The main finding of this study was that a sufficiently high dose of chlorpheniramine administered intravenously can protect against mild attacks of allergen-induced asthma on the basis of its Hi blocking properties. A second and quite unexpected finding was that regardless of the degree of bronchial reactivity to histamine, a fixed dose of chlorpheniramine given intravenously produced a comparable rate of protection against histamine-induced bronchoconstriction. The implication of the first finding is that in asthma, endogenous histamine plays a role not only in the resting bronchial tonus, but also in the acute bronchial changes induced by allergen challenge. The implication of the second finding is that the bronchial hyperreactivity to histamine is probably unrelated to the degree of association of chlorpheniramine, and most likely histamine, with the Hi receptor of the bronchial smooth muscle.
In any immunopharmacologic study of the human airways, the most difficult problem is to demonstrate that the changes in bronchial caliber occurring after the administration of a drug represent neither spontaneous variation nor the activity of another agent. Five lines of evidence indicate that in our study, the airway responses have been reasonably well-controlled. First of all, in contrast with previous studies with Hi blockers in allergen-induced asthma,»“ the nebulization of drugs and allergen has been conducted in a uniform fashion, with the flow, volume, and duration of aerosolization being controlled. The use of a volume ventilator has avoided the variability in breathing patterns, and hence, as just reported, the variability in the deposition of particles and airway response. The size of aerosol particles has also been double-checked. In essence, the delivery of drug or allergen has probably been controlled in greater detail than currently suggested by Chai et al. Second, in opposition to previous studies with Hi blockers, the intraindividual variability of airway responses has been checked by relying only on reproducible responses obtained over a short period of time, in free interval, at comparable baseline level.
Third, in this study, the antagonists have not affected the basal physiologic measurements as has been the case in some of the previously mentioned studies with Hi blockers. A larger dose of atropine (0.6 mg subcutaneously) is usually needed to dilate the bronchi of subjects with % FEVi/FVC comparable or even smaller than that of our subjects. As expected we found that at high FEVi and % FEVi/FVC, 10 mg chlorpheniramine given intravenously has no bronchodilating activity. Therefore, in this study, a concomitant change in baseline values of forced expiratory flows has not adulterated the antihistamine, anticholinergic, and antiallergic effects of chlorpheniramine and atropine.
Fourth, the magnitude of drug or allergen bronchoconstriction has been adjusted to the specific needs of the study, and ethical considerations. The use of an endpoint —A FEVi > 10%, appropriate for this study and physiologically valid if associated with wheezing is not proposed here as an alternative to the endpoint —A FEVi > 202. The latter is an excellent endpoint for routine assessment of bronchial hyperreactivity.
Fifth, the magnitude of airway responses at the threshold level in the same individual and across subjects was quite similar. Thus, it seems justifiable to use dose-ratios in comparing the effect of chlorpheniramine or atropine on drug or allergen-induced bronchoconstriction (https://onlineasthmainhalers.com/diagnosis-of-bronchial-asthma-by-clinical-evaluation-methods-and-materials.html).
In this study, 10 mg chlorpheniramine given intravenously could protect seven out of the nine subjects against mild immediate attacks of allergen-induced asthma. In all the previous studies in which this class of drugs has protected against immediate allergen-induced asthma, there were subjects who were less protected than the others.” In our study, one of the two subjects unprotected by the standard dose of 10 mg chlorpheniramine was protected in the usual fashion (ie, doubling of the threshold dose) by 15 mg of chlorpheniramine. This observation suggests that the use of a single dose of Hi blocker may not uncover the antiallergic effect of this drug. This error may be compounded by using as physiologic criterion, an airway response too large for the dose of Hi blocker used, eg, provocation dose 20 percent.
It was interesting that in spite of a half life of 28 hours, chlorpheniramine could not protect against the late asthmatic attacks. Similar observations were reported by Nakazawa et al with another drug displaying both Hi blocking and anticholinergic activity.
