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- Section XIV. Dermatology
Overview
The skin has many essential functions, including protection, thermoregulation, immune
responsiveness, biochemical synthesis, sensory detection, and social and sexual communication.
Therapy to correct dysfunction in any of these activities may be delivered topically, systemically,
intralesionally, or through ultraviolet radiation.
Topical therapy is a convenient method of treatment, but its efficacy depends on understanding the
barrier function of the skin, primarily within the stratum corneum. Corticosteroids and retinoids are
important systemic and topical therapeutic agents for skin disease. Oral steroids are employed in
high doses to treat very serious cutaneous eruptions, and, fortunately, structural modification of the
hydrocortisone molecule has produced compounds of increased potency that now can be used
topically to treat many dermatological diseases. Potent and efficacious retinoids for treatment of
acne and psoriasis are administered orally, and modification of these molecules has resulted in
topical agents that are being explored for their anticarcinogenic and antiaging effects. Oral
antimalarials, chemotherapeutic agents, immunosuppressive agents, and antihistamines frequently
are used for treatment of dermatological diseases. It is interesting that controlled ultraviolet (UV)
radiation therapy is a frequent mode of treatment for psoriasis, pruritus, and atopic dermatitis,
although UV radiation is itself responsible for the production of cutaneous cancers. However, the
prophylactic use of sunscreens may reduce or prevent premalignant and malignant skin lesions
induced by UV light, so their use is highly recommended. Major advances in the development and
use of antifungal agents, antiviral agents, and antibacterial agents for skin diseases have clearly
improved treatment options. Vitamin D analogs, retinoids, and anthralin are some of the topical
agents used for psoriasis.
Much of this chapter is organized according to specific dermatological disorders and drugs used in
their treatment. Separate sections are devoted to glucocorticoids and retinoids because of their broad
applications in dermatology. Agents with narrower spectra of uses are discussed under individual
dermatological disorders.
Dermatological Pharmacology: Introduction
History of Dermatology
The origins of dermatological pharmacology can be found in early Middle Eastern cultures. Early
Egyptians recorded medical knowledge on special papyri, where mentions of alopecia and its
treatment—consisting of equal parts of the fat of a lion, hippopotamus, crocodile, goose, snake, and
ibex—are made. Indians used arsenic in the treatment of leprosy and a mixture of mercury and
sulfur to treat pediculosis. A paste containing iron sulfate, bile, copper sulfate, sulfuret of arsenic,
and antimony was used for pruritus of the scrotum. The Greeks under Hippocrates and the Romans
under Celsus made many other contributions to the field of dermatology (King, 1927).
As late as the end of the nineteenth century, dermatological therapy was still archaic by today's
standards. At the first World Congress of Dermatology in Paris in 1889, one of the favorite
treatments of tinea capitis was "dermabrasion with sandpaper followed by application of a solution
of bichloride of mercury." Treatment of syphilis was thought to be best deferred until the secondary
stage, at which time application of a 50% mercurous oleate ointment was recommended (Shelley
and Shelley, 1992).
- The dermatological pharmacopeia has grown rapidly in the past century, as our understanding of
disease processes has improved. We have shifted our paradigm from the traditional axiom, which
relied heavily on the physical characteristics of medications for their effect, to one in which
chemical properties hold an equally important role. In the past, dermatological therapy consisted
mainly of symptom relief. With advances in technology and knowledge, medications that target
specific disease processes now are available.
The Structure and Function of Skin
The skin has many diverse functions, including protection, thermal regulation, sensory perception,
and immune responses. The skin, in a strict sense, consists of the epidermis and its underlying
dermis. However, one usually includes the soft tissue underlying the dermis in a discussion of the
skin because of its close apposition to and tendency to react as a unit with the overlying skin.
The top layer of the skin is the epidermis. It consists of keratinocytes, melanocytes (pigment),
Langerhans' cells (antigen presentation), and Merkel cells (sensory). Keratinocytes, the proliferative
portion of the epidermis, contain keratins, which provide internal structure. Each layer of the
epidermis expresses different keratins, and keratins often are used as keratinocyte differentiation
markers. Abnormal keratin expression is a feature of many skin diseases including psoriasis and
some ichthyotic disorders. As keratinocytes mature and differentiate, they become larger and flatter
and eventually lose their nuclei. The terminal point of keratinocyte differentiation is the formation
of the stratum corneum.
Formation of the stratum corneum is arguably the most important function of the epidermis. The
stratum corneum, or horny layer, protects the skin against water loss, prevents the absorption of
noxious agents, and can be thought of as consisting of bricks and mortar. Corneocytes form the
"bricks," and barrier lipids form the "mortar." Corneocytes are formed by proteins found in
keratinocytes and are located in the upper layers of the epidermis.
Granular cells, which are immediately below the stratum corneum, contain basophilic structures
called keratohyalin granules. These granules contain an inactive precursor protein called
profilaggrin. Dephosphorylation and proteolysis of profilaggrin to filaggrin occurs as granular cells
move into the horny layer. Filaggrin functions as a glue to bind the keratin filaments together to
form macrofibrils and subsequently is broken down into free amino acids that form products that
serve as UV filters and maintain skin hydration. Also, within granular cells, there are precursor
proteins—such as involucrin, loricrin, keratolinin, and others—which are cross-linked by
transglutaminases to form strong epsilon (gamma-glutamyl)–lysine isopeptide bonds forming the
cornified cell envelope. Defects in filaggrin and transglutaminases are the basis of some ichthyotic
disorders.
Lamellar granules also are found within granular cells. These are membrane-bound organelles that
contain probarrier lipids such as glycolipids, glycoproteins, and phospholipids. These lipids and
proteins are secreted via exocytosis at the interface between the granular layer and the horny layer
and are hydrolyzed to form ceramides and free fatty acids. Ceramides, fatty acids, and cholesterol,
which are known as the barrier lipids, make up the intercellular mortar of the stratum corneum
Drug Delivery in Dermatological Diseases
The skin is the largest organ of the body. It is unique in that it is easily accessible for the diagnosis
and treatment of disease. For most dermatological conditions, the success or failure of treatment
- regimens is readily apparent to both the patient and physician. Medications can be delivered
effectively to the skin by topical, systemic, and intralesional routes. Additionally, topical or
systemic therapy can be combined with phototherapy to treat certain skin disorders such as
psoriasis.
Utilization of topical medications in skin disease provides many advantages. Most obvious, the skin
is readily available for application of medications and the monitoring of therapy. Also, most topical
medications have negligible systemic absorption and, therefore, few side effects. Drug/drug
interactions are rare for this same reason. However, a good understanding of the pharmacokinetics
of skin is necessary for successful use of topical medications.
The primary barrier to absorption of exogenous substances through the skin is the stratum corneum.
