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Dermatologic Drug
Reactions and Common
Skin Conditions
Rebecca M. Law and David T.S. Law e|CHAPTER
KEY CONCEPTS
1 The skin is the largest organ of the human body. It performs
many vital functions such as (a) protecting the body
INTRODUCTION
against injury, physical agents, and ultraviolet radiation;
(b) regulating body temperature; (c) preventing dehydration, 1. 1 Skin is an essential part of the body. Although it is not
thus helping to maintain fluid balance; (d) acting as a sense commonly thought of as such, skin is an organ. In fact, it
organ; and (e) acting as an outpost for immune surveillance. is the human body’s largest organ, with an average surface
Skin also has a role in vitamin D production and absorption. area of about 1.8 m2.1 The organ system that includes the
skin is known as the integumentary system.
2 Age-related factors affect the epidermis and dermis.
Pediatric skin is thinner and better hydrated, which enhances 2. The human skin consists of an outer epidermis and an inner
topical drug absorption and potential drug toxicities. Elderly dermis. The epidermis primarily provides protection from
skin is drier, thinner, and more friable, which may predispose the environment and performs a critical barrier function—
to external insults. keeping in water and other vital substances and keeping out
foreign elements. The dermis is a connective tissue layer
3 Patients presenting with a skin condition should be that primarily provides resiliency and support for various
interviewed thoroughly regarding signs and symptoms, skin structures and appendages such as sweat glands, seba-
urgency, other subjective complaints, and medication ceous glands, hair, and nails.
history. The skin eruption should be carefully assessed
to help distinguish between a disease condition and a 3. Because the skin surface is such a visible part of the
drug-induced skin reaction. body, changes that are slow or subtle often go unnoticed.
Slowly enlarging and evolving moles or dry skin condi-
4 Drug-induced skin reactions can be irritant or allergic in nature. tions can go undetected even though such changes can be
5 Allergic drug reactions can be classified into exanthematous, life threatening in some cases (e.g., malignancy). Health
urticarial, blistering, and pustular eruptions. Exanthematous professionals who have direct contact with patients should
reactions include maculopapular rashes and drug be able to distinguish between common self-treatable skin
hypersensitivity syndrome. Urticarial reactions include urticaria, lesions and common skin lesions that must be seen and
angioedema, and serum sickness-like reactions. Blistering treated professionally, such as melanoma and squamous
reactions include fixed drug eruptions, Stevens-Johnson’s cell carcinoma.
syndrome, and toxic epidermal necrolysis. Pustular eruptions 4. Skin infections and infestations are not covered in this
include acneiform drug reactions and acute generalized chapter but are discussed in Chapter 88. Acne, psoriasis, and
exanthematous pustulosis. Other drug-induced skin reactions atopic dermatitis are discussed in Chapters 77 to 79.
include hyperpigmentation and photosensitivity.
6 Not all skin reactions are drug induced.
7 Contact dermatitis is a common skin disorder caused either
by an irritant or an allergic sensitizer. STRUCTURE AND
8 The first goals of therapy in the management of contact FUNCTIONS OF THE SKIN
dermatitis involve identification, withdrawal, and avoidance
of the offending agent. A thorough history, including work The integumentary system comprises the epidermis and dermis.
history, must be carefully reviewed for potential contactants. The epidermis, which is derived from ectoderm, is further divided
into four layers: stratum basale (basal layer), stratum spinosum
9 Other goals of therapy for contact dermatitis include
(prickle cell layer), stratum granulosum (granular layer), and stra-
providing symptomatic relief, implementing preventative
tum corneum (horny layer). The stratum corneum is the outermost
measures, and providing coping strategies and other
layer of skin and primarily is responsible for the barrier function.
information for patients and caregivers.
The epidermis is thick on the palms and soles and thin on other
10 Diaper dermatitis is most often seen in infants, although the parts of the body, with some variations. For example, the palms
condition may also be seen in older adults who wear diapers and soles contain sweat glands but lack sebaceous glands, which
for incontinence. Management includes frequent diaper are found almost everywhere else in the skin, with the highest
changes, air drying, gentle cleansing, and using barriers. concentration on the face and trunk areas. Sebaceous glands and
11 Skin cancers include squamous cell carcinoma, basal cell small hair follicles together form pilosebaceous units, which orig-
carcinoma, and malignant melanoma. inate in the dermis and have follicular ducts extending through the
epidermis to the skin surface. Sebaceous glands produce sebum,
347
Copyright © 2014 McGraw-Hill Education. All rights reserved.
