J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl.

2: 41-52 2007 Esmon Publicidad

Antihistamines in the treatment of chronic
urticaria
I Juregui,
1
M Ferrer,
2
J Montoro,
3
I Dvila,
4
J Bartra,
5

A del Cuvillo,
6
J Mullol,
7
J Sastre,
8
A Valero
5
1
Service of Allergy, Hospital de Basurto, Bilbao, Spain
2
Department of Allergology, Clnica Universitaria de Navarra, Pamplona, Spain
3
Allergy Unit, Hospital La Plana, Villarreal (Castelln), Spain
4
Service of Immunoallergy, Hospital Clnico, Salamanca, Spain
5
Allergy Unit, Service of Pneumology and Respiratory Allergy, Hospital Clnic (ICT), Barcelona, Spain
6
Clnica Dr. Lobatn, Cdiz, Spain
7
Rhinology Unit, ENT Service (ICEMEQ), Hospital Clnic, Barcelona, Spain
8
Service of Allergy, Fundacin Jimnez Daz, Madrid, Spain
Summary
Chroni c urt i cari a i s hi ghl y preval ent i n t he general popul at i on, and whi l e t here are mul t i pl e t reat ment s f or t he di sorder, t he resul t s obt ai ned
are not compl et el y sat i sf act ory. The second-generat i on H1 ant i hi st ami nes remai n t he sympt omat i c t reat ment opt i on of choi ce. Dependi ng on
t he di f f erent pharmacoki net i cs and H1 recept or af ni t y of each drug subst ance, di f f erent concent rat i ons i n ski n can be expect ed, t oget her
wi t h di f f erent ef cacy i n rel at i on t o t he hi st ami ne-i nduced wheal i nhi bi t i on t est - t hough t hi s does not necessari l y have repercussi ons upon
cl i ni cal response. The ant i i n ammat ory propert i es of t he H1 ant i hi st ami nes coul d be of rel evance i n chroni c urt i cari a, t hough i t i s not cl ear
t o what degree t hey i n uence t he nal t herapeut i c resul t . Bef ore movi ng on t o anot her t herapeut i c l evel , t he advi sabi l i t y of ant i hi st ami ne
dose escal at i on shoul d be consi dered, i nvol vi ng i ncrement s even above t hose approved i n t he Summary of Product Charact eri st i cs. Physi cal
urt i cari a, when mani f est i ng i sol at edl y, t ends t o respond wel l t o H1 ant i hi st ami nes, wi t h t he except i on of genui ne sol ar urt i cari a and del ayed
pressure urt i cari a. In some cases of chroni c urt i cari a, t he combi nat i on of H2 ant i hi st ami nes may prove ef f ect i ve - t hough onl y wi t h common
l i ver met abol i sm (CYP3A4 i soenzyme-medi at ed) H1 ant i hi st ami nes, due t o t he exi st ence of mut ual met abol i c i nt erf erences. The rol e of
l eukot ri ene ant agoni st s associ at ed t o ant i hi st ami nes i n appl i cat i on t o chroni c urt i cari a remai ns t o be cl earl y de ned.
Key words: Angioedema. Cyst einyl-leukot riene ant agonist s. Ant idepressant s. H1 ant ihist amines. H2 ant ihist amines. In ammat ion. Hist amine.
Ski n response t o hi st ami ne. Ski n. Chroni c urt i cari a. Aut oi mmune chroni c urt i cari a. Physi cal urt i cari a.
Resumen
La urt i cari a crni ca es una pat ol oga muy preval ent e en l a pobl aci n general , en cuyo t rat ami ent o se empl ean mul t i t ud de f rmacos si n
un resul t ado compl et ament e sat i sf act ori o. Los ant i hi st amni cos H1 de 2
a
generaci n se mant i enen como el pri mer t rat ami ent o si nt omt i co
de el ecci n. Segn l a di st i nt a f armacoci nt i ca y a ni dad por l os recept ores H1 de cada compuest o, cabe esperar di st i nt a concent raci n
en pi el y di st i nt a e caci a en l a i nhi bi ci n del habn i nduci do por hi st ami na, l o que no repercut e necesari ament e en l a respuest a cl ni ca.
