Flurandrenolide 0.05%
image Hydrocortisone probutate 0.1%
image Hydrocortisone valerate 0.2%
image Mometasone furoate 0.1%
image Triamcinolone acetonide 0.1%

Class 5—Lower Midstrength

image Betamethasone dipropionate 0.05%
image Betamethasone valerate 0.1%
image Fluocinolone acetonide 0.025%
image Flurandrenolide 0.05%
image Fluticasone propionate 0.05%
image Hydrocortisone butyrate 0.1%
image Triamcinolone acetonide 0.1%

Class 6—Mild Strength

image Desonide 0.05%
image Fluocinolone acetonide 0.01%

Class 7—Least Potent

image Dexamethasone 0.1%
image Flumethasone
image Hydrocortisone 0.1% to 2.0%
image The insoluble corticosteroids are sometimes injected. When injected, the drug is slowly released for 3 to 4 weeks. This method of administration is often reserved for refractory lesions. Drugs that are injected include triamcinolone and betamethasone.

Indications

image The list of skin conditions that are treatable with topical steroids is long. This incomplete list represents only the most common and responsive conditions:

image Psoriasis
image Atopic dermatitis
image Eczema
image Seborrheic dermatitis
image Contact or irritant dermatitis

Contraindication

image Active infection in skin: Because of the immunosuppressive property of topical steroids, application to known active infections should be avoided.

Side Effects

image All side effects are more common with higher-potency steroids, larger surface areas treated, and longer durations of treatment.
image Skin atrophy: Skin atrophy is demonstrated by thin shiny-appearing skin, telangiectasia (small readily visible blood vessels), ecchymoses (bruises), striae (stretch marks), hypertrichosis (increased hair), redness, and pigmentation changes.

image Hydrocortisone aceponate, prednicarbate, fluticasone propionate, and methylprednisolone aceponate have the lowest capacity to induce skin atrophy.

• Therefore they can be used to treat the face, scrotum, and large body surface areas in children, with minimal adverse effects.

image Higher-potency steroids can induce changes in as little as 2 weeks.

image Systemic absorption, leading to systemic side effects. Systemic side effects can occur but are not common. Systemic side effects include the following:

image Adrenal suppression
image Cushing’s syndrome, notably hyperglycemia (glucocorticoid effect)
image Sodium retention (mineralocorticoid effect)
image Hypertension (mineralocorticoid effect)
image Mood changes

image Other

image Glaucoma: Glaucoma occurs when the drug is administered periorbitally (around the eyes). This side effect is rare.

Important Notes

image There are many different topical steroids. Through modification of the original steroid (hydrocortisone), the antiinflammatory potency, mineralocorticoid versus glucocorticoid ratio, and side effects are changed.
image Many topical steroids are combined with antibacterial or antifungal medications. These combination drugs simultaneously treat two problems (inflammation and infection), and if the diagnosis of the lesion is unclear or it appears to be a mixed problem, then these drugs can be useful. Of course, if the lesion worsens, then the medication should be stopped, and further investigations are required.

image Combination drugs are more expensive than monotherapy.
image A KOH (potassium hydroxide) scraping is a quick diagnostic test for fungal elements in a skin lesion.

image Lower-potency steroids should be used on sensitive areas (face, genitals) and on children.
image Short duration (<3 weeks) should be the goal of steroid treatment if possible; longer duration increases the probability of side effects.

Advanced

image A fluorine molecule at specific sites in the corticosteroid molecules results in enhanced corticosteroid selectivity and potency.
image Changing hydroxyl groups increases the molecule’s lipophilicity, increasing the rate of percutaneous absorption as well as the corticosteroid receptor binding activity.

Evidence

Steroids and Psoriasis

image A 2009 Cochrane review (16 studies, N = 1916 patients) found that use of potent and very potent steroids over a 2- to 3-week period by patients with psoriasis resulted in statistically significant improvement, as measured by an “investigator assessment of overall global improvement.” Note that duration of effect investigated is short and that psoriasis is a chronic disease.