348
a lipid-like substance.1 (Increased production by sebaceous glands In addition, the healing time after skin injury may be prolonged in
is partially responsible for acne.2) aged skin. UV radiation is associated with accelerated skin aging
Skin cells are called keratinocytes. They produce keratin, a and skin cancers (e.g., malignant melanoma, basal cell carcinoma).
protein network that gives epithelial cells resilience to mechani- Skin should be constantly protected from UV damage by the use
cal stress. Keratinocytes begin at the stratum basale as box-shaped of sunscreens that block both UVA and UVB, with a sun protec-
basal cells. As the cells mature, they migrate toward the skin surface, tion factor (SPF) of at least 15, preferably 30 or higher. Sunscreens
elongating and flattening as they divide and differentiate, ending as should be applied 20 minutes before sun exposure and reapplied
corneocytes in the stratum corneum. Corneocytes are flattened kera- after sweating or swimming.
tinocytes containing keratin tonofibrils (filaments composed of ker- It should not be surprising that skin health is related to over-
SECTION
atin and keratohyalin granules). They are often termed dead because all health. Exercise and adequate sleep along with maintaining
they do not contain nuclei and are not capable of mitosis. Each cell a healthy, well-balanced diet are key factors. Ample daily fluid
covers a much larger surface area as a corneocyte compared with intake and regular use of moisturizers are important for skin
its basal origin. Overlapping corneocytes provide for the skin bar- hydration. Malnourishment can cause a patient to become immu-
rier.1 (Note that abnormal keratinocyte activity accounts for some nocompromised, which may adversely affect the ability of the
2 skin diseases. For example, psoriasis is associated with increased
keratinocyte cell turnover, and acne is partially caused by increased
skin to act as a barrier. Nutritional deficiencies can cause skin
problems, including dry skin. Specific food allergies can cause
keratin production.2) skin reactions (e.g., rashes, hives). Patients with atopic dermatitis
Organ-Specific Function Tests and Drug-Induced Diseases
Melanocytes are pigment-producing cells in the stratum often have multiple food sensitivities and allergies, resulting in
basale. They produce melanin, a yellow–brown/black pigment. hives and skin rashes and/or systemic manifestations. For skin
Melanin granules are spread out into a protective layer in the stra- cleansing, soapless cleansers may be preferable to soap because
tum corneum, reducing ultraviolet (UV) penetration into the skin. they may cause less skin irritation. Repeated and frequent expo-
UV radiation causes human skin to increase both melanin produc- sure to soap or other cleansers that cause cumulative irritation
tion and keratinocyte proliferation as a protective effort.1 (e.g., with surfactants and emulsifiers) can result in irritant con-
The skin surface is normally covered with a hydrolipid film tact dermatitis.
composed of sweat, oils (sebaceous lipids and free fatty acids),
corneocytes, protein decomposition products, and transepidermal
water. Some of these are natural moisturizing factors that help the
skin retain water. Thus, the hydrolipid film is a permeability barrier
PATIENT ASSESSMENT
that keeps the skin supple.1 When patients present with dermatologic disorders, a standard
Because of the presence of lactic acid and various amino acids approach to assessment should be used. This is especially impor-
from sweat, free fatty acids from sebum, and amino acids from shed- tant for pharmacists who must decide whether to recommend non-
ding corneocytes, human skin is normally acidic, generally with prescription therapies or refer patients to medical practitioners, and
a pH of 5.5 to 6. Bacteria thrive in an alkaline environment. As a to nurse practitioners and physician assistants, who must evaluate
result, the skin also functions as a protective acid mantle against symptoms and decide whether a supervising physician or derma-
invasion by pathogenic bacteria and fungi.1 tologist should be involved.
The dermis, which is derived from mesoderm, is a much thicker
layer that contains nerve endings and blood vessels. It is made up
of collagen and elastin, which provide support for various skin Patient History: Questions to Ask
structures and appendages. Eccrine (sweat) glands, hair follicles, 3 With all skin conditions, including possible drug-induced reac-
sebaceous glands, and arrector pili muscles originate in the dermis.
tions, a comprehensive patient history is important. These include
Subcutaneous tissue (adipose tissue with nerves and blood vessels)
questioning and physically assessing the patient to obtain the fol-
lies beneath the dermis.1
lowing information:
Skin is also involved in regulating body temperature, prevent-
ing dehydration, acting as a sense organ, and playing a role in vita- 1. Signs and Symptoms
min D production and absorption. a. Onset. When did the lesions first appear? It is important
to distinguish between an acute and a chronic condition.
b. Progression. Are the lesions improving or worsening or
Age-Related Changes and Other spreading? If lesions are worsening, how quickly are the
lesions becoming more severe or widespread?
