Medications for Allergy

Allergic rhinitis is an IgE-mediated inflammatory disease of the nasal mucosal membranes characterized mainly by sneezing, rhinorrhea, nasal pruritis, and congestion. It is the most common form of rhinitis, affecting 20 to 40 million Americans annually, and it is considered one of the most prevalent chronic diseases in the United States. It is also well documented that allergic rhinitis can negatively impact the quality of life and contribute significantly to loss of work productivity.

Allergic rhinitis may be categorized as seasonal “hay fever” or perennial (when symptoms persist year-round). Often, patients may react to multiple allergens and have seasonal exacerbation of symptoms in addition to perennial rhinitis. Tree, grass, and weed pollens are common seasonal allergens because they become airborne in large concentrations during a particular season of the year. Important perennial allergens include house dust mites, indoor molds, animal dander, and occupational allergens.

Management overview

Treatment options for allergic rhinitis include allergen avoidance, use of pharmacological agents for prevention and control of symptoms, and allergen immunotherapy for desensitization of patients in whom avoidance strategies and pharmacotherapy have failed to produce a satisfactory response.

Allergen avoidance

Whenever possible, environmental control measures should be emphasized as a fundamental part of the treatment plan. For instance, patients with pollen or outdoor mold allergies should remain in closed environments whenever possible. Patients sensitive to dust mites should enclose all mattresses and pillows with allergen-proof casings and eliminate carpeting, if possible, to reduce exposure; bedclothes should be frequently laundered in hot water to remove allergens. Although not always feasible, patients with animal allergies should consider removal of pets from home.

Antihistamines

Antihistamines (H1-antagonists) are typically prescribed as first-line agents for allergic rhinitis. They exert their actions by competitively antagonizing histamine at the H1- receptor sites and thereby suppress symptoms attributable to histamine release, such as sneezing, rhinorrhea, nasal itching, conjunctival itching, and lacrimation.

Antihistamines, however, are generally not effective in alleviating nasal congestion.

First-generation antihistamines

Various 1st-generation antihistamines are widely available with and without prescription. Although effective and economical, the usefulness of these agents is limited by their sedative and anticholinergic properties due to penetration of the central nervous system and poor receptor specificity.

All 1st-generation antihistamines are sedating to some degree and may cause performance impairment in 10% to 40% of users. In general, the ethanolamines (e.g., diphenhydramine) and phenothiazines (e.g., promethazine) are the most sedating. The ethylenedi-amines (e.g., pyrilamine) cause moderate sedation, and the alkylamines (e.g., chlorpheniramine, brompheniramine) are considered the least sedating. The use of lst-generation antihistamines at bedtime, which are less expensive, and newer nonsedating agents during the day has been advocated as a cost-saving strategy. This therapeutic approach may not be cost-effective, however, as residual effects of the bedtime dose may result in daytime sedation and performance impairment.

The anticholinergic effects of 1st-generation antihistamines (dry mucous membranes, urinary retention, blurred vision) may preclude their use in certain patients. Elderly patients are especially sensitive to these adverse effects. These older agents should be used cautiously in patients with narrow angle glaucoma or prostatic hypertrophy or in those taking other medications that may potentiate these side effects.

Although 2nd-generation antihistamines are generally prescribed due to ease of dosing and favorable side-effects profile, clinicians should be cognizant of available non-prescription antihistamines, as many patients may be self-managing with over-the-counter products (see Table 1).

Table 1 Selected 1st-generation antihistamines

Note: available OTC, often in combination with various decongestants, analgesics, and antitussives

Diagnosing and treating allergies

When a physician is evaluating a person for allergies, there are several steps involved. First, the patient’s history is taken. Then, the patient is examined. Depending on the patient’s symptoms, several tests might be done. Since some medications (especially antihistamines) can affect test results, a person should ask the health care provider which medications should be stopped days before the testing is to take place.

