CHAPTER 7
Pharmacotherapy of Allergic Rhinitis
There is little doubt that the best treatment of inhalant allergy is avoidance, whenever possible, as this prevents triggering of the allergic response. Unfortunately, this mode of therapy is often impractical due to the random way in which allergens are encountered, as well as patients’ disinclination to give up such things as cats, golf, gardening, or other activities that can produce allergenic exposure. On the other hand, the most definitive treatment of inhalant allergy is immunotherapy when properly administered over a sufficient length of time to affect the patient’s immune response to triggering antigens. Although the exact mechanism by which this occurs remains a source of conjecture, there is no doubt that immunotherapy presents the only hope for a “cure” for the allergic patient.
Unfortunately, there is no single therapy that is appropriate for all patients. Although avoidance at times is not practical, immunotherapy for all allergic patients would simply not be appropriate. Between these two poles lies the linchpin of treatment, which is pharmacotherapy. The patient practicing avoidance invariably comes in contact at some time with an allergen and requires the use of one or more pharmacotherapeutic agents to provide symptom relief. Furthermore, patients receiving immunotherapy do not necessarily become totally “immune” to their triggering allergens, and an overwhelming or prolonged exposure generally produces symptoms, which must be relieved by the use of these agents. Therefore, it is of prime importance for those dealing with upper respiratory allergy to understand the available pharmacotherapeutic tools and their appropriate use.
OVERVIEW OF AVAILABLE TOOLS
To understand the proper use of the drugs available to treat the symptoms of allergic rhinitis, it is necessary to have a clear understanding of the allergic reaction. This is detailed elsewhere in this text. In general, the medications available work in one or more of several areas.
Antihistamines
Classic antihistamines act primarily by competing with histamine for Hi-binding sites on the target organ. If an antihistamine is occupying that site, histamine cannot occupy the same site, so the antihistamine blocks the hista-mine-cellular interaction, which would otherwise produce consequences including sneezing, itching membranes, and rhinorrhea. Newer antihistamines also may have direct actions on inflammatory mediators, diminishing their production and/or negating their effects. For this reason, some of these preparations may be more effective than older compounds in relieving the symptoms of a reaction already in progress. It is important to note that antihistamines exert their effect primarily on the “wet” symptoms of allergy, but do not decongest nasal passages.
Decongestants
Decongestants, whether topically or systematically administered, function by causing constriction of the arterioles supplying the soft tissue of nasal turbinates. This α-adrenergic stimulation and the resultant diminution in pooled volume within the turbinates is the mechanism by which decongestants produce relief of nasal congestion.
Mast Cell Stabilizers
Mast cell stabilizers (e.g., cromolyn), which can also be thought of as a member of the class of nonsteroidal antiinflammatory agents, were originally thought to act by preventing the degranulation reaction that occurs when an antigen bridges two adjacent allergen-specific immunoglobulin E (IgE) molecules bound to a mast cell (or basophil). Although initial tests involving these drugs appeared to support this mechanism of action, later investigations suggest that these preparations also have specific mediator effects. This is certainly the case with nedocromil, and possibly some of the other new compounds in this class. In any case, these agents are capable of preventing an allergic reaction when used before an anticipated antigen exposure. When used preemptively in this fashion, these medications have their greatest utility in the management of allergic rhinitis. Conversely, the effect of mast cells stabilizers is diminished when initial use follows the onset of an allergic reaction.
Corticosteroids
Corticosteroids, as a class, exert a broad antiinflammatory action for many types of rhinitis. In the case of allergic rhinitis, the effect of this class of medications primarily addresses the late-phase reaction. The effect, however, is not confined to the late phase of the allergic reaction. For example, topical nasal steroids can attenuate the acute-phase reaction if administered regularly for 4 to 7 days. Despite the broad range of actions provided by this class of medications, it is important to realize that corticosteroids do not prevent allergic reactions, but merely attenuate the symptoms produced by the release of inflammatory mediators.
Anticholinergics
Anticholinergic agents act to inhibit mucous production in nasal mucosa. Systemic preparations are rarely used because of undesirable side effects such as dry mouth, dry eyes, and urinary retention. However, topical anticholinergics are available that are specific in their actions. These drugs inhibit rhinorrhea without producing systemic effects or affecting other symptoms of the allergic reaction.
GENERAL TREATMENT STRATEGY
The management of the symptoms of allergic rhinitis through the use of drugs can be visualized as proceeding in a stepwise fashion. Simple measures often relieve mild symptoms. Progressively more complex treatment schemes, using drugs with more potential for side effects or adverse interactions, may be necessary to treat severe problems. The first principle to keep in mind is to use the simplest, safest, and least expensive drug that will get the job done.