The low dose-ratio against allergen (2:1) shown by the relatively large dose of chlorpheniramine intravenously administered in these experiments suggests that if Hi blockers will ever find a place in the therapy of asthma, they would have to be administered by inhalation. In principle, this route should allow the topical administration of high doses with minimum systemic toxicity. The timing of allergen or drug nebulization in relation to administration of chlorpheniramine and atropine was predicted on the half life of these two latter drugs, (28 hours for the Hi blocker and 1.3-2.0 hours for atropine), and the moment when their target (bronchodilating) effect, due to the displacement of the corresponding agonist, was at its peak (60 to 120 minutes for 10 mg chlorpheniramine intravenously and probably 30 minutes for 0.6 mg atropine subcutaneously). From our data, it is now easy to understand why Schiller and Lowell could not detect any protection against allergen-induced bronchoconstriction after pretreatment with 0.6 to 1.2 mg tripelennamine intravenously. This drug is less potent than chlorpheniramine: compare for instance the dose/tablet of these drugs, 4 mg for chlorpheniramine, versus 25 or 50 mg for tripelennamine. These authors have injected doses of tripelennamine which simply could not achieve the blood levels needed to protect against allergen-induced asthma. In experiments, apparently not controlled for their reproducibility, the same drug has successfully prevented allergen-induced asthma when administered in higher doses. Although our inhalation tests with allergen were well controlled and reproducible, we feel that a dose ratio of chlorpheniramine against allergen of only 2:1 requires further confirmation with other methods and design, eg, use of high doses of inhaled Hi blocker, determination of protective effect against larger allergen-induced airway responses, etc. Thus, our study should not be construed as a plea for immediate use of Hi blockers in the therapy of asthma.
The dose-ratio of chlorpheniramine against histamine was found to be 4:1 in eight subjects and 8:1 in one subject (Fig 2). The protective effect of Hi blockers against histamine-induced asthma has been repeatedly reported,1mm* but to the best of our knowledge, it has never been expressed in terms of dose-ratio.
One may speculate that the dose-ratio of chlorpheniramine against histamine might be smaller for the bronchial smooth muscle than for other tissues, eg, peripheral vascular muscle. For instance, the dose of chlorpheniramine which protects against skin responses to histamine or allergen was found to be 4 mg three times daily, comparable to the dose of chlorpheniramine currently used in the treatment of urticaria or hay fever. From a pharmakokinetic study with chlorpheniramine (Peets et al), one may infer that the blood level produced by 12 mg chlorpheniramine administered orally as a single dose (ie, much more than the usual oral dose), is smaller than the blood level of 10 mg of the same drug administered intravenously. If this is true, the lower affinity of chlorpheniramine for the Hi receptor of the bronchial smooth muscle than for the Hi receptor of vascular smooth muscle might explain why in the doses currently used, only the vascular effects of histamine are antagonized by Hi blockers. However, alternate explanations for the efficacy of chlorpheniramine in extrabronchial allergic reactions should also be considered because the affinity constant of Hi blockers for Hi receptors tends to be very similar across organs and across species.
The higher dose-ratio of chlorpheniramine against histamine (4:1) than against allergen (2:1) (Fig 3) may be attributed to the fact that histamine is only one of the chemical mediators of allergen-IgE antibody reactions.
In three subjects, the anticholinergic activity of 10 mg chlorpheniramine intravenously and 0.4 mg atropine subcutaneously were found to be very similar (Fig 4). In vitro, in guinea pigs, the anticholinergic activity of chlorpheniramine is much smaller.’ This is probably an illustration of the well known discrepancy between in vivo and in vitro responses to bronchoconstrictor agents and underscores the need for human experiments in the pharmacology of airways.
Our findings of a smaller dose-ratio of chlorpheniramine against acetylcholine than against histamine are consistent with other data obtained in humans and animals.