Skin (scratch or puncture) testing

In this test, a variety of substances that are common to the region in which the person lives are evaluated. Tiny amounts of fluids containing allergens such as pollen, animal dander, dust mites, and molds are placed just under the surface of the skin. Within 15-20 minutes, swelling occurs at the site of any substance to which the person has an allergy. The severity of the reaction can indicate the person’s level of sensitivity.

Virtually painless, this form of testing offers immediate results and almost no risk of serious allergic reaction. This test is usually used to assess reactions to respiratory allergens.

Intradermal testing

These tests are similar to scratch or puncture tests, but are slightly more involved. Tiny amounts of allergens are injected under the skin. Intradermal tests are often done if the scratch or puncture test results are not complete or useful.

Blood (RAST) testing

In these tests, a person’s blood is combined with an allergen to determine whether any IgE antibodies react. If there is a reaction, there is likely an allergy to the tested substance. Although slightly more expensive than skin tests, this test is relatively painless, offers fast results, and provides almost no risk of serious allergic reaction. Blood testing is often used to evaluate reactions to insects and medications in people for whom skin testing is not an option.

Patch testing

For this type of test, allergen-specific adhesive patches are placed on a person’s skin and left for 72 hours. The sites that show swelling or redness indicate an allergic response. This form of testing is commonly used to assess reactions to metals and cosmetic additives.

Provocative testing

This type of testing is also called challenge testing. Usually, the substance in question is administered in an effort to provoke symptoms gradually. A trace amount of the allergen might be administered in an aerosol spray. The person’s reaction to the allergen indicates to the physician both the nature of and the severity of the symptoms. Provocative testing can be uncomfortable. Severe allergic reactions can occur.

An infant’s sensitivity to a food or even a food allergy might be diagnosed at home first. If a parent knows that there is a family history of food allergies, there is a way to avoid having an infant experience full-blown symptoms. By gradually introducing small amounts of new foods — one at a time — parents can isolate a reaction. If a few foods are grouped together in a single meal, it is far more difficult to figure out which one is causing the reaction. If, however, a parent already suspects that a child has a food allergy, it is best not to test this suspicion any further at home. Safer testing can be done in an allergist’s office.

A person can be treated for allergies, but not cured. The range of treatment options provides some relief for most people. As mentioned earlier, one common form of treatment involves ongoing allergen immunotherapy (also called allergy desensitization injections). Those who suffer from reactions to airborne allergens and insect stings find this form of treatment quite beneficial. Over time, a series of injections containing the offending allergens is given in an effort to build the immune system‘s defenses against them.

When a person first begins allergen immunotherapy, a very diluted form of the allergen compound is given. Gradually, more of the substance is added to the injection. Eventually, the allergist determines that the optimal dose has been reached. The allergist could also determine that the person is at risk of developing an allergic reaction if the injections continue. Whatever the determination is, at this point the therapy ends.

The entire process of allergen immunotherapy can last for years. There is some evidence that this type of therapy works by tricking the immune system. As increased amounts of the allergen are injected, the immune system starts to produce a blocking antibody (IgG). The IgG antibody competes with the allergy antibodies (IgE) for the allergen, takes it over, and then does two things that halt an allergic reaction: It prevents the mast cells from activating and it stops the release of histamines.

Most of the oral medications that are used to treat allergies fall into two categories: antihistamines and decongestants. Antihistamines prevent a histamine — a chemical that the body produces during an allergic reaction — from taking effect. Antihistamines are available over-the-counter in tablet and liquid form; they are also available as tablets, liquids, and injections with a prescription. Decongestants work by shrinking blood vessels and decreasing fluid leakage so that nasal congestion is reduced. Both liquid and tablet forms are available as over-the-counter and prescribed medications. Often, antihistamines and decongestants are combined in a single medication to address a greater number of symptoms.