Skin-Related Considerations c. Timeframe. Did the occurrence of skin lesions correlate
2 Age-related changes in the structure and functions of the epider- temporally with the use of any medications? This may
mis and dermis are important. help to distinguish between a drug-induced condition and
In general, pediatric skin contains more water and is thin- a disease-related condition.
ner, allowing for enhanced topical drug absorption in both the d. Location(s) and description of the lesions. Specific
rate and amount of drug absorbed. This increases the potential details about where the lesions occur and what they
for drug toxicities. Increased topical absorption and toxicity have look like will help to identify the type of skin condi-
been reported with the use of rubbing alcohol, boric acid powders, tion. For example, plaque psoriasis is usually diagnosed
and hexachlorophene emulsions and soaps in infants and young in this manner and not through laboratory means. How-
children. Even drugs that are not normally used topically may be ever, for conditions such as skin cancers,4 a skin biopsy
systemically absorbed. For example, a theophylline gel (17 mg may be needed to establish a definitive histopathologic
spread over an area 2 cm in diameter) applied to the abdomens diagnosis.
of premature infants produced therapeutic serum theophylline e. Presenting symptoms. Is there pruritus? Are the lesions
concentrations.3 painful? Pruritus is a common symptom for various skin
Well-hydrated, unbroken skin provides maximal protection conditions (e.g., atopic dermatitis, allergic and irritant
against microbial invaders. Aged skin tends to be drier, thinner, contact dermatitis, psoriasis, bullous pemphigoid, lichen
and more friable, which increases susceptibility to external insults. planus, pityriasis rosea) as well as systemic conditions
Copyright © 2014 McGraw-Hill Education. All rights reserved.
349
(e.g., chronic renal failure, hepatobiliary diseases, malig- be categorized as macules (eFig. 23-1), papules (eFig. 23-2),
nancy, parasitosis) and drug reactions.5 nodules (eFig. 23-3), blisters (eFig. 23-4), or plaque and lichenifi-
f. Previous occurrence. Has the patient presented with sim- cation (eFig. 23-5).
ilar lesions before? If so, that may be extremely helpful However, some skin conditions may cause more than one
in establishing a diagnosis and deciding on a course of type of lesion. For example, patients with acne vulgaris may pres-
treatment. ent with macules, papules, nodules, or a combination of these.
2. Urgency Another example is psoriasis—the most common type is plaque
e|CHAPTER
a. Severity, area, and extent of skin involvement. If a large psoriasis noted by discrete, well-defined plaques; however, there
area of the body is involved or if signs of severe dis- are other types of psoriasis such as guttate or erythrodermic with
ease such as skin sloughing or hives (and in some cases,
if the face is involved) are present, more urgent treatment
may be required, and an immediate referral to a physi-
cian would be appropriate if the patient was first seen by
another health professional such as a pharmacist. In some
cases, a dermatology consult or an emergency hospital
admission would be needed.
23
b. Signs of a systemic or generalized reaction or disease
Dermatologic Drug R
condition. Is there a fever? If there is any indication that
the patient has a systemic disease condition, whether
drug induced or disease related, and particularly if the
patient is febrile, this generally indicates a more urgent
situation requiring immediate medical attention. For
example, erythrodermic psoriasis is distinguishable from
plaque psoriasis and would require immediate medical
care. (See Chap. 78 for details about psoriasis.)