We found that a dose of atropine (0.4 mg subcutaneously administered), with the anticholinergic effect of 10 or 15 mg chlorpheniramine, intravenously, failed to prevent mild attacks of asthma (Fig 4). This was not unexpected because larger doses of atropine also failed to protect against allergen-induced asthma. Our observation suggests that the protective effect of chlorpheniramine in mild attacks of asthma is due to its Hi blocking activity and not to its anticholinergic activity.
A most intriguing finding in the present study was that 10 mg chlorpheniramine, administered intravenously, regardless of the degree of bronchial reactivity to histamine, had an almost constant dose-ratio against histamine: 4:1 in eight subjects and 8:1 in one subject. Thus, the subjects who reacted to lesser amounts of inhaled histamine showed a comparable rate of protection with the subjects who reacted to higher amounts of the same agonist. Interestingly, Douglas et al have reported that, in vivo, the guinea pigs have a similar dose ratio of atropine against acetylcholine, regardless of their widely different acetylcholine responsiveness.
Consider now the generally accepted equation of competitive antagonism: log (dose-ratio-1) = log concentration antagonist — log affinity constant of this antagonist for the receptor. The relationship between log (dose-ratio-1) and — log concentration antagonist is linear; this line has a slope of — 1 and its intersection with the x axis marks the log affinity constant (Fig 5). In eight subjects, a single dose of 10 mg chlorpheniramine, given intravenously, (presumed blood level around 30 mμg/ml) produced a unique dose-ratio against histamine of 4:1. As chlorpheniramine is the competitive antagonist of histamine and both bind on the same Hi receptor, the slope of the plot log (dose-ratio-1) versus-log concentration antagonist should be equal to —1. Thus, each of our individual data points would be located on a line with a slope of —1. Our data points were identical in eight subjects (dose-ratio 4:1), and their slope as well as their intersection of the x axis would also be identical. It results that these subjects, regardless of their degree of reactivity to inhaled histamine, have a similar association constant for chlorpheniramine or histamine. Stated differently, in our subjects the differences in histamine hyperreactivity were not related to differences in the binding of chlorpheniramine, and most likely histamine, to bronchial Hi receptor (Fig 5). Interestingly, the highest threshold to inhaled histamine (1.28 mg) was also the lowest histamine threshold in a group of normal subjects. One might then argue that the binding of chlorpheniramine (and histamine) by the bronchial Hi receptor of our asthmatic subjects is grossly within normal limits. If this is true, the hyperreactivity to histamine in these asthmatic subjects was related either to an increased number of “normal” Hi receptors and/or to an usual number of “normal” receptors but one or more lesions along the path leading from the recognition component of the receptor to muscular contraction. Although we think that this reasoning is consistent with our present understanding of agonist-antagonist interaction, we must also take into account the limitations of our data: data have been obtained in vivo and cannot have the accuracy of the in vitro experiments; the slope relating log (dose-ratio-1) to log concentration antagonist has been drawn through a single point; the behavior of receptors on tissues hyperreactive to the corresponding agonist has not been analyzed theoretically and experimentally. Furthermore, it would be dangerous to extend to the whole population of asthmatic subjects conclusions based on the pharmacologic behavior of the airways of eight subjects because the pharmacologic abnormality of asthmatic bronchi may not be uniform. For instance our ninth subject had a different dose ratio of chlorpheniramine against histamine, 8:1 instead of 4:1.
Studies specifically designed to determine the behavior of bronchial receptors in asthma are urgently needed. Our present data suggest that with the limitations imposed by human experiments, such a study is feasible.
Previously published articles on this topic on our website see below:
Effect of an Hi Blocker, Chlorpheniramine, on Inhalation Tests with Histamine and Allergen in Allergic Asthma
Investigation about Effect of an Hi Blocker, Chlorpheniramine, on Inhalation Tests with Histamine and Allergen in Allergic Asthma
Results of Effect of an Hi Blocker, Chlorpheniramine, on Inhalation Tests with Histamine and Allergen in Allergic Asthma