Las propi edades ant i i n amat ori as de l os ant i hi st amni cos H1 podran t ener rel evanci a en l a urt i cari a crni ca, aunque no se sabe en qu
grado i n uyen en el ef ect o t eraput i co nal . Ant es de pasar a ot ro escal n de t rat ami ent o, se di scut e si deberan i ncrement arse l as dosi s
de ant i hi st amni cos, i ncl uso por enci ma de l as aprobadas en cha t cni ca. Las urt i cari as f si cas, cuando ocurren de f orma ai sl ada, suel en
responder bi en a ant i hi st amni cos H1, con l a excepci n de l a verdadera urt i cari a sol ar y l a urt i cari a ret ardada por presi n. En al gunas
urt i cari as crni cas, l a asoci aci n de ant i hi st amni cos H2 puede ser e caz, pero sl o con ant i hi st amni cos H1 de met abol i smo hept i co
comn (CYP3A4), en base a i nt erf erenci as met abl i cas mut uas. An no est bi en de ni do el papel de l os ant agoni st as de l eucot ri enos
asoci ados a l os ant i hi st amni cos en l a urt i cari a crni ca.
Palabras clave: Angioedema. Ant agonist as de cist einil-leucot rienos. Ant idepresivos. Ant ihist amnicos H1. Ant ihist amnicos H2. In amacin.
Hi st ami na. Respuest a cut nea a hi st ami na. Pi el . Urt i cari a crni ca. Urt i cari a crni ca aut oi nmune. Urt i cari as f si cas.
I Juregui, et al
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 41-52 2007 Esmon Publicidad
42
1.- Introduction: Chronic urticaria and
angioedema
Urticaria and angioedema are among the most common
causes of consultation in dermatology, allergology and
emergency care. According to a recent population-based
study [1], the prevalence of chronic urticaria in Spain is
about 0.6% of the general population. The H1 antihistamines
remain the rst line symptomatic treatment for chronic
urticaria, according to the most recent European consensus
reports on the subject [2-4].
Urticaria and angioedema are similar processes [5]:
both alterations are characterized by a vascular skin reaction
with edema and dilatation of the postcapillary venules and
lymphatic vessels of the dermis. In the case of urticaria,
the phenomenon takes place within the supercial dermis,
and the result is wheal production (Figure 1). In contrast,
angioedema develops in the deep dermis and subcutaneous
cellular tissue, resulting in swelling of the overlying tissue
- particularly in more lax skin regions such as the lips or
eyelids (Figure 2). Urticaria and angioedema are associated
to a variable degree. Isolated angioedema is less frequent
and may correspond to a different pathogenesis. It typically
responds little or not at all to antihistamine therapy.
Chronic urticaria (CU) is dened as the appearance
of wheals on a recurrent basis, more than twice a week,
and during over 6 consecutive weeks [6]. However,
this denition encompasses too many different clinical
conditions, and there are other characteristics inherent to
what most clinicians refer to as CU [7]:
- The wheals persist for more than an hour (a fact that
distinguishes the condition from simple dermographism),
and less than 24-36 hours (which differentiates the disorder
from urticaria-vasculitis). The lesions may be indurated
and painful.
Figure 1. Urt i cari a Wheal s
Figure 2. Pal pebral angi oedema
Antihistamines in the treatment of chronic urticaria
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 41-52 2007 Esmon Publicidad
43
- The natural course is highly variable, with outbreaks
and remissions that can last from a few months to more
than 20 years.
- Although there usually are no systemic manifestations,
patients suffer important alterations in quality of life, to
a point equivalent even to that seen in severe coronary
disease [8,9].
- There is no underlying food or drug allergy.
On moreover considering the histopathological features
(Figure 3), CU is characterized by a perivascular inltrate
around the venules, without vasculitis or immune complex
deposits, at the expense of CD4+ cells with mixed Th1 /
Th2 characteristics and monocytes, no B lymphocytes, and
a variable presence of granulocytes (polymorphonuclear
cells (PMN), eosinophils, basophils) that form a late-phase
inltrate. Diminished peripheral basophil counts may be
observed, along with eosinophil activation products (MBP,
ECP), and the presence of adhesion molecules (integrins
and selectins) - reecting the existence of endothelial cell
activation [10].
