Medications for Allergy

A young man presents in late May. He asks what you can recommend for hay fever. On questioning, he tells you that he has not had hay fever before, but some of his friends get it and he thinks he has the same thing. His eyes have been itching a little and are slightly watery, and he has been sneezing for a few days. His nose has been runny and now feels quite blocked. He will not be driving, but is a student at the local sixth-form college and has exams coming up next week. He is not taking any medicines.

The pharmacist’s view

This young man is experiencing the classic symptoms of hay fever for the first time. The nasal symptoms are causing the most discomfort; he has had rhinorrhoea and now has congestion, so it would be reasonable to recommend a corticosteroid nasal spray, provided he is aged 18 years or over. If he is under 18 years, an oral or topical antihistamine could be recommended, bearing in mind that he is sitting for exams soon and so any preparation that might cause drowsiness is best avoided. His eyes are slightly irritated, but the symptoms are not very troublesome. You know that he is not taking any other medicines, so you could recommend acrivastine, loratadine or cetirizine. If the symptoms are not better in a few days, he should see the doctor.

The doctor’s view

A corticosteroid nasal spray is likely to be more effective. If he cannot use the OTC product because he is under 18 years, acrivastine (Benadryl), loratadine (Claritin) or cetirizine (Zyrtec) would be worth a try. Even though they are generally non-sedating, they can cause drowsiness in some patients. The student should be advised not to take his first dose just before the exam. If his symptoms do not settle, then referral is appropriate. He may benefit from sodium cromoglicate eye drops if his eye symptoms are not fully controlled by the antihistamine. It is often worthwhile trying an older antihistamine as an alternative because some people are unaffected by the sedative properties.

Comparative outdoor study of the efficacy, onset and duration of action, and safety of cetirizine (Zyrtec), loratadine (Claritin), and placebo for seasonal allergic rhinitis.

Cetirizine (Zyrtec) is an oral antihistamine taken once daily that goes to work rapidly. Believed to be a useful new drug in the control of seasonal allergic rhinitis, it had never been subjected to a controlled test in real outdoor conditions until May, when doctors assembled two groups of allergy sufferers in city parks in San Diego and Iowa City.

Test subjects were invited to sit in the park for most of two consecutive days and keep diaries detailing their experience of symptoms. They received one dose of cetirizine, or of loratadine (Claritin) — another new antihistamine — or of a placebo which, of course, had no effect on allergy symptoms and was intended as a control. All drugs were administered while patients were blindfolded.

Cetirizine (Zyrtec) was found to significantly lower the severity scores of the major symptom complex (MSC), one of two scales that researchers use to determine how bad an allergic reaction is. The MSC score is a compound of the frequency and severity of symptoms like sneezing, nose-blowing, sniffles, runny nose, itchy nose and watery eyes.

The total symptom complex (TSC) also measures itchy eyes or ears, itchy throat, cough, and postnasal drip. With these four symptoms also taken into account, cetirizine was again found to produce results significantly better than placebo.

Interestingly, loratadine produced almost exactly the same results as the placebo, both in MSC and TSC scores, and in patients’ appraisals given at the end of the test. Subjects were in fact more satisfied with placebo and more likely to see an improvement in their condition with placebo than with loratadine. Moreover, in three of the four periods this experiment was broken into, placebo was objectively shown to cause a greater reduction in MSC severity scores than loratadine. In other words, this antihistamine was essentially revealed to have been of no clinical benefit to the subjects involved in this test.

In terms of side-effects, patients taking loratadine were twice as likely (22.6%) to report headaches than those on cetirizine (10.8%). However, it should be borne in mind that 16.1% of the placebo group also reported headaches, so headaches were not necessarily side-effects of antihistamine use. Drowsiness was more prevalent in the cetirizine group (12.9%) than in the loratadine group (5.4%) or the placebo group (2.2%), though the cetirizine cohort was the only one that didn’t report any nausea, fatigue or abdominal pain.

Rates for dizziness and throat inflammation were actually highest among the takers of placebo, which suggests that these symptoms, when they occur after taking antihistamines, are not side-effects but coincidences. In fact, with the single exception of drowsiness, none of the side-effects commonly attributed to antihistamines occurred more frequently in the medicated group than in the placebo group. Fewer cetirizine patients reported side-effects of any kind than did placebo patients. All of this suggests that most so-called side-effects were really just the upset stomachs, headaches and physical tiredness that come over all of us from time to time.

Finally, while this study appears to discredit the usefulness of loratadine (Claritin), it should be noted that other studies, some of them conducted over a much longer trial period, have shown loratadine to relieve allergy symptoms. More testing remains to be done in this field before we find a definitive answer.

Questions – Answers:

1. How long does it take to know whether a person responds well to a drug or should try another one?

We would prescribe one drug first and see how it worked and then possibly switch to another if the first were not successful. We would look at results both in terms of the good news and bad news. We’re concerned not only with the benefits patients receive from a medication, but also the potential adverse effects. We’ll change medications for both those reasons, either lack of efficacy or for detrimental effects. The response with antihistamines is very fast, so patients know within a week or so whether they’re going to respond to a medication. At that time it would be reasonable for a patient to tell his or her doctor that something isn’t working or that an adverse effect has developed.

2. Would there be any benefit to using the two drugs together?

Probably not. They work in the same way, by blocking histamine receptors, and if one is not adequately effective, adding a second will not usually be more beneficial. Adding a second class of medication such as a decongestant or corticosteroid may make more sense.

3. Are different drugs better at different times of the year or for different varieties of pollen?

No. The basic mechanism of allergy is the same, whether it’s due to pollen, cat hair or dust mites. The response is produced by a chemical reaction initiated by the release of chemical mediators, and the itching, sneezing and stuffy nose are the same.

4. Is the effect of cetirizine changed by the use of other medications?

Allergy drugs don’t often interfere with each other, and a decongestant won’t make the antihistamine less effective.

5. Are there any long-term effects of using antihistamines?

No, there’s no cumulative effect. They only work when you take them, which means that not only is there no negative cumulative effect, there’s also no positive cumulative effect. If people have ongoing symptoms, they would often be better off taking their medication on a routine basis. People with seasonal problems may be better off taking antihistamines every day on a preventive basis. Just like brushing your teeth or wearing your glasses, it’s a way of managing your body to keep it healthier.

Comment medforallergy.com:

There are an increasing number of people with allergies, and they need to know that they don’t have to suffer. There is a greater understanding of the mechanism of allergies and an increasing number of effective agents to reduce those symptoms. People with allergies often don’t feel well and don’t perform as well at work or at school; allergies interfere with them socially, psychologically, emotionally. Some people treat themselves with over-the-counter medications, and these have a higher incidence of adverse effects, particularly sedation. I would encourage people to consult their physician about prescription drugs that will have fewer adverse effects.

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.

Nonsedating Antihistamine and Antihistamine / Decongestant Drug Interactions