Passage through this outermost layer marks the rate-limiting step for percutaneous absorption. The
major steps involved in percutaneous absorption include the establishment of a concentration
gradient, which provides a driving force for drug movement across the skin; the release of drug
from the vehicle into the skin—partition coefficient; and drug diffusion across the layers of the skin
—diffusion coefficient. The relationship of these factors to one another is summarized in the
following equation (Piacquadio and Kligman, 1998):
J=Cveh·Km·D/x
where J= rate of absorption; Cveh= concentration of drug in vehicle; Km= partition coefficient; D=
diffusion coefficient; and x= thickness of stratum corneum.
Physiological factors that affect percutaneous absorption include hydration, occlusion, age, intact
versus disrupted skin, temperature, and anatomic site. For example, drug absorption is enhanced by
improving hydration, the water content of the stratum corneum. This is achieved by decreasing
transepidermal water loss through physical occlusion or by the application of an occlusive ointment.
The permeability of skin is increased in preterm infants (Barker et al., 1987) and in elderly patients
with thin skin as well as in anatomic areas of the body with thinner stratum corneum. Lastly, some
substances are known to increase the penetration of drugs through the skin, including dimethyl
sulfoxide (DMSO), propylene glycol, and urea.
While intact skin provides a formidable barrier to percutaneous absorption, injured or diseased skin
may significantly increase or decrease absorption. Tape stripping of the stratum corneum greatly
increases percutaneous absorption. The thickened epidermal plaques of psoriasis may impede
absorption of topical medications, whereas the broken surface of eczema may allow excessive
absorption. In fact, topical absorption may be increased enough to cause systemic toxicity, such as
hypothalamic-pituitary-adrenal axis suppression from systemic absorption of potent topical steroids.
Vehicles
Many factors influence the rate and extent to which topical medications are absorbed. Most topical
medications are incorporated into bases or vehicles that bring drugs into contact with the skin. The
vehicle chosen for a topical medication will greatly influence the drug's absorption, and vehicles
themselves can have a beneficial effect on the skin if chosen appropriately. Ideally, vehicles are
easy to apply and remove, nonirritating, and cosmetically pleasing. In addition, the active drug must
be stable in the chosen vehicle and must be released readily. Many early formulations of topical
medications demonstrated less than optimal bioavailability due to insufficient knowledge of
biophysical properties of drugs and vehicles, i.e., the partitioning of drugs from vehicles into skin.
Hence, delivery of some older medications can be enhanced by dilution in an appropriate vehicle
- (Guin et al., 1993).
The choice of an appropriate vehicle in topical preparations is of great importance. Since a vehicle
makes up the greatest portion of a topical formulation, it has a significant impact on the absorption
and hence therapeutic effect of the active drug. Factors that determine the choice of vehicle and the
transfer rate of a drug across the skin are the drug's hydrophobic/hydrophilic partition coefficient,
molecular weight, and water solubility. Except for very small particles, water-soluble ions and polar
molecules do not penetrate intact stratum corneum.
A vehicle can be classified as monophasic, biphasic, or triphasic, depending upon its components
(Figure 65–1). Monophasic vehicles include powders, greases, and liquids. Powders, such as starch
or talc, absorb moisture and reduce friction, and they have a soothing, cooling effect. However,
powders adhere poorly to the skin and often clump, which limits their usefulness. Greases are
protective. They are anhydrous preparations that are either water-insoluble or fatty, such as
petrolatum (petroleum jelly), or water-soluble, such as polyethylene glycol. Fatty ointments are
more occlusive than water-soluble ointments. An important point to note is that ointments are not
by themselves hydrating; however, they restrict transepidermal water loss and hence preserve
hydration of the stratum corneum.
Figure 65–1. Topical Vehicle Formulations. (Modified from Polano, 1984, with
permission.)
- Liquids may be used as solvents for drugs, as they evaporate quickly and provide a cooling and
drying effect. For example, lotions are liquid preparations in which medications are dissolved or
suspended and are useful for hairy areas. Gels contain a liquid phase and have been converted into a
semisolid by addition of a polymer. Gels can be thought of as microscopic pockets of liquids
suspended in a mesh. Gels also are useful for hairy areas and tend to allow for greater penetration
than do lotions. Powders, greases, and liquids can be combined to create biphasic and triphasic
vehicles.
Biphasic vehicles include "shake lotions" (lotion plus powder), pastes (powder plus grease), and
creams (grease plus liquid). Shake lotions (e.g., calamine lotion) evaporate, leaving a residual
powder, and are cooling and soothing. Pastes are ointments into which powder is incorporated.
There are drying pastes, cream pastes, and protective pastes. Pastes are useful, for example, in the
treatment of ulcers and chronic dermatoses. Creams can be emulsified oil-in-water preparations
(e.g., vanishing creams) or water-in-oil emulsions (e.g., oily creams). With oil-in-water
preparations, water evaporates, leaving a thin film of drug on the skin. Although the evaporation
provides a cooling effect, it also makes oil-in-water preparations somewhat drying. Oil-in-water
creams contain preservatives, which prevent microbial growth but can cause allergic contact
dermatitis. Water-in-oil preparations contain less water and more oil than do vanishing creams.
Hence, water-in-oil preparations are emollient and moisturizing. Triphasic vehicles consist of cream
pastes or cooling pastes.
Newer vehicles include liposomes and microparticles. Liposomes are concentric spherical shells of
phospholipids in a water medium that may increase cutaneous bioavailability of the medication and
improve risk-benefit ratios. Liposomes most readily penetrate compromised epidermal barriers
(Korting et al., 1991). There are two stages of liposomal drug release. In the first stage, liposomes
remain in a liquid state and absorption is slow. In the second stage, the preparation dries and
intercalates in the lipids of the skin's surface and diffuses into the stratum corneum. Microparticles
are polymer-based microstructures in which drugs can be trapped. Microparticles allow for metered
drug release and can have the advantage of causing less irritation.
Variability in Topical Preparations
Substitution of generic for trade-name topical medications is commonplace. However, generic
topical preparations and name-brand products may not be equivalent. Criteria used to evaluate the
equivalence of two topical preparations include pharmaceutical or chemical equivalence, i.e., the
same active ingredient is contained in both preparations; the bioequivalence of two preparations,
which compares the bioavailability of the active ingredient in two different preparations; and the
therapeutic efficacy and toxicity of two different preparations of the same active ingredient. There
are many difficulties in assessing the bioavailability of topical agents. Blood levels typically are
very low and are not reliable indicators of drug availability in the skin. Indeed, topical medications
are intended to deliver optimal dosages of medication to the skin with minimization of systemic
absorption (Piacquadio and Kligman, 1998).
Differences in bioequivalence among generic and brand-name products have occurred with topical
steroids as measured by vasoconstrictor assays (see below). Although bioequivalence may be
established by vasoconstrictor assays, this may not equate with therapeutic equivalence (Olsen,
1991). One problem that arises in the use of either generic or brand-name topical steroids is the
variability of vehicles used. Although active ingredients may be the same, the vehicles may differ
significantly. Different inert ingredients in either generic or brand-name products may have an
adverse impact on patients, causing allergic reactions or skin irritation (Jackson et al., 1989). There
- also may be variations in therapeutic effect due to variations in rate or extent of absorption among
products or to variable shelf lives.
