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Antihistamines in the Treatment of Asthma


Drug Information

Name: Cetirizine
Chemical Formula: C21H25ClN2O3
Synonyms: Cetirizina [Spanish], Cetirizinum [Latin], Cetrizine Hcl
Brand Names: Alerlisin, Cetryn, Formistin, Hitrizin Film Tablet, Reactine, Setir, Virlix, Ziptek, Zirtek, Zyrlex, Zyrtec

Both allergic rhinitis and bronchial asthma are common human maladies. These conditions often co-exist, and it has been speculated that rhinitis is a risk factor for bronchial asthma. A recent evaluation of 125 adolescents and 348 adults with asthma found that 99% of allergic asthmatics also suffered from rhinitis and 78% of those defined as having non-allergic asthma also had rhinitis. In 81% of the adults and 72% of the adolescents it was reported that upper airway symptoms started before, or simultaneously with, the onset of asthma. Thus, physicians must clearly consider allergic asthma as an illness involving the total airway.

Huse et al. evaluated the frequency of symptoms in children with allergic respiratory disorders in two U.S. managed care organizations. They found that the monthly rate of asthma attacks was 47% in children with asthma alone and 63% (p < 0.05) in those with asthma plus allergic rhinitis. Daily wheezing or cough was reported in 20% of children with asthma alone versus 35% of those with both asthma and rhinitis (p < 0.05).

Halpern et al. evaluated the economic impact of allergic respiratory disorders. They compared patients with asthma alone or asthma plus allergic rhinitis, and observed that the combined illnesses resulted in approximately double the use of prescription medications, out-patient visits and the total cost of care.

The allergic response in the nose resembles quite closely that seen in the lower airways of patients with asthma. Experimental allergen challenge models for both rhinitis and asthma have permitted investigation of the cellular and molecular events taking place in both illnesses. Both have an early and late phase response following allergen challenge. The mast cell has high-affinity receptors for IgE, and the binding of allergens to IgE triggers early release of histamine and other mediators in rhinitis and asthma. Subsequently, effector cells consisting of lymphocytes, eosinophils and basophils are attracted into the target tissue to produce an inflammatory reaction. These cells release additional mediators affecting the allergic response. There is evidence that cytokines are the key factors directing this response in both rhinitis and asthma. Cytokines are synthesized and released by mast cells, basophils, eosinophils, Th2 cells, epithelial cells and others. The chemotactic cytokines, called chemokines, are of special importance through their ability to recruit the effector cells and to increase cellular function and mediator secretion during allergic reactions. A significant role for chemokines is initiation of histamine release from basophils. Inhibition of cytokine and chemokine synthesis profoundly reduces the course of allergic rhinitis.

Avoidance is the treatment of choice for respiratory allergies, but it is usually not entirely effective. Thus, pharmacotherapy is an essential element to the management of both upper and lower respiratory disorders. Histamine is a major mediator released by tissue mast cells during the early phase of allergic reactions. Blood basophils are recruited to sites of allergic inflammation, and are the chief source of histamine released during the late phase of allergic responses in both the nose and lungs. Specific therapy focused on this mediator is thus very important.


Drug Information

Name: Loratadine
Chemical Formula: C22H23ClN2O2
Synonyms: Loratadina [Spanish], Loratadinum [Latin]
Brand Names: Aerotina, Alarin, Alavert, Alerpriv, Allertidin, Bedix Loratadina, Biloina, Bonalerg, Civeran, Claratyne, Clarinase, Clarinase Reperabs, Claritin, Claritin Reditabs, Claritin-D, Claritine, Clarityn, Clarityne, Fristamin, Histaloran, Lergy, Lertamine, Lesidas, Lisino, Lomilan, Loracert, Loradex, Loradif, Loranox, Lorantis, Lorastine, Loratyne, Loraver, Lorfast, Loritine, Lowadina, Nularef, Optimin, Polaratyne, Pylor, Restamine, Rhinase, Rinomex, Roletra, Sanelor, Sensibit, Sinhistan Dy, Sohotin, Tadine, Talorat Dy, Velodan, Versal, Zeos