For an acute allergic reaction that involves a great deal of congestion, a physician might recommend a decongestant in the form of drops or a nose spray. The over-the-counter form of medication should not be used for more than three or four consecutive days. Otherwise, it can actually increase nasal congestion. A prescription form of this medication can be used for a longer period without producing this side effect.

Nasal steroid inhalers or sprays can offer fast relief by reducing inflammation and swelling, as well as by slowing the rate at which histamines are released. These sprays deliver a very fine mist directly into the lining of the nose. They temporarily constrict the blood vessels in the swollen tissues within the nose. They also temporarily open a larger passage to allow for the free flow of air. When the effects of the spray wear off, the swelling returns. Sometimes, the swelling has grown worse. When this happens, most people just reuse the spray. Unfortunately, a series of brief periods of relief can lead to longer bouts of congestion. It is important to note that decongestant nasal sprays can be overused. If a person does overuse these sprays, his or her heart rate can increase and blood pressure can rise.

The good news is that most allergy symptoms can be treated easily and safely. The bad news is that, on rare occasions, an allergic reaction can be deadly. As we discussed earlier, anaphylaxis is a severe, sometimes fatal, allergic reaction. It is usually treated with an injection of epinephrine, and antihistamines and steroids are also given. The sooner the allergic person gets treatment, the less severe the symptoms will be. Epinephrine can stop the progression of anaphylaxis; antihistamines and steroids cannot. Antihistamines and steroids should never be given instead of epinephrine, because, while they can help recovery, they cannot reverse the symptoms of anaphylaxis.

Often, a person who has a severe food allergy learns about it only after exposure to the trigger. Such exposure can happen as a result of breathing in or eating the substance. After the symptoms are treated, contact an allergist for follow-up care. The allergist can help determine what trigger caused the reaction. This is very important in preventing anaphylaxis from happening again.

Although triggers that are foods may be easy to avoid, it might be trickier when the allergen is a food additive. This is why it is crucial to be under a doctor’s care. If anaphylaxis happens again, the person might already have an injection of epinephrine handy. Using this medicine will keep symptoms under control until the person can be taken to a hospital. An allergist can even offer treatments that can help build immunity to some triggers. For example, if anaphylaxis is triggered by insect stings, ongoing allergy shots can help build tolerance to the venom.

Here are some suggestions for what can be done to assist someone who is experiencing anaphylaxis:

1. Ahead of time, learn enough about the symptoms to recognize when the reaction is occurring.

2. Get medical help as soon as possible.

3. Do not allow a person who is undergoing this type of reaction to drive.

4. Even if the person receives treatment at the location where the reaction occurred, it is vital that he or she go to an emergency room, where the condition can be monitored.

5. Make a note of what could have caused the reaction and what amount of time elapsed between exposure and reaction. Having this information could help to prevent a future reaction.

Preventing and controlling allergies

For most allergies, preventing or controlling symptoms requires a few simple steps. Depending on the severity and frequency of the reaction, almost all symptoms can be minimized by changes in environment and the person’s behavior. Once the triggers are known, they should be avoided. Changes to the home, school, and work environments can significantly reduce the person’s exposure to a variety of allergens.

The most important behavioral change that a person can make to help prevent and control allergies is to use all available methods of treatment. Allergen immunotherapy can help build tolerance against specific allergens. Other medications can help prevent or control symptoms that do recur. A person who suffers from allergies can also improve his or her general health by eating nutritious foods, exercising regularly, and getting enough rest.

At the very beginning of life and during early childhood, measures can be taken to help prevent some allergies. Researchers have known for some time that breast milk is far more nutritious for infants than formula, cow’s milk, or soy milk. Studies show that infants who are breast-fed are less likely to develop allergies to a variety of substances. The lower incidence of allergy in children who were breastfed might result from the mother’s immunities being transferred to the child through the breast milk.

Asthma and Allergies: The Science Inside

Another way to help lower the risk of allergy — specifically, peanut or nut allergy — involves not exposing children under the age of three to peanut products. Allergists believe that one reason that there are so many children in the United States with peanut allergies might be the extensive early exposure they have to peanuts. Many young American children regularly eat foods that contain peanuts or peanut products.