CU may be physical (triggered by specic physical
stimuli) or idiopathic [11]. At least one-third of all idiopathic
presentations are of an autoimmune nature, with the possible
association of thyroid autoimmunity with or without
clinically manifest hypothyroidism [12]. In addition to
the presence of antithyroid antibodies (more frequent than
in the general population) [13], these patients may have
IgG antibodies targeted against circulating IgE or (much
more often) against the subunit of the IgE high-afnity
receptor (FcR-I) [14]. Such antibodies can be detected
by skin testing with autologous serum, though the results
are scantily reproducible because of the great variability
depending on who performs the test [15]. They also can
be detected by in vitro demonstration of the capacity of
patient serum to induce healthy basophil degranulation
[16]. Likewise, immunoblotting with patient serum can
demonstrate the presence of a 30-35 kD IgG-binding band
corresponding to the subunit of FcR-I. These antibodies
can appear in other autoimmune processes such as lupus
or dermatomyositis, though in autoimmune CU they
correspond to subclass IgG1 or IgG3, capable of activating
complement and generating C5a, i.e., they are functional - a
fact considered to be specic of autoimmune CU [17].
2. Effects of antihistamines upon the
skin
Histamine plays a key role in the papule-erythema reaction
typical of urticaria, and the antihistamines alleviate the itching
Figure 3. Urt i cari a Hi st opat hol ogy
I Juregui, et al
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 41-52 2007 Esmon Publicidad
dose comparative study found levocetirizine to be the most
potent of the antihistamines examined, followed by ebastine,
fexofenadine and mizolastine, with similar potencies - though
ebastine took four hours in eliciting an effect different from
that of placebo. Loratadine was again seen to be the least
potent molecule [27]. Outside the context of these studies,
the antihistamine with the longest skin histamine reaction-
suppressing effect (4 to 6 weeks) was found to be astemizole.
This could be a result of its important distribution volume
and the long elimination half-life of its principal metabolite,
demethylastemizole [28]. It is interesting to comment that
there is often no correlation between inhibition of the skin
reaction to histamine and the clinical efcacy of the different
drug compounds, when assessed in terms of symptoms scores
or the impairment of patient quality of life [9].
2.3. Differences between plasma concentration / skin
concentration
Many classical as well as second-generation antihistamines
undergo rst-step metabolization in the liver. As a result, their
plasma levels are usually undetectable only a few hours after
administration of the dose; nevertheless, the drug effect persists
for much longer as a result of increased tissue concentrations
of the original drug or of its active metabolites [29].
Simons compared the plasma and skin concentrations of
different antihistamines, and correlated them to peripheral
anti-H1 activity. He found signicant differences in favor of
fexofenadine 120 mg versus diphenhydramine 50 mg [30], and
in favor of fexofenadine 180 mg or loratadine 10 mg versus
chlorpheniramine 8 mg [18] in terms of time to action, effect,
and reduce the number, size and duration of the urticarial
lesions.
2.1. Mechanisms of action of the antihistamines
The efcacy of the antihistamines in application to urticaria
is attributed to their H1 activity upon the afferent C nerve bers
of the skin, which reduces itching. They also act upon the
axonic reexes of the skin, which reduces erythema, and upon
the endothelium of the postcapillary venules - which reduces
extravasation and therefore wheal formation [18].
On the other hand, most of the antihistamines appear to
possess antiinammatory actions, including the reduction
of pre- and neoformed mediators, reductions in cytokine,
chemokine and adhesion molecule expression - and thus
reduction in inammatory cell recruitment and inammation
[19]. These actions may be attributed mainly to two types of
mechanisms:
a) Stabilization of the mast cell and basophil membranes,
and inhibition of the transmembrane flux of calcium
and intracellular cAMP [20]. The effect is independent
of the H1 receptor, and is considered to be due to drug-
membrane ionic interactions [21]. This is seen particularly
in vitro and at experimental concentrations, and induces a
decrease in preformed (histamine, tryptase) and neoformed
mediators (prostaglandins, leukotrienes) of the mast cells and
basophils.
b) Inhibition of cytoplasmic transcription factors, such
as nuclear factor kappa-B (NF-kB), which activates with H1
activation and migrates towards the nucleus where it interacts
with nuclear DNA - stimulating the transcription of cytokines,
chemokines and adhesion molecules, and the generation
of nitric oxide (NO) [22] (Figure 4). The inhibition of this
phenomenon is linked to interaction of the antihistamine with
the H1 receptor, and is therefore to a certain extent a class
effect.
