CARDIOVASCULAR AND RESPIRATORY EFFECTS OF THE ANTIHISTAMINE AGENT, -DIMETHYLAMIXOETHYL BENZHYDRYL ETHER HYDROCHLORIDE (BENADRYL HYDROCHLORIDE)

¹ Research Laboratories, Parke, Davis & Company, Detroit, Michigan

1. In the phenobarbitalized dog, intravenous Benadryl Hydrochloride (1-16 mgm./kgm., at 1-43 mgm./kgm./min.) typically elicited primary vascular depression (median duration, 2 min.) followed by rise in arterial pressure (median duration, > 46 min.). Both phases were basically independent of important arterial reflex zones, vagal cardiac innervation, heart rate changes, peripheral cholinergic mechanisms, and nervous or mechanical respiratory changes. The minimal latent period was ca. 8 sec.

2. The degrees of primary fall were most satisfactorily related, as "probits" fall, with the logarithm of the product of dose per kilogram by its rate of injection. One mgm./kgm. at 0.75 mgm./kgm./min., under the conditions used, would be expected to lower blood pressure by 0.05% to 19% (95% confidence limits). The corresponding dose-rate product lies somewhat above the highest human intraordinary products reviewed, and probably, in corresponding blood level, above ordinary oral doses used.

3. The secondary pressure rise was low-grade (maximum, 26 mm. Hg; median, > 7 mm. Hg), decreased on repetition of injection, and was not clearly correlated with dose. With large doses it was masked by the primary depression for as long as > 1.4hr.

4. Small doses were associated with a variable small cardiac acceleration (maximum, 20%) independent of blood-pressure changes, larger doses with a small primary deceleration (maximum, 22%), masking the acceleration and independent of vagus or carotid nerves. No gross disturbances in cardiac rhythm were observed in limited electro-cardiographic recordings.

5. In the isolated rabbit heart, a dose equal to one of papaverine hydrochloride which elicits slight fluctuations in ventricular contractions and strong durable increase in coronary flow, caused slight to moderate, repeatedly reversible depression of contractions, and a fleeting increase in coronary flow followed by more lasting, mild decrease in flow. The flow changes were not dependent upon mechanical changes and none of the effects was entirely dependent on anti-histamine action.

6. One mgm./kgm. frequently caused slight to moderate, transient stimulation of respiration when injected at rates of 1.2 to 43 mgm./kgm./min. One mgm./kgm. at 19 or more mgm./kgm./min. caused in addition an early restriction in depth of breathing frequently reaching temporary apnea. In such cases, and with larger doses, stimulation was expressed ultimately as acceleration or polypnea, intense and lasting well over an hour with large doses.

Vagotomy eliminated cleanly the restriction in depth and a major part of the acceleration (potentiated pulmonary proprioceptives?). Carotid denervation eliminated a weak chemo- and pressoreceptive stimulation component. In the absence of both mechanisms respiration was essentially undisturbed by large doses.