2
A
Organ-Specific Function Tests and Drug-Induced Diseases
eFIGURE 23-2 Papules are small, solid, elevated lesions that are
usually less than 1 cm in diameter. The major portion of a papule
C
projects above the plane of the surrounding skin. A. Papules
may result, for example, from metabolic deposits in the
dermis (a), from localized dermal cellular infiltrates (b), and eFIGURE 23-3 Nodules are palpable, solid, round, or ellipsoidal
from localized hyperplasia of cellular elements in the dermis lesions. Depth of involvement or substantive palpability, rather
and epidermis (c). Papules with scaling are referred to as than diameter, differentiates a nodule from a papule. A. Nodules
papulosquamous lesions, as in psoriasis (see Chap. 78). B. Clinical may extend into the dermis or subcutaneous tissue (a) or be
examples of papules. The examples are two well-defined and located in the epidermis (b). B. A well-defined, firm nodule with
dome-shaped papules of firm consistency and brownish color, a smooth and glistening surface through which telangiectasia
which are dermal melanocytic nevi. C. Multiple, well-defined (dilated capillaries) can be seen; there is central crusting
and coalescing papules of varying size are seen. Their violaceous indicating tissue breakdown and thus incipient ulceration
color, glistening surface, and flat tops are characteristic of lichen (nodular basal cell carcinoma). C. Multiple nodules of varying size
planus. (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, can be seen (melanoma metastases). (Reprinted with permission from
Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and
IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s
New York: McGraw-Hill, 2003:18.) Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)
e|CHAPTER
A B 23
Dermatologic Drug R
eFIGURE 23-4 Vesicles and bullae are the technical terms for blisters. Whereas vesicles are circumscribed lesions that contain fluids,
bullae are vesicles that are larger than 0.5 cm in diameter. A. Whereas subcorneal vesicles (a) result from fluid accumulation just below
the stratum corneum, spongiotic vesicles (b) result from intercellular edema. B. Multiple translucent subcorneal vesicles are extremely
fragile, collapse easily, and thus lead to crusting (arrows). These lesions are staphylococcal impetigo. (Reprinted with permission from Stewart MI,
Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General
Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)
B SI, Gilchrest B, Paller AS, Leffell DJ, eds. Fitzpatrick’s Dermatology in General Medicine,
7th ed. http://www.accessmedicine.com/content.aspx?aID=2965385).
Irritant reactions are localized. Examples include chemical Urticaria and angioedema are simple eruptions that are caused
vaginitis, such as those resulting from vaginal douches, spermicides, by drugs in about 5% to 10% of cases. Other causes include foods
and imidazoles; and vesication, produced by drug extravasation, as (likely the most significant offenders) and physical factors such as
with agents such as anthracyclines. cold or pressure, infections, and exposure to latex. The condition
urticarial, blistering, or pustular eruptions (eFig. 23-6).8 Skin reac- It is characterized by hives, extremely pruritic red raised wheals;
tions accompanied by fever are generally more serious systemic angioedema; and mucous membrane swelling. These symptoms
disorders. These may be life threatening in some cases, although typically occur within minutes (anaphylactic) to hours (anaphy-
afebrile skin reactions are not always minor (e.g., urticaria, lactoid) (eFig. 23-7). Individual lesions typically last less than
angioedema). 24 hours, but new lesions may continually develop. Offending
Maculopapular skin reaction is an afebrile exanthematous drugs include penicillins and related antibiotics, aspirin, sulfon-
eruption that is considered the most commonly encountered aller- amides, x-ray contrast media, opiates, and others. Latex allergy
gic skin reaction. Signs and symptoms of a maculopapular skin is linked to the natural rubber latex (NRL) proteins, which bind
rash include erythematous macules and papules that may be pru- with human IgE and result in contact urticaria, asthma, and ana-
ritic. No fever, blisters, or pustules are present. The lesions usually phylaxis.11 Aside from latex gloves and medical products, other
begin within 7 to 10 days after starting the offending medication sources of NRL proteins include rubber insoles of shoes, bal-
and generally resolve within 7 to 14 days after drug discontinu- loons, inflatable mattresses, and poinsettia plants.
ation. However, in a previously sensitized patient, the onset may Serum sickness–like reactions are complex urticarial eruptions
be earlier (within 2–3 days). The lesions may spread and become presenting with fever, rash (usually urticarial), and arthralgias, usu-
confluent. Usual drug culprits include penicillins, cephalosporins, ally within 1 to 3 weeks after starting the offending drug. This is
sulfonamides, and some anticonvulsant medications. not a true serum sickness, and the patient does not have immune
Drug hypersensitivity syndrome is an exanthematous eruption complex formation, vasculitis, or renal lesions.8
accompanied by fever, lymphadenopathy, and multiorgan involve- Fixed drug eruptions are simple eruptions presenting as pru-
ment (including the kidneys, liver, lung, bone marrow, heart, and ritic, red, raised lesions that may blister. Symptoms can include
brain). Signs and symptoms usually begin 1 to 4 weeks after burning or stinging. Lesions may evolve into plaques.8 These so-
starting the offending drug, and the reaction may be fatal if not called “fixed” drug eruptions recur in the same area each time the
promptly treated. offending drug is given. Lesions appear within minutes to days and
eFIGURE 23-6 Types of cutaneous drug eruptions. (SJS, Stevens-Johnson’s syndrome; TEN, toxic epidermal necrolysis; AGEP, acute
generalized exanthematous pustulosis.) (Adapted from Knowles S. Drug-induced skin reactions. In: Patient Self-Care (PSC). Ontario, Canada: Canadian Pharmacists
Association, 2002.)