Almost all the new antihistamines have been subjected
to in vitro and in vivo studies in this sense (Table 1), though
there are obvious differences among the different molecules.
Thus, cetirizine and levocetirizine have shown antiallergic and
antiinammatory action even at therapeutic concentrations
[19] - though in cutaneous processes such as CU, the true
relevance of these antiinammatory properties in terms of the
nal therapeutic effect is not known (the importance in any
case is much less than that of the glucocorticoids).
2.2. Antihistamines and inhibition of skin response to
histamine
Since all H1 antihistamines inhibit skin reaction to
histamine, the latter is considered to be a standardized
biological test of antihistamine action that can be used to
compare the in vivo effect of the different compounds [23].
In previous cross-over studies [24,25] comparing the
suppression of skin papule and erythema formation induced
by intradermal histamine injection following a single
antihistamine dose, cetirizine was found to offer the most
signicant effect versus other antihistamines - the order of
the inhibitory effect being as follows: cetirizine > epinastine >
terfenadine > ebastine > fexofenadine > loratadine > placebo.
In another study, mizolastine showed efcacy similar to that
of terfenadine, with signicantly less efcacy than cetirizine,
and greater efcacy than loratadine [26]. Likewise, a single-
44
Figure 4. Ant iinammat ory effect s of t he ant ihist amines
H1 recept or i nact i vi t y due t o i nt eract i on wi t h t he ant i hi st ami ne prevent s
act i vat i on of cyt opl asmi c t ranscri pt i on f act ors such as Nucl ear Fact or
B (NF-B), requi red f or t he expressi on of cyt oki nes, chemoki nes and
adhesi on mol ecul es.
Antihistamines in the treatment of chronic urticaria
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 41-52 2007 Esmon Publicidad
45
and duration of effect. In addition, Simons demonstrated
broad differences between the plasma and skin concentrations
- such differences reaching a peak after 24 hours. On the other
hand, this author showed that the skin concentration - not the
plasma concentration - correlated to drug potency in inhibiting
wheal and erythema formation in response to intradermal
histamine injection. This supports the use of such second-
generation antihistamines instead of rst-generation drugs in
application to urticaria and other skin disorders treated with
antihistamines.
The skin drug concentration is also dependent upon the
apparent distribution volume (Vd
a
), or ratio between the
amount of drug in the tissues and its concentration in plasma.
Vd
a
decreases with increasing drug binding to the plasma
proteins, and is directly proportional to tissue afnity for
the drug compound. It would be expected that larger Vd
a

values correspond to increased skin penetration. However,
extensive tissue distribution is not considered necessary for
the mechanism of action of the antihistamines, since the H1
receptor is an external receptor, and the pharmacological
effect is thus achieved without cell penetration [31]. Thus,
cetirizine and levocetirizine have the lowest Vd
a
possible - a
fact that exerts no inuence upon their effect in terms of the
inhibition of skin response, though it probably entails a lesser
risk of dose-dependent toxicity and of problems derived from
drug accumulation.
