Alkylamines (Prototype: Chlorpheniramine).

These are among the most

potent H1 antagonists. The drugs are less prone than some H1 antagonists to
produce drowsiness and are more suitable agents for daytime use, but again, a
significant proportion of patients do experience sedation. Side effects involving
CNS stimulation are more common than with other groups.

Therapeutic Uses

H1 antagonists have an established and valued place in the symptomatic

treatment of various immediate hypersensitivity reactions. In addition, the
central properties of some of the series are of therapeutic value for suppressing
motion sickness or for sedation.

Allergic Diseases. H1 antagonists are most useful in acute types of allergy that
present with symptoms of rhinitis, urticaria, and conjunctivitis. Their effect is
confined to the suppression of symptoms attributable to the histamine released
by the antigen-antibody reaction. In bronchial asthma, histamine antagonists
have limited efficacy and are not used as sole therapy (see Chapter 27). In the
treatment of systemic anaphylaxis, in which autacoids other than histamine play
major roles, the mainstay of therapy is epinephrine; histamine antagonists have
only a subordinate and adjuvant role. The same is true for severe angioedema, in
which laryngeal swelling constitutes a threat to life.

Other allergies of the respiratory tract are more amenable to therapy with H1
antagonists. The best results are obtained in seasonal rhinitis and conjunctivitis
(hay fever, pollinosis), in which these drugs relieve the sneezing, rhinorrhea, and
itching of eyes, nose, and throat. A gratifying response is obtained in most
patients, especially at the beginning of the season when pollen counts are low;
however, the drugs are less effective when the allergens are most abundant,
when exposure to them is prolonged, and when nasal congestion is prominent.
Topical preparations of antihistamines such as levocabastine (LIVOSTIN),
azelastine (ASTELIN), ketotifen (ZADITOR), and olopatadine (PATANOL) have
been shown to be effective in allergic conjunctivitis and rhinitis. Nasal sprays or
topical ophthalmic preparations of these agents are available in the United.
States. Histamine causes the release of inflammatory cytokines and eicosanoids
and increases expression of endothelial adhesion molecules (Holgate et al.,
2003; Gelfand et al., 2004). In addition, H1 receptors, either via constitutive
activity or after stimulation by agonists, can activate the proinflammatory
transcription factor NF-κ B (Leurs et al., 2002). Thus H1 antihistamines have been
investigated for potential antiinflammatory properties. Although H1
antihistamines do exhibit a variety of antiinflammatory effects in vitro and in
animal models, in many cases the doses required are higher than those normally
achieved therapeutically, and clinical effectiveness has not yet been proven
(Holgate et al., 2003; Gelfand et al., 2004).

Certain allergic dermatoses respond favorably to H1 antagonists. Benefit is most

striking in acute urticaria, although the itching in this condition is perhaps better
controlled than are the edema and the erythema. Chronic urticaria is less
responsive, but some benefit may occur in a fair proportion of patients.
Furthermore, the combined use of H1 and H2 antagonists sometimes is effective
when therapy with an H1 antagonist alone has failed. As mentioned earlier,
doxepin may be effective in the treatment of chronic urticaria that is refractory
to other antihistamines. Angioedema also responds to treatment with H1
antagonists, but the paramount importance of epinephrine in the severe attack
must be re-emphasized, especially in life-threatening laryngeal edema
(see Chapter 10). In this setting, it may be appropriate to also administer an H1
antagonist by the intravenous route.

H1 antagonists have a place in the treatment of pruritus. Some relief may be

obtained in many patients suffering atopic dermatitis and contact dermatitis
(although topical corticosteroids are more effective) and in such diverse
conditions as insect bites and poison ivy. Various other pruritides without an
allergic basis sometimes respond to antihistamine therapy, usually when the
drugs are applied topically but occasionally when they are given orally. However,
the possibility of producing allergic dermatitis with local application of H1
antagonists must be recognized. Again, doxepin may be more effective in
suppressing pruritus than are other antihistamines. Since these drugs inhibit
allergic dermatoses, they should be withdrawn well before skin testing for
allergies. The urticarial and edematous lesions of serum sickness respond to H1
antagonists, but fever and arthralgia often do not.

Many drug reactions attributable to allergic phenomena respond to therapy with

H1 antagonists, particularly those characterized by itch, urticaria, and
angioedema; serum-sickness reactions also respond to intensive treatment.
However, explosive release of histamine generally calls for treatment with
epinephrine, with H1 antagonists being accorded a subsidiary role. Nevertheless,
prophylactic treatment with an H1 antagonist may reduce symptoms to a
tolerable level when a drug known to be a histamine liberator is to be given.

H1 Antihistamines. These medications are used widely in the treatment of

allergic disorders. H1 antihistamines are most effective in relieving the symptoms
of seasonal rhinitis and conjunctivitis (e.g., sneezing, rhinorrhea, and itching of
the eyes, nose, and throat). In bronchial asthma, they have limited beneficial
effects and are not useful as sole therapy. H1-histamine antagonists are useful
adjuncts to epinephrine in the treatment of systemic anaphylaxis or severe
angioedema. Certain allergic dermatoses, such as acute urticaria, respond
favorably to H1 antagonists, which help to relieve the itch in atopic dermatitis or
contact dermatitis but have no effect on the rash. Chronic urticaria is less
responsive, but some benefit may occur, especially when combined with H2
antagonists.

Side effects are most prominent with first-generation H1 antihistamines (e.g.,

diphenhydramine, chlorpheniramine, doxepin, and hydroxyzine), which cross the
blood-brain barrier and cause sedation. Some of the first-generation H1-receptor
antagonists also have anticholinergic properties that can be responsible for
symptoms such as dryness of the mouth and respiratory passages, urinary
retention or frequency, and dysuria. The second-generation drugs
(e.g., cetirizine, loratadine, desloratadine, and fexofenadine) are largely devoid
of these side effects because they do not penetrate the CNS and do not have
antimuscarinic properties. Thus they are usually the drugs of choice for the
treatment of allergic disorders.

The significant sedative effects of some first-generation antihistamines have led

to their use in treating insomnia, although there are better drugs for this
purpose. Hydroxyzine and diphenhydramine are used in some cases as weak
anxiolytics. Some first-generation H1 antagonists (e.g., dimenhydrinate, cyclizine,
meclizine, and promethazine) can prevent motion sickness, although
scopolamine is more effective. Antiemetic effects of these H1 antihistamines can
be beneficial in treating vertigo or postoperative emesis.

Many H1 antihistamines are metabolized by CYPs. Thus, inhibitors of CYP activity

such as macrolide antibiotics (e.g., erythromycin) or imidazole antifungals (e.g.,
ketoconazole) can increase H1 antihistamine levels, leading to toxicity. Some
newer antihistamines, such as cetirizine, fexofenadine, levocabastine, and
acrivastine, are not subject to these drug interactions.

Caution should be used in treating pregnant or lactating women with certain H1

antihistamines, especially first-generations drugs, because of their possible
teratogenic effects or symptomatic effects on infants owing to secretion into
breast milk; cetirizine and loratadine are probably the best choices if H1
antihistamines are required, but if they are not effective, diphenhydramine can
be used safely in pregnant (but not breast-feeding) women.