Systemic and Intralesional Administration
Systemic administration of medication in dermatology usually involves oral ingestion but also can
involve the intramuscular route (e.g., methotrexate, glucocorticoids). Systemic medications are used
when therapeutic effects cannot be obtained with topical medication. A good example is the
treatment of onychomycosis (fungal infection of the nail). Topical medications do not adequately
penetrate the hard keratin of the nail; hence, systemic therapy is necessary for successful treatment.
Systemic absorption of oral and parenteral medications is discussed in Chapter 1: Pharmacokinetics:
The Dynamics of Drug Absorption, Distribution, and Elimination.
Intralesional medications are used mainly for inflammatory lesions but can be used for treatment of
warts and neoplasms. Medications injected intralesionally have the advantage of direct contact with
the underlying pathology, no first-pass metabolism, and the formation of a depot of drug. Systemic
absorption of medication varies with the drug being used. For instance, when 20 mg of intralesional
triamcinolone acetonide is injected, plasma cortisol levels can be suppressed for a few days. In
considering the use of intralesional medications, it is important to be cognizant of the systemic
absorption of the medication being used.
In summary, when treating cutaneous diseases, it is not only the drug selected but also factors such
as route of administration, integrity of normal versus abnormal barrier functions of the skin, and the
vehicle that are important in determining ultimate clinical efficacy.
Glucocorticoids
Topical Agents
Shortly after the synthesis of hydrocortisone in 1951, topical steroids were recognized as effective
agents for the treatment of skin disease (Sulzberger and Witten, 1952). New halogenated
glucocorticoids with greatly enhanced potency were synthesized in the mid-1950s. With the
development of appropriate vehicles, these agents rapidly became the mainstay of therapy for many
inflammatory skin diseases.
Topical glucocorticoids have been grouped into seven classes in order of decreasing potency (Table
65–1). Potency is measured using a vasoconstrictor assay, in which an agent is applied to skin under
occlusion and the area of skin blanching assessed, and the psoriasis bioassay, in which the effect of
steroid on psoriatic lesions is quantified (McKenzie and Stoughton, 1962; Dumas and Scholtz,
1972). Other assays of steroid potency involve suppression of erythema and edema following
experimentally induced inflammation.
Therapeutic Uses
Many inflammatory skin diseases respond to topical or intralesional administration of
glucocorticoids. Absorption varies among different body areas; the steroid to be used is chosen 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. Most practitioners become familiar
with one or two drugs in each class so as to deliver the appropriate strength of drug. Twice-a-day
application is sufficient; more frequent application does not improve response (Yohn and Weston,
- 1990). In general, hydrocortisone or an equivalent is the most potent steroid used on the face or in
occluded areas such as the axilla or groin. Tachyphylaxis can occur, and switching to a different
glucocorticoid or using the drug less frequently often can restore sensitivity to the drug (Singh and
Singh, 1986).
Intralesional injection of glucocorticoids usually is done with insoluble preparations of
triamcinolone [triamcinolone acetonide (KENALOG-40, others) and triamcinolone hexacetonide
(ARISTOSPAN)], which solubilize gradually and therefore have a prolonged duration of action. The
hexacetonide can further prolong the therapeutic effect. Intralesional steroids are particularly
valuable if the inflammatory area is in fat, as in an inflammatory scalp alopecia or panniculitis.
Intralesional injections also may be used to deliver high doses of medication to more superficial
inflammatory dermatoses, including psoriasis, discoid lupus, and inflamed cysts.
Toxicity and Monitoring
Use of higher-potency topical glucocorticoids is associated with increased local and systemic
toxicity. Locally there is skin atrophy, striae, telangiectasias, purpura, acneiform eruptions, perioral
dermatitis, overgrowth of skin fungus and bacteria, hypopigmentation in pigmented skin, and
rosacea. The striae are most common in intertriginous areas but can occur diffusely. The perioral
dermatitis and rosacea occur on the face when withdrawal of the steroid is attempted; for this
reason, use of halogenated glucocorticoids on the face should be avoided. Long-term application
near the eye can cause cataracts or glaucoma. There is sufficient absorption of the most highly
potent topical glucocorticoids through inflamed skin to cause systemic toxicity, including
suppression of the hypothalamic-pituitary-adrenal axis and growth retardation, particularly in young
children (Bondi and Kligman, 1980; Wester and Maibach, 1993). Factors that increase systemic
absorption include the amount of steroid applied, the extent of the area treated, the frequency of
application, the length of treatment, the potency of the drug, and the use of occlusion.
Intralesional glucocorticoids can cause cutaneous atrophy and hypopigmentation. To minimize this
atrophy, doses on the face usually are limited to 1 to 3 mg/ml of triamcinolone acetonide. Systemic
side effects, including suppression of the hypothalamic-pituitary-adrenal axis, usually are minimal
if total doses are kept below 20 mg of triamcinolone acetonide per month.
Systemic Agents
Therapeutic Uses
Systemic glucocorticoid therapy is used for a number of severe dermatological illnesses (Table 65–
2). In general, it is best to reserve glucocorticoids for acute treatment of transient illnesses or for
management of life-threatening dermatoses. Chronic therapy of atopic dermatitis with oral
glucocorticoids is problematic, given the side effects associated with their long-term use ( see
Chapter 60: Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs;
Inhibitors of the Synthesis and Actions of Adrenocortical Hormones). Recent studies suggest that
glucocorticoids do not prevent development of postherpetic neuralgia (Wood et al., 1994).
Daily morning dosing with prednisone usually is necessary initially, although occasionally split
daily doses are used to enhance efficacy. Fewer side effects are seen with every-other-day dosing,
and prednisone is tapered to every other day as soon as possible. The intramuscular route is
occasionally used to assure compliance, although this route is not recommended because of erratic
absorption and prolonged hypothalamic-pituitary-adrenal axis suppression associated with the
- longer-acting preparations typically injected. Pulse therapy with large daily doses of
methylprednisolone sodium succinate (SOLU-MEDROL) is given intravenously for resistant pyoderma
gangrenosum, pemphigus vulgaris, bullous pemphigoid, organthreatening systemic lupus
erythematosus, and dermatomyositis (Werth, 1993). The dose usually is 0.5 to 1.0 g given over 2 to
3 hours. More rapid infusion has been associated with increased rates of hypotension, electrolyte
shifts, and arrhythmias.
Toxicity and Monitoring
Oral glucocorticoids have numerous systemic effects, as discussed in Chapter 60:
Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of
the Synthesis and Actions of Adrenocortical Hormones. Most side effects are dose-dependent.
