Goodman and Gilman Manual of Pharmacology and Therapeutics
Special Systems Pharmacology
The skin is a multifunctional and multicompartment organ. Figure 65–1 outlines general features of skin structure and percutaneous absorption pathways. Drugs can be applied to skin for 2 purposes: to directly treat disorders of the skin and to deliver drugs to other tissues.
Figure 65–1 Cutaneous drug delivery. Diagrammatic representation of the 3 compartments of the skin as they relate to drug delivery: surface, stratum (Str.), and viable tissues. After application of a drug to the surface, evaporation and structural/compositional alterations occur that determine the drug’s bioavailability. The stratum corneum limits diffusion of compounds into the viable skin and body. After absorption, compounds either bind targets in viable tissues or diffuse within the viable tissue or into the cutaneous vasculature, and thence to internal cells and organs. (Reproduced with permission from Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York: McGraw-Hill; 2008, Figure 215–1. Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved.)
Non-pharmacological therapy for skin diseases includes the entire electromagnetic spectrum applied by many sources, such as lasers, X-rays, visible light, and infrared light. These approaches may be used alone or to enhance the penetration or alter the nature of drugs and prodrugs. Freezing and ultrasound are other physical therapies that alter epidermal structure for direct treatment or to enhance percutaneous absorption of drugs. Chemicals are used to decrease the effect of various wavelengths of ultraviolet (UV) light and ionizing radiation.
Stratum Corneum. The stratum corneum (outer 5-600 μm) is the major barrier to percutaneous absorption of drugs and to the loss of water from the body. Many drugs may partition into the stratum corneum and form a reservoir that will diffuse into the rest of skin even after topical application of the drug has ceased. The stratum corneum differs in thickness, with the palm and sole being the thickest (400-600 μm) followed by the general body stratum corneum (10-16 μm), and the scrotum (5 μm). Facial and post-auricular regions have the thinnest stratum corneum.
Living Epidermis. The living layers of the epidermis with metabolically active cells comprise a layer ~100 thick (Figure 65–2). Intercalated in the living epidermis are pigment-producing cells (melanocytes), dendritic antigen-presenting cells (Langerhans cells), and other immune cells (γ-δ T-cells); in diseased epidermis, many immunological cells, including lymphocytes and polymorphonuclear leucocytes, may be present and be directly affected by applied drugs.
Figure 65–2 Structure of the epidermis. The epidermis matures progressively from the stratum basale (SB) to the stratum spinosum (SS), stratum granulosum (SG), and stratum corneum (SC). Important structural and metabolic proteins are produced at specific layers of the epidermis. (Reproduced with permission from Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 7th ed. New York: McGraw-Hill; 2008, Figure 45–2. Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved.)
Dermis and Its Blood Vessels. The superficial capillary plexus between the epidermis and dermis is the site of the majority of the systemic absorption of cutaneous drugs (see Figure 65–1). There are large numbers of lymphatics as well. Beneath the 1.2-mm-thick dermis with its collagen and proteoglycans that may bind drugs there, targets for drugs include mast cells (permanent residents and producers of many inflammatory mediators) and infiltrating immune cells producing cytokines. Hair follicles form a lipid-rich pathway for drug absorption. Sweat glands are not known as a pathway for the absorption of drugs. Some drugs (e.g., griseofulvin, ketoconazole) are excreted to the skin by this route.
MECHANISMS OF PERCUTANEOUS ABSORPTION. Passage through the outermost layer is the rate-limiting step for percutaneous absorption. Preferable characteristics of topical drugs include low molecular mass (<600 Da), adequate solubility in both oil and water, and a high partition coefficient so the drug will selectively partition from the vehicle to the stratum corneum. Except for very small particles, water-soluble ions and polar molecules do not penetrate significantly through intact stratum corneum. The exact amount of drug entering or leaving the skin in clinical situations usually is not measured; rather, the clinical endpoint (e.g., reduction in inflammation) usually is the desired effect.
A hydrated stratum corneum allows more percutaneous absorption and often is achieved through the selection of drugs formulated in occlusion vehicles such as ointments and the use of plastic films, wraps, or bags for the hands and feet and shower or bathing caps for the scalp, or through the use of medications that are impregnated on patches or tapes. Occlusion may be associated with increased growth of bacteria with resultant infection (folliculitis) or maceration and breakdown of the epidermis. Transport of most drugs is a passive thermodynamic process, and heat generally increases penetration. Ultrasonic energy or laser-induced vibration also can be used to increase percutaneous absorption. The latter may function by the production of lacunae in the stratum corneum.
The epidermis contains a variety of enzyme systems capable of metabolizing drugs that reach this compartment. A specific CYP isoform, CYP26A1, metabolizes retinoic acid and may control its level in the skin. In addition, transporter proteins that influence influx (OATP) or efflux (MDR, P-glycoprotein) of certain xenobiotics are present in human keratinocytes. Genetic variants of enzymes that regulate the cellular influx and efflux of methotrexate have been associated with toxicity and effectiveness in patients with psoriasis.
PHARMACOLOGIC IMPLICATIONS OF EPIDERMAL STRUCTURE. The healthcare provider, when proposing topical application of drugs (Table 65–1), must consider proper dosage and frequency of application, extent and condition of the permeability barrier, patient age and weight, physical form of the preparation to be applied, and whether intralesional or systemic administration should be used. Various drug vehicles have specific advantages and disadvantages (Table 65–2). Newer vehicles include liposomes and microgel formulations that can enhance solubilization of certain drugs, thereby enhancing topical penetration and diminishing irritancy. Children have a greater ratio of surface area to mass than adults do, so the same amount of topical drug can result in a greater systemic exposure.
Important Considerations When a Drug Is Applied to the Skin
Vehicles for Topically Applied Drugs
Glucocorticoids have immunosuppressive and anti-inflammatory properties. They are administered locally, through topical and intralesional routes, and systemically, through intramuscular, intravenous, and oral routes. Mechanisms of glucocorticoid action are discussed in Chapter 42.
TOPICAL GLUCOCORTICOIDS. Topical glucocorticoids have been grouped into 7 classes in order of decreasing potency (Table 65–3).
Potency of Selected Topical Glucocorticoids
Therapeutic Uses. Many inflammatory skin diseases respond to topical or intralesional administration of glucocorticoids. Absorption varies among body areas; the steroid is selected on the basis of its potency, the site of involvement, and the severity of the skin disease. Often, a more potent steroid is used initially, followed by a less potent agent. Twice-daily application of topical glucocorticoids is sufficient, and more frequent application does not improve response. In general, only nonfluorinated glucocorticoids should be used on the face or in occluded areas such as the axillae or groin. Intralesional preparations of glucocorticoids include insoluble preparations of triamcinolone acetonide (KENALOG-10) and triamcinolone hexacetonide (ARISTOSPAN), which solubilize gradually and therefore have a prolonged duration of action.
Toxicity. Chronic use of class 1 topical glucocorticoids can cause skin atrophy, striae, telangiectasias, purpura, and acneiform eruptions. Because perioral dermatitis and rosacea can develop after the use of fluorinated compounds on the face, they should not be used on this site. Occlusion increases the risk of HPA suppression.
SYSTEMIC GLUCOCORTICOIDS. Systemic glucocorticoid therapy is used for severe dermatological illnesses and generally reserved for allergic contact dermatitis to plants (e.g., poison ivy) and for life-threatening vesiculobullous dermatoses such as pemphigus vulgaris and bullous pemphigoid. Chronic administration of oral glucocorticoids is problematic, given the side effects associated with their long-term use (see Chapter 42).
Daily morning dosing with prednisone generally is preferred, although divided doses occasionally are used to enhance efficacy. Fewer side effects are seen with alternate-day dosing; if chronic therapy is required, prednisone usually is tapered to every other day as soon as practical. Pulse therapy using large intravenous doses of methylprednisolone sodium succinate (SOLU-MEDROL, others) is an option for severe resistant pyoderma gangrenosum, pemphigus vulgaris, systemic lupus erythematosus with multi-system disease, and dermatomyositis. The dose usually is 0.5-1 g given over 2-3 h. More rapid infusion has been associated with increased rates of hypotension, electrolyte shifts, and cardiac arrhythmias.
Toxicity and Monitoring. Oral glucocorticoids have numerous systemic effects, as discussed in Chapter 42. Most side effects are dose-dependent.
