Pharmacologic management of
atrial fibrillation (AF) is a pressing problem. This
arrhythmia afflicts >5 million individuals in the United States and prevalence is estimated to rise to 12 million by 2050. Although the pill-in-the-pocket regimen for self-administered AF
cardioversion introduced over a decade ago has proven useful, significant drawbacks exist. Among these are the relatively long latency of effects in the range of hours along with potential for
hypotension and other adverse effects. This experience prompted development of a new strategy for increasing plasma concentrations of
antiarrhythmic drugs rapidly and for a limited time, namely, pulmonary delivery. In preclinical studies in Yorkshire pigs, intratracheal administration of
flecainide was shown to cause a rapid, reproducible increase in plasma drug levels. Moreover, pulmonary delivery of
flecainide converted AF to normal sinus rhythm by prolonging atrial depolarization, which slows intra-atrial conduction and seems to be directly correlated with efficacy in converting AF. The rapid rise in plasma
flecainide levels optimizes its anti-AF effects while minimizing adverse influences on ventricular depolarization and contractility. A more concentrated and soluble formulation of
flecainide using a novel
cyclodextrin complex
excipient reduced net drug delivery for AF conversion when compared to the
acetate formulation. Inhalation of the
beta-adrenergic blocking agent metoprolol slows ventricular rate and can also terminate AF. In human subjects, oral inhalation of
flecainide acetate with a hand-held, breath-actuated
nebulizer results in signature prolongation of the QRS complex without serious adverse events. Thus, pulmonary delivery is a promising advance in pharmacologic approach to management of AF.