Long-term use is associated with a number of complications, including psychiatric problems,
cataracts, myopathy, avascular necrosis, and hypertension. In addition, patients with psoriasis who
are taking glucocorticoids may have a pustular flare as the medication is tapered. Patients treated
with multiple intramuscular glucocorticoid injections have the same side effects as those treated
orally.
Pulsed intravenous glucocorticoids can cause hypo tension or hypertension, hyperglycemia,
hypokalemia or hyperkalemia, anaphylactic reactions, acute psychosis, seizures, and sudden death.
Congestive heart failure and pulmonary edema can develop. After brief high-dose treatment is
stopped, a steroid withdrawal syndrome with transient arthralgias, myalgias, and joint effusions can
develop, but without overt addisonian crisis (Kimberly, 1988).
Retinoids
Retinoids include natural compounds and synthetic derivatives of retinol that exhibit vitamin A
activity (see Chapter 64: Fat-Soluble Vitamins: Vitamins A, K, and E). Retinoids have many
important and diverse functions throughout the body, including roles in vision, regulation of cell
proliferation and differentiation, bone growth, immune defense, and tumor suppression
(Chandraratna, 1998). Because vitamin A affects normal epithelial differentiation, it was
investigated as a treatment for cutaneous disorders but was abandoned initially because of
unfavorable side effects. With the synthesis of multiple retinoids, agents with specific effectiveness
and decreased toxicity were developed. Small changes in structure resulted in major changes in
function (Figure 65–2). First-generation retinoids include retinol, tretinoin (all trans-retinoic acid),
isotretinoin (13-cis-retinoic acid), and alitretinoin (9-cis-retinoic acid). Second-generation retinoids,
which include etretinate and its metabolite acitretin, were created by alteration of the cyclic end
group. Third-generation retinoids contain further modification and are called arotinoids. Members
of this generation include tazarotene and bexarotene. Adapalene is a derivative of naphthoic acid
with retinoid-like properties; chemically it does not fit precisely into any of the three generations of
retinoids.
Figure 65–2. Three Generations of Retinoids. Major structural changes of each
generation are indicated in blue.
- An understanding of retinoid receptors is necessary before the actions of retinoids in the regulation
of cell proliferation and differentiation can be discussed. Two families of retinoid receptors exist.
Retinoic acid receptors (RARs) are members of the thyroid/steroid superfamily of receptors. RARs
are further divided into alpha, beta, and gamma subtypes. The second family of retinoid receptors is
the retinoid X receptor family (RXRs). Retinoid X receptors also are subdivided into alpha, beta,
and gamma subtypes. Human skin contains mainly RAR beta and gamma receptors.
Retinoids regulate gene transcription through activation of nuclear receptors. Retinoids (ligands)
bind transcription factors (nuclear receptors), and the ligand-receptor complex formed then binds to
the promoter region of a target gene (Saurat, 1999). The gene products formed contribute to both
desirable pharmacological effects and unwanted side effects (Shroot, 1998).
The structure of a particular retinoid determines which type of retinoid receptor will be bound and
hence what pharmacological effects will be produced. The basic structure of the retinoid molecule
consists of a cyclic end group, a polyene side chain, and a polar end group. Alteration of side chains
and end groups creates the various classes of retinoids. First- and second-generation retinoids are
able to bind several retinoid receptors due to the flexibility imparted by their alternating single and
double bonds. This relative lack of receptor specificity may lead to greater side effects. Third-
generation retinoids are much less flexible than first- and second-generation retinoids and,
therefore, interact with fewer retinoid receptors (Chandraratna, 1998).
- Acute retinoid toxicity is similar to vitamin A intoxication. General side effects of retinoids include
dry skin, nose bleeds from dry mucous membranes, conjunctivitis, and hair loss. Less frequently,
musculoskeletal pain, pseudotumor cerebri, or mood alterations have been observed. Oral retinoids
are potent teratogens and cause severe fetal malformations. Systemic retinoids should be used with
great caution in females of childbearing potential.
Retinoids are used in the treatment of many diverse diseases and are effective in the treatment of
inflammatory skin disorders, skin malignancies, hyperproliferative disorders, photoaging, and many
other disorders (Table 65–3). Their uses in some of these disorders, such as psoriasis and acne, are
discussed below.
Pruritus
The term pruritus is derived from the Latin prurire, which means "to itch" (Kantor, 1996). Pruritus
occurs in a multitude of diverse disorders ranging from the itch of dry skin (xerosis) to the itch of
internal malignancy (Table 65–4). The treatment of pruritus varies greatly with the disorder in
which it is seen. Many treatment modalities are available for pruritus (Table 65–5).
General, non-disease-specific measures can be helpful in treating most cases of pruritus (Table 65–
6). General measures usually are sufficient for xerosis. Inflammatory disorders such as atopic
dermatitis, contact dermatitis, and lichen simplex chronicus respond better to treatment with potent
topical steroids and antihistamines. Atopic dermatitis is discussed below.
Cholestasis-associated pruritus may respond to cholestyramine (QUESTRAN; see Chapter 36: Drug
Therapy for Hypercholesterolemia and Dyslipidemia), ursodeoxycholic acid (ACTIGALL),
ondansetron (ZOFRAN; see Chapter 38: Prokinetic Agents, Antiemetics, and Agents Used in
Irritable Bowel Syndrome), or rifampin (see Chapter 48: Antimicrobial Agents: Drugs Used in the
Chemotherapy of Tuberculosis, Mycobacterium Avium Complex Disease, and Leprosy ; Connolly
et al., 1995). Recently, nalmefene (REVEX) (20 mg twice per day; see Chapter 23: Opioid
Analgesics) has been shown to be effective in cholestatic pruritus (Bergasa et al., 1999). The
pruritus of uremia is treated most effectively with ultraviolet B radiation (UVB). Prurigo, a
ubiquitous disorder associated with itchy nodules of the skin, is notoriously difficult to treat. In
addition to topical and intralesional steroids, prurigo may respond to the opioid antagonist
naltrexone (see Chapter 23: Opioid Analgesics) at a dose of 50 mg per day (Metze et al., 1999) or
to the proton pump inhibitor omeprazole (see Chapter 37: Agents Used for Control of Gastric
Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux Disease ; Ohtsuka et al.,
1999).
Atopic Dermatitis
Atopic dermatitis is an inflammatory condition of the skin that commonly begins in infancy and
childhood and can extend into the adult years. In some geographic regions, up to 10% of children
have atopic dermatitis, and the incidence is increasing (Zaki et al., 1996). Environmental pollutants
and indoor allergens, such as dust mites, may be responsible for this increase.
Hallmarks of atopic dermatitis are itchy papules and plaques. In infants, lesions occur on the face
and extensor surfaces, which are common sites of trauma. In later childhood and adulthood, flexural
involvement is more common. Acute, subacute, and chronic lesions occur. Acute lesions consist of
itchy papulovesicles or wheals. Subacute papules and plaques show excoriation and chronic plaques
are thickened and dry. Physical traits of atopic children include redundant folds of the lower eyelid,
- fissured lips, and increased palmar skin markings. Infections are common in atopic children,
particularly herpes simplex, molluscum contagiosum, fungus, and Staphylococcus aureus. Up to
90% of lesions of atopic dermatitis are colonized by S. aureus.