FYI

image Steroids are discussed further in Chapters 17 (systemic steroids) and 24 (inhaled steroids).

Keratolytics

Description

Keratolytics break down keratin in the skin.

Prototype and Common Drugs

α-Hydroxy Acids

image Prototype: salicylic acid
image Others: lactic acid, glycolic acid

Urea

Moa (Mechanism of Action)

image Keratin is a fibrous insoluble protein found in the skin, hair, and nails. In some dermatologic conditions the amount of keratin is increased, resulting in a thicker epidermis termed hyperkeratosis. One of the most commonly recognized causes of hyperkeratosis is warts. Psoriasis and eczema are two other common hyperkeratotic conditions.
image The stratum corneum is the outermost layer of the epidermis where the keratin is present; it is composed of the dead squamous cells that are produced in the stratum germinativum. The primary roles of the stratum corneum are to prevent water evaporation and to impart physical strength to the skin (Figure 13-2).
image Desmosomes are structures that contain both intracellular and extracellular components; they are important because they are attached to keratin and function to impart cell-to-cell adhesion and create resistance to physical stresses on the epithelium.
image Keratolytics reduce the thickness of the stratum corneum by incompletely understood mechanisms, but probably via a combination of the following:

image Acids directly solubilize the protein components of desmosomes.
image Acids activate endogenous hydrolytic enzymes by changing the pH of the stratum corneum.
image Acids diffuse into the stratum corneum and bind water; the acids act as humectants (they increase the water content) of the stratum corneum. Increasing the water content softens the tissues, making them easier to physically debride.

image

Figure 13-2

Pharmacokinetics

image Salicylic acid is available in concentrations ranging from 0.5% to 60%. In concentrations over 6%, salicylic acid is destructive to tissue.
image Systemic absorption does occur with salicylic acid and can cause salicylate overdose. Increased concentrations increase this complication.
image Keratolytics are applied topically in various bases: cream, ointment, and plasters. Plasters are applied for a few days (4 to 5) and then removed, and an occlusive dressing is commonly applied over the topical agent to prevent it from being washed away and to prevent application to normal skin.

Indications

image Hyperkeratotic lesions: warts and many other less common dermatologic conditions
image Cosmetic: chemical peels

Contraindication

image Open wounds should not be treated with keratolytics.

Side Effects

image Local skin irritation

image Redness, itching, and tenderness may occur.

image Salicylic acid toxicity

image Absorption of salicylic acid occurs, and at higher concentrations of salicylic acid, children are at increased risk for systemic toxicity.

Important Notes

image Salicylic acid is the most commonly used keratolytic for warts. Treatment duration depends on the size and depth of the warts. Treatment can persist for many weeks before all tissue containing the human papillomavirus (HPV) is destroyed and debrided.
image Anhydrous (without water) preparations are less irritating, allowing higher concentrations of acid to be tolerated.
image Higher concentrations of keratolytic increase the probability of increased irritation in the skin.
image Molluscum contagiosum is a skin condition caused by the pox virus that results in very small papules and has been treated with keratolytics.

Evidence

Warts

image Salicylic acid versus placebo: A Cochrane review in 2006 (five studies, N = 322) demonstrated increased efficacy of salicylic acid (73%) over placebo (48%), a relative risk (RR) of 1.6 for cure.

Molluscum Contagiosum

image A Cochrane review in 2009 (nine studies, N = 495) did not find strong evidence to support the use of salicylic acid in patients with molluscum contagiosum.

Imiquimod

Description

Imiquimod modifies the immune response in skin.

Prototype

image Imiquimod

Moa (Mechanism of Action)

image Imiquimod enhances both the innate and the acquired immune systems and thereby stimulates a response against abnormal skin cells, which are then eliminated through the body’s own mechanisms.
image Imiquimod exerts its actions through the following sequence of events:

image Binding to Toll-like receptors on B cells
image Increased release of inflammatory mediators, including interferon, TNF, and many interleukins: IL-1, IL-6, IL-8, and IL-10
image Increased immune cell activity:

• Activating macrophages and Langerhans cells
• Inducing proliferation and maturation of B lymphocytes
• Increasing natural killer T cell activity

image Imiquimod also has direct apoptosis activity with tumor cells.
image The net effect of applying topical imiquimod to the skin is an increased inflammatory reaction in the dermis, and through this reaction, abnormal cells are destroyed in the heightened inflammatory environment.