Table 1. Inhi bi t ory ef f ect s of ant i hi st ami nes upon i n ammat ory cel l s, cyt oki nes, chemoki nes and adhesi on mol ecul es
Drug In vitro In vivo/ex vivo
Cetirizine/Levocetirizine Adhesion eosinophils
67
Recruit. eosinophils-skin
68, 69, 70

Chemotaxis eosinophils and neutrophils
72
Recruit. eosinophils-bronchiole
71
Chemotaxis T lymphocytes and monocytes
75
Inhibition ICAM-1 in nasal secretion
73
Survival eosinophils
76
Inhibition ICAM-1 in conjunctival secretion
74
IL-8, MCP-1/ RANTES
78

NF-B19
Terfenadine/Fexofenadine
80. 81
Chemotaxis eosinophils Inhibition ICAM-1 in nasal secretion
79

Adherence eosinophils
Generation of superoxide
IL-6, IL-8, TNF-, GM-CSF
Loratadine
80. 81
Chemotaxis eosinophils
82
Recruit. eosinophils-eye
83
IL-8, RANTES, ICAM-1s
84
Inhibition ICAM-1 in nasal secretion
85
Inhibition ICAM-1 in conjunctival secretion
86
Desloratadine
87
Chemotaxis eosinophils
Generation superoxide
TNF-, IL-1, IL-6, IL-8, IL-13
P-selectin, ICAM-1
Apoptosis de eosinlos
Activation NF-B
Azelastine
88
Chemotaxis eosinophils Recruit. eosinophils-nose
Chemotaxis neutrophils Inhibition ICAM-1 in nasal secretion
Generation superoxide Inhibition ICAM-1 in conjunctival secretion
IL-4, IL-5
Activation NF-B
Mizolastine Recruit. neutrophils
89

5-lipoxygenase
90

VEGF, TNF-, KC
91

Rupatadine PAF, TNF-
92

ICAM- 1: Int ercel l ul ar adhesi on mol ecul e- 1. ICAM- 1s: sol ubl e ICAM- 1 (i n secret i ons). IL- 1, IL- 2, et c.: Int erl euki n- 1, Int erl euki n- 2, et c. MCP- 1:
Monocyt e chemot act i c prot ei n- 1. RANTES: Chemoki ne regul at ed by t he act i vat i on of - secret ed by - and expressed i n normal T cel l s. NF- B: Nucl ear
Fact or kappa- B. TNF- : Tumor necrosi s f act or- al pha. GM- CSF: Granul ocyt e and Macrophage Col ony St i mul at i ng Fact or. VEGF: Vascul ar Endot hel i al
Grow t h Fact or. KC: Kerat i nocyt e deri ved chemoki ne. PAF: Pl at el et act i vat i on f act or
I Juregui, et al
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 41-52 2007 Esmon Publicidad
Lastly, there are differences among the antihistamines
in terms of their H1 receptor afnity, detectable both in
preclinical in vitro studies and in clinical trials in humans. A
recent study has demonstrated signicant differences between
desloratadine, fexofenadine and levocetirizine in terms of
in vivo receptor occupation after 4 and 24 hours, in direct
proportion to the percentage inhibition of wheal and erythema
formation (Table 2) [32].
3. Current tendencies in the pharmaco-
logical treatment of chronic urticaria
In chronic urticaria there are clinical trials and
isolated observations with multiple treatments either as
monotherapy or in combination, involving rst- and second-
generation antihistamines, H2 antihistamines, doxepin,
other antidepressants, leukotriene antagonists, corticoids,
cyclosporine and other immunosuppressors, calcineurin
inhibitors, sulfasalazine, intravenous immunoglobulins,
plasmapheresis or phototherapy. There are also isolated
studies of experimental treatments with different immune
modulators that may nd applications in the future [11]:
zileuton, rituximab, mycophenolate mofetil, leunomide or
the TNF- inhibitors, iniximab and etanercept.
Within this potential range of treatments, the non-sedating
(or second-generation) H1 antihistamines (AH-2G) are the only
drugs with class 1 evidence and grade A recommendation [2-
4]. They are therefore regarded as the rst line symptomatic
treatment option. The AH-2G offer good to moderate response
in 44-91% of all types of urticaria, and in 55% of patients
with CU [11].
The rst-generation H1 antihistamines (AH-1G) should
be reserved for those patients not controlled with AH-2G,
particularly when the symptoms interfere with sleep at night
[11]. All the antihistamines are more effective in alleviating
itching (pruritus) than in reducing the frequency, number and
size of wheals [7].
Some authors postulate that in young adults without
associated pathology, the antihistamine dosage should be
raised to above the levels recommended by the manufacturer,
before deciding to change or add other alternative treatments
[5] - a suggestion that has class 3 evidence and grade C
recommendation [3]. A recent study using cetirizine in 22
patients with severe CU contradicts this suggestion - no
improvement being recorded in the second week of treatment
after increasing the dose three-fold [33].
4. First-generation antihistamines in
chronic urticaria
The antihistamines marketed before 1981 (AH-1G) share
sedative and atropinic effects that probably inuence low
adhesion to therapy - though they may be useful in patients
with symptoms that interfere with sleep at night.
