Urticaria: Current therapy

Nicholas A. Soter, MD New York, N.Y.

Although the ideal treatment for urticaria is identification and removal of its cause, no
underlying cause can be discerned in the majority of instances. The chief clinical problem is the
treatment of chronic idiopathic urticaria. Hfreceptor antagonists are the major class of
therapeutic agents used in the management of chronic idiopathic urticaria. The 111 antagonists
have been divided into subgroups based on their chemical structure. The second-generation HI
antagonists now available are particularly advantageous for individuals who must remain alert
while working. Terbutaline, a ~-adrenergic agonist, is of occasional benefit as an adjunct
therapy in combination with an 1-11antagonist. The oral administration of disodium
cromoglycate is ineffective in patients with chronic idiopathic urticaria, although a few
individuals with urticaria caused by food allergy may respond to this drug. It is best to avoid
repeated injections of epinephrine and the systemic administration of corticosteroids. Urticaria
has a capricious course: it may respond to the administration of placebos or it may resolve
spontaneously. About 50% of the patients with urticaria are free of lesions within 1 year, but
20% continue to have episodes for more than 20 years. (J ALLERGYCL1NIMMUNOL
1990;86:1009-14.)

Circumscribed, raised, erythematous, evanescent TABLE I. Pathobiologic considerations in the

areas (wheals) of edema that involve the superficial pharmacologic management of urticaria
portions of the dermis are known as urticaria. Angio-
Remove initiating stimulus Foods
edema is an edematous process that extends into the
Medications
deep dermis and subcutaneous tissue. Patients with
Infections
urticaria or angioedema also may have respiratory, Physical stimuli
gastrointestinal, or cardiovascular involvement. Effector cells and inflammatory Block the release
Hence a thorough history and physical examination mediators of mediators
are important in the evaluation of patients with epi- Block the effect
sodes of either urticaria or angioedema. About 50% of mediators
of dermatologically allergic patients have both urti- Receptor sites on target tissues Cutaneous mi-
caria and angioedema, about 40% have only urticaria, crovasculature
and about 10% have only angioedema.l Cells
Recurrent episodes of urticaria or angioedema, last-
ing longer than 8 to 12 weeks, are termed chronic.
Although the ideal treatment for either urticaria or TREATMENT OF CHRONIC
angioedema is the identification and removal of its IDIOPATHIC URTICARIA
cause, for most cases no underlying cause can be
General considerations
discerned. Thus the treatment of chronic idiopathic The pathobiologic areas at which the treatment of
urticaria is a major clinical problem, whereas the treat- urticaria is directed include the initiating stimulus,
ment of acute urticaria is less problematic because the effector cells and their inflammatory mediators, and
cause is frequently discernible and the case is of lim- receptor sites on target tissues (Table I). A cure can
ited duration. In many instances, patients with acute be expected only with therapy that is directed against
urticaria do not find it necessary to seek medical care. the initiating event. Therapy directed at the activity
of effector cells in most instances involves mast cells,
by blocking either the release or generation and release
From the Departmentof Dermatology,New YorkUniversitySchool of mediators or the effects of released mediators. Re-
of Medicine, New York, N.Y. lease can be blocked by stabilizing the membrane and
Reprint requests: Nicholas A. Soter, MD, Department of Derma-
tology, New York University Medical Center, 550 First Ave., modulating cyclic nucleotide levels or calcium flux.
New York, NY 10016. Therapy directed at target tissues involves the cuta-
1 / 0 / 25850 neous microvasculature and cells.
1009
1010 Soter
TABLE II. First-generation
H<receptor antagonists
Chemical class Generic name*
Alkylamine Chlorpheniramine rnaleate
Ethanolamine Diphenhydramine hydrochloride
Ethylenediamine Tripelennamine hydrochloride
Phenothiazine Promethazine hydrochloride
Piperidine Cyproheptadine hydrochloride
Piperazine Hydroxyzine hydrochloride
*Commonlyused representativeexamples.