In the case of life-threatening allergic reactions, prevention is possible only if the trigger can be completely avoided. This is difficult to do, so additional measures must be taken to control symptoms. If a person has had an anaphylactic allergic reaction in the past, a physician might suggest carrying a supply of epinephrine at all times.

Regardless of whether the trigger is or is not known, the symptoms certainly are. Having a supply of a medication that can offer immediate relief will help get the symptoms under control until the person can be taken to a hospital. Since this medication is given in the form of an injection, the person who carries it must know how to administer it. However, because there is a possibility that the person having the reaction might be incapable of completing the injection, a companion should also know how to administer it. Another measure that can help save the life of a person known to have anaphylactic reactions is even easier to do: Have the person wear a medical bracelet that indicates to medical personnel and others the nature of the person’s allergic condition and any possible triggers.

Although some of the symptoms of these two conditions are similar, first-line treatment differs, making distinction important.

Occasionally, minor medical conditions for which patients seek advice for self-treatment resemble each other. One of the most common conditions presented to pharmacists is the common cold. However, allergic rhinitis, which affects 20% of the U.S. population, mimics the common cold in many respects.

The patient may not be able to distinguish one from the other, but the pharmacist can facilitate patient self-treatment and/or triage. Treatment goals are different for each condition.

Etiologies

Etiologies of the common cold and allergic rhinitis are markedly different. Viruses cause the common cold.

At least half of cold episodes are produced by the the rhinovirus family. Other cold pathogens include coronavirus, influenza A or B virus, parainfluenza virus, respiratory syncytial virus, adenovirus, and enterovirus.

Unlike the common cold, allergic rhinitis is neither infectious nor communicable. This IgE-mediated condition may be caused by a wide variety of allergens. Allergists group the syndrome into two types: perennial or seasonal. Identifying whether symptoms exist year-round (perennial) or occur only at certain times of the year (seasonal), provide clues regarding the specific etiologic agents.

Perennial allergic rhinitis is is caused by an allergen that the patient may have contact with at virtually any time. Examples include automotive exhaust, cosmetics, hair spray components, pillows, cigarette smoke, household cleaning substances, toiletries, upholstery, and house pets. One of the most common perennial offenders is the house dust mite. This microscopic creature is found in incredibly high numbers throughout the house, especially where people spend a lot of time, such as the bedroom and livingroom. The mite ingests protein, including skin cells shed from humans or animals. Patients are usually not allergic to the mite itself, but to the feces it yields to the environment.

Seasonal allergic rhinitis is caused by an allergen present only during certain times of the year. Patients might experience the most severe symptoms when flowering plants are producing pollen, when ragweed is blooming, or when wheat is being harvested. Trees, grasses and all types of weeds may sensitize patients. During the rainy season, residual moisture causes rampant growth of molds and mildews, other common causes of seasonal allergic rhinitis.

Manifestations

Common cold symptoms vary somewhat depending on which viral invader is responsible. However, virtually all cold viruses produce some degree of nasal blockage, runny nose, cough, and sore throat. Patients may also experience headache or other body aches, occasional sneezing, weakness, dizziness, and postnasal drip. The patient may also note that one or more family members, coworkers
or playmates have the condition. Symptoms may occur 3–4 times yearly, each lasting for a period of 2–3 days (sneezing, sore throat) to as long as 2 weeks (cough, nasal discharge, postnasal drip, throat clearing).

