Modern Medicine of Canada, Jan. 1990

Compared to the classic antihistamines, the newer second generation antihistamines offer a much brighter hope of effective treatment. Their lack of side effects and longer duration of action are significant improvements, as is their seemingly antiasthmatic action. Even newer antihistamines, not yet available to the public, may hold still more promise, particularly for mediator release.

Dale and Laidlaw, in 1911, identified and described the properties of histamine [1]. Besides being a potent vasoactive substance, they noted, it has many functions, one of which is that of an active mediator in the pathogenesis of human allergic diseases, such as allergic rhino-conjunctivitis, urticaria, and asthma. Vasodilatation, vascular permeability, contraction of airway smooth muscle, and an increase in mucus secretion account for much of the symptomatology of these diseases. Interest increased to find substances that could counteract these effects.

The first substance identified as having an antihistaminic effect was thymo-ethyl-diethylamine or compound F929, an amine of phenolic ether. This compound was synthesized by Ernest Fourneau in 1937 and described by Bovet and Staub in the course of their work in the department of therapeutic chemistry at the Pasteur Institute. It protected the guinea pig against lethal doses of histamine and lessened the symptoms of anaphylaxis. While it proved too weak and too toxic for clinical use, its discovery led to an unrelenting search for substances with histamine blocking activity that could be used clinically.

Work by Halpern and others in France produced the first antihistamine used succesfully in humans in 1942. This substance was phenbenzamine, or Antergan. Pyrilamine maleate, or Neo-Antergan, was produced in 1944. At the same time, scientists were working in the same field in the United States, and in 1946, diphenhydramine and tripellinamine were introduced; they are still in use today. Since 1946, many antihistamines have been produced and used extensively as the first drug of choice by physicians prescribing for patients with an allergy.

The classical antihistamines, as they are often called, have a chemical configuration more or less similar to that of histamine.

There are six classes of antihistamines (Table 1), and they are more or less equivalent in efficacy but dissimilar in their side effects.Tbese side effects help to further differentiate them and their clinical indications.

The ethylenediamines, for instance, will often cause GI symptoms and some sedation. The ethanolamines have anticholinergic effects; one of them, dimenhydrinate, is used as an antiemetic or to control motion sickness. Diphenhydramine is available as an over-the-counter sleeping preparation. The alkylamines are potent when used in small doses; while well tolerated, they have a more sedative effect. The phenothiazines also have marked anticholinergic effects and a strongly sedative effect as well. The piperazines are used to treat motion sickness; hydroxyzine is often used as a tranquilizer.

Physicians' attitudes toward the use of antihistamines have undergone some notable changes. In the late 1940's and into the 1950's, antihistamines were considered "wonder drugs" and were used to treat any disease associated in any way with allergy, including asthma.

Herxheimer, in 1948, showed that histamine could induce bronchial constriction in asthmatics. Soon afterwards, in 1951, Hawkins and Schild showed that histamine release and bronchial constriction occurred simultaneously when lung tissue of patients with allergic asthma was exposed to specific antigens in vitro. Their work suggested that antihistamines would be helpful to persons with asthma , even though, in 1950, Feinberg had written a paper showing that asthma had proved unresponsive to the antihistamines then available.

In 1955, an editorial in The Lancet stated that antihistamines were not only not beneficial to asthmatics but might even be harmful. Subsequently, antihistamines were no longer used to treat asthma. Until recently, medical students have been taught not to use antihistamines when managing asthmatics because these drugs dry up secretions and make them more viscous, thus possibly aggravating the asthma. Now things have changed. Reports have gradually appeared stating that there is no harm in using antihistamines in the treatment of asthmatics if these patients have symptoms that require the use of these drugs. The American Academy of Allergy declared in September 1988 that antihistamines could safely be used to treat asthmatics if indicated.

Histamine is one of many mediators involved in type I hypersensitivity reactions. It is stored preformed in basophils and mast cells, along with proteolytic enzymes such as tryptase and chemotactic and activating factors. These are released following antigen (allergen)-sensitized mast cell antibody reactions, together with newly formed mediators such as leukotrienes and prostaglandins. Histamine is an activator and a spasmogen responsible for vasodilatation and vascular permeability, as well as for bronchial smooth muscle contraction.

HOW DO THE ANTIHISTAMINES WORK?

Although the antigen-induced release of histamine from sensitized peripheral lymphocytes was first reported more than 40 years ago, it was not until 1966 that Ash and Schild advanced the idea that histamine's activities were mediated through two types of receptors. Their suggestion was supported by Black and co-workers in 1972. The allergy-related effects of histamine are mediated through H 1 receptors and the gastrointestinal effects through H 2 receptors.