Pharmacotherapy of Asthma

Since their introduction more than 50 years ago, H1 antihistamines have been key drugs in the world-wide management of allergic rhinitis. The first drugs of this class were somewhat limited because of their known side-effects, which may be attributed to their multiple sites of action other than histamine antagonism. The second-generation drugs of this class, introduced within the past 15 years, are more specific and potent, longer acting and have fewer side-effects. Simons et al. evaluated the potency of these compounds for inhibition of the cutaneous wheal response to histamine challenge. They found that the rank order from most to the least effective was: cetirizine, terfenadine, loratadine, astemizole, chlorpheniramine and placebo. Beyond their inhibition of H1 receptors, additional anti-allergic properties have been attributed to this class of compounds. These experiments have been extensively reviewed recently.


Drug Information

Name: Chlorpheniramine
Chemical Formula: C16H19ClN2
Synonyms: Chloropheniramine, Chlorophenylpyridamin, Chlorophenylpyridamine, Chloroprophenpyridamine, Chlorphenamine, Chlorpheniramine Maleate, Chlorprophenpyridamine, Clorfeniramina, Dexchlorpheniramine, Dexchlorpheniramine Maleate
Brand Names: Aller-Chlor, Allergican, Allergisan, Antagonate, Chlo-Amine, Chlor-Trimeton, Chlor-Trimeton Allergy, Chlor-Trimeton Repetabs, Chlor-Tripolon, Chlorate, Chloropiril, Cloropiril, Efidac 24 Chlorpheniramine Maleate, Gen-Allerate, Haynon, Histadur, Kloromin, Mylaramine, Novo-Pheniram, Pediacare Allergy Formula, Phenetron, Piriton, Polaramine, Polaronil, Pyridamal 100, Telachlor, Teldrin

Second-generation H1 Antagonists

Second-generation H1 antagonists at higher concentrations have been observed to reduce the release of inflammatory mediators. Okayama and Church observed that terfenadine, ketotifen and cetirizine block release in vitro of histamine and prostaglandin D2 from human mast cells obtained from lung, tonsil and skin. Dobashi et al. utilized a guinea pig model to evaluate the effects of antihistamines. They found that cetirizine blocked antigen-induced release of histamine and leukotriene D4 from the lung. They concluded that the effect of cetirizine was mediated by a decrease in the short-term influx of calcium into mast cells.

Small and Barrett evaluated the effects of cetirizine in ragweed-sensitive humans. After taking 10 mg daily for a week they observed a significant reduction in the early phase response induced by nasal allergen challenge and in the release of both histamine and prostaglandin D2. Baroody et al. found that loratadine and terfenadine treatment reduced the recovery of histamine in the nose of allergen-challenged subjects. However, there was no effect on prostaglandin D2 or leukotriene C4 recovery. Naclerio et al. observed that cetirizine reduced the levels of leukotriene C4 in nasal secretions. Nevertheless, this drug did not affect the amount of histamine and prostaglandin D2 recovered. They speculated that cetirizine might be acting at a site other than the mast cell. Alternatively cetirizine might selectively inhibit 5-lipoxygenase. Finally, it should be noted that Kalayci et al. observed that, in children with allergic rhinitis owing to dust mites, cetirizine blocked the release of leukotrienes from basophils challenged in vitro with allergen. Furthermore, they showed a correlation between nasal symptoms after allergen challenge and the release of allergic mediators. Thus, the mechanism for the action by cetirizine might be inhibition of mediator release from basophils recruited to the nose.

