Medications for Allergy

Second-generation antihistamines

The newer antihistamines are devoid of anticholinergic and sedative effects with the exception of cetirizine, which may be mildly sedating in some patients. The low incidence of side effects is attributed to their high selectivity for peripheral H1-receptors and low propensity to cross the blood-brain barrier. Three 2nd-generation antihista-mines for oral administration are currently available in the United States: cetirizine, fexofenadine, and loratadine. All appear effective in mitigating the symptoms of allergic rhinitis. Table 2 lists available agents and dosages.

Table 2 Second-generation antihistamines

Cardiotoxicity associated with astemizole and terfenadine is the most serious side effect associated with the 2nd-generation antihistamines. Serum accumulation of these agents may deleteriously prolong the QT interval. Serious ventricular arrhythmias (including Torsades de pointes), cardiac arrest, and death have ensued as a result of overdoses and concomitant use of medications that impair the metabolism of terfenadine and astemizole (potent inhibitors of cytochrome P450 3A4 isoenzymes, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, fluoxamine). These reactions and interactions have not been associated with the currently available agents. (Both terfenadine and astemizole have since been voluntarily withdrawn from the US market; terfenadine has been replaced with its nonarrhythmogenic metabolite, fexofenadine.)

Azelastine is a new topically administered 2nd-generation antihistamine that has demonstrated efficacy in improving both early- and late-phase symptoms of allergic rhinitis. Symptomatic response may be seen as early as 30 minutes after dose. In comparative trials, intranasal azelastine appears equally as efficacious as oral antihistamines but generally less effective than corticosteroids in relieving nasal symptoms. The most commonly reported adverse effects are bitter taste, application site irritation, and somnolence. Azelastine is administered 2 sprays per nostril twice daily.

After seven-and-one-half long years under FDA review, Pfizer’s antihistamine cetirizine (Zyrtec) has received marketing approval for the treatment of seasonal and perennial allergic rhinitis and chronic idiopathic hives. Cetirizine, a metabolite of hydroxyzine, is a selective inhibitor of peripheral histamine-1 receptors. This selectivity reportedly improves the potency and reduces the side effects of cetirizine (Zyrtec) relative to other antihistamines. According to the manufacturer, cetirizine has been used in more than 2.3 billion patient-days of therapy in more than 90 countries, and is the most frequently prescribed antihistamine in Europe.

In multicenter, randomized, double-blind trials involving adults and children (aged 12-16 years) treated for up to eight weeks, cetirizine significantly reduced symptoms of seasonal and perennial allergic rhinitis (nine trials, 5-10 mg/day) and of chronic idiopathic urticaria (two trials, 5-20 mg/day). Generally, the 10 mg dose was superior to the 5 mg dose, and the 20 mg dose gave no added benefit.

In comparative trials, cetirizine proved to be at least as effective as, and in most cases superior to, chlorpheniramine (Chlor-Trimeton, Piriton, Chlor-Tripolon), hydroxyzine (Vistaril, Atarax), astemizole, terfenadine, and loratidine (Claritin) for reducing symptoms of allergic rhinitis (nasal itching and congestion, sneezing, postnasal discharge, and redness, itching and watering of the eyes. In asthmatics with allergic rhinitis, cetirizine safely reduced allergic symptoms without exacerbating the asthma. Indeed, in healthy volunteers cetirizine actually blocked bronchoconstriction when histamine was given by nebulizer.

In clinical trials involving patients with hives, cetirizine was more effective than placebo and at least as effective as terfenadine, hydroxyzine, and aztemizole for alleviating wheal, pruritus, and erythema. Volunteers given histamine by intradermal injection responded to a single 10- mg dose of cetirizine; skin wheal and flare reaction was inhibited within 20 minutes in 50% of subjects and within one hour in 95% of subjects. This activity persisted for at least 24 hours. In studies conducted for up to 12 hours following cutaneous challenge, cetirizine inhibited the allergic inflammatory response (late phase recruitment of eosinophils, neutrophils, and basophils).

Cetirizine (Zyrtec) is well tolerated. The most common side effects in clinical trials were somnolence, fatigue, dry mouth, pharyngitis, and dizziness. These effects were mild or moderate and, except for sedation, their incidence was not significantly different from placebo. Because some of the newer antihistamines can cause adverse cardiac effects, cetirizine has been evaluated extensively for eletcrophysiologic activity and drug interactions. Terfenadine (Seldane/Dow) and astemizole (Hismanal/Janssen) can cause conduction abnormalities when administered concurrently with a variety of drugs. By contrast, cetirizine did not demonstrate any clinically significant effects on the QTc interval, even in high doses (60 mg, six times the recommended dose) and in combination with ketoconazole, erythromcyin, or azithromycin. No pharmacokinetic interactions were observed with pseudoephedrine, antipyrine, ketoconazole, erythromycin or azithromycin. The only drug interaction found was with theophylline, which reduced cetirizine clearance by 16%. Cetirizine had no effect on theophylline pharmacokinetics.