Antihistamines are H 1 receptor antagonists, acting on the effect of histamine by competing with it for the receptors. They do not influence the release of histamine and have no effect on H 2 receptors. The binding of the antihistamine to receptors is reversible. In allergic situations the concentration of histamine is high, and to be effective the antihistamine concentration must be high to compete adequately for the receptor.

This situation unfortunately increases the side effects of the antihistamine, which limits the dosage and is thus a possible cause of therapeutic failure in some cases. When effective, the antihistamines will reduce the effects of histamine so that pruritis, edema, hypersecretion, or sneezing will diminish, as will smooth muscle contraction, to a certain extent.

SIDE EFFECTS

Side effects of classical antihistamines might be gastrointestinal (nausea, vomiting, epigastric distress, or diarrhea), though these occur fairly infrequently, or anti-cholinergic (dryness of mouth, nose, and throat), which are observed a little more often. Atropine-like effects (blurred vision or urinary retention) are rare. In children and some sensitive adults, excitement, restlessness, and irritability can occur, but the most common side effect is sedation. This sedation may vary depending on the age and sensitivity of the individual, the antihistamine used, and the dose taken. Studies indicate that sedation occurs in 10 to 20% or antihistamine users. Besides sedation, other symptoms of central nervous system depression may be disturbed coordination, dizziness, or lack of concentration. While sedation may be desirable at bedtime, it is obviously a serious side effect in the daytime, and antihistamines should not be used if patients must drive or handle equipment requiring alertness and motor coordination [2].

SECOND GENERATION H 1 ANTAGONISTS

The pharmaceutical industry has spent a great deal of time and effort in trying to reduce the side effects caused by antihistamines. Estelle Simons has said: "The perfect H 1 receptor antagonist would be highly potent and would produce clinical benefits within an hour after ingestion. It would have a duration of action of at least 24 hours and be completely devoid of undesirable effects." None of the classic H I receptor antagonists meets these criteria but newer antihistamines -the so-called second generation antihistamines - have come very close. Three new, long acting, H I receptor antagonists are now available in Canada: terfenadine (60 mg bid or 120 mg id), astemizole (10 mg id), and loratadine (10 mg id); the first two are available also in suspension form for children.

NEW ANTIHISTAMINES

These new antihistamines are different from the classic antihistamines structurally and in their pharmacodynamics. There is rapid gastrointestinal absorption of all three, though less so for astemizole if it is not taken on an empty stomach. Peak plasma levels of terfenadine and loratadine are reached within one to two hours. Astemizole is slower, although peak plasma concentrations could be attained one to four hours after a single dose. These medications differ markedly, however, in their elimination half-life. The elimination half-life of terfenadine and loratadine is 16 to 18 hours. These two drugs, like the classic antihistamines, can be stopped 48 hours before allergy tests. Astemizole, is quite different. Its elimination half-life is 20 hours, but that of its major active metabolite (desmethylastemizole) is about 12 days. Routinely, astemizole must be stopped at least 10 days prior to allergy tests. A positive histamine control is usually done because astemizole has been reported as responsible for negative tests for close to one month after discontinunation of the medication.

All three antihistamines have very different receptor binding profiles than the classic antihistamines. Although all three appear to be highly specific for H 1 sites, the receptor binding may be more complex than the simple competitive binding described for the classic antihistamines. They bind more slowly to the H 1 receptor, and once bound they dissociate very slowly and are not easily displaced from the site. This characteristic translates into maintenance of a high degree of H I receptor blockade for longer periods of time. This response helps to reduce or eliminate histamine-induced reactions during the time between doses and to improve patient compliance. In addition, it may possibly help to maintain a more adequate H 1 receptor blockade even in the presence of high tissue concentration of histamine.

Unlike first-generation antihistamines, which have a potency of about 30%, these three seem to achieve virtually 100% of peripheral H 1 receptor binding [4].

Besides the obviously longer duration of action, the most important feature of these new antihistamines is the lack of side effects, notably sedation. None of the three is entirely without sedative effect, but experiments have shown their low affinity for the cerebral H 1 receptors and their inability or limited ability to pass the blood-brain barrier. Individually of course, their effects vary.

Tester-Dalderup, in 1988, summarized the relative incidence of sedation in various studies and found that drowsiness with placebo is reported in about 10% of cases in many studies. In six terfenadine studies drowsiness was reported as occuring between 2.2 and 12.6% of cases. Astemizole was reported to cause drowsiness from 0 to 14.7% of cases in another six studies [5]. Loratadine does not appear in the comparative evaluation since evaluators comment that it is too early to express opinion on its claimed lack of sedative effects.

EFFECTIVENESS

Numerous therapeutic trials have been reported, comparing all three of the new drugs to classic antihistamines and assessing the performance of one against that of another over the years, in Canada, the United States, and elsewhere.