Retinoids comprise natural and synthetic compounds that exhibit vitamin A–like biological activity or bind to nuclear receptors for retinoids (see Figures 3–12 and 6–8). Characteristics of topical and systemic retinoids are summarized in Tables 65–4 and 65–5. Systemic retinoids are used to treat acne and disorders of keratinization.
First-generation retinoids include retinol (vitamin A), tretinoin (all-trans-retinoic acid; vitamin A acid), isotretinoin (13-cis-retinoic acid), and alitretinoin (9-cis-retinoic acid). Second-generation retinoids, also known as aromatic retinoids, include acitretin and methoxsalen (also known as etretinate; not marketed in the U.S.). Third-generation retinoids were designed to optimize receptor-selective binding and include tazarotene, bexarotene, and adapalene.
Mechanism of Action. Retinoids exert their effects on gene expression by activating 2 families of receptors—retinoic acid receptors (RARs) and retinoid X receptors (RXRs)—that are members of the steroid receptor superfamily. Upon binding to a retinoid, RARs and RXRs form heterodimers (RAR-RXR), which subsequently bind specific DNA sequences called retinoic acid–responsive elements(RAREs) that activate transcription of genes whose products produce the desirable pharmacological effects of these drugs and their unwanted side effects (see Table 6–5 and Figures 3–12 and 6–8).
Targeted Therapeutic Actions. Retinoids that target RARs predominantly affect cellular differentiation and proliferation; retinoids that target RXRs predominantly induce apoptosis. Hence, tretinoin, adapalene, and tazarotene, which target RARs, are used in acne, psoriasis, and photoaging (disorders of differentiation and proliferation), whereas bexarotene and alitretinoin, which target RXRs, are used in mycosis fungoides and Kaposi sarcoma (to induce apoptosis of malignant cells).
Retinoid Toxicity. Acute retinoid toxicity is similar to vitamin A intoxication. Side effects of systemic retinoids include dry skin, nosebleeds from dry mucous membranes, conjunctivitis, reduced night vision, hair loss, alterations in serum lipids and transaminases, hypothyroidism, inflammatory bowel disease flare, musculoskeletal pain, pseudotumor cerebri, and mood alterations. RAR-selective retinoids are more associated with mucocutaneous and musculoskeletal symptoms, whereas RXR-selective retinoids induce more physiochemical changes. Because all oral retinoids are potent teratogens, they should be used carefully in females of childbearing potential and not in pregnant patients. Suicide or suicide attempts have been associated with the use of isotretinoin.
Through incompletely understood mechanisms, topical retinoids correct abnormal follicular keratinization, reduce P. acnes counts, and reduce inflammation, thereby making them the cornerstone of acne therapy. Topical retinoids are first-line agents for non-inflammatory (comedonal) acne and often are combined with other agents in the management of inflammatory acne.
Fine wrinkles and dyspigmentation, 2 important features of photoaging, also are improved with topical retinoids. Within the dermis, this is believed to result from inhibition of activator protein-1 (AP-1) that normally activates synthesis of matrix metalloproteinases in response to UV irradiation. In the epidermis, retinoids induce epidermal hyperplasia in atrophic skin and reduce keratinocyte atypia.
Toxicity and Monitoring. Adverse effects of all topical retinoids include erythema, desquamation, burning, and stinging (see relative irritancy in Table 65–4). These effects often decrease with time and are lessened by concomitant use of emollients. Patients also may experience photosensitivity reactions (enhanced reactivity to UV radiation) and have a significant risk for severe sunburn. Although there is little systemic absorption of topical retinoids and no alteration in plasma vitamin A levels with their use, it is recommended use of topical retinoids should be avoided during pregnancy.
Topical tretinoin (all-trans-retinoic acid) is photolabile and should be applied once nightly for acne and photoaging. Benzoyl peroxide also inactivates tretinoin and should not be applied simultaneously. Formulations with copolymer microspheres (RETIN-A MICRO) or prepolyolprepolymer-2 (AVITA) that gradually release tretinoin to decrease irritancy are available.
Adapalene (DIFFERIN) has similar efficacy to tretinoin, but unlike tretinoin, it is stable in sunlight, stable in the presence of benzoyl peroxide, and tends to be less irritating at the 0.1% concentration.
Tazarotene (TAZORAC, AVAGE) is approved for the treatment of psoriasis, photoaging, and acne vulgaris. Tazarotene gel, applied once daily, may be used as monotherapy or in combination with other medications, such as topical corticosteroids, for the treatment of localized plaque psoriasis. Topical corticosteroids improve the efficacy of therapy and reduce the side effects of burning, itching, and skin irritation that are commonly associated with tazarotene.
Alitretinoin (PANRETIN) is a retinoid that binds all types of retinoid receptors and is applied 2 to 4 times daily to cutaneous lesions of Kaposi sarcoma. Alitretinoin should not be applied concurrently with insect repellants containing diethyltoluamide (DEET, N, N-diethyl-m-toluamide) because it may increase DEET absorption.
Topical bexarotene (TARGRETIN) is approved for early-stage (IA and IB) cutaneous T-cell lymphoma. Its application is titrated up from every other day to 2-4 times daily over several weeks to improve patient tolerance. Patients using bexarotene should avoid products containing DEET due to an increased risk for DEET toxicity.
Systemic retinoids (Table 65–5) are approved for the treatment of acne, psoriasis, and cutaneous T-cell lymphoma.
Therapeutic Use; Contraindications. Off-label uses include ichthyosis, Darier disease, pityriasis rubra pilaris, rosacea, hidradenitis suppurativa, chemoprevention of malignancy, lichen sclerosus, subacute lupus erythematosus, and discoid lupus erythematosus. Relative contraindications include leukopenia, alcoholism, hyperlipidemia, hypercholesterolemia, hypothyroidism, and significant hepatic or renal disease.
Toxicity and Monitoring. Acute toxicities may include mucocutaneous or laboratory abnormalities; bony changes may occur after chronic use at high doses. Mucocutaneous side effects may include cheilitis, xerosis, blepharoconjunctivitis, cutaneous photosensitivity, photophobia, myalgia, arthralgia, headaches, alopecia, nail fragility, and increased susceptibility to staphylococcal infections. Some patients develop a “retinoid dermatitis” characterized by erythema, pruritus, and scaling. Very rarely, patients may develop pseudotumor cerebri, especially when systemic retinoids are combined with tetracyclines. There are reports that chronic administration at higher doses can cause diffuse idiopathic skeletal hyperostosis (DISH) syndrome, premature epiphyseal closure, and other skeletal abnormalities.
Systemic retinoids are highly teratogenic. There is no safe dose during pregnancy. Although the risk appears to be minimal, men should avoid retinoid therapy when actively trying to father children. Prescribing of isotretinoin in the U.S. is restricted via the risk-mitigation iPLEDGE system. Serum lipid elevation is the most common laboratory abnormality. Less common laboratory abnormalities include elevated transaminases, decreased thyroid hormone, and leukopenia. A baseline evaluation of serum lipids, serum transaminases, and complete blood count (CBC) and a pregnancy test should be obtained prior to starting any systemic retinoids. Laboratory values should be checked monthly for the first 3-6 months and once every 3 months thereafter.
Isotretinoin (ACCUTANE, others) is approved for the treatment of recalcitrant and nodular acne vulgaris. The drug has remarkable efficacy in severe acne and may induce prolonged remissions after a single course of therapy. Clinical effects generally are noted within 1-3 months of starting therapy. Approximately one-third of patients will relapse, usually within 3 years of stopping therapy. Although most relapses are mild and respond to conventional management with topical and systemic anti-acne agents, some may require a second course of isotretinoin. There are several reports of patients developing signs of depression while on isotretinoin. Current guidelines recommend monthly monitoring of all patients on isotretinoin for signs of depression.
Acitretin (SORIATANE, SORIATANECK) is approved for use in the cutaneous manifestations of psoriasis. Full clinical benefit occurs at 3-4 months. Acitretin has a t1/2 of ~50 h, however, when combined with alcohol, acitretin is esterified in vivo to produce etretinate, which has a t1/2 of >3 months. Thus, female patients of childbearing age should avoid pregnancy for 3 years after receiving acitretin to avoid retinoid-induced embryopathy.