Urticaria or angioedema can be divided into five
pathophysiologic groups: IgE-mediated urticaria,
complement-mediated urticaria, urticaria caused by
direct effects on mast cell membranes, urticaria related
to agents that alter arachidonic acid metabolism, and
idiopathic urticaria? Thus the diversity of underlying
pathobiologic mechanisms accounts for part of the
difficulty in treating urticaria or angioedema. Thera-
peutic failures also may be caused by patient non
compliance, side effects of drugs, and inadequate
doses of drugs.
HI-receptor antagonists
Hi-receptor antagonists are the major class of ther-
apeutic agents used in the management of urticaria or
angioedema.3.4 In addition to their antihistaminic ac-
tions, they possess a number of other effects, includ-
ing sedation, anticholinergic activity, local anesthesia,
and antiemetic or antimotion-sickness activities. The
first-generation Hi-receptor antagonists have been di-
vided into groups based on their chemical structure
(Table I1). These chemical groups have nearly equal
therapeutic efficacy, so side effects and pharmacoki-
netic considerations are the important factors in the
selection of a drug for an individual patient.
Hi-receptor antagonists are absorbed from the stom-
ach and small intestine and reach peak blood levels
within 1 to 2 hours. The duration of action is variable.
Biotransformation of most H1 antagonists occurs in
the liver, and the conjugated metabolites are cleared
through the kidneys.
About 25% of individuals receiving classic Hi-
receptor antagonists have an adverse reaction, with
sedation the most commonly reported problem. The
sedative effect is prominent in the ethanolamine and
phenothiazine groups, whereas the agents of the ethyl-
amine class have a less pronounced sedative effect.
Tolerance to the sedative effects develops in most
individuals within a few days of continual adminis-
tration of Hi-receptor antagonists. If tolerance does
j. ALLERGY CLIN. IMMUNOL.
DECEMBER 1990
not develop, an agent from another group can be used
(Table II).
An accentuation of central depressive effects can
result when Hi-receptor antagonists are ingested in
combination with alcohol. Other effects on the central
nervous system include dizziness, tinnitus, incoor-
dination, blurred vision, and diplopia. Also, the ef-
fects on the central nervous system may be stimula-
tory, such as nervousness, insomnia, tremor, and
irritability. Effects on the gastrointestinal system in-
clude anorexia, nausea, vomiting, diarrhea, and epi-
gastric distress. Some Hi-receptor antagonists have
anticholinergic properties that may result in dry mu-
cous membranes, difficulty in micturition, urinary re-
tention, dysuria, urinary frequency, and impotence.
The cardiovascular effects of Hi-receptor antagonists
usually are not experienced after oral administration.
Hi-receptor antagonists should be administered in
low doses at appropriate intervals and increased as
tolerated. If the chosen Hrreceptor antagonist is not
effective or tolerated, empiric trials of agents from
different groups should be carried out. Combinations
of Hi-receptor antagonists also can be used. Once
control of urticaria has been achieved, the Hrreceptor
antagonist dose should be tapered rather than discon-
tinued abruptly to prevent flares.
New H1 antagonists have been developed recently.
Terfenadine and astemizole are available in the
United States; as yet cetirizine and loratadine are not
approved. These therapeutic agents are particularly
advantageous for individuals who must remain alert
during their occupations or daily lives.
Astemizole is the only second-generation antihis-
tamine currently indicated for the treatment of urti-
caria. It is well tolerated with minimal side effects.
Sedation is similar to that of placebo, but weight gain
has been reported in 3.6% of patients taking the drug.
The long half-life of astemizole (terminal half-life,
91/2 days) may be of concern when it is administered
to patients of childbearing potential. Although not
indicated for urticaria, terfenadine is often used and
can be beneficial. Cetirizine (currently available in
Europe and pending approval of the Food and Drug
Administration in the United States), a low-sedating
metabolite of hydroxyzine, has proved as efficacious
as its parent compound but with reduced sedative side
effects.