In an unpublished survey by Richard Mabry of patients suffering from allergic rhinitis, the attributes of drug treatment were ranked in this order of importance: efficacy, side effects, cost, and dosing regimen. A similar survey of physicians treating these patients provided a strikingly similar ranking: efficacy, side effects, dosing regimen, and cost. Clearly, both patient and physician want the medication to work, preferably without side effects that impair productivity or quality of life. After that, patients are more worried about cost than convenience, whereas the reverse is true of physicians. Keeping these issues in mind, as the reader embarks upon becoming more familiar with the individual characteristics of each class of medication that plays a role in the treatment of allergy, logical pharmacotherapeutic plans can be tailored in such a way as to better meet the individual needs of each patient, while decreasing side effects and eliminating duplication of treatment. A logical treatment algorithm is presented at the end of this chapter.
NURSE’S NOTE
The allergy care provider, who sees patients on a frequent basis to administer immunotherapy injections, must continually remind patients about the proper (and sometimes regular) use of their medications. Some key points to remember are the following:
1. Every patient with allergic rhinitis who is receiving immunotherapy should have available basic medications for symptom prevention and relief: cromolyn, antihistamines, and decongestants. Forms of all these may be obtained without prescription, although the nonsedating antihistamines do require a prescription. Patients must also be continually reeducated about what symptoms each type of medication relieves.
For patients using over-the-counter antihistamines, it may be necessary to suggest that they take them primarily at bedtime, to avoid daytime sedation. On the other hand, decongestants are best taken in the morning, to avoid the side effect of insomnia.
2. Patients must be reminded that cromolyn and antihistamines work best when used before an anticipated allergy exposure, and encouraged to use them in this way. Some patients feel that immunotherapy gives them free reign to be exposed to their allergens without ever suffering symptoms. Unfortunately, this is not always the case, especially early in a course of treatment. Pharmacotherapy always remains a necessary tool in treating patients with allergic rhinitis.
3. Patients who have been placed on nasal steroid sprays must be reminded of (or initially educated about) the proper way of administering them (as outlined later in this chapter). Furthermore, it is necessary to emphasize that these sprays are not like decongesting nasal sprays. which can be used on an as-needed basis. Rather, steroid nasal sprays should be used regularly, in the dosage prescribed, for a specific duration (usually a particular season or time of expected allergen exposure). If patients experience local side effects, such as nasal bleeding and crusting, they should discontinue the sprays and see the physician to be evaluated for septal damage.
4. If patients are placed on antibiotics for complicating infections, they must be reminded to complete the full course. Likewise, when infections produce thick secretions, patients should not depend on their antihistamines. In this situation, most patients receive from the physician a combination decongestant-mucolytic (e.g., pseudoephedrine/guaifen-esin) to be used during the infection.
PATIENT-DIRECTED TREATMENT
Most patients come to the specialist having already taken one or more nonprescription medications. If this is the case, then the patient’s response will influence the physician’s choice of further drug therapy. Before any conclusions can be drawn from this information, though, it is important to take time to review the symptom relief expectations and medication usage patterns of the patient, as these factors may impact both the real and perceived effectiveness of these treatments (e.g., use of cromolyn after exposure to an allergen, or judging the effectiveness of an antihistamine based on congestion). In this situation, simple education of the patient may be most effective. With this in mind, if over-the-counter antihistamines provided good symptom relief but caused undesirable side effects, such as sedation, the substitution of a nonsedating preparation may be a valid first step. If an over-the-counter antihistamine-decongestant combination caused undesirable stimulation, this will be even more pronounced if the decongestant were combined with a nonsedating antihistamine. If there was absolutely no response to these over-the-counter remedies, it is unlikely that prescription antihistamines and decongestants will be entirely effective in controlling symptoms.
Patients with allergy often seek relief of nasal congestion from over-the-counter decongestants administered either orally or as nose drops or sprays. The systemic decongestant present in most over-the-counter combinations is pseudoephedrine, which is also used in most prescription antihistamine-decongestant combinations. Less commonly used, and less effective, is phenylephrine. Ephedrine is still encountered, although rarely, in either over-the-counter or prescription preparations. Phenylpropanolamine, which in the recent past was a common component of over-the-counter medications and cold preparations, was recently removed from the market due to its association with stroke in some patients.
Because of the chronic and often severe nature of their disease, patients with allergic rhinitis often use topical nasal vasoconstrictors regularly for prolonged periods, resulting in the problem of rebound rhinitis. This should be a consideration for the physician when taking an allergy history, as the first step in diagnosing (and treating) a complicating medicamentous rhinitis is asking the patient about the use of decongesting nasal sprays or drops.