The goals of treatment in atopic dermatitis are skin hydration, decreased bacterial colonization,
control of itching, decreased inflammation, and elimination of exacerbating factors. Cutaneous
hydration helps to eliminate fissures and cracks in the skin from which pathogens may enter.
Hydration consists of soaking in a lukewarm bath, followed immediately by the application of thick
emollient creams.
Glucocorticoids
Topical glucocorticoids are useful for decreasing inflammation. Higher-potency topical steroids are
indicated for thick, chronically rubbed plaques on the extremities. Lower potency, nonfluorinated
topical steroids should be used for facial lesions for short (less than 2 weeks) periods of time.
Potential side effects of topical steroids include striae and atrophy of the skin. Topical steroids
should be used no more than 2 or 3 times per day and should be discontinued as quickly as possible
to avoid potential side effects.
Antihistamines
Oral antihistamines, particularly H1-receptor antagonists (see Chapter 25: Histamine, Bradykinin,
and Their Antagonists) with sedative properties, are useful for the control of pruritus. Hydroxyzine
hydrochloride (ATARAX) is given in a dose of 0.5 mg/kg every 6 hours and provides sedation. Other
sedative H1 blockers include diphenhydramine (BENADRYL; others), promethazine (PHENERGAN),
and cyproheptadine (PERIACTIN). Nonsedative antihistamines include cetirizine (ZYRTEC),
loratadine (CLARITIN), and fexofenadine hydrochloride (ALLEGRA). Doxepin, which has both
tricyclic antidepressant and sedative antihistamine effects (see Chapter 19: Drugs and the Treatment
of Psychiatric Disorders: Depression and Anxiety Disorders), is a good alternative for severe
pruritus. Doxepin also is available as a 5% cream (ZONALON), and it can be used effectively in
conjunction with low- to moderate-potency topical steroids.
Leukotriene Receptor Antagonist
The leukotriene antagonist zafirlukast (see Chapter 28: Drugs Used in the Treatment of Asthma), in
a dosage of 20 mg twice daily, has improved atopic dermatitis in some patients. Side effects include
pharyngitis, headache, and infrequent elevation of alanine aminotransferase values (Carucci et al.,
1998).
Immunosuppressive Agents
Immunosuppressive agents (see Chapter 53: Immunomodulators: Immunosuppressive Agents,
Tolerogens, and Immunostimulants) should be considered when hydration, topical steroids, and
antihistamines have not provided adequate clearing of atopic dermatitis. Cyclosporine (NEORAL;
others) is used in many dermatological and autoimmune diseases. Although used in the treatment of
atopic dermatitis, cyclosporine is not approved by the United States Food and Drug Administration
(FDA) for the purpose. T-cell activation and proliferation are inhibited by cyclosporine (Faulds et
al., 1993). The initial dose of cyclosporine usually is 5 mg/kg per day, which allows for rapid
improvement, with maintenance dosage of 3 mg/kg per day (Zonneveld et al., 1996). Alternatively,
it has been suggested that a body weight–independent dose of 150 mg per day is both efficacious
- and well tolerated (Czech et al., 2000). Cyclosporine appears to be safe and effective for children
when given in short courses (Zaki et al., 1996). Potential side effects of cyclosporine therapy
include nephrotoxicity, hypertension, gingival hyperplasia, and hypertrichosis. Complete blood
counts, blood pressure measurements, and serum creatinine levels should be monitored regularly.
A promising new topical immunosuppressive agent is tacrolimus (PROTOPIC), which was isolated
from Streptomyces tsukubaenis in Tsukuba, Japan, in 1984. Tacrolimus is a neologism composed of
the words Tsukaba Macrolide immunosuppressive, and the oral form currently is used in kidney,
liver, and heart transplants (see Chapter 53: Immunomodulators: Immunosuppressive Agents,
Tolerogens, and Immunostimulants). Tacrolimus binds to an intracellular receptor in T cells that
interferes with cytokine-mediated processes active in atopic dermatitis. Topical tacrolimus currently
is being evaluated in clinical trials and shows great promise in the treatment of refractory atopic
dermatitis (Ruzicka et al., 1999).
Psoriasis
Psoriasis is characterized by epidermal hyperproliferation overlying immune-mediated dermal
inflammation. Clinically, this results in erythematous scaling plaques most commonly present on
the elbows, knees, and scalp. The cracking, scaling plaques of psoriasis may be widespread and
even painful, with the potential for significant disability. Flare-ups of psoriasis can occur randomly
but have been known to follow periods of physical and emotional stress, cutaneous trauma,
infection, and as a reaction to certain medications, including -adrenergic receptor antagonists,
lithium, antimalarials, and systemic steroids (Christophers and Mrowietz, 1999).
The selection of therapy for psoriasis is multifactorial. The overall health status of the patient must
be taken into account, particularly hepatic and renal function, childbearing potential, and the
presence or absence of psoriatic arthritis. Another major consideration is the percent of body
surface area involved. For practical purposes, patients with less than 15% body surface involvement
can be treated effectively with topical agents. A notable exception to this is significant involvement
of the hands or feet, which may be recalcitrant to topical treatment.
Topical Agents Used in Treatment of Psoriasis
Topical therapy for psoriasis includes multiple options (Figure 65–3), the first of which are
emollients to soften and moisturize psoriatic plaques. Topical keratolytic agents, formulated with
urea or salicylic acid, also are useful in the treatment of localized or limited psoriasis; and topical
coal tar preparations in the form of ointments, emollient-base creams, lotions, and shampoos have
been used over the past century. Topical steroids are the mainstay of treatment for localized
psoriasis. A vitamin D analog, calcipotriene, is useful for the topical treatment of psoriasis, as a
solution, an ointment, or a cream. Anthralin and the topical retinoid tazarotene also are beneficial.
These topical agents will be discussed below in more detail.
Figure 65–3. Treatment of Psoriasis. In psoriasis, a hyperproliferative disease, all
four modes of therapeutic delivery are used: topical therapy, phototherapy,
intralesional therapy, and systemic therapy. Major normal cutaneous structures
are shown. PUVA, psoralens and ultraviolet A; UVB, ultraviolet B.
- Coal Tar
Coal tar has a limited effect when employed as the sole treatment for psoriasis, and it is now mainly
combined with ultraviolet light in the 290 to 320 nm range (UVB) for this indication. It is
manufactured as a byproduct of the processing of coke and gas from bituminous coal and is
extremely complex, rich in polycyclic hydrocarbons, and variable in composition. Little is known
about its mode of action, which may be related to antimitotic effects (Lowe et al., 1983). Coal tar is
phototoxic in the ultraviolet light range of 320 to 400 nm (UVA) and visible ranges, with the action
spectrum lying between 340 and 430 nm. Exposure of the skin in this range produces erythema and
smarting, "tar smarts," which prevent exploitation of coal tar's photodynamic potential for the
treatment of psoriasis.
