Antazoline is a first-generation antihistaminic agent with additional anticholinergic properties, first described in 1947 [1]. Its antiarrhythmic potential was first discovered in the 1950s of the last century [2‐4]. In subsequent years, the effects of antazoline administered both orally and intravenously on different types of arrhythmias were assessed. There were antiarrhythmic effects against premature atrial and ventricular beats, nodal reentrant tachycardia and atrial and ventricular tachycardia. Initially, poor effect was noticed against atrial fibrillation (AF), probably because the great part of sinus rhythm restoration attempts was made among patients with longstanding persistent arrhythmia [5‐8]. Only one paper described 66% success rate in AF treatment [9]. Moreover, complications from oral use of antazoline, mainly immunological and hematological, caused its widespread chronic use as an antiarrhythmic agent to be abandoned [10]. In 2000, new data on the efficacy of antazoline was published. Retrospective analysis of 1325 patients treated with intravenous antazoline for paroxysmal AF revealed that antazoline restored sinus rhythm in 52% of the patients [11]. Recent data indicate an even higher success rate approaching 80%. The superiority of the antazoline over placebo in sinus rhythm restoration in recent onset AF has been confirmed in the AnPAF study. Complications of ad hoc administered antazoline seem to be rare and benign [12‐15]. The effect of antazoline on electrophysiological parameters of the heart in vivo has not yet been examined. Thus, the aim of this study was to evaluate changes in electrophysiological parameters of the heart muscle and conduction system as a response to increasing doses of antazoline.

We enrolled 15 patients (8 males, 19–72 years old, EF 61 ± 2.5%) undergoing EPS and RF ablation. The indications for EPS were AVNRT (n = 6), AVRT (n = 4), and AFL (n = 5). After 100 mg bolus, a significant reduction in SRCL and QTc prolongation was noticed. After a total dose of 200 mg, we observed significant prolongation of HV, QRS, hRA-CSos and hRA-CSd intervals and RA- and LA-ERP. After a total dose of 300 mg, QT interval prolonged significantly. Increasing the dose of antazoline had no impact on AH, WP, AVN-ERP, and SNRT. The results are summarized in Table 1 and on Fig. 1. In one patient, after total dose of 300 mg of antazoline, we induced common atrial flutter with incremental atrial pacing. Arrhythmia cycle length was 200 ms with 2:1 atrioventricular conduction. The basic EPS finding in this patient was AVNRT and there was no evidence of pre-existing common atrial flutter. Arrhythmia was terminated with overdrive atrial pacing. After full dose of antazoline, two patients reported hot flush sensation and one nausea that resolved without any intervention.

To our knowledge, this is the first study assessing effect of antazoline on electrophysiological parameters of the human heart. The data on antazoline effectiveness in ad hoc AF termination is constantly growing. After several nonrandomized observational studies the result of randomized clinical trial comparing antazoline and placebo for sinus rhythm restoration in paroxysmal AF has been published showing high effectiveness in sinus rhythm restoration exceeding 70%. The rate of spontaneous sinus rhythm recoveries in placebo arm was only 10% [15]. While chronic antiarrhythmic therapy is practically impossible due to serious complications, it is still a very attractive option for rapid AF termination and in some countries it is registered and widespread used for this purpose.

Our results clearly indicate influence of antazoline on heart conduction system and muscle. Measured parameter changes: HV prolongation, QRS widening, atrial refractory period prolongation, and conduction velocity slowing are similar to agents classified as class I of Vaughan Williams classification of antiarrhythmic drugs. The constellation of changes of parameters in EPS suggests an influence of antazoline mainly on sodium channels. Moreover, known anticholinergic properties place antazoline near class Ia agent: quinidine. This data is consistent with the ELEPHANT study results. The early effect on surface ECG is similar to sodium channel blocker. In the ELEPHANT study, observation time was longer and revealed potential potassium channels inhibition and more pronounced QT interval prolongation in the later phase of observation [16]. In our group observation, period was probably too short to disclose these changes, but QT prolongation was also noticed.

QTc prolongation is very important finding of our study. QTc change resulted mainly from rhythm acceleration without simultaneous absolute QT interval shortening. Many patients with paroxysmal AF are treated for rhythm control with medications prolonging QT interval, mainly class III antiarrhythmic drugs. It is necessary to keep caution in these patients or consider abandoning use of antazoline for sinus rhythm restoration.

Our observations confirm another important property of antazoline: rapid onset of action. We noticed significant influence on electrophysiological parameters in measurements obtained after a total dose of 200 mg and 20 min from the beginning of first bolus. Shortening of SRCL appeared almost immediately, after first bolus, and remained at the same level after further doses. This effect apparently results from rapid anticholinergic action of antazoline. Clinical data showed short time to AF cessation during WPW ablation. From the beginning of antazoline infusion, it took on average 7 min to restore sinus rhythm ¹². In the AnPAF study, mean time to sinus rhythm restoration was only 16 min [15]. This period could have been shorter than that required to significantly change the electrophysiological properties of the atria in our observation and only the SRCL has changed this early; however, the antazoline administration protocol differed between the studies. Thus, inhibition of parasympathetic ganglia may play an important role in quick AF cessation. Among antiarrhythmic drugs, only the recently approved vernakalant is comparably fast in sinus rhythm restoration [17, 18]. Other commonly used agents usually require hours to achieve AF termination.

One of the most common side effects of antiarrhythmic therapy is bradycardia related to sinus node dysfunction or conduction disturbances. We did not notice any negative effects of antazoline either on sinus node function nor atrioventricular conduction. It has even accelerated sinus rhythm. Thanks to such properties, it may potentially become the drug of choice in patients with tachycardia—bradycardia syndrome, diagnosed sinus node dysfunction, or impaired atrioventricular conduction not protected with permanent pacemaker.

Our observations, together with previous studies on antazoline efficacy, build a basis for large scale, randomized trials on antazoline as a drug of choice for rapid, ad hoc treatment of recent onset AF.

Antazoline has an effect on electrophysiological parameters of the atrial muscle and has rapid onset of action. No negative effect on sinus node function and atrioventricular conduction in a unique property among antiarrhythmic drugs.