Antitussive Action of Antihistamines Is Independent of Sedative and Ventilation Activity in the Guinea Pig

Abstract

We studied the oral actions of antihistamines from six chemical classes, namely: the ethanolamines (ENA, diphenhydramine and clemastine); ethylenediamines (EDA, pyrilamine and tripelennamine); piperidines (PPD, terfenadine and astemizole); piperazines (PPZ, hydroxyzine and cetirizine); phenothiazines (PTZ, promethazine), and the alkylamines (ALA, chlorpheniramine and bromopheniramine) on cough reflexes, pentobarbital-induced sedation and minute ventilation in the conscious guinea pig. Antihistamines of the ENA class had minimal effects on capsaicin-induced cough although both diphenhydramine (30 and 100 mg/kg p.o.) and clemastine (30 and 100 mg/kg p.o.) increased sedation time (ST). The PPZ class demonstrated both antitussive and sedating activity. The minimum effective oral antitussive dose (MED) of cetirizine and hydroxyzine was 30 and 10 mg/kg, respectively. The EDA did not exhibit antitussive activity. Tripelennamine (10, 30 and 100 mg/kg p.o.) but not pyrilamine enhanced ST. The MED for the PTZ, promethazine, was 10 mg/kg, and at 100 mg/kg promethazine increased ST. The ALA group displayed antitussive activity but only chlorpheniramine (10 mg/kg p.o.) had any effects on ST. The MED for chlorpheniramine and bromopheniramine was 3 and 10 mg/kg p.o., respectively. The PPD antihistamines, namely terfenadine and astemizole, inhibited cough (MED 30 and 10 mg/kg p.o.) without sedative effects. Of the antihistamines tested only promethazine (100 mg/kg p.o.) depressed ventilation responses; however, this dose of promethazine was associated with adverse behavioral effects. The present findings indicate that the antitussive actions of antihistamines are not directly related to histamine H₁-receptor blockade because several antihistamines did not antagonize capsaicin-induced cough. In addition, the antitussive actions of antihistamines are independent of their sedative or ventilation effects.

Antitussive Drugs—Past, Present, and Future

“…Of note, a subsequent series of experiments in conscious guinea pigs evaluating oral administration of an example of one of each of the six chemical classes (see above), concluded that the antitussive actions of H 1 -receptor antagonists are not directly related to histamine H 1 -receptor blockade, because several H 1 -receptor antagonists did not inhibit capsaicin-induced cough. Furthermore, the antitussive actions of the older H 1 -receptor antagonists were independent of their sedative effects and effects on minute ventilation (McLeod et al, 1998). Other studies have documented the antitussive effect of oxatomide in unanesthetized guinea pigs challenged with citric acid (Braga et al, 1993), the ability of epinastine to potentiate the antitussive effect of dihydrocodeine against capsaicininduced cough in mice (Kamei et al, 1999), and the ability of azelastine to suppress capsaicin-induced cough in conscious guinea pigs through a mechanism perhaps partly due to inhibition of substance P release from sensory nerves (Ito et al, 2002).…”

“…One explanation for the widely recognized observation that first-generation H 1 -antihistamines, but not the secondgeneration, nonsedating agents, are effective antitussives, is that the former penetrate the CNS and also have anticholinergic activity. However, the rank order potency of these agents as muscarinic receptor antagonists does not support this hypothesis (Bolser, 2008) nor does a sedative effect offer an adequate explanation based on animal studies demonstrating a lack of correlation between the antitussive and sedating effects of H 1 -antihistamines (McLeod et al, 1998). Overall though, the evidence for certain older H 1 -receptor antagonists having an antitussive effect seems to be unrelated to H 1 -receptor antagonism.…”

The Conventional Antihistamine Drug Cyproheptadine Lacks QT-interval–Prolonging Action in Halothane-Anesthetized Guinea Pigs: Comparison With Hydroxyzine

“…The effective doses of hydroxyzine and cyproheptadine in animals have been reported to be 10 and 0.1 mg/kg, respectively (13,14), whereas their clinically recommended doses are 150 and 12 mg per os daily, respectively. Thus, the doses of hydroxyzine in this study were approximately estimated to be subtherapeutic to therapeutic ranges, whereas those of cyproheptadine were comparable to therapeutic to supratherapeutic ones.…”

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“…Cetirizine (0.6 mg/kg & 1.2 mg/kg) potentiated sleeping time in this paradigm. McLeod RL in 1998 has reported sedating activity of cetrazine at 30 mg/kg p.o in mice 14 . I.C.V.…”