Use of H2 antagonists
The combination of H1 and H2 antagonists has been
used in cases of chronic idiopathic urticaria? -8 Ci-
metidine hydrochloride, the H2 antagonist used most
frequently in clinical studies, is absorbed from the
VOLUME 86
NUMBER 6, PART 2
small intestine. Maximal blood levels are achieved
within 80 to 90 minutes, and effective concentrations
are present for 4 to 6 hours after an oral dose. The
drug is eliminated unchanged in the urine within 24
hours. Both the absorption of the drug and the duration
of its therapeutic effect may be prolonged by ingestion
with meals.
Side effects occurring after the administration of
cimetidine hydrochloride include headache, dizziness,
and gastrointestinal symptoms. Mental confusion in
elderly individuals has been noted. 9 Cimetidine hy-
drochloride binds to androgen receptors, and this fea-
ture presumably is responsible for the occasional in-
stances of gynecomastia and azoospermia in young
male patients.l~ An important side effect of cimetidine
hydrochloride is its interference with the action of
hepatic microsomal enzymes that metabolize drugs.
This interaction may lead to potentiation of the effects
of numerous other therapeutic agents, including war-
farin, diphenylhydantoin, phenobarbital, diazepam,
and propranolol. Although cimetidine hydrochloride
initially was thought to have no effect on the bone
marrow, a rev~ersible granulocytopenia may occur
rarely. The presence of an H2 histamine receptor on
T-suppressor lymphocytes may in part explain the
augmentation of delayed-type hypersensitivity re-
sponses to intradermal antigens noted in some pa-
tients. 11 Although cimetidine hydrochloride binds to
nitrites in the gastrointestinal tract and may yield po-
tential carcinogens in the form of nitroso compounds,
prolonged administration has failed to result in gastric
neoplasms.1Z'13
The Hz antihistamine ranitidine hydrochloride does
not bind to androgen receptors, and it does not inter-
fere with hepatic microsomal enzymes.
Other therapeutic approaches
The tricyclic antidepressant doxepin hydrochloride,
which has activity against both Hi and Hz histamine
receptors, may be of value in chronic idiopathic ur-
ticaria. 14-16[3-Adrenergic agonists, such as terbutaline
sulfate, are of benefit as an adjunct in combination with
an H1 antihistamine. 17-2~The oral administration of
disodium cromoglycate is ineffective in patients with
chronic idiopathic urticaria, 21 although a few individ-
uals with urticaria caused by food allergy may have
a beneficial response to administration of this drug.ZZ
Systemic corticosteroid therapy has no place in the
routine management of chronic idiopathic urticaria,
because the side effects of corticosteroids are out of
proportion to their therapeutic benefits in most pa-
tients. If corticosteroids are required in severe refrac-
tory urticaria, an alternate-day regimen should be at-
C u r r e n t t h e r a p y f o r urticaria 1011
tempted. Epinephrine injections frequently are em-
ployed, particularly in hospital emergency units, but
their use is indicated only when laryngeal edema or
compromise of the respiratory tract complicates at-
tacks.
In some instances it is important to avoid aspirin
and other nonsteroidal antiinflammatory drugs, as well
as nonspecific factors such as alcohol, excessive heat,
and exertion that aggravate the episodes of urticaria.
Nonsteroidal antiinflammatory agents have not been
of benefit in the treatment of chronic idiopathic urti-
caria. 23 Lotions containing menthol may provide tem-
porary relief of the pruritus.
Aprotinin, a kallikrein inhibitor, was effective in
some patients with chronic urticaria. 24' 25 The intra-
venous route of administration and potential side ef-
fects have limited its use. The protease inhibitor tran-
examic acid also was of benefit in chronic urticaria. 26
These latter two agents, however, have not been ap-
proved for use in the United States.
The role of dietary manipulation in chronic idio-
pathic urticaria is difficult to assess. Although con-
sidered to be of limited value by dermatologists, di-
etary restriction is widely used by allergists. In ad-
dition to foods, preservatives, food colorings, and
natural salicylates are potentially responsible for ep-
isodes of chronic urticaria in some instances. Removal
of these agents from the diet is difficult but has been
associated with therapeutic benefit in some individ-
uals. 27 In patients with penicillin allergy, avoidance
of dairy products, which may contain traces of pen-
icillin, may be of value.