Bexarotene (TARGRETIN) is a retinoid that selectively binds RXRs. Oral and topical formulations of bexarotene are approved for use in patients with cutaneous T-cell lymphoma. Studies suggest that bexarotene induces apoptosis of malignant cells. Because it is metabolized by CYP3A4, inhibitors of CYP3A4 (e.g., imidazole antifungals, macrolide antibiotics) will increase and inducers of CYP3A4 (e.g., rifamycins, carbamazepine, dexamethasone, efavirenz, phenobarbital) will decrease plasma levels of bexarotene. Side effects are more common than with other retinoids, with an increased incidence of significant lipid abnormalities and hypothyroidism secondary to a reversible RXR-mediated suppression of TSH gene expression, pancreatitis, leukopenia, and GI symptoms. Thyroid function should be measured before initiating therapy and periodically thereafter.
CALCIPOTRIENE. Calcipotriene (DOVONEX, others) is a topical vitamin D analog that is used in the treatment of psoriasis.
Mechanism of Action. Calcipotriene exerts its effects through the vitamin D receptor (VDR) (see Chapter 44). Upon binding the VDR, the drug-receptor complex associates with the RXR-α and binds to vitamin D response elements on DNA, increasing expression of genes that modulate epidermal differentiation and inflammation lead to improvement in psoriatic plaques.
Therapeutic Use. Calcipotriene is applied twice daily to plaque psoriasis on the body, often in combination with topical corticosteroids. Hypercalcemia and hypercalciuria may develop when the cumulative weekly dose exceeds the recommended 100 g/week limit and resolves within days of discontinuation of calcipotriene. Calcipotriene also causes perilesional irritation and mild photosensitivity.
β-Carotene. β-Carotene (see Figure 64–6) is a precursor of vitamin A that is in green and yellow vegetables. No β-carotene products are currently FDA-approved. Dietary supplementation with β-carotene is used in dermatology to reduce skin photosensitivity in patients with erythropoietic protoporphyria. The mechanism of action is not established but may involve an antioxidant effect that decreases the production of free radicals or singlet oxygen. However, a recent meta-analysis concluded that β-carotene, vitamin A, and vitamin E given singly or combined with other antioxidant supplements actually increase mortality. FDA’s Maximum Recommended Therapeutic Dose (MRTD) for β-carotene is 0.05 mg/kg/day.
Phototherapy and photochemotherapy are treatment methods in which UV or visible radiation is used to induce a therapeutic response either alone (phototherapy) or in the presence of an exogenous photosensitizing drug (photochemotherapy), such as a psoralen (furocoumarin) derivative that absorbs UV energy and becomes reactive (Table 65–6). Patients treated with these modalities should be monitored for concomitant use of other potential photosensitizing medications, such as phenothiazines, thiazides, sulfonamides, NSAIDs, sulfonylureas, tetracyclines, and benzodiazepines.
Dermatologists subdivide the UV region into UVB (290-320 nm), UVA2 (320-340 nm), UVA1 (340-400 nm), and UVC (100-290 nm) radiation. UVC radiation is almost completely absorbed by stratospheric ozone. UVB is the most erythrogenic and melanogenic type of radiation. It is the major action spectrum for sunburn, tanning, skin cancer, and photoaging. UVA radiation is only a thousandth as erythrogenic as UVB but penetrates more deeply into the skin and contributes substantially to photoaging and photosensitivity diseases.
PUVA: PSORALENS AND UVA. Orally administered methoxsalen followed by UVA (PUVA) is FDA-approved for the treatment of vitiligo and psoriasis.
Pharmacokinetics. Dissolved psoralens (e.g., OXSORALEN ULTRA) are absorbed rapidly after oral administration, whereas crystallized forms (e.g., 8-MOP) are absorbed slowly and incompletely. Fatty foods also reduce absorption. There is a significant, but saturable, first-pass elimination in the liver. For these reasons, peak photosensitivity varies significantly between individuals but typically is maximal 1-2 h after ingestion. Methoxsalen has a serum t1/2 of~1 h, but the skin remains sensitive to light for 8-12 h.
Mechanism of Action. The action spectrum for oral PUVA is between 320 and 340 nm. Two distinct photoreactions take place. Type I reactions involve the oxygen-independent photoaddition of psoralens to pyrimidine bases in DNA. Type II reactions are oxygen dependent and involve the transfer of energy to molecular oxygen, creating reactive oxygen species. Through incompletely understood mechanisms, these phototoxic reactions stimulate melanocytes and induce antiproliferative, immunosuppressive, and anti-inflammatory effects.
Therapeutic Uses. Methoxsalen is supplied in soft gelatin capsules (OXSORALEN-ULTRA) and hard gelatin capsules (8-MOP) for oral use. The dose is 10-70 mg, depending on weight (0.4-0.6 mg/kg), taken ~2 h before UVA exposure. A lotion containing 1% methoxsalen (OXSORALEN) is available for topical application for vitiligo and can be diluted for use in bath water to minimize systemic absorption. An extracorporeal solution (UVADEX) is available for cutaneous T-cell lymphoma (see “Photopheresis”).
Approximately 90% of psoriatic patients have clearing or virtual clearing of skin disease within 30 treatments with methoxsalen. Remission typically lasts 3-6 months; thus, patients often require maintenance therapy with intermittent PUVA or other agents. Vitiligo typically requires between 150 and 300 treatments. Localized vitiligo can be treated with topical PUVA and more extensive disease with systemic administration. PUVA also is employed off label in the treatment of atopic dermatitis, alopecia areata, lichen planus, and urticaria pigmentosa.
Toxicity and Monitoring. The major side effects of PUVA are listed in Table 65–6. Ocular toxicity can be prevented by wearing UVA-blocking glasses the day of treatment.
Photopheresis. Extracorporeal photopheresis (ECP) is a process in which extracorporeal peripheral blood mononuclear cells are exposed to UVA radiation in the presence of methoxsalen. Methoxsalen (UVADEX) is injected directly into the extracorporeal plasma before radiation and reinfusion. The treated lymphocytes are returned to the patient, undergoing apoptosis over 48-72 h. ECP is used for cutaneous T-cell lymphoma and off label for various other T-cell medicated diseases, including graft-versus-host disease, transplantation rejection, scleroderma, and type I diabetes mellitus. Initially, patients receive therapy every 1-4 weeks, and intervals are increased as the patient improves. ECP can be combined with adjunctive therapies, including PUVA, topical chemotherapy, systemic chemotherapy, radiation, biological agents, and retinoids.
Photodynamic Therapy (PDT). PDT combines the use of photosensitizing drugs and visible light for the treatment of dermatological disorders. Two drugs are approved for topical PDT: aminolevulinic acid (ALA; LEVULAN KERASTICK) and methylaminolevulinate (MAL; METVIXIA). Both are prodrugs that are converted into protoporphyrin IX within living cells (Figure 65–3). In the presence of specific wavelengths of light (see Table 65–6) and oxygen, protoporphyrin produces singlet oxygen, which oxidizes cell membranes, proteins, and mitochondrial structures, leading to apoptosis. PDT is approved for use on precancerous actinic keratoses and also is commonly used on thin, nonmelanoma skin cancers; acne; and for photorejuvenation. Incoherent (nonlaser) and laser light sources have been used for PDT. The wavelengths chosen must include those within the action spectrum of protoporphyrin (see Table 65–6) and ideally those that permit maximum skin penetration. Light sources in use emit energy predominantly in the blue portion (maximum porphyrin absorption) or the red portion (better tissue penetration) of the visible spectrum. Because the t1/2 of the accumulated porphyrins is ~30 h, patients should protect their skin from sunlight and intense light for at least 48 h after treatment to prevent phototoxic reactions.
Figure 65–3 Heme biosynthesis pathway. A. Under physiological conditions, heme inhibits the enzyme δ aminolevulinic acid (ALA) synthetase by negative feedback. However, δ when ALA is provided exogenously, this control point is bypassed, leading to excessive accumulation of heme. B. Heme.
Histamine (see Chapter 32) is a potent vasodilator, bronchial smooth muscle constrictor, and stimulant of nociceptive itch receptors. Additional chemical itch mediators can act as pruritogens on C fibers, including neuropeptides, prostaglandins, serotonin, acetylcholine, and bradykinin. Furthermore, receptor systems (e.g., vanilloid, opioid, and cannabinoid receptors) on cutaneous sensory nerve fibers may modulate itch and offer novel future targets for anti-pruritic therapy.