In contrast to common cold symptoms, which exhibit a gradual onset and slow progression, onset of allergic rhinitis can be sudden. Some allergic rhinitis symptoms are distinctive and others nonspecific. Among the nonspecific symptoms are rhinorrhea and nasal congestion. These are considered two of the cardinal symptoms of allergic rhinitis, and they overlap with the common cold. Other signs and symptoms of allergic rhinitis can help differentiate it from the common cold. For instance, allergic rhinitis produces nasal pruritus, absent in the common cold. Itch often occurs in the posterior nose, where it cannot easily be alleviated. As a result, the patient may wrinkle the nose constantly (“bunny nose”), and may rub the nose upward with the heel of the hand in a gesture known as the “allergic salute.” Allergic rhinitis produces sneezes that are different in both quality and quantity from those of the common cold. Common cold sneezes are infrequent and deep, occurring as an attempt to relieve or clear bronchial or nasal congestion. In allergic rhinitis, implantation
of an allergen on the nasal mucosa causes a paroxysm of sneezes (as many as 10–20), which may be light and relatively quiet. The cold rarely causes ophthalmic problems, which are frequently a component of allergic rhinitis. Allergic patients may complain of a profuse, watery discharge or tearing. They may also exhibit a network of lines (Morgan’s or Dennie’s lines) that extend away from the inner
corner of the eye down-ward in a fan-like pattern. Finally, patients may have blue-black discolorations beneath both eyes. These “allergic shiners” occur when the venous network that drains the infraorbital area anastomoses with nasal vessels that are congested from allergen, causing a backup of venous blood. Allergic rhinitis is more likely than the common cold to affect the sense of smell, causing hyposmia or anosmia. The pharmacist may ask about the patient’s sense of taste, because inability to smell radically reduces the taste of foods.

Counseling Important with Common Cold and Allergic Rhinitis

Certain drugs and conditions contraindicate some self-treatments for allergic rhinitis and the common cold. Ingredients such as dextromethorphan and pseudoephedrine may produce a deadly interaction when taken with monoamine oxidase inhibitors. Phenylpropanolamine (the safety of which has been recently brought into question by the FDA) should never be taken with any other product containing phenylpropanolamine or pseudoephedrine. A sore throat accompanied by fever, headache, rash, inflammation, nausea or vomiting should not be self-treated. Similarly, cough accompanied by rash, fever or persistent headache and chronic cough as seen in smoking, asthma, or emphysema should not be self-treated. Patients with hypertension, diabetes mellitus, thyroid disease or
prostatic hypertrophy should avoid products containing decongestants. Self-treatments may be accompanied by numerous other warnings. Pharmacists should ensure patients understand these warnings and precautions.

Complications

The common cold is a self-limiting condition for most patients, although some develop complications, such as otitis media and sinus infections. Allergic rhinitis is more likely to produce complications because of its recurrence. Patients who have perennial allergic rhinitis may be affected virtually constantly. Thus, allergic rhinitis is now recognized as a risk factor for the development of conditions such as asthma, sinusitis, otitis media, and nasal polyps.

Prevention

With both conditions, prevention is the preferable treatment strategy. The primary method of transmission of the common cold virus is transfer of the virus to the nasal, oral or ophthalmic mucosa through contaminated hands. Seemingly innocuous activities such as wiping a tear from the eye can allow successful inoculation. Washing the hands frequently helps prevent infection.

Prevention of allergic rhinitis is achieved by avoidance of the allergen and control of the environment to eliminate or minimize the allergen (e.g., weekly laundering of bedding, carpet removal, using dust mite sprays, getting rid of pets, smoking cessation, installation of HEPA filters).

How to Treat A Cold and Hay Fever

Two common conditions are the cold and allergic rhinitis (hay fever). They may cause similar symptoms, but the cold is caused by a virus and hay fever is caused by an allergic reaction. Their treatments also differ, but both can be relieved with nonprescription products a pharmacist can help you select.

Treatment for the Common Cold: With the common cold, the nose alternates between being congested and running. Congestion may be treated with a topical decongestant (spray, inhalant, or drops) or an oral nasal decongestant. One example of a topical decongestant is the chemical oxymetazoline, which should be used no more often than every 12 hours. Never exceed the time of use on the label of any spray or drop (usually three days). The chemicals in the product can damage your nose. If you have already been using a drop or spray beyond three days, you must stop to allow the nasal tissues to return to nor-mal. If you choose an oral nasal decongestant, an ingredient such as pseudoephedrine is safe and effective.

