The synthesis of Fleicainide in 1972 was the culmination of a systematic search for flourinated local anesthetic analogues of Procainamide.

Cause moderate Phase 0 depression Prolong repolarization Increased duration of action potential Eg: Quinidine , Procainamide, Disopyramide

Weak Phase 0 depression

Strong Phase 0 depression No effect of depolarization No effect on action potential duration. Eg: Flecainide, Propafenone

Shortened depolarization
Decreased action potential duration Eg: Lidocane, Mexiletine , Phenytoin

5
Sodium Channel Blockade: 1A>1B>1C Increasing the ERP: 1A>1C>1B (Lowered)

Fleicainide is well absorbed after oral administration with >90% bioavaiability. 27 % of the oral drug is excreted unchanged in urine. The remainder of the drug is biotransformed into two major metabolites, meta-o-dealkylated fleicainide and its lactam both of which are conjugated and excreted in urine. The metabolites although active are significantly less potent than the parent drug. In normal persons the elimination half-life of fleicainide has been estimated to be 7-23 hours (mean 14 hours) permitting twice a day administration.

Two important clinical situations requiring dose adjustments are heart failure in which mean half-life is estimated to be 19 hours, and ESRD in which elimination half-life may be as high as 58 hours. Loading doses are not required and maintainance doses should be altered in no less than 4 days. It has significant interaction with digoxin raising digoxin levels.

This serious side-effect is particularly problematic in certain associated conditions reaching as high as 20% in patients with severe LV dysfunction and in patients with previous sustained VT taking > 400mg/day of drug. The risk factors therefore are:1. Severe LV dysfunction. 2. Patients taking >400 mg/day. 3. Plasma concentrations of > 1000 ng/ml.

Occurrence of transient CNS effects like dizziness, and difficulty in visual accommodation is fairly common requiring lowering of dose. Fleicainide markedly prolongs PR and QRS durations. Prolongations of upto 30% of baseline are reasonably well tolerated but potential for AV nodal and infra-nodal block is obvious PROARRHYTHMIA is a serious adverse event of fleicainide therapy..

Fleicainide is very effective in suppressing high frequency ventricular depolarisations and nonsustained VT and it surpasses other Class I drugs in this respect. Because of this one of the first trials with fleicainide was for this indication.

CAST was a land-mark trial which was designed to test the hypothesis that suppression of frequent VPCs in patients with previous MI ad EF <55% by three drugs fleicainide, encainide and morcizine would decrease mortality.

Despite the fact that studies have not shown any benefit for rhythm control over rate control, rhythm control has its role in many sub-sets:1. Patients with first documented AF to prevent substrate deterioration and AF indused remodelling. 2. Patients who continue to be symptomatic inspite of adequate rate control. 3. Patients in whom rate control cannot be achieved. 4. Patients who have developed TIC.

Thus according to current guidelines fleicainide is recommended with Class I indication in pharmacological cardioversion in patients with AF who donot have structural heart disease and have normal LV function which usually comprises of 80 % of patients with PAF and 50 % of patients with persistant AF. The Euro Heart Survey on AF actually shows that only 17% and 13% patients with paroxysmal and persistant AF are actually receiving a Class Ic drug. Thus there is a need of implementing guideline based therapy rather than persist with amiodarone.

Fleicainide is highly effective in the acute setting for cardioversion of AF. In hemodynamically stable patients with acute onset (<48 hrs) AF in patients with normal LV function fleicainide restores SR in up to 95% of patients within 1 hr from the start of infusion. In head-to-head comparison trial fleicainide (2mg/kg bolus plus a second 1mg/kg if first bolus did not convert) restored SR in 90% compared to 72% for propafenone and 68% with amiodarone. Fleicainide is also safe in patients of WPW who present with AF and may be safer and more effective than even procainamide which is recommended as first-line drug in this serious and potentially life-threatening condition.

Prior to initiating fleicainide therapy patients should be checked for contraindications including structural heart disease, second or third degree AV block, LBBB, RBBB+LAHB, asymptomatic NSVT, cardiogenic shock, LVEF <35%, post MI, hepatic and renal impairment. During treatment QRS duration should be regularly monitored. Conversion to SR may be associated with a prolonged asystole and in 0.2% AF may be converted to Afl with 1:1 conduction leading to accelration of ventricular rate. Because of this it is recommended that the first oral loading dose be administered under strict ECG monitoring in hospital setting.

Patients: Age: 18-75; New-onset (<48hrs) AF; mean HR >70 bpm; SBP of =/> 100mm Hg; at least 1 but fewer than 12 episodes in previous year. Exclusions: ventricular pre-excitation or bundle branch block (QRS interval, >120 msec); ischemic heart disease; dilated or hypertrophic cardiomyopathy; left ventricular dysfunction (ejection fraction,<50 percent); renal or hepatic dysfunction. Intervention: Patients were admitted and were given either fleicainide or propofeneone. Fleicainide was given in a dose of 300 mg for patient weighing =/> 75 kgs and 200 mg otherwise. Propofenone was given in a 600 mg dose for those weighing 75 kgs or more and 450 mg otherwise. Before discharge all patients who had been treated successfully were instructed to take the drug within 5 minutes of any subsequent onset of palpitations.

Flecainide is one of the first-line treatment recommendations for maintaining SR following cardioversion in the current guidelines. These guidelines advise that patients with recurrent PAF may benefit from rhythm control with flecainide, particularly younger age groups with normal cardiac function. In the acute setting, flecainide is recommended for pharmacological cardioversion of PAF of no more than 7 days duration, and there is also strong evidence supporting the use of flecainide prior to electrical cardioversion. Fleicanide has a definite role as a pill-in-pocket approach. When used appropriately fleicanide is a relatively safe drug especially when compared to Amiodarone and is backed by 25 years of use.

In PAF, flecainide has been shown to significantly reduce the number of AF recurrences, and lengthen the time between episodes. A meta-analysis of 60 studies with flecainide showed that 65% of patients were responsive to treatment in the shortterm, and 49% in the long-term, indicating that the clinical benefit of flecainide for maintaining SR is sustained.

In limited studies of patients with a history of ventricular tachycardia, Flecainide has been successful 30% to 40% of the time in fully suppressing the inducibility of arrhythmias by programmed electrical stimulation. Flecainide does not usually alter heart rate, although bradycardia and tachycardia have been reported occasionally. In animals and isolated myocardium, a negative inotropic effect of Flecainide has been demonstrated. Decreases in ejection fraction, consistent with a negative inotropic effect, have been observed after single administration of 200 to 250 mg of the drug in man. Following oral administration, the absorption of Flecainide is nearly complete. Peak plasma levels are attained at about three hours in most individuals (range, 1 to 6 hours). Flecainide does not undergo any consequential presystemic biotransformation (first-pass effect). Food or antacid do not affect absorption.

Fleicainide

Amodarone

Thank you

The apparent plasma half-life averages about 20 hours and is quite variable (range, 12 to 27 hours) after multiple oral doses in patients with premature ventricular contractions (PVCs). With multiple dosing, plasma levels increase because of its long half-life with steady-state levels approached in 3 to 5 days; once at steadystate, no additional (or unexpected) accumulation of drug in plasma occurs during chronic therapy. In healthy subjects, about 30% of a single oral dose (range, 10% to 50%) is excreted in urine as unchanged drug. The two major urinary metabolites are meta0-dealkylated Flecainide (active, but about one-fifth as potent) and the meta-0dealkylated lactam of Flecainide (non-active metabolite).