Histamine is in mast cells, basophils, and platelets. Human skin mast cells express H1, H2, and H4 receptors. Both H1 and H2 receptors are involved in wheal formation and erythema; only H1 receptor agonists cause pruritus (see Chapter 32). However, blockade of H1 receptors does not totally relieve itching, and combination therapy with H1 antagonists (see Table 32–2) and H2 blockers (see Chapter 45) may be superior to the use of H1 blockers alone.
Oral antihistamines, particularly H1 receptor antagonists, have anticholinergic activity and are sedating (see Chapter 32), making them useful for the control of pruritus. First-generation sedating H1 receptor antagonists include hydroxyzine, diphenhydramine (BENADRYL, others), promethazine, and cyproheptadine. Doxepin is a good alternative to traditional oral antihistamines for severe pruritus. A 5% topical cream formulation of doxepin (PRUDOXIN, ZONALON), which can be used in conjunction with low- to moderate-potency topical glucocorticoids, also is available. Allergic contact dermatitis to doxepin has been reported. The anti-pruritic effect from topical doxepin is comparable to that of low-dose oral doxepin therapy.
Second-generation H1 receptor antagonists lack anticholinergic side effects and are described as nonsedating largely because they do not cross the blood-brain barrier. They include cetirizine (ZYRTEC, others), levocetirizine dichloride (XYZAL), loratadine (CLARITIN, others), desloratadine (CLARINEX), and fexofenadine hydrochloride (ALLEGRA, others). While second-generation “nonsedating” H1 receptor blockers are as effective as the first-generation H1 blockers, they are metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 and should not be coadministered with medications that inhibit these enzymes (e.g., imidazole antifungals, macrolide antibiotics).
Topical agents are very effective for the treatment of superficial bacterial infections and acne vulgaris. Systemic antibiotics also are prescribed commonly for acne and deeper bacterial infections. The pharmacology of individual antibacterial agents is discussed in Section VII, Chemotherapy of Microbial Diseases (Chapters 53-56). Only the topical and systemic antibacterial agents principally used in dermatology are discussed here.
Acne. Acne vulgaris is the most common dermatological disorder treated with either topical or systemic antibiotics. The anaerobe P. acnes is a component of normal skin flora that proliferates in the obstructed, lipid-rich lumen of the pilosebaceous unit, where O2 tension is low. P. acnes generates free fatty acids that are irritants and may lead to microcomedo formation and resulting inflammatory lesions. Suppression of cutaneous P. acnes with antibiotic therapy is correlated with clinical improvement. Commonly used topical antimicrobials in acne include clindamycin (CLEOCIN T, others), erythromycin (ERYDERM, others), benzoyl peroxide, and antibiotic–benzoyl peroxide combinations (BENZACLIN, DUAC, others). Other antimicrobials used in treating acne include sulfacetamide (KLARON, others), sulfacetamide/sulfur combinations (SULFACET-R, others), metronidazole (METROCREAM, METROGEL, NORITATE), and azelaic acid (AZELEX, others). Systemic therapy is prescribed for patients with more extensive disease and acne that is resistant to topical therapy. Effective agents include tetracycline (SUMYCIN, others), doxycycline (MONODOX, others), minocycline (MINOCIN, others), and trimethoprim–sulfamethoxazole (BACTRIM, others). Antibiotics usually are administered twice daily, and doses are tapered after control is achieved.
The tetracyclines are the most commonly employed antibiotics because they are inexpensive, safe, and effective. The initial daily dose usually is 1 g in divided doses. Although tetracyclines are antimicrobial agents, efficacy in acne may be more dependent on anti-inflammatory activity. Minocycline has better GI absorption than tetracycline and may be less photosensitizing than either tetracycline or doxycycline. Side effects of minocycline include dizziness and hyperpigmentation of the skin and mucosa, serum sickness–like reactions, and drug-induced lupus erythematosus. With all the tetracyclines, vaginal candidiasis is a common complication that is readily treated with local administration of antifungal drugs.
Cutaneous Infections. Gram-positive organisms, including Staphylococcus aureus and Streptococcus pyogenes, are the most common cause of pyoderma. Skin infections with gram-negative bacilli are rare, although they can occur in diabetics and patients who are immunosuppressed; appropriate parenteral antibiotic therapy is required for their treatment.
Topical therapy frequently is adequate for impetigo, the most superficial bacterial infection of the skin caused by S. aureus and S. pyogenes. Mupirocin (pseudomonic acid, BACTROBAN, others) is effective for such localized infections. It inhibits protein synthesis by binding to bacterial isoleucyl-tRNA synthetase. Mupirocin is inactive against normal skin flora. Mupirocin is available as a 2% ointment or cream, applied 3 times daily. A nasal formulation is indicated to eradicate methicillin-resistant S. aureus (MRSA) nasal colonization. Retapamulin ointment 1% (ALTABAX) also is FDA-approved for the topical treatment of impetigo caused by susceptible strains of S. aureus or S. pyogenes in patients >9 months of age. Retapamulin selectively inhibits bacterial protein synthesis by interacting at a site on the 50S subunit of bacterial ribosomes.
Neomycin is active against staphylococci and most gram-negative bacilli, however, it may cause allergic contact dermatitis, especially on disrupted skin. Bacitracin inhibits staphylococci, streptococci, and gram-positive bacilli. Polymyxin B is active against aerobic gram-negative bacilli. Neomycin, bacitracin, and polymyxin B (NEOSPORIN ORIGINAL OINTMENT, DOUBLE ANTIBIOTIC OINTMENT, others) are sold alone or in various combinations with other ingredients (e.g., hydrocortisone, lidocaine, or pramoxine) in a number of over-the-counter formulations.
Deep Skin Infections. Because streptococcal and staphylococcal species also are the most common causes of deep cutaneous infections, penicillins (especially β lactamase–resistant β-lactams) and cephalosporins are the systemic antibiotics used most frequently in their treatment (see Chapter 53). A growing concern is the increased incidence of skin and soft-tissue infections with hospital- and community-acquired MRSA and drug-resistant pneumococci. Infection with community-acquired MRSA often is susceptible to trimethoprim–sulfamethoxazole. In addition to various traditional systemic antibiotics (such as erythromycin), novel antibacterial agents such as linezolid, quinupristin–dalfopristin, and daptomycin also have been approved for the treatment of complicated skin and skin-structure infections (see Chapter 53).
Fungal infections are among the most common causes of skin disease in the U.S., and numerous effective topical and oral antifungal agents have been developed. Griseofulvin, topical and oral imidazoles, triazoles, and allylamines are the most effective antifungal agents available. The pharmacology, uses, and toxicities of antifungal drugs are discussed in Chapter 57. Recommendations for cutaneous antifungal therapy are summarized in Table 65–7.
Recommended Cutaneous Antifungal Therapy
The azoles miconazole (MICATIN, others) and econazole (SPECTAZOLE, others) and the allylamines naftifine (NAFTIN) and terbinafine (LAMISIL, others) are effective topical agents for the treatment of localized tinea corporis and uncomplicated tinea pedis. Topical therapy with the azoles is preferred for localized cutaneous candidiasis and tinea versicolor. Systemic therapy is necessary for the treatment of tinea capitis or follicular-based fungal infections. Oral griseofulvin has been the traditional medication for treatment of tinea capitis. Oral terbinafine is a safe and effective alternative to griseofulvin in treating tinea capitis in children.
Viral infections of the skin are very common and include human papillomavirus (HPV), herpes simplex virus (HSV), condyloma acuminatum (HPV), molluscum contagiosum (poxvirus), and chicken pox (varicellazoster virus [VZV]). Acyclovir (ZOVIRAX), famciclovir (FAMVIR, others), and valacyclovir (VALTREX) frequently are used systemically to treat HSV and VZV infections (see Chapter 58). Cidofovir (VISTIDE) may be useful in treating acyclovir-resistant HSV or VZV and other cutaneous viral infections. Topically, acyclovir, docosanol (ABREVA), and penciclovir (DENAVIR) are available for treating mucocutaneous HSV. Podophyllin (25% solution) and podofilox (CONDYLOX, others) 0.5% solution are used to treat condylomata. The immune response modifier imiquimod (ALDARA) is discussed below. Interferons α-2b (INTRON A), α-n1 (not commercially available in the U.S.), and α-n3 (ALFERON N) may be useful for treating refractory or recurrent warts.
AGENTS USED TO TREAT INFESTATIONS
Infestations with ectoparasites such as lice and scabies are common throughout the world. These conditions have a significant impact on public health in the form of disabling pruritus, secondary infection, and in the case of the body louse, transmission of life-threatening illnesses such as typhus. Topical and oral medications are available to treat these infestations.