Coal tar ointment contains crude coal tar, usually 2% to 5%, dispersed in petroleum jelly. The use
of coal tar with daily UVB irradiation—known as the Goeckerman regimen—is a highly effective
therapy for psoriasis. It improves the efficacy of suberythemogenic UVB, probably by additive
effects rather than by photoactivation of the tar. More refined extracts of tars are formulated as
solutions, gels, shampoos, and baths, usually with limited efficacy as primary agents.
Folliculitis is the primary side effect of coal tar. Irritation and allergic reactions are rare; and,
although coal tar has been shown to be a carcinogen in animal experiments, carcinomas provoked
by clinical application are rare (Dodd, 1993).
Calcipotriene
Calcipotriene (DOVONEX), a vitamin D analog, was approved for the topical treatment of psoriasis
in 1993. Chance observation of improvement of psoriasis in an osteoporotic patient receiving an
- oral derivative of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], the active form of vitamin D (see
Chapter 62: Agents Affecting Calcification and Bone Turnover: Calcium, Phosphate, Parathyroid
Hormone, Vitamin D, Calcitonin, and Other Compounds), stimulated interest in the development of
the drug as an antipsoriatic agent (Morimoto and Kumahara, 1985). 1,25-(OH)2D3 has a major role
in the maintenance of calcium homeostasis but is now known to be involved in many other
physiological functions. The vitamin binds to an intracellular receptor, a member of the gene
superfamily including steroid, thyroid hormone, and retinoid receptor genes. The receptor–vitamin
D complex binds to specific genes and modulates and controls transcription. The receptor is present
in human epidermal keratinocytes, dermal fibroblasts, islets of Langerhans' cells, macrophages, and
T lymphocytes. At physiological concentrations, 1,25-(OH)2D3 causes a decrease in the
proliferation and an increase in the morphologic and biochemical differentiation of cultured
keratinocytes (Smith et al., 1986). In clinical studies, both oral and topical 1,25-(OH)2D3 are
effective antipsoriatic agents, but their use is limited by induction of hypercalciuria (Smith et al.,
1988; Langner et al., 1992).
Calcipotriene is a synthetic 1,25-dihydroxyvitamin D3 analog with a double bond and ring structure
on the side chain as follows:
These modifications result in rapid transformation into inactive metabolites. This drug is 200-times
less potent than 1,25-(OH)2D3 in causing hypercalciuria and hypercalcemia, and its affinity for the
vitamin D receptor is equal to that of 1,25-(OH)2D3. Efficacy in psoriasis has been demonstrated in
double-blind, placebo-controlled studies (Kragballe, 1989).
Calcipotriene is applied twice daily to plaque psoriasis on the body. Improvement is detectable
within 1 to 2 weeks, and maximum clinical response occurs within 6 to 8 weeks. Some
improvement takes place in most patients, with complete resolution occurring in up to 15%. The
drug is slightly more effective than either the corticosteroid betamethasone 17-valerate or short-
contact anthralin treatment. Maintenance therapy usually is necessary, and tachyphylaxis does not
occur (Kragballe, 1992).
Reports of hypercalcemia with calcipotriene are rare and usually have been associated with
excessive use of the drug (Hardman et al., 1993). Calcipotriene should be used with caution in
intertriginous areas because of facilitated absorption, which results in irritation. Routine laboratory
monitoring is not necessary if usage guidelines are followed. It is available in an ointment, cream,
- or solution.
Anthralin
Chrysarobin, the active ingredient of Goa powder, was first used in 1877 for the treatment of
psoriasis. It was replaced in 1916 by the synthetic compound anthralin (1,8-dihydroxy-9-anthrone;
dithranol; DRITHOCREME), which has the following structure:
The anthralin molecule is unstable, having an oxidizable center at C10 that leads to the formation of
degradation products that produce the characteristic violet-brown staining of skin and clothes. The
mechanism of the antipsoriasis effect of anthralin is unknown, but it inhibits cellular respiration by
inactivation of mitochondria (Reichert et al., 1985).
Anthralin is applied topically in concentrations of 0.1% to 1.0%. The drug also can be prepared in
higher strengths in petroleum jelly or zinc paste with the addition of salicylic acid as an antioxidant.
Standard therapy is to apply a lower concentration (0.1%) for several hours for at least a week and
then gradually increase the concentration. A modification of this treatment, called short-contact
therapy, is possible because anthralin penetrates damaged skin faster and to a greater extent than
normal skin (Schaefer et al., 1980). Therefore, application for 1 hour or less optimizes the
therapeutic effect while minimizing the irritation. Short-contact therapy is initiated with higher
concentrations (0.25% or 0.5%) applied for 20 to 30 minutes, and the concentration is increased
more rapidly. With either the standard or short-contact regimens, the medication must be
completely removed by bathing or shampooing at the end of the contact time.
The primary side effects of anthralin are staining and irritation of the uninvolved skin. Because of
individual variation in skin sensitivity, close monitoring of irritation and careful progression of
treatment are necessary. Treatment of intertriginous and facial lesions is not advisable, and
permanent staining of clothes and bathroom fixtures is annoying. In an effort to decrease irritation
and staining, anthralin also has been microencapsulated in crystalline monoglycerides.
Tazarotene
The topical retinoid tazarotene (TAZORAC), an acetylenic class of retinoid, has been developed in
the form of a gel to be used for the treatment of psoriasis and acne vulgaris (Duvic and Marks,
1998). This retinoid binds to all three members of the retinoic acid receptor family. In mice,
tazarotene has been shown to block ornithine decarboxylase activity, which is associated with cell
proliferation and hyperplasia. In cell culture, it has been shown to suppress a marker of epidermal
inflammation and to inhibit cornification of the keratinocyte.
Tazarotene gel, applied once a day to dry skin, may be used as monotherapy or in combination with
other medications, such as topical steroids, for the treatment of localized plaque psoriasis. This is
the first topical retinoid to be indicated for the treatment of psoriasis. Side effects of burning,
itching, and skin irritation may be noted by some patients. Patients should avoid exposing treated
- areas to sun or sun lamps unless medically necessary. In as much as this topical drug is a member of
the retinoid family, women of childbearing age should avoid pregnancy while using this
medication.
Systemic Agents Used in Treatment of Psoriasis
The use of systemic medications for the treatment of psoriasis may be indicated by the extent or
severity of the disease. Involvement of body surface area greater than 15%, inflammation of hands
or feet, pustular outbreaks, or arthritis all can be indications for systemic treatment.