Cetirizine (Zyrtec) is rapidly absorbed orally, with peak serum concentrations achieved within one hour. Food delays absorption and reduces the peak blood concentration, but has no effect on the extent of absorption. The mean elimination half-life is about eight hours. Cetirizine undergoes minimal hepatic metabolism and is excreted primarily in the urine; 70% of the dose is recovered in the urine and 10% in the feces, for a combined total recovery of about 80%. Approximately 50% of the dose is excreted in the urine as unchanged drug. Because of low first-pass metabolism and extended half-life, cetirizine can be given once daily. The drug is available in 5 and 10 mg tablets, but most patients respond best to the 10 mg, given once daily with or without food. Since cetirizine (Zyrtec) has the potential to cause somnolence, patients should be cautioned against driving or operating dangerous machinery. Concurrent use with alcohol or other CNS depressants should be avoided.

It is well-known that people in certain parts of the planet are far more likely to suffer from allergic rhinitis than in other parts, though it is not so clear why that happens. In Denmark, just over one in every 100 visits to a family physician involves seasonal allergic rhinitis, though in Britain the figure is one in 50 and in Australia almost one in 10. The disease is more of an urban than a rural phenomenon, a fact which has led many researchers to point a finger at air pollution as an aggravating condition.

Air pollution may indeed play a role in the increased incidence of this condition, perhaps because gases such as ozone and nitrous oxide are harming epithelial cells, the bloodless surface covering of human tissues, glands, and organs. But one study suggested that the role of air pollution may have been exaggerated. The children of Leipzig, despite breathing the notoriously polluted and sulfur dioxide-laden air of former East Germany, were found to have lower rates of rhinitis than children in the western, alpine city of Munich.

Physicians and rhinologists have traditionally divided allergic patients into those whose symptoms were seasonal and those who suffered all year round. Yet a single patient with a number of seasonal reactions to allergens that peak at different times of year may appear to have a year-round allergy. In any case, an individual with severe perennial symptoms should receive different drug treatments from an individual with mild seasonal symptoms.

For the person who suffers moderate, occasional allergic rhinitis symptoms, there are a variety of pharmacological allies available. Allergen avoidance is, as always, the ideal solution, but it may prove practically impossible for allergy sufferers who have no choice but to share the air they breathe with allergenic pollen. It helps, however, to know when the pollen count of a particular allergenic plant is going to begin climbing, and when it will peak, in order to begin therapy beforehand.

Treatment may include the use of non-sedating oral antihistamines, or topical antihistamines or so-called mast cell stabilizers to the nose and eyes. Mast cells act as receptors for the allergenic pollen, and for the antibody immunoglobulin E which the body uses to defend itself. Its reaction to these signals is to release substances such as histamine that worsen rhinitis symptoms.

Oral antihistamines, which are used to prevent this histamine reaction, offer a number of alternatives in terms of speed of onset and duration of effect for the treatment of milder seasonal rhinitis, available under names such as terfenadine, cetirizine (Zyrtec), astemizole (Hismanal) and acrivastine (Semprex). Topical antihistamines such as levocabastine (Livostin) and azelastine (Astelin), however, are becoming more widely used because their effect can be concentrated on the most affected organ. Topical sodium cromoglycate, long used in treatment of allergic rhinitis symptoms, still has a place today because the absence of significant side effects permits regular use without worry.

Those who suffer from more severe forms of seasonal allergic rhinitis should be treated according to whether they are primarily eye sufferers or primarily nose sufferers. If their symptoms are mostly in the nose, they should receive topical nasal steroids before the beginning of the pollen season to minimize early damage to cells and inflammation, which would release aggravating substances such as histamines and tryptase. Eye treatment may also be necessary for mostly nasal sufferers.

If the eye is the source of most discomfort, choices are limited to the topical use of sodium cromoglycate in conjunction with nasal steroids to lessen general irritation. The only readily-available alternative to that is an oral antihistamine.

Should allergic rhinitis be really severe and treatment beyond the limits of such drugs, the patient will probably need to see a specialist who may, in a crisis, recommend short-term systemic corticosteroids. Immunotherapy may also be considered at this juncture. These more drastic treatments represent the weapons of last resort against seasonal allergic rhinitis at present, but with allergic mechanisms better understood every year, it may not be that way for long.