The only antihistamines proven safe and effective for runny nose and sneezing of the common cold are clemastine, doxylamine and chlorpheniramine. Sore throat caused by a cold may be self-treated if the pain is minor. Do not treat it more than 2 days. If sore throat lasts more than 7 days, you should see a physician. Lozenges for sore throat contain ingredients such as benzocaine, menthol, dyclonine, phenol/sodium phenolate, hexylresorcinol and benzyl alcohol. Oral painkiller products such as acetaminophen, ibuprofen, ketoprofen or naproxen are also helpful and soothing.

Cough due to colds may be safely treated for as long as 7 days. If the cough is productive (brings up mucus), the ingredient guaifenesin can help break up the chest congestion (water intake is also important). If the cough is dry and hacking, a cough suppressant (dextromethorphan) can stop the cough.

Treatment for Hay Fever: When the problem is hay fever, antihistamines act against the process that causes the symptoms. Many different antihistamines are effective for this purpose and help relieve runny nose, sneezing, nasal itching, and watery, itchy eyes. Recently, eye drops have become available containing naphazoline plus an antihistamine (pheniramine or antazoline). They may help eye symptoms such as tearing, redness or itch. At times, hay fever causes nasal congestion, which is not well treated by antihistamines. You may want to try using decongestant pills containing pseudoephedrine, or adhesive breathing strips, which are placed over the bridge of the nostrils and open up the nasal passages.

Patients may also choose cromolyn sodium nasal solution, which may prevent allergies if used up to one week before contact with an allergen. It also relieves runny/itchy nose, sneezing, and stuffy nose.

Ask Your Pharmacist: Your pharmacist can help you choose products containing the ingredients recommended on this page to treat specific symptoms. Be sure to carefully read all warning and caution labels on products you select. The pharmacist also can tell you if a product should not be used if you take prescription medicine.

Questions

[1] The major use of second-generation histamine Hj-receptor blockers is the treatment of which of the following complaints?

A. Cough associated with influenza

B. Hay fever

C. Motion sickness

D. Sleeplessness

[2] You see a long-distance truck driver in the clinic who complains of serious allergic rhinitis. Which of the following would be the best anti-histamine to prescribe?

A. Diphenhydramine

B. Fexofenadine

C. Meclizine

D. Promethazine

[3] Which of the following statements is correct?

A. Antihistamine agents used for allergic rhinitis have antagonistic activity against both H₁ and H₂ receptors.

B. Antihistamine agents are generally useful in the treatment of asthma.

C. Antihistamines are the preferred agent in the treatment of acute anaphylaxis.

D. Second-generation antihistamines have fewer anticholinergic effects than first-generation antihistamines.

Answers

[1] B. First-generation agents that cause sedation have been used as sleeping aids, and some have antiemetic effects.

[2] B. The other agents are sedating.

[3] D. Second-generation antihistamines have less sedating and anticholinergic side effects than first-generation agents.

Pharmacology pearls

Second-generation antihistamines do not penetrate the blood-brain barrier and have little sedative effect.

Antihistamines are of little or no benefit in treating the common cold.

Histamine, β-aminoethylimidazole, is formed in many tissues by decarboxy-lation of the amino acid L-histidine by the enzyme histidine decarboxylase. Mast cells and basophils are the principal histamine-containing cells in most tissues. Histamine is stored in vesicles in a complex with heparin and released by either an immunologic trigger or following a mechanical or chemical stimulus. Once released, histamine produces a number of responses including local vasodilation, transudation of fluid through endothelial cells, and stimulation of nerve ending, producing pain and itching. In the lung, histamine is a bronchoconstrictor, and this action is magnified in patients with asthma. Histamine has actions in the GI tract and causes contraction of smooth muscle; it is also a potent secretagogue for gastric acid secretion, pepsin, and intrinsic factor. In the brain, histamine acts as a neurotransmitter.