Some cancer chemotherapeutic agents have been used with good results in psoriasis, especially
methotrexate, but also 6-thioguanine and hydroxyurea. The systemic retinoid acitretin can be used
either as monotherapy or in conjunction with PUVA. Immune modulators have become important
in the treatment of psoriasis, especially as the driving force in the pathophysiology of psoriasis
appears to center on the T cell (Gottlieb et al., 1995).
Notably absent from the list of recommended systemic agents for the treatment of psoriasis are
glucocorticoids. While short-lived reductions in inflammation may be seen with use of systemic
steroids, unpredictable and severe exacerbations of plaque-type and pustular psoriasis have occurred
following the use of these drugs.
Cytotoxic Agents
The antimetabolite methotrexate (RHEUMATREX) is an analog of folic acid that competitively
inhibits dihydrofolate reductase (see Chapter 52: Antineoplastic Agents). Methotrexate has made a
significant impact on the treatment of widespread and severe psoriasis. Its primary therapeutic
mechanism centers on suppression of immune-competent cells in the skin, principally T cells (Jeffes
et al., 1995). By virtue of immune suppression, methotrexate dampens signals for epidermal
inflammation and hyperproliferation. It is useful in treating a number of cutaneous conditions
including psoriasis, pityriasis lichenoides, lymphomatoid papulosis, pemphigus vulgaris, pityriasis
rubra pilaris, lupus erythematosus, and dermatomyositis.
A usual starting dose for methotrexate therapy is 5 to 7.5 mg per week. This dose may be gradually
increased up to 20 to 30 mg per week if needed. When the drug is taken orally, the weekly dose is
divided into three doses given at 12-hour intervals to optimize absorption. Doses must be decreased
for patients with impaired renal clearance. Methotrexate should never be coadministered with
trimethoprim–sulfamethoxazole or other drugs that can cause bone marrow suppression, as severe
or possibly fatal bone marrow suppression can occur with such combinations. Fatalities have
occurred during concurrent treatment with methotrexate and nonsteroidal antiinflammatory agents.
Methotrexate exerts significant antiproliferative effects on the bone marrow; therefore, complete
blood counts should be monitored serially. Physicians administering methotrexate should be
familiar with the use of folinic acid (leucovorin) to "rescue" patients with hematologic crises caused
by methotrexate-induced bone marrow suppression. Careful monitoring of liver function tests is
necessary but may not be adequate to identify early hepatic fibrosis in patients taking methotrexate.
Hepatic fibrosis from methotrexate appears to be more common in psoriasis than in rheumatoid
arthritis. Consequently, liver biopsy is recommended when the cumulative dose reaches 1.5 g. A
baseline liver biopsy also is recommended for those patients with increased risk for hepatic fibrosis,
such as history of alcohol abuse or hepatitis B or C. Patients with significantly abnormal liver
function tests, symptomatic liver disease, or evidence of hepatic fibrosis should not use this drug
- (Roenigk et al., 1998).
Hydroxyurea and 6-thioguanine also are used occasionally in the treatment of psoriasis. Neither of
these treatments is as effective as methotrexate, but either one can be useful in situations where
methotrexate is contraindicated due to liver disease. Both drugs may cause significant bone marrow
suppression; therefore, careful monitoring is required (Leavell et al., 1973; Zackheim et al., 1994).
Acitretin
Acitretin (SORIATANE) is the major metabolite of etretinate, an aromatic retinoid. Both drugs have
been shown to be useful in the treatment of psoriasis, including pustular and erythrodermic
psoriasis. Etretinate, an early retinoid which is no longer commercially available, has an elimination
half-life of 100 days due to its high lipophilicity. Acitretin, however, has an elimination half-life of
two to three days. Unfortunately, acitretin is readily esterified to produce etretinate in vivo, and this
reaction is further enhanced by alcohol (Katz et al., 1999).
The optimal dosing range for acitretin in adults is 25 to 50 mg per day. This gives an appropriate
balance of efficacy with an acceptable level of side effects. Improvement of plaque psoriasis occurs
gradually, requiring up to three to six months for optimal results. As a monotherapy, acitretin has an
overall rate of complete remission of less than 50% (Ling, 1999); response rates are higher when
the drug is used in combination with ultraviolet light (Lebwohl, 1999). Pustular and erythrodermic
psoriasis usually respond more rapidly than common plaque psoriasis at doses of 10 to 25 mg per
day. Excellent control of these conditions usually can be achieved with acitretin (Goldfork and
Ellis, 1998).
Toxicity related to acitretin can resemble hypervitaminosis A. Common side effects include dry
skin and mucous membranes, xerophthalmia, and hair thinning. Less frequently, arthralgias and
decreased night vision have been noted. While other side effects are occasionally reported, serious
side effects, such as hepatotoxicity or pseudotumor cerebri, are rare (Katz et al., 1999).
Acitretin is a potent teratogen and may cause major human fetal abnormalities. This drug should
not be used by females who are pregnant or who intend to become pregnant during therapy
or at any time for at least three years following discontinuation of therapy. Patients should not
donate blood for transfusion during acitretin therapy and for three years following therapy to avoid
exposing a pregnant recipient's fetus to the drug. Laboratory monitoring should include a baseline
pregnancy test in all female patients and a complete blood count, lipid profile, and hepatic profile in
all patients. Serial follow-up of laboratory tests should be conducted every one to two weeks until
stable and thereafter at intervals as clinically indicated.
Cyclosporine and Mycophenolate Mofetil
The immunosuppressant cyclosporine (see Chapter 53: Immunomodulators: Immunosuppressive
Agents, Tolerogens, and Immunostimulants), derived from the fungus Beauveria nivea, is highly
effective in the treatment of psoriasis (Ellis et al., 1991). Cyclosporine inhibits the phosphatase
calcineurin and transcription of the IL-2 gene in T cells (Schreiber and Crabtree, 1992, Rao, 1994).
It also inhibits antigen presentation by Langerhans' cells and degranulation of mast cells (Dupuy et
al., 1991; Triggiani et al., 1989), which contribute to the pathogenesis of psoriasis.
Hypertension and renal dysfunction are major concerns associated with the use of cyclosporine. The
risk of developing these problems is markedly reduced by keeping the daily dosage less than 5
- mg/kg and by rotating therapy periodically (Shupack et al., 1997). Hematological indices and renal
function must be carefully monitored. Patients on long-term systemic immune suppression also may
develop increased numbers of nonmelanoma skin cancer (Cockburn and Krupp, 1989).
Mycophenolate mofetil (CELLCEPT; see Chapter 53: Immunomodulators: Immunosuppressive
Agents, Tolerogens, and Immunostimulants) is another effective immune suppressant with a utility
very similar to that of cyclosporine (Kitchin et al., 1997). Usual doses range from 1 to 2 g per day.
Common side effects include gastrointestinal intolerance, as manifested by diarrhea, nausea,
vomiting, abdominal cramping, and bone marrow suppression. Notably, the problems of
hypertension and renal dysfunction seen with cyclosporine are not associated with mycophenolate
mofetil. As is typical with immunosuppressants, hematological monitoring and close clinical
follow-up are required.