It has been observed that cetirizine blocks the influx of eosinophils into the skin and lungs following allergen challenge. Turner et al. confirmed that cetirizine reduced the eosinophil response to antigen challenge in a primate model of asthma. The cause of this effect is not entirely clear. Fasce et al. evaluated the effects of cetirizine on children with respiratory symptoms resulting from mite sensitization. They reported that long-term administration of this drug caused a significant reduction in nasal epithelial expression of the adhesion molecule ICAM-1 and of inflammatory cell recruitment. Ciprandi et al. used a similar model to evaluate the effects of cetirizine on allergic conjunctivitis. Again, ICAM-1 expression and influx of eosinophils and neutrophils were blocked during both the early and late phase response after allergen challenge. Thus one potential mechanism to explain the inhibition of eosinophil influx by cetirizine might be reduced expression of adhesion molecules.


Drug Information

Name: Terfenadine
Chemical Formula: C32H41NO2
Synonyms: Ternadin
Brand Names: Aldaban, Allerplus, Cyater, Seldane, Teldane, Teldanex, Terdin, Terfex, Triludan

Effectiveness of Antihistamines

Antihistamines are clearly effective in relieving the major symptoms of allergic rhinitis: sneezing, rhinorrhoea and itching. Meltzer et al. compared cetirizine, loratadine and placebo in controlling the symptoms of patients with seasonal allergic rhinitis in a park setting. Cetirizine proved superior to both of the other therapies. Lockey et al. compared cetirizine, terfenadine and placebo for the same condition and found cetirizine more effective in symptom control. Bousquet et al. evaluated cetirizine and placebo in patients with perennial allergic rhinitis; they observed that active treatment significantly improved an assessment of quality of life by use of a standardized questionnaire.

Harvey et al. recently reported the results of a comprehensive clinical study of three antihistamines in a managed care environment. Patients were randomly assigned to receive for two weeks (phase I) cetirizine, chlorpheniramine or terfenadine for management of seasonal allergic rhinitis. At the end of phase I, patients could elect to continue their current treatment or to change to another drug for an additional four weeks (phase II). Patient satisfaction at the end of phase I was as follows: chlorpheniramine = 29%, terfenadine = 50% and cetirizine = 69%. Both investigators and patients thought cetirizine and chlorpheniramine more effective than terfenadine (p < 0.01) in both phases I and II. Finally, quality of life scores improved most in the cetirizine-treated group and least with terfenadine.

The potential role of antihistamines in lower respiratory reactions has been considered since 1949, when Herxheimer used earlier compounds successfully in the therapy of asthma. However these drugs were not potent or specific, and the side-effects were thought intolerable. Bronchoconstriction was also reported anecdotally. Holgate and co-workers evaluated the inhibitory properties of old and new antihistamines on histamine inhalation challenge. They found that cetirizine and terfenadine were the most potent inhibitors of histamine-induced bronchospasm, more so than loratadine and older antihistamines. This class of drug did not affect methacholine sensitivity. Finally, Wasserfallen et al. observed that cetirizine blocked the late phase bronchial allergic response to allergen inhalation, but not the early phase. However, Bentley et al. recently found that cetirizine did not inhibit either the early or late bronchial response to allergen challenge.

In his original paper Herxheimer reported that antihistamines could serve as bronchodilators. This observation was confirmed in later reports for other drugs in this class, including chlorpheniramine and terfenadine. Spector et al. evaluated the response to single doses (5, 10 or 20 mg) of cetirizine when compared with inhaled albuterol. They observed that all concentrations of cetirizine significantly improved all parameters of obstructive airways disease, but did not change vital capacity. The effects of albuterol were similar to 10 and 20 mg cetirizine for the first two hours, but all three doses of cetirizine were more effective than albuterol at seven and eight hours. Overall, cetirizine seemed additive with albuterol as to bronchodilatation.