Permethrin is a synthetic pyrethroid that interferes with insect sodium transport proteins, causing neurotoxicity and paralysis. Resistance due to mutations in the transport protein has been reported inCimex (bed bugs) and other insects. A 5% cream is available for the treatment of scabies, and a 1% cream, a cream rinse, and topical solutions are available OTC for the treatment of lice. Permethrin is approved for use in infants >2 months of age. Other agents used in the treatment of lice are pyrethrins + piperonyl butoxide (lotion, gel, shampoo, and mousse) and KLOUT shampoo (acetic acid + isopropanol).
Lindane has been used as a commercial insecticide as well as a topical medication. Due to several cases of neurotoxicity in humans, the FDA has labeled lindane as a second-line drug in treating pediculosis and scabies and has highlighted the potential for neurotoxicity in children and adults weighing <110 pounds. Lindane is contraindicated in premature infants and patients with seizure disorders.
Malathion (OVIDE) is an organophosphate that binds acetylcholinesterase in lice, causing paralysis and death. It is approved for treatment of head lice in children >6 years of age.
Benzyl alcohol (ULESFIA) 5% lotion is approved for the treatment of lice. Benzyl alcohol inhibits lice from closing their respiratory spiracles, which allows the vehicle to obstruct the spiracles and causes the lice to asphyxiate.
Ivermectin (STROMECTOL) is an oral anthelmintic drug (see Chapter 51) approved to treat onchocerciasis and strongyloidiasis. Recently, ivermectin lotion (SKLICE) was approved to treat lice. It also is effective in the off-label treatment of scabies. Minor CNS side effects include dizziness, somnolence, vertigo, and tremor. For both scabies and lice, ivermectin typically is given at a dose of 200 μg/kg, which may be repeated in 1 week. It should not be used in children weighing <15 kg.
Less effective topical treatments for scabies and lice include 10% crotamiton cream and lotion (EURAX) and extemporaneously compounded 5% precipitated sulfur in petrolatum. Crotamiton and sulfur may be considered for use in patients in whom lindane or permethrin is contraindicated.
Antimalarials used in dermatology include chloroquine (ARALEN, others), hydroxychloroquine (PLAQUENIL, others), and quinacrine (ATABRINE) (see Chapter 49). Common dermatoses treated with antimalarials include cutaneous lupus erythematosus, cutaneous dermatomyositis, polymorphous light eruption, porphyria cutanea tarda, and sarcoidosis. The mechanism by which antimalarial agents exert their anti-inflammatory therapeutic effects is unknown. The usual dosages of antimalarials are 200 mg twice a day (maximum of 6.5 mg/kg/day) of hydroxychloroquine, 250-500 mg/day (maximum of 3 mg/kg/day) of chloroquine, and 100-200 mg/day of quinacrine. Clinical improvement may be delayed for several months. Hydroxychloroquine is the most common antimalarial used in dermatology. Patients with porphyria cutanea tarda require lower doses of antimalarials to avoid severe hepatotoxicity.
CYTOTOXIC AND IMMUNOSUPPRESSANT DRUGS
Cytotoxic and immunosuppressant drugs are used in dermatology for immunologically mediated diseases such as psoriasis, autoimmune blistering diseases, and leukocytoclastic vasculitis. See Table 65–8 for their mechanisms of action.
Mechanisms of Action of Selected Cytotoxic and Immunosuppressant Agents
METHOTREXATE. Methotrexate is used for moderate to severe psoriasis. It suppresses immunocompetent cells in the skin, and it also decreases the expression of cutaneous lymphocyte-associated antigen (CLA)–positive T-cells and endothelial cell E-selectin, which may account for its efficacy. Methotrexate is useful in treating a number of other dermatological conditions, including pityriasis lichenoides et varioliformis, lymphomatoid papulosis, sarcoidosis, pemphigus vulgaris, pityriasis rubra pilaris, lupus erythematosus, dermatomyositis, and cutaneous T-cell lymphoma.
Methotrexate (RHEUMATREX, others) often is used in combination with phototherapy and photochemotherapy or other systemic agents. Widely used regimens include three 2.5-mg oral doses given at 12-h intervals once weekly, or weekly intramuscular injections of 10-25 mg (maximum of 30 mg/wk). Doses must be decreased for patients with impaired renal clearance. Methotrexate should never be coadministered with probenecid, trimethoprim–sulfamethoxazole, salicylates, or other drugs that can compete with it for protein binding and thereby raise plasma concentrations to levels that may result in bone marrow suppression. Fatalities have occurred because of concurrent treatment with methotrexate and nonsteroidal anti-inflammatory agents. Methotrexate exerts significant antiproliferative effects on the bone marrow; therefore, CBCs should be monitored serially. Physicians administering methotrexate should be familiar with the use of folinic acid (leucovorin) to rescue patients with hematological crises caused by methotrexate-induced bone marrow suppression. Careful monitoring of liver function tests is necessary. Methotrexate-induced hepatic fibrosis may occur more commonly in patients withpsoriasis than in those with rheumatoid arthritis. Consequently, liver biopsy is recommended when the cumulative dose reaches 1-1.5 g. Patients with abnormal liver function tests, symptomatic liver disease, or evidence of hepatic fibrosis should not use this drug. Many clinicians routinely administer folic acid along with methotrexate to ameliorate side effects. Methotrexate is contraindicated during pregnancy and lactation.
AZATHIOPRINE. Azathioprine (IMURAN, others) is discussed in Chapter 35. In dermatological practice, the drug is used off label as a steroid-sparing agent for autoimmune and inflammatory dermatoses, including pemphigus vulgaris, bullous pemphigoid, dermatomyositis, atopic dermatitis, chronic actinic dermatitis, lupus erythematosus, psoriasis, pyoderma gangrenosum, and Behçet disease.
Starting dosage is 1-2 mg/kg/day. Because it takes 6-8 weeks to achieve therapeutic effect, azathioprine often is started early in the course of disease management. Careful laboratory monitoring is important. The enzyme thiopurine S- methyltransferase (TPMT) activity should be measured before initiating azathioprine therapy (see Chapter 35).
FLUOROURACIL. Topical formulations of fluorouracil (5-FU) (CARAC, others) are used in multiple actinic keratoses, actinic cheilitis, Bowen disease, and superficial basal cell carcinomas not amenable to other treatments.
Fluorouracil is applied once or twice daily for 2-8 weeks, depending on the indication. The treated areas may become severely inflamed during treatment, but the inflammation subsides after the drug is stopped. Intralesional injection of 5-FU has been used for keratoacanthomas, warts, and porokeratoses.
INGENOL MEBUTATE. Ingenol mebutate (PICATO) gel, an extract from the plant Euphorbia peplus, is FDA approved for actinic keratoses.
In experimental studies, it was reported to rapidly cause mitochondrial swelling and apoptosis of dysplastic keratinocytes. The gel is applied once daily for 2-3 consecutive days. Adverse effects may include local skin irritation, pain, pruritus, and infection at application site, periorbital edema, nasopharyngitis, and headache.
Cyclophosphamide is an effective cytotoxic and immunosuppressive agent. Both oral and intravenous preparations of cyclophosphamide are used in dermatology. Cyclophosphamide is FDA-approved for treatment of advanced cutaneous T-cell lymphoma.
Other uses include treatment of pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, paraneoplastic pemphigus, pyoderma gangrenosum, toxic epidermal necrolysis, Wegener granulomatosis, polyarteritis nodosa, Churg-Strauss angiitis, Behçet disease, scleromyxedema, and cytophagic histiocytic panniculitis. The usual oral dosage is 2-3 mg/kg/day in divided doses, and there often is a 4- to 6-week delay in onset of action. Alternatively, intravenous pulse administration of cyclophosphamide may offer advantages, including lower cumulative dose and a decreased risk of bladder cancer. Cyclophosphamide has many adverse effects, including the risk of secondary malignancy and myelosuppression, and is used only in the most severe, recalcitrant dermatological diseases.
Mechlorethamine hydrochloride (MUSTARGEN) and carmustine (BICNU) are used topically to treat cutaneous T-cell lymphoma.