The most widely used in application to CU have been
the ethanolamines (diphenhydramine [34], clemastine),
hydroxyzine, dexchlorpheniramine, and the more classical
piperidines such as cyproheptadine, azatadine and ketotifen.
Ketotifen proved to be more effective than clemastine in a
study involving 305 patients with CU - though the incidence
of adverse effects was similar (20-21% of patients) [35].
5. Second-generation antihistamines in
chronic urticaria
As has already been commented, the AH-2G are considered
to be the rst-line symptomatic treatment for CU, and are the
only drugs with class 1 evidence and grade A recommendation
[3], based on numerous randomized clinical trials versus both
placebo and AH-1G (Tables 3 and 4).
It is a common tendency among clinicians to consider
the different AH-2G to be comparable in terms of efcacy
and safety. However, the AH-2G constitute a heterogeneous
group of compounds with structural, antihistamine potency,
pharmacological, metabolic, drug interaction and safety
characteristics that differ from one molecule to another - though
they share the same tissue receptors. Although it is logical to
test different drugs in a given patient if some H1 antihistamine
proves ineffective, we personally doubt the efficacy of
combining different AH-2G with each other or with AH-1G,
forcing them to compete for the same receptors and increasing
the risk of drug interactions and adverse effects.
Table 4 presents several randomized clinical trials
comparing cetirizine in CU versus both hydroxyzine [36] and
loratadine [37], of similar clinical efcacy but with a safety
prole superior to that of hydroxyzine. Although the clinical
trials did not nd cetirizine to alter psychomotor performance
at a dose of 10 mg/day [38], some studies conducted under
conditions of routine clinical practice suggest that it may cause
greater subjective sedation than placebo or loratadine [39].
The antihistamine activity of cetirizine is based on the
L-enantiomer, and the afnity of levocetirizine for the H1
receptors doubles that of the racemic mixture; as a result, it is
considered to be pharmacologically equivalent to cetirizine at
Table 2. In vivo occupat i on of H1 recept ors and w heal and eryt hema
i nhi bi t i on [ 30]
DL FF LC
Receptor occupation after 4 h (%) 71 95 90
Receptor occupation after 24 h (%) 43 12 57
Maximum wheal inhibition after 4 h (%) 34 100 100
Wheal inhibition after 24 h (%) 32 15 60
Maximum erythema inhibition after 4 h (%) 19 83 89
Erythema inhibition after 24 h (%) 41 35 74
DL: Desl orat adi ne. FF: Fexof enadi ne. LC: Levocet i ri zi ne
46
Antihistamines in the treatment of chronic urticaria
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 41-52 2007 Esmon Publicidad
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I Juregui, et al
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 41-52 2007 Esmon Publicidad
half the dosage. Levocetirizine has been studied in application
to CU versus placebo in at least two trials [40], with very
favorable results - particularly as refers to the number of days
of itching per month (p<0.001). A study (the so-called CUTE
survey) has also been made versus desloratadine in 816 patients
divided into two homogeneous groups - though the results in
this case remain to be published [41].
In relation to CU, many other AH-2G have been evaluated
versus placebo, in periods of 4-6 weeks, including fexofenadine
[42], ebastine [43], mizolastine [44], desloratadine [45],
rupatadine [46] or epinastine [47]. The different AH-2G have
also been compared with each other in the context of CU.
In addition to the above mentioned study of levocetirizine
versus desloratadine, trials have been made of ebastine versus
terfenadine [43], cetirizine versus loratadine or mizolastine,
mizolastine versus loratadine, emedastine versus loratadine
[48], and others (Tables 3 and 4). In general, no signicant
differences are observed in the control of symptoms, patient
quality of life, or safety prole.
6. Chronic urticaria and antihistamines in
special situations
6.1. Pregnancy
The data available on the use of antihistamines during
pregnancy are of an observational nature. Most antihistamines
are classied as belonging to category B (risk not demonstrated
in animals, with no human studies) or C (demonstrated risk in
animals or lack of animal or human studies) of the United States
Food and Drug Administration (FDA)[49](Table 5). Category
B includes the AH-2G, cetirizine and loratadine; nevertheless,
the AH-1G are considered the drugs of choice, since they offer
greater cumulative experience [50]. It is advisable to avoid
AH-1G in the third trimester of pregnancy, due to the risk of
neonatal seizures [11].