Terfenadine has been shown to be as effective as drugs used for comparison. Increasing the dose did not increase the drug's efficacy. Most of the studies were done in allergic rhinitis. The results in different skin disorders, including urticaria, have shown that terfenadine is superior to clemastine in reducing itching and hives, and in providing overall relief. A similar study comparing terfenadine, chlorpheniramine, and placebo showed good to excellent results in 83% of patients taking terfenadine as compared to 71% of patients on chlorpheniramine and 29% on placebo.

A number of studies have been reported relating to the effect of terfenadine on asthma. Unlike classic antihistamines, which were considered unsuitable for controlling asthma because of claims that their activity on other receptors produced adverse effects, one study has shown terfenadine to be effective against exercise-induced asthma; in another study terfenadine produced a significant bronchodilatation in mild asthmatics.

A double-blind, placebo controlled, cross-over trial of terfenadine in 52 patients with mild perennial asthma was conducted in France in 1987. Terfenadine proved to be effective in reducing patients' self-rated symptom scores and consumption of inhaled salbutamol when given at double the usual daily dosage [6]

Astemizole has been shown to have a slower onset and a much longer duration of action than any other antihistamine. Holgate noted that it takes three to five days dosing with astemizole for the drug to reach maximum effect. For this reason, it was suggested that astemizole be used as a prophylactic: dosing would be started before the pollen season and continued until pollen counts subside. An alternative approach has been to administer astemizole at higher doses, giving twice or three times the recommended dose of 10 mg daily for the first three days of treatment. Again, according to Holgate, this regimen proved better for maintenance of allergy control than did occasional use [7].

The long half-life of astemizole permits once-a-day dosing for effective therapy of allergy symptoms. However, in the event of an untoward effect, this longer half-life might prove inconvenient, e.g., in women desiring a pregnancy. Increased appetite and weight gain have been cited as side effects in some patients. Placebo-controlled trials of astemizole to relieve seasonal rhiriitis and conjunctivitis showed it to be as good as clemastine or terfenadine and superior to chlorpenirarnine. Similar results were obtained in studies of urticaria. As for astemizole's anti- asthmatic effects, reports are similar to those deriving from studies done with terfenadine [8].

Loratadine is a derivative of azatadine, a member of the piperidine group of classic antihistamines. As with the last two newer antihistamines, many studies have been carried out comparing it to terfenadine, chlorpheniramine, diphenhydramine, astemizole, and clemastine, in the treatment of rhinitis and urticaria. Administered once daily, loratadine is very similar to terfenadine in many respects: in its onset of action; elimination half-life; and lack of side effects, particularly sedation. Comparative effectiveness studies showed it to be as effective as classic antihistamines, terfenadine, and astemizole. Because none of the newer non-sedating antihistamines are any more effective in relieving nasal congestion than the classic antihistamines, clinical trials are being conducted and reported on combining loratadine and pseudoephedrine [9].

Compared to the classic antihistamines, the newer, second generation antihistamines offer a much brighter hope of effective treatment

FUTURE

At the meeting of the European Academy of Allergy in 1987, no fewer than 60 papers were presented on various newer second generation antihistamines. During the 1988 meeting of the European Academy of Allergy in Copenhagen, a symposium was held on a topic that a few years ago would have been unheard of: "Histamine and Antihistamines in Asthma". At the recent Academy of Allergy meeting held in San Antonio, over 30 papers dealt with newer antihistamines.

Levocabastine. This drug is said to be 15,000 times as potent as chlorpheniramine, 1,500 times as potent as terfenadine, and 65 times as potent as astemizole. Prepared as a topical agent, it was compared with sodium cromoglycate, in various studies of its effectiveness, as a nasal spray to control allergic rhinitis and proved as effective. In the treatment of conjunctivitis, it was again compared to cromoglycate and proved superior, according to some studies carried out in Europe.

Cetirizine is a carboxylic acid metabolite of the piperazine, hydroxyzine. Unlike other H 1 receptor antagonists, it is not metabolized in the liver but eliminated primarily by renal clearance. Peak serum concentration occurs within one hour of dosage. Cetirizine has a half-life of eight to nine hours. Its potency and effectiveness seem to be similar to those of chlorpheniramine and terfenadine. This H I receptor antagonist also has antiallergic properties, in addition to its antihistaminic effects. In animal and human studies, it was shown to reduce mediator release and cellular recruitment.

Ketotifen. This drug is a potent H I antagonist, possessing rather marked anticholinergic activities, as well as sedation. It also seems to have some influence on mediator release, notably histamine, from mast cells, at least in vitro. It has a half-life of 20 hours and a duration of action of 12 hours. Ketotifen has been found to be effective in treating the commonly accepted indications for an antihistamine. In addition, a great deal of work has been done with it in the treatment of asthma. In recent years this work has been based on the observation that ketotifen has some effect on antigen-induced release of histamine following bronchial provocation. Results have varied. The drug is available in Europe, and clinical trials are once again under way in Canada to establish its long-term effects on asthma.