Both can be applied topically as a solution or in an extemporaneously compounded ointment form. It is important to monitor CBCs and liver function tests because systemic absorption can cause bone marrow suppression and hepatitis. Other side effects include allergic contact dermatitis, irritant dermatitis, secondary cutaneous malignancies, and pigmentary changes. Carmustine also can cause erythema and post-treatment telangiectases.
Chapter 35 describes the mechanisms of action and clinical pharmacology of these agents. Figure 35–1 shows their main molecular effects as immunosuppressants.
Cyclosporine. Cyclosporine (NEORAL, GENGRAF, others) is a potent immunosuppressant isolated from the fungus Tolypocladium inflatum. Cyclosporine is FDA-approved for the treatment of psoriasis. Other cutaneous disorders that typically respond well to cyclosporine are atopic dermatitis, alopecia areata, epidermolysis bullosa acquisita, pemphigus vulgaris, bullous pemphigoid, lichen planus, and pyoderma gangrenosum. The usual initial oral dosage is 2.5 mg/kg/day given in 2 divided doses.
Hypertension and renal dysfunction are the major adverse effects associated with the use of cyclosporine. These risks can be minimized by monitoring serum creatinine (which should not rise >30% above baseline), calculating creatinine clearance or glomerular filtration rate in patients on long-term therapy or with a rising creatinine, maintaining a daily dose of <5 mg/kg, and regularly monitoring blood pressure. Alternation with other therapeutic modalities may diminish cyclosporine toxicity. Patients with psoriasis who are treated with cyclosporine are at increased risk of cutaneous, solid organ, and lymphoproliferative malignancies. The risk of cutaneous malignancies is compounded if patients have received phototherapy with PUVA.
Tacrolimus. Tacrolimus (FK506, PROTOPIC) is available in a topical form for the treatment of skin disease and also is marketed in oral and injectable formulations (PROGRAF). Systemic tacrolimus has shown some efficacy in the treatment of inflammatory skin diseases such as psoriasis, pyoderma gangrenosum, and Behçet disease. When administered systemically, the most common side effects are hypertension, nephrotoxicity, neurotoxicity, GI symptoms, hyperglycemia, and hyperlipidemia.
Topical formulations (0.03% and 0.1%) of tacrolimus ointment are approved for the treatment of atopic dermatitis in adults and children >2 years of age. Other uses in include intertriginous psoriasis, vitiligo, mucosal lichen planus, graft-versus-host disease, allergic contact dermatitis, and rosacea. Ointment is applied to the affected area 2 times daily and generally is well tolerated. An advantage of topical tacrolimus over topical glucocorticoids is that tacrolimus does not cause skin atrophy and therefore can be used safely in locations such as the face and intertriginous areas. Common side effects at the site of application are transient erythema, burning, and pruritus. Other adverse effects include skin tingling, flu-like symptoms, headache, alcohol intolerance, folliculitis, acne, and hyperesthesia. Systemic absorption generally is very low and decreases with resolution of the dermatitis. Topical tacrolimus should be used with extreme caution in patients with Netherton syndrome because these patients have been shown to develop elevated blood levels of the drug after topical application.
Pimecrolimus. Pimecrolimus 1% cream (ELIDEL) is a macrolide approved for the treatment of atopic dermatitis in patients >2 years of age. Its mechanism of action and side-effect profile are similar to those of tacrolimus. Pimecrolimus has less systemic absorption. Similar precautions with regard to UV exposure should be taken during treatment with pimecrolimus. Tacrolimus and pimecrolimus should only be used as second-line agents for short-term and intermittent treatment of atopic dermatitis (eczema) in patients unresponsive to, or intolerant of, other treatments. These drugs should be avoided in children <2 years of age.
OTHER IMMUNOSUPPRESSANT AND ANTI-INFLAMMATORY AGENTS
MYCOPHENOLATE MOFETIL. Mycophenolate mofetil (CELLCEPT), a prodrug, and mycophenolate sodium (MYFORTIC) are immunosuppressants approved for prophylaxis of organ rejection in patients with renal, cardiac, and hepatic transplants (see Chapter 35).
Mycophenolic acid functions as a specific inhibitor of T and B lymphocyte activation and proliferation. The drug also may enhance apoptosis. Mycophenolate mofetil is used increasingly to treat inflammatory and autoimmune diseases in dermatology in dosages ranging from 1-2 g/day orally; this agent is particularly useful as a corticosteroid-sparing agent in the treatment of autoimmune blistering disorders, and has been used effectively in the treatment of inflammatory diseases such as psoriasis, atopic dermatitis, and pyoderma gangrenosum. Isolated cases of progressive multifocal leukoencephalopathy (PML) and pure red cell aplasia have been reported in solid organ transplant patients receiving mycophenolate mofetil.
IMIQUIMOD. Imiquimod (ALDARA) exerts immunomodulatory effects by acting as a ligand at toll-like receptors in the innate immune system and inducing the cytokines interferon-α (IFN-α), tumor necrosis factor-α (TNF-α), and IL-1, IL-6, IL-8, IL-10, and IL-12.
Approved for the treatment of genital warts, imiquimod is applied to genital or perianal lesions 2 times a week usually for a 16-week period (and repeated as necessary). Imiquimod also is approved for the treatment of actinic keratoses. No more than 36 single-use packets per 16-week course of therapy should be prescribed for actinic keratoses. The drug is FDA-approved for the treatment of nodular and superficial basal cell carcinomas at a dosage of 5 applications per week for 6 weeks. Off-label applications include the treatment of nongenital warts, molluscum contagiosum, extramammary Paget disease, and Bowen disease. Irritant reactions occur in virtually all patients; the degree of inflammation parallels therapeutic efficacy.
Systemic vinblastine (VELBAN, others) is approved for use in Kaposi sarcoma and advanced cutaneous T-cell lymphoma. Intralesional vinblastine also is used to treat Kaposi sarcoma. Intralesional bleomycin (BLENOXANE, others) is used for palliative treatment of squamous cell carcinoma and recalcitrant warts and has cytotoxic and pro-inflammatory effects. Intralesional injection of bleomycin into the digits has been associated with a vasospastic response that mimics Raynaud phenomenon, local skin necrosis, and flagellate hyperpigmentation. Systemic bleomycin has been used for Kaposi sarcoma (see Chapter 61). Liposomal anthracyclines (specifically doxorubicin [DOXIL, CAELYX]) may provide first-line monotherapy for advanced Kaposi sarcoma.
Dapsone is used in dermatology for its anti-inflammatory properties, particularly in sterile (non-infectious) pustular diseases of the skin. Dapsone prevents the respiratory burst from myeloperoxidase, suppresses neutrophil migration by blocking integrin-mediated adherence, inhibits adherence of antibodies to neutrophils, and decreases the release of eicosanoids and blocks their inflammatory effects. Seealso Figure 56–5 and accompanying text in Chapter 56.
Dapsone is approved for use in dermatitis herpetiformis and leprosy. It is particularly useful in the treatment of linear immunoglobulin A (IgA) dermatosis, bullous systemic lupus erythematosus, erythema elevatum diutinum, and subcorneal pustular dermatosis. In addition, reports indicate efficacy in patients with acne fulminans, pustular psoriasis, lichen planus, Hailey–Hailey disease, pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, leukocytoclastic vasculitis, Sweet syndrome, granuloma faciale, relapsing polychondritis, Behçet disease, urticarial vasculitis, pyoderma gangrenosum, and granuloma annulare.
An initial dosage of 50 mg/day is prescribed, followed by increases of 25 mg/day at weekly intervals, titrated to the minimal dosage necessary for effect. Potential side effects of dapsone include methemoglobinemia and hemolysis. The glucose-6-phosphate dehydrogenase (G6PD) level should be checked in all patients. The H2 blocker cimetidine, at a dose of 400 mg 3 times daily, alters the degree of methemoglobinemia by competing with dapsone for CYPs. Toxicities include agranulocytosis, peripheral neuropathy, and psychosis.
THALIDOMIDE. Thalidomide (THALOMID) is an anti-inflammatory, immunomodulating, anti-angiogenic agent experiencing resurgence in the treatment of dermatological diseases. For details of its actions, see Chapter 35 under “Immunostimulants” and Figure 62–2 and associated text.