The efficacy of the second-generation antihistamines in bronchial asthma has been reviewed recently. It is now obvious that all drugs in this class are safe for administration to patients with asthma. Terfenadine in higher doses (180 mg three times daily) proved effective for reducing the symptoms of asthma; however, recently Wood-Baker et al. reported that terfenadine, 120 mg twice daily, did not change any variable of asthma control: forced expiratory volume in one second, peak expiratory flow or symptom scores. Note that this dose of terfenadine can no longer be considered safe in view of its known actions on cardiac function. Ekstrom et al. found loratadine ineffective in moderate to severe asthma. Busse et al. evaluated the efficacy of aselastine 6 mg daily in patients with chronic asthma requiring inhaled steroids. They found that the drug significantly reduced the dose of steroids when compared with the placebo.

Grant et al. compared the response of 186 patients with both seasonal allergic rhinitis and asthma to cetirizine, 10 mg daily, and placebo for six weeks. Treatment was begun just before the autumn pollen season. As expected, rhinitis symptoms were significantly improved beginning at week one and for most of the study. Furthermore, asthma symptoms of chest tightness, wheezing, dyspnoea and cough were also improved beginning in the first week. The total asthma symptom scores were superior in the cetirizine group for five out of six weeks. Since the study groups had very mild asthma, no significant changes in pulmonary function were noted. In a smaller study of 28 patients with asthma, Aaronson confirmed that cetirizine, 20 mg daily, was clinically effective in both rhinitis and asthma when compared with placebo. Asthma symptoms of chest tightness, wheezing, shortness of breath and nocturnal asthma were significantly reduced. Although not statistically significant, cetirizine also reduced albuterol use, and improved peak expiratory flow rates compared with placebo.

The mode of action of cetirizine in the clinical improvement of asthma symptoms is not established. Corren et al. have previously shown that nasal provocation with allergens results in a significant increase in bronchial hyper-reactivity as measured by methacholine sensitivity. Presumably the mechanism of action for this effect is by means of propagation of the nasal inflammatory response through the airway, or systemically. Using Corren’s model, Aubier et al. evaluated the effects of cetirizine treatment. Twelve allergic patients with a positive methacholine test were studied. In a cross-over design, patients received either cetirizine, 10 mg daily, or placebo for two weeks and then underwent methacholine challenge; there was no difference between the groups. Subsequently, nasal allergen challenge was performed. Bronchial hyper-reactivity was similar for both groups an hour later, but the cetirizine-treated group had significantly less increase in bronchial hyper-reactivity at six hours. This finding would suggest that the effects of nasal allergen challenge on bronchial muscle reactivity can be blocked by cetirizine. Also it has been observed that treatment with nasal corticosteroids can block the increase in bronchial hyper-responsiveness during a natural pollen season.

In a recent abstract, Corren et al. compared a combined therapy using loratadine 5 mg plus pseudoephedrine 120 mg (Claritin D) twice daily with placebo. They observed that the combined treatment was more effective in reducing asthma symptoms as well as improving pulmonary function. Since neither loratadine nor pseudoephedrine alone is effective in asthma, the combination might prove useful for this purpose. Since the combination is effective for most symptoms of allergic rhinitis, it could be speculated that control of upper airway inflammation might affect the course of asthma.

Drug Information

Name: Astemizole
Chemical Formula: C28H31FN4O
Brand Names: Alermizol, Astemisan, Astemisol, Astemison, Hismanal, Histamen, Histaminos, Histazol, Kelp, Laridal, Metodik, Nono-Nastizol A, Paralergin, Retolen, Waruzol


Allergic responses in the upper and lower airways often occur together and have many similarities in terms of pathophysiology. H1 antihistamines are effective in managing upper airway allergic reactions. The second-generation drugs are clearly safe for administration to patients with concomitant asthma. Furthermore, cetirizine and perhaps combined loratadine-pseudoephedrine therapy are also effective in reducing asthma symptoms. The mechanism of action for these treatments is unclear. Determining the role of antihistamines in the management of asthma will require additional well-controlled clinical trials. Clearly, treatment of asthma alone, without attention to concomitant nasal symptoms, may reduce the overall response in the lung.


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