PHYSICIAN-DIRECTED TREATMENT: A LOGICAL APPROACH
Antihistamines
These compounds typically exert their antiallergic action by occupying H1-receptor sites on the cells of a target organ, preventing histamine released during the allergic reaction from producing the typical symptoms of sneezing and rhinorrhea. Newer antihistamines may have additional actions on other allergic mediators.
In 1937, Bovet and Staub noted the antihistaminic effects of certain phenolic ethers. By 1945, the first antihistamines for human use, diphenhydramine (Benadryl) and tripelennamine (PBZ), were introduced. By 1997, more than 20 different antihistamines and more than 100 different antihis-tamine-containing products were available in the United States. This proliferation of drugs continues, with each new preparation claiming its own advantages. However, it is necessary also to be aware of the disadvantages of each, as well as the properties that are unique for each drug or class.
Antihistamines may be classified by their chemical structure, depending on the attachment of nitrogen, oxygen, or carbon to a substituted ethylamine moiety. Classes and examples are listed in Table 7-1 and properties are summarized in Table 7-2. These drugs are effective in reducing sneezing and rhinorrhea during episodes of allergic rhinitis. Most, however, are marked by side effects of drowsiness and sedation, as well as anticholinergic effects that may cause bladder neck obstruction and increased intraocular pressure in susceptible individuals. For this reason, they carry a warning against use during the operation of machinery or other tasks that require alertness. They should also be used with caution in patients with prostatic hypertrophy and narrow-angle glaucoma.
Classification | Generic name | Trade name (example) |
|---|---|---|
Ethanolamines | Diphenhydramine | Benadryl |
Clemastine | Tavist | |
Ethylenediamines | Tripelennamine | PBZ |
Alkylamines | Chlorpheniramine | Chlor-Trimeton |
Brompheniramine | Dimetane | |
Piperazines | Hydroxyzine | Atarax |
Phenothiazines | Promethazine | Phenergan |
Piperadines | Cyproheptadine | Periactin |
Action: |
Relief of sneezing, itching, rhinorrhea |
Mode of action: |
First generation: by competitive inhibition, occupying H1receptor sites |
Second and third generation: by above action plus multiple direct actions on mediators and inflammatory processes |
Side effects: |
Conventional: sedation, anticholinergic effects (dry mouth, bladder neck obstruction, elevated intraocular pressure) |
Second and third generation: arrhythmias (see below), weight gain, hair loss, urinary retention, sedation in high doses (some preparations) |
Drug interactions: |
Conventional: CNS depressants, anticholinergics, MAO inhibitors |
Second generation: cardiac arrhythmias may result from coadministration of terfenadine or astemizole with systemic antifungals, erythromycin, clarithromycin, trolean-domycin, nefazodone (Serzone), grapefruit juice, quinine |
Another potential adverse effect of first-generation antihistamines is interaction with other drugs. For example, they may increase the sedative effects of tranquilizers, sedatives, and alcohol. In turn, monoamine oxidase (MAO) inhibitors may potentiate the sedative effects of antihistamines. A lesser-known side effect of ethylenediamine compounds is the production of gastrointestinal symptoms (e.g., nausea, constipation, abdominal pain). Paradoxical stimulation by antihistamines may be seen in infants and older patients.
Because of problems with first-generation antihistamines, a new generation of antihistamines was developed. This began with the introduction in 1985 of terfenadine, followed in 1989 by the commercial availability of astemizole. Because these compounds are relatively lipid-insoluble, they do not cross the blood-brain barrier and thus do not produce sedation. In addition, they were found not to cause excessive anticholinergic stimulation, and so could be used in patients with prostatic hypertrophy and narrow-angle glaucoma. Finally, they did not demonstrate the phenomenon of antihistamine tolerance, or “tachyphylaxis,” which had been observed with first-generation compounds.