Inasmuch as many patients respond to the admin-
istration of placebos28 and urticaria/angioedema fre-
quently remits spontaneously, the evaluation of ther-
apeutic intervention often is difficult. In addition, the
physician should provide not only medications but
also support and reassurance.
TREATMENT OF PHYSICAL URTICARIA
Some forms of urticaria are elicited by physical
stimuli, such as various types of mechanical trauma,
heat, cold, light, and water. Because physical urticaria
can be induced in the laboratory, it has been used as
an experimental paradigm to study the pathogenesis
of urticaria and angioedema. These experimental
models allow observation of the clinical manifesta-
tions, the study of histologic alterations in tissues, the
search for mediators released into the circulation or
suction blister aspirates, and the performance of ther-
apeutic manipulation. 29
The treatment of physical urticaria includes avoid-
ance of the precipitating stimulus, the administration
1012 Soter
TABLE III. Approach to the management of
chronic urticaria or angioedema
Identification and removal of precipitating cause
Administration of Hi-receptor antagonists; empiric
trials of each subclass
Combinations of H~-receptor antagonists
Administration of H1- and H2-receptor antagonists
Addition of 13-adrenergic agonist to H,-receptor antag-
onists
Rare use of systemic corticosteroids for intractable ep-
isodes; attempt alternate-day regimens
of antihistamines, and desensitization by repeated ex-
posure to the eliciting stimulus. Hi-receptor antago-
nists or combined H~ and H2 antagonists are of value
in some patients with dermatographism, and they
reduce the size o f the wheals in experimental stud-
ies.30 36 Cyproheptadine hydrochloride and hydroxy-
zinc hydrochloride are useful in acquired cold urti-
caria. 37-4~ Cold urticaria was managed successfully
during hypothermic cardiopulmonary bypass after
the administration of H1- and Hz-receptor antag-
onists# ~ Hydroxyzine hydrochloride is especially
efficacious in the treatment of cholinergic urticaria# 2
In one study the oral administration of the impeded
androgen danazol was of benefit in cholinergic urti-
caria and was associated with increased levels o f oL~-
antichymotrypsin# 3 The administration of propranolol
hydrochloride prevents attacks o f adrenergic urti-
caria# 4 Some individuals with solar urticaria respond
to the administration o f H~-receptor antagonists# 5
The use of oral methoxsalen plus ultraviolet A
photochemotherapy46, 47 and the exposure to wave-
bands other than those eliciting urticaria have been
effective in some patients with solar urticaria. 4s The
combination of H~ and H2 antagonists may alleviate
local heat urticaria. 49 Repeated exposure to the elic-
iting stimulus has been reported to benefit a few pa-
tients with physical urticaria induced by cold, 5~
light,51, 52 local heat, 53 and vibration. 54 The topical
application of local anesthetics 55 or capsaicin 56 abol-
ished the wheal and erythema in local heat urticaria.
H~-receptor antagonists have a limited effect on pres-
sure urticaria, especially the delayed form, whereas
nonsteroidal antiinflammatory agents and systemic
corticosteroids appear to be beneficial in some indi-
viduals. 57 Locally applied scopolamine has alleviated
aquagenic pruritus, 5s and oral Hi antihistamines also
may be of benefit. 59 Ketotifen has prevented mast
cell degranulation and clinical urticaria in patients
with dermatographism, cold-induced urticaria, and
exercise-induced urticaria, respectively. 6~ A few
J, ALLERGY CLIN, IMMUNOL.
DECEMBER 1990
patients with various forms o f physical urticaria
have responded tO treatment with ultraviolet B pho-
totherapy. 6~
A preliminary report suggests that fasting or a re-
striction diet was associated with improvement in five
of six patients with delayed pressure urticaria and
associated chronic urticaria. 62
In summary, identification of the cause and its re-
moval is the ideal treatment for urticaria/angioedema.