The actions of histamine are mediated by four distinct membrane receptors that are coupled to G-proteins. The H_: receptor, located in smooth muscle cells, endothelium, and brain, is coupled to increased diacylglycerol and Ca²⁺ release. The H₂ receptor is located in gastric mucosa mast cells, immune cells, and brain, and is coupled to increased cAMP. There is no clinical pharmacology yet for H₃ (located in the brain and peripheral neurons) or H₄ (found on eosinophils and neutrophils) receptors, but both of these receptors are targets for therapeutic agents and are under intense investigation. Histamine itself has a variety of untoward effects and is useful only diagnostically to assess bronchial hyperreactivity.

Antihistamines

Compounds that block the active state of histamine H_: receptors have been used for years and are widely marketed both as prescription and over-the-counter medications. The current group of available drugs can be divided into first-generation and second-generation agents. In general, first-generation agents can cross the blood-brain barrier, and they have a number of effects in the brain, including sedation and reduction in nausea. Table Currently available antihistamines lists some currently used H_: antagonists.

Table: Currently available antihistamines

I = available in an injection preparation; ANTI-CHOL = Anticholinergic

All of these drugs block the action of H₁ receptors, and they do not possess significant affinity for the H₂ receptor. However, many of the first-generation agents have significant anticholinergic activity, and this is responsible for a significant degree of their central effects. Second-generation agents are less lipid-soluble and do not penetrate the blood-brain barrier and hence have much fewer central adverse effects.

The major use of H₁-receptor blockers is in the treatment of allergic reactions. Histamine is released by IgE-sensitized cells, especially mast cells and antihistamines can reduce the rhinitis, conjunctivitis, sneezing, and urticaria associated with this reaction. They are most effective in acute allergic reactions with a relatively low antigen burden, and effectiveness diminishes in chronic disorders. Antihistamines are not effective as monotherapy for bronchial asthma. Antihistamines are marketed for treatment of the common cold, but they have very limited effectiveness in this application and their adverse effects (e.g., sedation) outweigh their benefit. Some of the first-generation agents, especially dimenhydrinate, meclizine, cyclizine, and promethazine, are useful for the prophylaxis of motion sickness and vertigo. Promethazine is the most potent in this regard but has pronounced sedative activity that limits its usefulness. The sedating action of some antihistamines has been exploited in their use as sleeping aids.

Diphenhydramine is the most commonly used antihistamine in sleeping preparations. The major adverse effect of the first-generation agents is sedation. The anticholinergic activity produces atropine-like effects including dry mouth, urinary retention, and cough. Second-generation agents avoid these effects but do have adverse effects such as headache, back pain, and in the GI tract cause nausea, loss of appetite, and constipation or diarrhea. Of the presently available second-generation antihistamines, cetirizine causes the highest incidence of fatigue and somnolence (approximately 10%); loratadine appears to have the lowest incidence of this effect (approximately 1-2%). These agents may produce cardiovascular adverse effects such as hypotension, bradycardia or tachycardia, and electrocardiograph (ECG) changes.

Administration

All of the agents listed in Table Currently available antihistamines are available for oral use, and some of the first-generation agents are available for parenteral use. Topical application of diphenhydramine is useful in the treatment of minor allergic dermatologic reactions. Azelastine is administered by nasal spray.

Pharmacokinetics

Following oral administration, the Hj antagonists reach peak levels in about 2-3 hours and last 6-24 hours depending on the agent.

H₂-Receptor Antagonists

Histamine is a potent gastric acid secretagogue and this action is mediated by histamine H₂ receptors. Cimetidine, ranitidine, nizatidine, and famotidine are H₂-specific antagonists and are used to treat gastroesophageal reflux disease and peptic ulcers.

Case: Antihistamines. Questions – Answers

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.