Thalidomide is FDA-approved for the treatment of erythema nodosum leprosum. There are reports suggesting its efficacy in actinic prurigo, aphthous stomatitis, Behçet disease, Kaposi sarcoma, and the cutaneous manifestations of lupus erythematosus, as well as prurigo nodularis and uremic prurigo. Thalidomide has been associated with increased mortality when used to treat toxic epidermal necrolysis. In utero exposure can cause limb abnormalities (phocomelia), as well as other congenital anomalies. It also may cause an irreversible neuropathy. Because of its teratogenic effects, thalidomide use is restricted to specially licensed physicians who fully understand the risks. Thalidomide should never be taken by women who are pregnant or who could become pregnant while taking the drug.
Biological agents (see Chapters 35 and 62) include recombinant cytokines, interleukins, growth factors, antibodies, and fusion proteins.
Five biological agents are approved for the treatment of psoriasis (Table 65–9). Psoriasis is a disorder of Th1 cell-mediated immunity (Figure 65–4), with the epidermal changes being secondary to the effect of released cytokines. Biological therapies modify the immune response in psoriasis through (1) reduction of pathogenic T-cells, (2) inhibition of T-cell activation, (3) immune deviation (from a Th1 to a Th2 immune response), and (4) blockade of the activity of inflammatory cytokines. The appeal of biological agents in the treatment of psoriasis is that they specifically target the activities of T lymphocytes and cytokines that mediate inflammation versus traditional systemic therapies that are broadly immunosuppressive or cytotoxic.
Biological Agents Commonly Used in Dermatology
Figure 65–4 Immunopathogenesis of psoriasis. Psoriasis is a prototypical inflammatory skin disorder in which specific T-cell populations are stimulated by as-yet undefined antigen(s) presented by antigen-presenting cells (APCs). The T-cells release pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-γ) (IFN-γ), that induce keratinocyte and endothelial cell proliferation. CLA, cutaneous lymphocyte-associated antigen.
INHIBITORS OF T-CELL ACTIVATION
ALEFACEPT. Alefacept (AMEVIVE) is an immunobiological agent approved for the treatment of moderate to severe psoriasis.
Alefacept consists of a recombinant fully human fusion protein composed of the binding site of the leukocyte function–associated antigen 3 (LFA-3) protein and a human IgG1 Fc domain. The LFA-3 portion of the alefacept molecule binds to CD2 on the surface of T-cells, thus blocking a necessary co-stimulation step in T-cell activation (Figure 65–5). Importantly, because CD2 is expressed preferentially on memory-effector T-cells, naive T-cells are largely unaffected by alefacept. A second important action of alefacept is its ability to induce apoptosis of memory-effector T-cells through simultaneous binding of its IgG1 portion to immunoglobulin receptors on cytotoxic cells and its LFA-3 portion to CD2 on T-cells, thus inducing granzyme-mediated apoptosis of memory-effector T-cells. This may lead to a reduction in CD4+ lymphocyte counts, requiring a baseline CD4+ lymphocyte count before initiating alefacept and then biweekly during therapy.
Figure 65–5 Mechanisms of action of selected biological agents in psoriasis. Newer biological agents can interfere with 1 or more steps in the pathogenesis of psoriasis, resulting in clinical improvement. See text for details. ICAM-1, intercellular adhesion molecule 1; LFA, lymphocyte function–associated antigen; MHC, major histocompatibility complex; TCR, T-cell receptor.
EFALIZUMAB. Efalizumab (RAPTIVA) is a humanized monoclonal antibody against the CD11a molecule of LFA-1.
By binding to CD11a on T-cells, efalizumab prevents binding of LFA-1 to intercellular adhesion molecule (ICAM)-1 on the surface of antigen-presenting cells, vascular endothelial cells, and cells in the dermis and epidermis (see Figure 65–5), thereby interfering with T-cell activation and migration and cytotoxic T-cell function. A transient peripheral leukocytosis occurs in some patients taking efalizumab, which may be due to the inhibition of T-cell trafficking. Other side effects include thrombocytopenia, exacerbation of psoriasis. Therefore, CBCs should be obtained at baseline and periodically thereafter. Caution should be exercised in patients who develop neurological signs while on efalizumab.
TUMOR NECROSIS FACTOR INHIBITORS
TNF-α is central to the TH1 response in active psoriasis, inducing inflammatory cytokines, upregulating intracellular adhesion molecules, inhibiting apoptosis of keratinocytes and inducing their proliferation. Blockade of TNF-α reduces inflammation, decreases keratinocyte proliferation, and decreases vascular adhesion, resulting in improvement in psoriatic lesions.
Because TNF-α inhibitors alter immune responses, patients on all anti-TNF-α agents are at increased risk for serious infection and for malignancies. Other adverse events include exacerbation of congestive heart failure and demyelinating disease in predisposed patients. All patients should be screened for tuberculosis, history of demyelinating disorder, cardiac failure, active infection, or malignancy prior to therapy.
ETANERCEPT. Etanercept (ENBREL) is a soluble, recombinant, fully human TNF receptor fusion protein consisting of 2 molecules of the ligand-binding portion of the TNF receptor (p75) fused to the Fc portion of IgG1. Etanercept binds soluble and membrane-bound TNF, thereby inhibiting the action of TNF. Etanercept used at 0.4 mg/kg twice weekly in pediatric psoriasis is safe and efficacious. Etanercept use is associated with an increased risk of infections (bacterial sepsis, tuberculosis), including leading to hospitalization or death.
INFLIXIMAB. Infliximab (REMICADE) is a mouse-human chimeric IgG1 monoclonal Ab that binds to soluble and membrane-bound TNF-α. Infliximab is a complement-fixing Ab that induces complement-dependent and cell-mediated lysis when bound to cell-surface-bound TNF-α. Neutralizing antibodies to infliximab may develop. Concomitant administration of methotrexate or glucocorticoids may suppress this Ab formation.
ADALIMUMAB. Adalimumab (HUMIRA) is a human IgG1 monoclonal Ab that binds soluble and membrane-bound TNF-α. Like infliximab, it can mediate complement-induced cytolysis on cells expressing TNF. Unlike infliximab, adalimumab is fully human, which reduces the risk for development of neutralizing antibodies.
A FUSION PROTEIN TARGETING CUTANEOUS T-CELL LYMPHOMA
DENILEUKIN DIFTITOX. Denileukin diftitox or DAB389–IL-2 (ONTAK) is a fusion protein composed of diphtheria toxin fragments A and B and the receptor-binding portion of IL-2. DAB389–IL-2 is indicated for advanced cutaneous T-cell lymphoma in patients with >20% of T-cells expressing the surface marker CD25.
The IL-2 receptor (IL-2R) is present on malignant and activated T-cells but not resting B and T-cells. Following binding to the IL-2R, DAB389–IL-2 is internalized by endocytosis. The active fragment of diphtheria toxin then is released into the cytosol, where it inhibits protein synthesis via ADP ribosylation of elongation factor-2 (EF-2), leading to cell death. Response rate is 30%. Adverse effects include pain, fevers, chills, nausea, vomiting, and diarrhea; immediate hypersensitivity reaction in 60% of patients; and capillary leak syndrome in 20-30% of patients.
Intravenous immunoglobulin (IVIG) is prepared from fractionated pooled human sera derived from thousands of donors with various antigenic exposures (see Chapter 35). Preparations of IVIG are composed of >90% IgG, with minimal amounts of IgA, soluble CD4, CD8, HLA molecules, and cytokines. In dermatology, IVIG is used off label as an adjuvant or rescue therapy for autoimmune bullous diseases, toxic epidermal necrolysis, connective tissue diseases, vasculitis, urticaria, atopic dermatitis, and graft-versus-host disease.
Although the mechanism of action of IVIG is not understood fully, proposed mechanisms include suppression of IgG production, accelerated catabolism of IgG, neutralization of complement-mediated reactions, neutralization of pathogenic antibodies, downregulation of inflammatory cytokines, inhibition of autoreactive T lymphocytes, inhibition of immune cell trafficking, and blockage of Fas-ligand/Fas-receptor interactions. IVIG is contraindicated in patients with severe selective IgA deficiency (IgA <0.05 g/L). These patients may possess anti-IgA antibodies that place them at risk for severe anaphylactic reactions. Other relative contraindications include congestive heart failure and renal failure.
Photoprotection from the acute and chronic effects of sun exposure is readily available with sunscreens. The major active ingredients of available sunscreens include chemical agents that absorb incident solar radiation in the UVB and/or UVA ranges and physical agents that contain particulate materials that can block or reflect incident energy and reduce its transmission to the skin. The FDA has recently issued new rules for standardizing sunscreen efficacy, reviewed in an update (May 12, 2012) to the online version of Goodman & Gilman.