Because of the difficulty in identifying such factors,
treatment for chronic idiopathic urticaria focuses on
measures to provide symptomatic relief (Table III).
The decision to treat chronic idiopathic urticaria de-
pends on its frequency and severity and focuses on
empiric trials o f H~-receptor antagonists. In refractory
urticaria, combinations of H~ and H2 antagonists may
be used. It is desirable to avoid repeated injections of
epinephrine and the systemic administration of cor-
ticosteroids. Urticaria has a capricious course, may
respond to the administration of placebos, and
may resolve spontaneously. About 50% of patients
with urticaria are free of lesions within 1 year, but
20% continue to have episodes for more than 20
years.
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Urticaria: Clinical efficacy of cetirizine in

comparison with hydroxyzine and placebo
James Kalivas, MD, a Debra Breneman, MD, b Michael Tharp, MD, c
Suzanne Bruce, MD, e Michael Bigby, MD, e and nine other investigators
Kansas City, Kan., Cincinnati, Ohio, Dallas and Houston, Texas, and
Boston, Mass.

Chronic urticaria is a problem for both physician and patient. In an effort to avoid the risks
associated with corticosteroid treatment, many first-generation Hi-receptor antagonists have
been tried and found to induce undesirable levels of sedation when given in amounts sufficient to
control urticaria. Cetirizine, a pharmacologically active oxidized metabolite of hydroxyzine, was
developed to provide selective Hi-receptor inhibition without depression of the central nervous
system. In a 4-week, multicenter, double-blind, placebo-controlled safety and efficacy study,
cetirizine, in a once-a-day dose (5 to 20 mg), was equivalent in efficacy to hydroxyzine in
divided doses (25 to 75 mg/day). The incidence of somnolence in the cetirizine group was not
significantly different from that of the placebo group. However, in the hydroxyzine group, the
incidence of somnolence was significantly higher than that in the placebo group (p = 0.001).
The results of this study demonstrate that cetirizine has a greater safety margin over the older
parent drug hydroxyzine. ( J ALLERGYCLIN IMMUNOL 1990;86:1014-8.)

From the University of Kansas Medical Center, a Kansas City, Kan- Chronic urticaria, that is, hives persisting for m o r e
sas, University of Cincinnati Medical Center, b Cincinnati, Ohio, than 6 w e e k s , is a p r o b l e m that v e x e s the physician
University of Texas Health Science Center, c Dallas, Texas, Bay-
as well as the patient. 1 In an effort to avoid the serious
lor College of Medicine, d Houston, Texas, and Beth Israel Hos-
pital," Boston, Mass. Other investigators in private practice risks associated with l o n g - t e r m corticosteroid therapy,
were as follows: Donald Aaronson, MD, Des Plaines, Ill.; m a n y different antihistamines h a v e been tried clini-
Peter Boggs, MD, Shreveport, La.; Edwin Bronsky, MD,
Murray, Utah; Salmon Goldberg, MD, Northbrook, Ill.; Eugenia
Hawrylko, MD, Brooklyn, N.Y.; Harold Kaiser, MD, Minne-
Abbreviation used
apolis, Minn.; Gerald Klein, MD, Vista, Calif.; John Leonardy,
MD, Atlanta, Ga.; and Herbert Mansmann, MD, Philadelphia, CNS: Central nervous system
Pa.
Portions of this article were presented at a scientific exhibit at the
Forty-seventh Annual Meeting of the American Academy of Der- cally. T h e older classic antihistamines cause undesir-
matology, Washington, D.C., December 3-8, 1988.
able levels o f sedation in the doses often n e e d e d to
Reprint requests: James Kalivas, MD, Director, Division of Der-
matology, Department of Medicine, University of Kansas Med- control the s y m p t o m s of urticaria. 2-~
ical Center, 39th and Rainbow Blvd., Kansas City, KS 66103. Cetirizine, a p h a r m a c o l o g i c a l l y active o x i d i z e d me-
1/0/25851 tabolite o f h y d r o x y z i n e , was d e v e l o p e d to p r o v i d e

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