Photochemotherapy
Electromagnetic radiation is a form of energy defined by its wavelength; it has been classified into
different regions, as shown in Figure 65–4. Dermatologists are most concerned with the regions of
ultraviolet radiation (UVC, 100 to 290 nm; UVB, 290 to 320 nm; and UVA, 320 to 400 nm) and
with visible radiation (400 to 800 nm). UVC is absorbed by the ozone layer and does not reach the
earth's surface. UVB, the most erythrogenic and melanogenic type of radiation, causes sunburn,
suntan, skin cancer, and photoaging. The longer wavelengths of UVA are 1000-times less
erythrogenic than UVB; however, they penetrate more deeply and contribute to photoaging and
photosensitivity diseases. They also enhance UVB-induced erythema and increase the risk of UVC-
induced carcinogenesis. Visible radiation is responsible for occasional photosensitive eruptions.
Figure 65–4. The Electromagnetic Spectrum. Solar radiation is defined in terms
of wavelength. Ultraviolet and visible radiation (enlarged) are used
therapeutically in dermatology; UVB for phototherapy, UVA for
photochemotherapy (PUVA, psoralens plus UVA), and visible light for
photodynamic therapy.
Despite its side effects, nonionizing electromagnetic radiation is employed therapeutically.
Phototherapy and photochemotherapy are treatment methods in which radiation of an appropriate
wavelength is used to induce a therapeutic response in the absence and presence, respectively, of a
photosensitizing drug. The radiation must be absorbed by a target molecule—a chromophore—
which is an endogenous molecule in phototherapy and an exogenous drug in photochemotherapy.
Patients should not be taking any extraneous photosensitizing medications prior to initiation of
- therapy. Common photosensitizing medications include, but are not limited to, phenothiazines,
thiazides, sulfonamides, nonsteroidal antiinflammatory agents, sulfonylureas, tetracyclines, and
benzodiazepines.
PUVA: Psoralens and UVA
History
Photochemotherapy with psoralen-containing plant extracts was employed in Egypt and India in
1500 B.C. for the treatment of vitiligo. El Mofty at the University of Cairo first used a purified
psoralen for the treatment of vitiligo in 1947. In 1974, Parrish et al. reported successful treatment of
severe psoriasis with 8-methoxypsoralen (P) and UVA, and coined the acronym PUVA. PUVA has
been approved for the treatment of vitiligo and psoriasis. Its widespread use with extensive follow-
up has provided comprehensive data on toxicity and efficacy.
Chemistry
Psoralens belong to the furocoumarin class of compounds, which are derived from the fusion of a
furan with a coumarin. They occur naturally in many plants, including limes, lemons, figs, and
parsnips. Two psoralens, 8-methoxypsoralen (methoxsalen) and 4,5,8-trimethylpsoralen
(trioxsalen;TRISORALEN) are available in the United States. Methoxsalen is used primarily due to its
superior absorption. Structures of the two psoralens are shown below.
Pharmacokinetics
The psoralens are absorbed rapidly after oral administration. Photosensitivity, on average, is
maximal 1 to 2 hours after ingestion of methoxsalen. Liquid formulations are superior to the
previously used crystalline preparation and produce a more rapid, higher, and more reproducible
peak serum level. There is a significant but saturable first-pass elimination in the liver, which may
account for variations in plasma levels among individuals after a standard dose. Methoxsalen has a
serum half-life of approximately 1 hour, but the skin remains sensitive to light for 8 to 12 hours.
Despite widespread distribution of the drug through the body, it is activated only in the skin where
the UVA penetrates.
Mechanism
The mechanism of photosensitivity production by PUVA is not known. The action spectrum for
oral PUVA is between 320 and 400 nm. Two distinct photoreactions take place. Type 1 reactions
involve the oxygen-independent formation of mono- and bifunctional adducts in DNA. Type II
reactions are oxygen-dependent and involve sensitized transfer of energy to molecular oxygen. The
therapeutic effects of PUVA in psoriasis may result from a decrease in DNA-dependent
proliferation after adduct formation. However, alteration in the immune system caused by PUVA
- also may play a role (Gupta and Anderson, 1987).
PUVA promotes melanogenesis in normal skin. Increased pigmentation results from the transfer of
melanosomes from melanocytes to epidermal cells; however, there is no change in the size of
melanosomes or in their distribution pattern.
Therapeutic Uses
Methoxsalen is supplied in soft gelatin capsules (OXSORALEN-ULTRA) and hard gelatin capsules (8-
MOP). The dose is 0.4 mg/kg for the soft capsule and 0.6 mg/kg for the hard capsule taken 1.5 to 2
hours before UVA exposure. A lotion containing methoxsalen (OXSORALEN) also is available for
topical application. It can be diluted for bath water delivery, a method that produces low systemic
psoralen levels. Phototoxicity is increased with topical psoralen use, and the UVA dose therefore
must be carefully regulated.
In both American and European multicenter cooperative studies of PUVA for the treatment of
psoriasis, initial success rates close to 90% were achieved (Melski et al., 1977; Hensler et al.,
1981). In the United States, treatment is administered 3 times weekly and in Europe 4 times weekly.
Relapse occurs within 6 months after cessation of treatment in most patients. Various maintenance
regimens have been recommended with variable success.
PUVA can induce melanocyte stimulation in vitiligo, resulting in cosmetic repigmentation. Success
rates are highest in young individuals with recent onset of disease involving nonacral areas.
Localized vitiligo is treated topically with a 1%methoxsalen lotion. Diffuse disease is treated with
systemic administration of trioxsalen or methoxsalen. Methoxsalen is more effective.
PUVA also is employed in the treatment of cutaneous T-cell lymphoma, atopic dermatitis, alopecia
areata, lichen planus, urticaria pigmentosa, and some forms of photosensitivity.
Toxicity and Monitoring
The major acute side effects of PUVA include nausea, blistering, and painful erythema. PUVA-
induced inflammation is more delayed than that of UVB, reaching a peak 48 to 72 hours after
exposure.
Chronic effects occur within the skin. Actinic keratoses, PUVA lentigines, photoaging, and
nonmelanoma skin cancer are consequences of chronic PUVA therapy. Squamous-cell carcinomas
occur at 10 times the expected frequency (Stern et al., 1988). Extensive PUVA therapy, 250 or
more treatments, may increase risk for malignant melanoma. Careful monitoring of patients for
cutaneous carcinomas is essential (Stern et al., 1997).
Acne
Acne is the most common skin disorder in the United States, affecting approximately 7% of the
population annually. Although usually confined to the skin, acne can have devastating physical and
psychological consequences. An understanding of the pathophysiology of acne is imperative for
successful diagnosis and treatment of the disease.
Acne is a disease of the pilosebaceous unit. The events occurring in the formation of acne are
plugging of the follicle, accumulation of sebum, growth of Propionibacterium acnes, and
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