Azelastine. Azelastine is still in the experimental stage. It seems to have antileukotriene activity in the guinea pig. In human studies, it showed no effect on the airway response to methacholine, but it has some protective effect on the airways against histamine-induced bronchoconstriction in mild asthmatics.

Mequitazine. Mequitazine belongs to the phenothiazine group of antihistamines. Its absorption is rather slow: peak serum levels are obtained about six hours following administration. The elimination half-life is 38 hours. This drug's efficacy is comparable to that of chlorpheniramine, but it produces very little sedation. It is administered in doses of 5 mg every 12 hours. Mequitazine is available in Europe, where most of the clinical trials were done. These trials showed it to be as effective as terfenadine and more effective than ketotifen in relieving rhinitis. When used to treat skin disorders, it proved effective in reducing pruritis.

Acrivastine. Acrivastine, a derivative of tripolidine, is absorbed rapidly. Its elimination half-life is short, less than two hours. This drug, too, is nonsedating, given in doses of 4 or 8 mg TID and when compared to terfenadine in two studies carried out in England, it showed equivalent results in treatment of rhinitis. Compared to clemastine in another study of allergic rhinitis, also done in England, it showed similar results but produced no sedative effects.

Tazifylline. Tazifylline is one of a group of theophylline and theobromine piperazine derivatives studied in the search for antihistamines with a pulmonary bronchospasmolytic effect in allergy-induced conditions. In animal studies tazifylline markedly inhibited histamine-induced bronchoconstriction. No information is yet available on its use in clinical trials in humans.

Oxatomide. This antihistamine is also active as an antagonist against serotonin and leukotrienes; further-more, it has an inhibitory effect on antigen and chemically induced histamine release from mast cells. Nevertheless, clinical results of its use in the treatment of asthma have been disappointing. As an antihistamine it seems comparable to other antihistamines, though it may function a little better in reducing pruritis resulting from skin disorders.

CONCLUSION

The interest in antihistamines has remained strong over the years. A great deal more could be said about these drugs, though much is still unknown. Antihistamines are still used as the treatment of choice for everyday allergic problems. Because more potent second-generation antihistamines without side effects are now available, and some reports are appearing on their beneficial effects in treating asthma, we shall be hearing more and more on this topic. Already the effect of these drugs on the release of mediators is being investigated more and more. The second-generation antihistarnines are improving, and antihistamines may once again be called "wonder drugs."

Nonproprietary and brand names of drugs:

ETHYLENEDIAMINES: antazoline (Antistine); tripelennamine (Pyribenzamine)

ETHANOLAMINES: diphenhydramine (Benadryl); clemastine (Tavist); dimenhydrinate (Gravol).

ALKYLAMINES: brompheniramine (Dimetane); dexchlorpheniramine (Polaramine); chlorpheniramine (Chlor-Tripolon)

PHENOTHIAZINES: promethazine (Phenergan); trimeprazine (Panectyl).

PIPERAZINES: cyclizine (Marzine); hydroxyzine (Atarax); meclizine (Bonamine); thiethylperazine (Torecan).

PIPERDINES: cyproheptadine (Periactin); azatadine (Optimine),

SECOND-GENERATION ANTIHISTAMINES: terfenadine (Seldane); astemizole (Hismanal); loratadine (Claritin).

REFERENCES

1. Dale HH, Laidlaw PP. The physiologic action of beta-imidazolyl-ethylamine. J Physiol 1911;41:318-344

2.Trzeciakowski JP, Levi R. Antihistamines. In: Middleton E, Reed CE, Ellis EF. Allergy: Principles and Practice (2nd ed.) St-Louis: The C.V. Mosby Co. 1983: 575-592

3. Simons F, Estelle R, Simons, Keith J.: New H I receptor antagonists: A Review. Am J Rhin 1988; 2(1)21-25

4. Kaliner MA, Check WA. Non-sedating antihistamines. Allergy Proc 1988; 9:649-663

5. Tester-Dalderup C. Antihistamines. Drugs Today 1988; 24(2):117-131

6. Taytard A. Beaumont, D, Sepene M, et al. Treatment of mild allergic asthma with the specific H 1 antihistamine, terfenadine: a double blind placebo-controlled study. J Allergy Clin Immunol (abstract) 1987; 79:188

7. Holgate ST, Haworth PH. Treating hay fever, Br Med J 1985 : 291-292

8. Holgate ST, Emanuel MB, Haworth pH. Astemizole and other H 1 antihistamine drug treatment of asthma. Br J Dis Chest 1984; 78:180-183

9. Clissuld SP, Surkin EM, Goa KI.: Loratadine: a preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs. 1989; 37:42-57

Modern Medicine of Canada, January 1990