6.2. Chronic urticaria in pediatrics
All antihistamines can be used in children over 12 years of
age. In relation to the AH-1G, there are pediatric formulations
for the following drugs: hydroxyzine and alimemazine (> 6
months), dexchlorpheniramine (> 1 year), diphenhydramine,
clemastine, promethazine, cyproheptadine and ketotifen (>
2 years). In the case of the AH-2G, there are no pediatric
formulations for fexofenadine, mizolastine or rupatadine.
For the indication of CU, only cetirizine, loratadine and
desloratadine are approved for treatments in patients up to
2 years of age, while ebastine and levocetirizine are only
contemplated in the corresponding Summaries of Product
Characteristics for urticaria in children over 6 years of age
[51].
6.3. Kidney or liver failure
For most AH-2G, only 10-20% of the administered dose is
eliminated through the kidneys - the exceptions being cetirizine
(60%) and levocetirizine (85% renal elimination) [52]. On the
other hand, most of these drugs undergo presystemic (rst-step)
metabolization in the liver, via cytochrome P-450 or CYP - the
exceptions being cetirizine, levocetirizine, fexofenadine and
desloratadine. In view of the above, in patients with liver or
kidney failure, a reduction of the dose of all AH-2G is advised,
in accordance with the corresponding Summaries of Product
Characteristics.
7. Other antihistamines and associations
7.1. Antidepressants with antihistamine action
Tricyclic antidepressants have been successfully used,
including amitriptyline or doxepin [53], which possesses
potent H1 antihistamine effect and H2 antihistamine activity
- though use is greatly limited by the associated sedative and
anticholinergic effects, reinforcement with alcohol, and the
relative risk of arrhythmias - particularly as a consequence of
drug interactions, resulting in prolongation of the QT interval
of the ECG [7].
7.2. H2 antihistamines
The efcacy of H2 antihistamines in the treatment of CU is
open to controversy. The blood vessels of the skin have H1 and
H2 receptors, and activation of both types of receptor induces
wheal and erythema formation - though H2 activation has very
little effect upon the warmth and itching [7].
H1-H2 antihistamine associations have been widely
used and studied. In this sense, greater efcacy has been
observed for associations with H1 antihistamines presenting
liver metabolism in common with H2 antihistamines, such
as chlorpheniramine [54], hydroxyzine [55] or terfenadine
[56], than associations with cetirizine [57]. It is thus believed
that the combined effect is due more to H1-H2 antihistamine
interactions at the level of CYP3A4 or other isoenzyme
families - with a resulting mutual increase in the area under
the plasma drug concentration-time curve (AUC) - than to any
genuine synergic effect. In view of the above, the routine
use of H1-H2 antihistamine combinations is presently not
justied.
7.3. Associations of antihistamines to leukotriene
antagonists
Although not approved for use in CU, some clinical trials
suggest that these associations may be of some interest in
application to different types of urticaria. Montelukast has
Table 5. Uni t ed St at es FDA ri sk cat egori es f or H1 ant i hi st ami nes i n
pregnancy
Category Compounds
B Chlorpheniramine, dexchlorpheniramine
Tripelennamine
Dimenhydrinate, doxylamine
Azatadine, cyproheptadine, loratadine
Hydroxyzine, cetirizine
C Brompheniramine
Diphenhydramine, carbinoxamine, clemastine
Astemizole, terfenadine, fexofenadine,
ebastine, mizolastine
Topical H1 antihistamines: azelastine,
levocabastine...
48
Antihistamines in the treatment of chronic urticaria
J Investig Allergol Clin Immunol 2007; Vol. 17, Suppl. 2: 41-52 2007 Esmon Publicidad
been used in CU in association to cetirizine, fexofenadine,
loratadine and desloratadine, in different randomized trials
[58], and in general has shown signicant differences versus
the antihistamine alone - at least as regards the symptoms
count and results of quality of life questionnaires [59].
However, montelukast as monotherapy has not been found to
be useful in CU [60]. The addition of zarlukast to cetirizine
has shown greater efcacy than placebo in patients with
autoimmune CU [61], though not so in other trials involving
patients with various forms of CU [62]. It has been suggested
that leukotriene antagonists could be particularly interesting
in patients with CU who present intolerance to aspirin or the
additives - though the subject is open to controversy, and all
recent reviews in the eld conclude that the role of these drugs
in CU has not yet been well dened [63,64].