Pharmacokinetics

image Imiquimod is supplied as a 5% cream. It has a half-life of 2 to 4 hours and needs to remain on the skin (without being washed) for 10 hours after application.
image A typical course of therapy consists of application three to seven times a week for 6 to 16 weeks, depending on the lesion that is being treated.

Indications

image Genital and perianal warts resistant to conventional therapy
image Actinic keratoses
image Basal cell carcinoma

Contraindications

image None

Side Effects

image Local skin reactions:

image Mild burning, stinging, itching, redness, or swelling, mostly related to the inflammatory response produced by the drug

image Long-term skin reactions:

image Pigmentation changes, including hypopigmentation and hyperpigmentation. The mechanism for development of hypopigmented lesions is not fully understood but could involve antimelanocyte autoantibodies and/or other inflammatory processes that selectively destroy melanocytes.

image Skin reactions of concern that require assessment by a physician:

image Blistering, flaking, crusting, open sores, or any type of severe form of reactions listed previously

image Systemic reactions (related to a mild widespread inflammatory response):

image Fatigue, diarrhea, flulike symptoms, headache

Important Notes

image Lesions suspected to be cancerous (basal cell carcinoma) should be biopsy proven before therapy is started. Treatment success rates are about 80% with imiquimod alone.
image Actinic keratosis lesions that do not respond to treatment should undergo biopsy to ensure that there is no carcinoma within the lesion.
image Typical therapy for genital warts is through physical destruction (ablation), such as cryoablation (freezing to a temperature that destroys the cells) using liquid nitrogen (temperature of −196° C). Liquid nitrogen is applied to a small applicator (e.g., a cotton-tipped swab) and applied to the wart for 10 to 20 seconds.

image Imiquimod is not first-line treatment for warts because cheaper effective treatments exist that require less treatment time. Resistance to first-line treatment is more common in patients who are immunocompromised—for example, patients with AIDS.

image Imiquimod is much more expensive than other therapies for warts.

Advanced

image Differentiating squamous cell carcinoma from (benign) actinic keratoses can be difficult but is important because squamous cell carcinomas should generally not be treated with imiquimod. The following five characteristics increase the probability that the lesion is carcinoma and not keratosis:

image Hyperkeratosis: How raised is the lesion above normal skin?
image Full thickness: Does the lesion feel superficial, or does it extend deep into the skin?
image Surrounding induration: thickness or indrawing in the tissue adjacent to the lesion
image Surrounding erythema
image Tenderness

image Toll-like receptors are important in mediating the innate immune response. At least 15 different receptors have been identified.

Evidence

Imiquimod versus Vehicle (Placebo) for Basal Cell Carcinoma

image A Cochrane review in 2007 (five studies N = 1145 patients) found a short-term success rate (defined histologically with biopsy) of 87% to 88% at 6 weeks and 76% at 12 weeks. This was a not a comparison with other therapy, but a trial comparing surgery with imiquimod is underway. Furthermore, 12 weeks is a very short period of time to declare success in cancer treatment. More studies are required to define the usefulness of imiquimod in treatment of basal cell carcinoma.

Imiquimod for Anogenital Warts

image A review of four studies (1641 patients) found complete clearance rates of 37% to 52% in patients treated with imiquimod and partial clearance in 50% to 90% of patients. Recurrence rates were as high as 19% at 3 months.

FYI

image Warts are caused by HPV. There are different subtypes of this virus; some subtypes cause warts, and some subtypes cause cancer of the cervix (and precancer of the cervix called cervical dysplasia). There now exists a vaccine against some of the subtypes that cause cervical cancer.
image Resiquimod is a more potent Toll-like receptor agonist in development.

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