Flecainide A Preliminary Review of its Pharmacodynamic Properties and Therapeutic Efficacy

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Abstract
Synopsis: Flecainide1 is a Class I antiarrhythmic drug of the local anaesthetic type. It can be given either intravenously or orally and its pharmacokinetic properties allow relatively long (12 hours) dosing intervals with oral administration. In several open and a few controlled therapeutic trials, orally administered flecainide has brought about a greater than 90% suppression of ventricular ectopic beats in about 80% of patients. A similar percentage of patients (83%) experienced at least an 80% suppression of their ventricular tachycardia in these trials. A slightly greater response rate was reported with intravenous infusion of flecainide. Initial results in arrhythmias complicating the Wolff-Parkinson-White syndrome have been favourable. Comparative trials are few in number but flecainide has proved to be more effective than quinidine, and possibly more effective than disopyramide, mexiletine, tocainide and propafenone, in suppressing ventricular ectopic activity. The most commonly reported extracardiac adverse effects have been dizziness and visual disturbances. Proarrhythmic effects have been reported in 7 to 8% of patients, with a higher incidence in patients with serious ventricular tachycardia and reduced myocardial function. The moderate negative inotropic effects of flecainide can become clinically significant in patients with impaired ventricular function. Thus flecainide, with its convenient dose schedule and apparently low incidence of serious side effects, would appear to be a useful addition to the antiarrhythmic agents available. Further studies are needed though, to confirm its long term tolerability when used prophylactically. Pharmacodynamic Studies: In both animals and man, flecainide has electrophysiological effects on the action potential which place it firmly in Vaughan Williams Class I. It slows depolarisation of the cardiac cell, but unlike most other antiarrhythmic agents it has little effect on the duration of the action potential and so it is further classified into subclass ? along with the other antiarrhythmic agents lorcainide and encainide. Flecainide has been shown to significantly depress conduction within the working myocardium. It depresses right atrial (PA/PR interval) and ventricular conduction (QRS duration 11 to 27%), as well as that throughout the specialised conduction system. It increases atrioventricular nodal conduction times (15 to 22%), but its greatest effect is on the His-Purkinje system, prolonging the HV interval (27 to 47%). Although flecainide was reported to lengthen ventricular effective refractory periods, the J–T interval (index of ventricular repolarisation) was not prolonged, suggesting that the drug does not significantly affect ventricular repolarisation. Studies in patients with sinus node dysfunction showed an increase in corrected sinus nodal recovery time following intravenous flecainide, although sinus cycle length and sinoatrial conduction time were not significantly changed. Flecainide has been shown to depress conduction in accessory pathways, with retrograde conduction being the most profoundly affected. Haemodynamic studies in healthy subjects, patients with heart failure, patients with coronary artery disease, and patients with recent myocardial infarctions have differed in their results of the effects of flecainide on heart rate, with some studies recording significant increases whilst others found no overall significant alterations. Apart from significant increases in pulmonary wedge pressures, blood pressure (where measured) seemed to be unaffected by flecainide administration. However, in most studies flecainide administration produced a negative inotropic effect on the heart, with decreased systolic ejection fractions, decreased myocardial contractility, increased systolic volumes, and decreased stroke and stroke work indices. Pharmacokinetic Studies: Oral administration of flecainide results in extensive absorption, with bioavailability approaching 90 to 95%. Flecainide does not appear to undergo significant hepatic first-pass metabolism. Mean peak plasma concentrations reached in healthy subjects 2 to 3 hours after a single dose of 200mg were 341 µg/L. In patients with chronic ventricular ectopic beats, and other groups of patients with arrhythmias, flecainide 200 to 600mg daily produced plasma concentrations within the range 200 to 1000 µg/L. Intravenous administration of 0.5 to 2 mg/kg to healthy subjects resulted in a range of plasma concentrations from 70 to 340 µg/L. Studies of the extent of protein binding of flecainide have reported values within the range 32 to 58%. The volume of distribution in healthy subjects following an intravenous infusion of flecainide 2 mg/kg averaged 512L. Recovery of unchanged flecainide in urine of healthy subjects accounted for approximately 42% of a 200mg oral dose of 14C-flecainide, while the 2 major metabolites — the meta-O-dealkylated and the dealkylated lactam metabolite — accounted for a further 14% each. The elimination half-life was slightly greater in patients with chronic arrhythmias (12 to 27h) than in healthy subjects (7 to 23h) after repeated oral administration, or after intravenous administration (7 to 19h). Slower renal clearance values which lead to longer elimination half-lives in patients with congestive heart failure suggest the need for modest reductions of dosage in these patients. Alterations in kinetic parameters in the elderly may also warrant reductions in dosage. Although enhancement of metabolism may to some extent compensate for impairment of renal excretion of unchanged flecainide, reduction of dosage is recommended in renal patients with creatinine clearances of less than 20 ml/min/m2. Studies relating flecainide plasma levels to clinical effects vary in their findings but it appears that a plasma concentration of about 200 to 1000 µg/L represents the likely desirable therapeutic range. Therapeutic Trials: Although uncontrolled trials are of limited use in assessing the therapeutic efficacy of antiarrhythmic agents, the added numbers and experience can be used to confirm the results of controlled trials. In several open studies, oral doses of flecainide within the range 200 to 600mg daily brought about a greater than 90% suppression of ventricular ectopic beats in about 80% of patients and a greater than 80% suppression of ventricular tachycardia in about 83% of patients. This suppression was maintained during long term therapy in the small number of patients studied in this way. Intravenous infusions of flecainide 1 to 2 mg/kg produced the same level of suppression (90%) in a slightly greater percentage of patients (85%) with ventricular ectopic beats than occurred with oral administration, with several of the patients experiencing complete suppression. Similarly, infusions of flecainide 2 mg/kg brought about termination of ventricular tachycardias in about 85% of patients. Placebo-controlled studies of flecainide in patients with ventricular ectopic beats and/or ventricular tachycardia have generally been single-blind in design and have involved only small numbers of patients, a factor which must be taken into consideration when looking at the relatively high overall success rate of about 89% of patients experiencing a greater than 90% suppression of ventricular ectopic beats compared with a placebo ‘baseline’. Due to its greater effect on conduction within the accessory pathway, flecainide has been used successfully in patients with Wolff-Parkinson-White syndrome and in others with arrhythmias involving anomalous pathways (85 to 90% of patients experiencing termination of re-entrant tachycardias). Comparative trials of flecainide have so far been restricted to the oral form of the drug and have involved 5 other antiarrhythmic agents: quinidine, disopyramide, tocainide, propafenone and mexiletine. Flecainide was reported to be more effective than all of them in the suppression of ventricular arrhythmias, with the exception of repetitive ventricular ectopic beats by propafenone, with which it was equally effective. However, except for quinidine with which flecainide has been compared in a reasonable number of patients, all other comparative studies, although crossover in design, were very small and the apparent superiority of flecainide needs further confirmation. Comparisons with newer compounds of similar type, have so far been limited to 1 preliminary study with tocainide. Side Effects: Flecainide at therapeutic dosages has been well tolerated by most patients. The most commonly reported extracardiac adverse effects include dizziness in 30% of patients, visual disturbances (28%), headache (9%), and nausea (9%). It is known that most antiarrhythmic agents have the ability to induce arrhythmias as well as suppress them, and the percentage of patients in which this effect occurs is important. Proarrhythmic effects have so far been reported as occurring in 7 to 8% of patients on flecainide therapy. Drug Interactions: Elevated digoxin plasma levels, probably due to decreased volumes of distribution, have been observed during coadministration of flecainide and digoxin in healthy subjects. Propranolol and flecainide have resulted in additive, but not significant, negative effects in cardiac function in healthy subjects. However, the possibility of exaggerated effects from this combination in patients with reduced left ventricular function should be considered. Increases in elimination half-lives associated with reduced nonrenal clearance of flecainide in healthy volunteers given cimetidine would suggest a possible need for flecainide dose adjustment in some patients during coadministration. Dosage and Administration: The dosage of flecainide should be individualised for each patient on the basis of response and toleration. Plasma flecainide concentrations within the range 200 to 1000 µg/L can generally be maintained with a daily dose of 200 to 600mg, given usually in 2 or sometimes 3 divided doses. Initial intravenous therapy in the form of slow injections or infusions of flecainide 1 to 2 mg/kg can be given in order to produce a rapid clinical effect. Intravenous therapy can be replaced by oral administration as soon as the patient’s condition allows it. A starting dose of 100mg orally every 12 hours may be increased in unresponsive patients by increments of 50mg every 12 hours after a minimum of 4 days’ therapy. Patients with serious ventricular arrhythmia, especially sustained ventricular tachycardia, congestive heart failure, myocardial dysfunction, renal impairment or liver damage may require downward dosage adjustments.