e|CHAPTER
23
Dermatologic Drug R
A B C
eFIGURE 23-7 A. Wheals are rounded or flat-topped papules or plaques that are characteristically evanescent, disappearing within
hours. An eruption consisting of wheals is termed urticaria and usually itches. B. Wheals may be tiny papules 3 to 4 mm in diameter, as
in cholinergic urticaria. C. Alternatively, wheals may present as large, coalescing plaques, as in allergic reactions to penicillin or other
drugs or alimentary allergens. (Reprinted with permission from Stewart MI, Bernhard JD, Cropley TG, Fitzpatrick TB. The structure of skin lesions and fundamentals of
diagnosis. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:18.)
macrolides, and calcium channel blockers. drug as quickly as possible and avoiding the use of potential cross-
sensitizers. In most instances, that is the only specific treatment
Other Drug-Induced Skin Reactions Hyperpigmentation of
required. In severe cases, a short course of systemic corticosteroids
the skin (eFig. 23-8) may be related to increased melanin (e.g.,
may be needed. In a few instances, it may be possible to continue the
hydantoins), direct deposition (e.g., silver, mercury, tetracyclines,
e|CHAPTER
Contact dermatitis is a common skin problem for which cytokines.14 ACD is the clinical manifestation of contact hypersen-
5.7 million physician visits are made per year.14 Almost any of the sitivity;15 skin allergens tend to be low-molecular-weight molecules
more than 85,000 chemicals in the world environment may be a skin (haptens) that become immunogenic after conjugation with skin
irritant, and more than 3,700 substances have been identified as con-
tact allergens.14 Although all age groups may be affected, ACD is
rare in the first years of life (<10 years), but the rate of occurrence in
older children may exceed that in adults.14
The prevalences of ACD to individual allergens is similar in
children and adults; allergens include nickel, fragrances, Toxicoden-
23
dron (formerly known as Rhus), and rubber chemicals.14 There may
Dermatologic Drug R
be a slight female preponderance, presumably caused by exposure
to specific contactants in jewelry and cosmetics.14
The clinical presentation of contact dermatitis is that of an
eczematous inflammation with erythema, vesicles, papules, crust-
ing, fissuring, or scaling (eFigs. 23-10 and 23-11). The area may
itch, burn, or sting and may be extremely pruritic. The severity may
range from a mild, short-lived condition to a severe and persistent
condition but is rarely life threatening.14 The gross and histologic
dermatitis involves identifying, withdrawal, and avoidance of the sistent dermatitis despite removal of offenders, and a small number
offending agent. A thorough history, including work history, must of workers change jobs because of severe recalcitrant occupational
be carefully reviewed for potential contactants. Nonwork activities contact dermatitis.14
such as hobbies (e.g., painting, gardening, camping, fishing) may A final goal of therapy is to provide patient and caregiver infor-
be additional potential sources of exposure. Patch testing is the gold mation and support, helping them to develop coping strategies for
2 standard for identifying a contact allergen,14 but it is impractical to
test an unlimited number of allergens.
contact dermatitis, as required.
e|CHAPTER
A
23
Dermatologic Drug R
eactions and Common Skin Conditions
eFIGURE 23-12 Squamous cell carcinoma. This case of
squamous cell carcinoma must be differentiated in diagnosis
from chondrodermatitis nodularis helicis, which, unlike
carcinoma, is painful. (Reprinted with permission from Grossman D, Leffell DJ.
Squamous cell carcinoma. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s
Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:738.)
A B
eFIGURE 23-14 Melanomas. These two superficial spreading melanomas illustrate the ABCDs of melanoma. A, asymmetry. The lesions
are not symmetrical and often have irregular borders. B, Border. Note the highly irregular, uneven, and notched border. C, Color. The
color is variegated with different shades of brown, black, and tan. D, Diameter. The diameter is usually (but not always) more than 6 mm
in melanomas. (Reprinted with permission from Langley RGB, Barnhill RL, Mihm MC Jr, et al. Neoplasms: Cutaneous melanoma. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds.
Fitzpatrick’s Dermatology in General Medicine, 6th ed. New York: McGraw-Hill, 2003:925.)
patient survival adversely.17 Treatment may also include systemic and Management of the Adult Patient, 6th ed. Philadelphia,
antineoplastic therapy, such as temozolomide or dacarbazine for PA: Lippincott Williams & Wilkins, 2009:1340–1346.
metastatic melanoma. 6. Shellow WVR. Evaluation of disturbances in pigmentation.
In: Goroll AH, Mulley AG, eds. Primary Care Medicine: