Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, adrenergic induced arrhythmia frequently leading to sudden death. CPVT stems from mutations that cause excess Ca2+ release through RyR2 channels in the sarcoplasmic reticulum (SR). Although excess Ca2+ release in diastole is a key factor in CPVT, not all RyR2 antagonists have an antiarrhythmic action. Our previous studies comparing the anti-arrhythmic blocking action of flecainide with the pro-arrhythmic blocking action of tetracaine found that flecainide reduced the amount of Ca2+ released during localised diastolic release events (Ca2+ sparks) but increased their frequency (Hilliard et al., 2010). The likelihood that each Ca2+ spark could generate an arrhythmogenic Ca2+ wave was reduced because the Ca2+ sparks were smaller. In contrast, tetracaine increased Ca2+ released during a spark and the frequency of Ca2+ waves. We examine the inhibiting action of flecainide and tetracaine on RyR2 activity in lipid bilayers with a view to understanding the opposite actions of these drugs on heart rhythm. We incorporated the experimentally determined kinetics of drug binding to RyR2 into a computational model of Ca2+ release from the SR in cardiac cells and found that the different blocking kinetics of tetracaine and flecainide can explain the different effects of actions of these drugs.