Because they did not cause unwanted side effects, and because they were new, most clinicians expected these drugs to be more effective than first-generation antihistamines in controlling allergy symptoms. However, terfenadine and astemizole were determined to be equipotent with (but not better than) first-generation antihistamines such as chlorpheniramine.1
Like the preparations they replaced, terfenadine and astemizole were found to have side effects and potential drug interactions of their own. Both were noted to cause problems with urinary retention,2 but these were felt to be rare.3 Weight gain from astemizole and hair loss from terfenadine were also reported. However, the most serious and potentially catastrophic problem with these two drugs was that of ventricular arrhythmias.4
It has now been determined that administration of drugs or substances that inhibit the metabolism of terfenadine or astemizole, or the ingestion of very large doses (as in suicide attempts), may result in ventricular arrhythmias. Drugs incriminated in this regard are degraded in the same hepatic metabolic pathway as are terfenadine and astemizole, namely, the P-450 CLYP3A4 cytochrome oxidase path. Preparations that should not be given in conjunction with terfenadine and astemizole include macrolide antibiotics (erythromycin, clarithromycin, troleandomycin), systemic antifungals (keto-conazole, itraconazole), the tranquilizer nefazodone, and quinine in large doses. Even grapefruit juice (in quantities as small as 8 ounces twice daily) has been incriminated in this regard.5
Because of these adverse effects, a third generation of antihistamines has been developed, including compounds that appear to be free of cardiotoxicity. The earliest members of this class were loratadine and acrivastine. Then cetirizine (a relatively nonsedating congener of hydroxyzine) and fexofenadine (the acid metabolite of terfenadine, with equal activity but no cardiotonic side effects) were added. These preparations are generally considered to be nonsedating in normal doses, although loratadine and cetirizine in large doses apparently can cause some degree of sedation.6
A move toward topical preparations in the treatment of allergic rhinitis has included the development of several antihistamines delivered in this fashion. This concept is not new, as the effectiveness of chlorpheniramine administered as a nasal spray was reported in 1983.7 The first intranasal antihistamine introduced in the United States was azelastine, which appears to be equivalent to other antihistamines in potency. Unfortunately, a high incidence of taste perversion has been noted among patients using it. Topical nasal formulations of levocabastine have been introduced in Canada and Mexico, but introduction is pending in the United States. This preparation is said to be 15,000 times more potent than chlorpheniramine, with a duration of effect of 24 hours or more and few if any side effects.8
As has been noted, the primary effect of antihistamines is to diminish pruritus, sneezing, and rhinorrhea. The choice of the drug employed depends on the physician’s experience, the patient’s circumstances, and (often) the patient’s response to samples of various antihistamines. Within those parameters, “whatever works” is generally the best drug. Representative second- and third-generation antihistamines are listed in Table 7-3.
Antihistamine | Formulation | Adult/pediatric dose |
Second generation: | ||
Terfenadine (Seldane)* | Tablets, 60 mg | 60 mg BID |
Astemizole (Hismanal) | Tablets, 10 mg | 10 mg daily |
Acrivastine (Semprex D)** | Tablets, 8 mg | 8 mg TID |
Loratadine (Claritin) | Tablets, 10 mg | 10 mg daily |
Syrup, 1 mg/ml | 2-12 year, 5 mg daily | |
Ketotifen (Zaditen) | Tablets, 1 mg | 1 mg BID |
Syrup, 1 mg/ml | >3 year, 1 mg BID | |
Ebastine (Ebastel) | Tablets, 10 mg | 10 mg daily |
Third generation: | ||
Fexofenadine (Allegra) | Capsules, 60 mg | 60 mg BID |
Cetirizine (Zyrtec) | Tablets, 10 mg | 10 mg daily |
Syrup, 5 mg/ml | 6-11 year, 5-10 mg daily | |
Topical: | ||
Azelastine (Astelin) | Solution, 0.1% | 2 sprays/nostril BID |
Levocabastine (Livostin) | Suspension, 0.5 mg/mL | 2 sprays/nostril BID |
* Seldane was removed from the U.S. market in February 1998.
** Also contains 60 mg of pseudoephedrine.
Antihistamine-Decongestant Combinations
Antihistamines may be prescribed alone or in combination with a decongestant. In the latter situation, the α-adrenergic agonist drug is added to relieve nasal congestion, which is the major portion of the allergic symptom complex that is not addressed by antihistamines alone. As is the case in over-the-counter combinations, the decongestant most commonly combined with an antihistamine is pseudoephedrine, in a total daily dose of 180 to 240 mg. The next most common orally administered decongestant is phenylpropanolamine, the daily dose of which should not exceed 150 mg. Much less utilized is phenylephrine (average daily dose, 40 mg), which is useful as a topical vasoconstrictor but less effective when administered systemically. Although one of the earliest treatments for allergic rhinitis was a combination of ephedrine and amobarbital (Amytal), ephedrine is now rarely used as a systemic decongestant. Properties of decongestants are summarized in Table 7-4.
Action: |
Relief of nasal congestion |
Mode of action: |
α-adrenergic stimulation, producing vasoconstriction in stroma of inferior turbinates |
Side effects: |
Topical: habituation (rebound rhinitis), systemic effects (see below) |
Systemic: stimulation (cardiovascular and CNS), anorexia |
Drug interactions: |
Tricyclic antidepressants, MAO inhibitors, p-adrenergic blockers, antihypertensives, CNS stimulants |