8. Antihistamines in physical urticarias
The physical urticarias, where wheals are produced in
response to different physical stimuli, can develop isolatedly
or in association to other types of CU. With the exception
of genuine solar urticaria and delayed pressure urticaria, the
lesions generally tend to respond to antihistamines, used as
rst-line symptoms treatment in the same way as in other
types of CU.
8.1. Dermographism (factitious urticaria)
This is the most frequent type of physical urticaria and
CU. The physical stimulus giving rise to dermographism
can be quantied by scratching the back of the patient with
a calibrated instrument (dermographometer) [7], used to
measure treatment response in many clinical trials with
rst- and second-generation antihistamines either alone or in
combination with H2 antihistamines. In these trials superior
response is observed with antihistamine versus placebo - no
signicant differences being recorded among the different H1
antihistamines. Dermographism is the type of CU in which the
association to H2 antihistamines has yielded the best results
in clinical trials [7,11].
8. 2. Cholinergic urticaria
Cholinergic urticaria is observed in 10% of all young
adults, and tends to respond to antihistamine treatment. A
clinical trial with cetirizine, involving 24 well selected patients
has been published [65].
8.3. Acquired cold urticaria
This presentation can be associated to disorders produced
by cryoglobulins or other cold-reactive proteins, though in
90% of cases the condition is idiopathic [7] and responds
to antihistamine therapy. Studies have been made with the
piperidine antihistamines cyproheptadine, ketotifen and
desloratadine, and with the piperazines cinnarizine and
cetirizine - with good results in all cases. Consequently,
AH2G are recommended, due to their superior tolerance
prole [11].
8.4. Solar urticaria
This is an infrequent disorder, characterized by the
development of wheals within minutes after exposure of
the skin to ultraviolet or visible light. A photostimulator can
be used to identify the causal wavelength. Solar urticaria is
considered to respond poorly to antihistamines. In a cohort
study of 87 patients, one-third responded well to antihistamine
therapy, while in 65% of cases there was only a weak or no
response [66].
8.5. Delayed pressure urticaria
Delayed pressure urticaria develops on areas of the skin
to which pressure has been applied (soles, buttocks and waist,
palms of the hands after carrying heavy bags or tools), between
30 minutes and several hours after application of the pressure.
It can be observed in up to 40% of all cases of CU [7], though
in some patients it represents the main problem - responding
poorly to antihistamines, including high-dose cetirizine and
other antihistamines [7].
9. Conclusions
The H1 antihistamines remain the rst line symptomatic
treatment for chronic urticaria (evidence 1/A), according
to the most recent European diagnostic and treatment
consensus reports on the subject. Depending on the different
pharmacokinetics, Vd
a
and H1 receptor affinity of each
drug substance, different concentrations in skin can be
expected, together with different efcacy in relation to the
histamine-induced wheal inhibition test - though this does
not seem to imply signicant differences in the comparative
clinical trials. At present, we do not know the ultimate
therapeutic relevance of the antiinammatory properties of
the antihistamines in relation to processes such as chronic
urticaria. A number of authors suggest that before moving
on to another therapeutic level, antihistamine dose escalation
should be considered, involving increments even above those
approved in the Summary of Product Characteristics - though
this recommendation is debatable and is supported by only
weak evidence. Physical urticaria, when manifesting isolatedly
and not associated to other types of chronic urticaria, tends to
respond well to antihistamines, with the exception of genuine
solar urticaria and delayed pressure urticaria. In some cases of
chronic urticaria, the combination of H2 antihistamines may
prove effective - though only with common liver metabolism
(CYP3A4 isoenzyme-mediated) H1 antihistamines, due to the
existence of mutual metabolic interferences. In any case, this
approach is generally not recommended. Likewise, there are
not enough data to recommend combination with leukotriene
antagonists - the role of which in chronic urticaria remains to
be established.
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Ignacio Juregui Presa
Servicio de Alergia.
Hospital de Basurto
Avda. Montevideo, 18
48013 Bilbao, Spain
E-mail: ignacio.jaureguipresa@osakidetza.net
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