There is evidence that the regular use of sunscreens can reduce the risk of actinic keratoses and squamous cell carcinomas of the skin. Except for total sun avoidance, sunscreens are the best single method of protection from UV-induced damage to the skin. However, there is a need for more definitive answers to questions related to the efficacy of sunscreens in reducing skin cancer risk.
UVA Sunscreen Agents. Currently available UVA filters in the U.S. include (1) avobenzone, also known as Parsol 1789; (2) oxybenzone; (3) titanium dioxide; (4) zinc oxide; and (5) ecamsule (MEXORYLSX). Additional UVA sunscreens, including bemotrizinol (TINOSORB S) and bisoctrizole (TINSORB M), are not available in the U.S.
UVB Sunscreen Agents. There are numerous UVB filters, including p-aminobenzoic acid (PABA) esters (e.g., padimate O), cinnamates (e.g., octinoxate), octocrylene, and salicylates (e.g., octisalate).
TREATMENT OF PRURITUS
Pruritus (itching) occurs in a multitude of dermatological disorders, including dry skin or xerosis, atopic eczema, urticaria, and infestations. Itching also may be a sign of internal disorders, including malignant neoplasms, chronic renal failure, and hepatobiliary disease. In addition to treating the underlying disorder, a general approach to the treatment of pruritus can be made by classifying pruritus into 1 of 4 clinical categories (Table 65–10). Long experience shows that gold works well for treatment of the itching palm.
Agents Used for the Treatment of Pruritus
DRUGS FOR HYPERKERATOTIC DISORDERS
Keratolytic agents reduce hyperkeratosis through myriad mechanisms (e.g., breaking of intercellular junctions, increasing stratum corneum water content, increasing desquamation). Common disorders treated with keratolytics include psoriasis, seborrheic dermatitis, xerosis, ichthyoses, and verrucae.
α-Hydroxy acids can reduce the thickness of the stratum corneum by solubilizing components of the desmosome, activating endogenous hydrolytic enzymes, and drawing water into the stratum corneum, allowing cell separation to occur. They also appear to increase glycosaminoglycans, collagen, and elastic fibers in the dermis and are used in various formulations to reverse photoaging. The FDA requires that cosmetics containing α-hydroxy acids be labeled with a sunburn alert warning that the product may increase sensitivity to the sun. α-Hydroxy acids used include glycolic, lactic, malic, citric, hydroxycaprylic, hydroxycapric, and mandelic.
Salicylic acid functions through solubilization of intercellular cement, reducing corneocyte adhesion, and softening the stratum corneum. Salicylism may occur with widespread and prolonged use, especially in children and patients with renal or hepatic impairment, and use should be limited to <2 g to the skin surface in a 24-h period. Salicylic acid, while chemically not a true a β-hydroxy acid, often is listed as such on cosmetic labels. Other β-hydroxy acids ingredients in cosmetics include β-hydroxybutanoic acid, δ-tropic acid, and trethocanic acid. Sun protection should accompany the topical application of these agents.
Urea, at low concentrations, increases skin absorption and retention of water, leading to increased flexibility and softness of the skin. At concentrations >40%, urea denatures and dissolves proteins and is used to dissolve calluses or avulse dystrophic nails.
Sulfur is keratolytic, anti-septic, anti-parasitic, and anti-seborrheic. It exerts its keratolytic effect by reacting with cysteine within keratinocytes, producing cystine and hydrogen sulfide (H2S). H2S breaks down keratin, causing dissolution of the stratum corneum.
Propylene glycol (as 60-100% solutions in water) increases the water content of the stratum corneum and enhances desquamation. It is most effective in disorders with retention hyperkeratosis.
DRUGS FOR ANDROGENETIC ALOPECIA
Androgenetic alopecia, commonly known as male and female pattern baldness, is the most common cause of hair loss in adults >40 years of age. It is a genetically inherited trait with variable expression. In susceptible hair follicles, dihydrotestosterone binds to the androgen receptor; the hormone-receptor complex activates the genes responsible for the gradual transformation of large terminal follicles into miniaturized vellus follicles. Treatment of androgenetic alopecia is aimed at reducing hair loss and maintaining existing hair.
Minoxidil. Minoxidil (ROGAINE, others), developed as an antihypertensive agent (see Chapter 27), was noted to be associated with hypertrichosis in some patients. Topical minoxidil is available as a 2% or 5% solution. Minoxidil enhances follicular size, resulting in thicker hair shafts, and stimulates and prolongs the anagen phase of the hair cycle, resulting in longer and increased numbers of hairs. Treatment must be continued or any drug-induced hair growth will be lost. Allergic and irritant contact dermatitis can occur, and care should be taken in applying the drug because hair growth may emerge in undesirable locations. This is reversible on stopping the drug. Patients should be instructed to wash their hands after applying minoxidil.
Finasteride. Finasteride (PROPECIA, other) inhibits the type II isozyme of 5α-reductase, the enzyme that converts testosterone to dihydrotestosterone (see Chapter 41) and that is found in hair follicles. Balding areas of the scalp are associated with increased dihydrotesterone levels and smaller hair follicles than nonbalding areas. Orally administered finasteride (1 mg/day) has been shown to variably increase hair growth in men over a 2-year period. Finasteride is approved for use only in men. Pregnant women should not be exposed to the drug because of the potential for inducing genital abnormalities in male fetuses. Adverse effects of finasteride include decreased libido, erectile dysfunction, ejaculation disorder, and decreased ejaculate volume. As with minoxidil, treatment with finasteride must be continued, or any new hair growth will be lost.
TREATMENT OF HYPERPIGMENTATION
These agents are most effective on hormonally or light-induced pigmentation within the epidermis. They have limited efficacy on post-inflammatory pigmentation within the dermis.
Hydroquinone. Hydroquinone (1,4-dihydrobenzene; TRI-LUMA) decreases melanocyte pigment production by inhibiting the conversion of dopa to melanin through inhibition of the enzyme tyrosinase. Other mechanisms include inhibition of DNA and RNA synthesis, degradation of melanosomes, and destruction of melanocytes. There are multiple formulations, to which penetration enhancers, microsponges, and sunscreen ingredients are added. Adverse effects may include dermatitis and ochronosis.
Monobenzone. Monobenzone (BENOQUIN), causes permanent hypopigmentation and should not be used for routine hormonally induced or post-inflammatory hyper-pigmentation.
Azelaic. Azelaic acid (AZELEX, FINACEA) inhibits tyrosinase activity but is less effective than hydroquinone. Because it has mild comedolytic, antimicrobial, and anti-inflammatory properties, it also is often used in acne and papulopustular rosacea.
Mequinol. Mequinol (4-hydroxyanisole, methoxyphenol, hydroquinone monomethyl ether, or p-hydroxyanisole) is a competitive inhibitor of tyrosinase. It is available as a 2% prescription product (SOLAGé) in combination with 0.01% tretinoin and vitamin C for skin lightening.
Capsaicin is an alkaloid derived from plants of the Solanaceae family (i.e., hot chili peppers). Capsaicin interacts with the transient receptor potential vanilloid (TRPV1) receptor on C-fiber sensory neurons. TRPV1 is a ligand-gated nonselective cation channel of the TRP family, modulated by a variety of noxious stimuli. Chronic exposure to capsaicin first stimulates and then desensitizes this channel to capsaicin and diverse other noxious stimuli. Capsaicin also causes local depletion of substance P, an endogenous neuropeptide involved in sensory perception and pain transmission. Capsaicin is available at various concentrations as a cream (ZOSTRIX, others), lotion (CAPSIN), gel, roll-on, and transdermal patch. Capsaicin is FDA-approved for the temporary relief of minor aches and pains associated with backache, strains, and arthritis, and is used for off-label treatment of postherpetic neuralgia and painful diabetic neuropathy.
Podophyllin, podophyllum resin, a mixture of chemicals from the plant Podophyllum peltatum (mandrake or May apple), contains podophyllotoxin (podofilox), which binds to microtubules and causes mitotic arrest in metaphase. Podophyllum resin (10-40%) is applied by a physician and left in place for no longer than 2-6 h weekly for the treatment of anogenital warts. Irritation and ulcerative local reactions are the major side effects. It should not be used in the mouth or during pregnancy. Podofilox is available as a 0.5% solution for home application 2 times daily for 3 consecutive days, repeated weekly as needed up to 4 cycles.