Acute Inhibition of the Human Kv1.5 Channel by H1 Receptor Antagonist Dimenhydrinate: Mode of Action.

Dimenhydrinate, an H1 receptor antagonist, is generally used for the prevention and treatment of nausea and vomiting. However, cardiac arrhythmias have been reported to be associated with the overdose of histamine H1 receptor antagonists, indicating the probable effect of antihistamines on ion channels. By using a two-microelectrode voltage clamp, we have herein studied the electrophysiological effects of dimenhydrinate on the human Kv1.5 channel in the Xenopus oocyte expression system. Dimenhydrinate acutely and reversibly suppressed the amplitudes of the peak and the steady-state current, within 6 min. The inhibitory effect of dimenhydrinate on the peak and the steady-state Kv1.5 currents increased progressively from -10 to +50 mV. At each test voltage, the drug suppressed both the peak and the steady-state currents to a similar extent. When the oocytes were stimulated at the rates of 5- and 30-s intervals, dimenhydrinate-induced a use-dependent blockade of the human Kv1.5 channel. Dimenhydrinate expedited the timecourse of the Kv1.5 channel activation more effectively than the timecourse of its inactivation. However, the activation and inactivation curves of the channel were not altered by the H1 receptor antagonist. In conclusion, we found that dimenhydrinate inhibits the human Kv1.5 channel by changing the channel's activation mode, thereby possibly increasing the possibility of triggering cardiac arrhythmias and affecting atrial fibrillation.

[Poisoning by diphenhydramine--forensic-toxicologic interpretation of analytic results ]. / Vergiftungen mit Diphenhydramin--Forensisch-toxikologische Beurteilung von Analysenbefunden.

Several poisonings by diphenhydramine were reported shortly after it had been introduced as an antihistamine in 1945. In the Federal Republic of Germany its combination with 8-chlorotheophylline (dimenhydrinate) is available as a hypnotic without prescription. Replacing the dangerous diethylpentenamide diphenhydramine is a drug which is also often abused. Fatal poisonings, suicide attempts, and traffic accidents were increasingly observed. In seven cases drug-influenced road users caused traffic accidents. We observed blood concentrations of diphenhydramine as high as in four cases of clinically treated patients after ingestion of large doses. This indicates a serious drug abuse. The measurement of the concentration of diphenhydramine and its major metabolite (diphenmethoxy acetic acid) in blood and urine is a means of recognizing chronic use and misuse of diphenhydramine. As the metabolite accumulates in blood one may find an elevated level after multiple dosing. Shortly after taking a single dose no or only low metabolite concentration is found. The concentration of diphenhydramine and its metabolite was measured in several fatal cases. In one of these cases the concentration in body fluids and tissues was in a range not observed until now.