|Systematic (IUPAC) name|
|Biological half-life||20 hours (range 12-27 hours)|
|ATC code||C01BC04 (WHO)|
|Molar mass||414.343 g/mol[[Script error: No such module "String".]]|
Flecainide acetate (Pronunciation: \ˌfle-ˈkā-ˌnīd\) is a class Ic antiarrhythmic agent used to prevent and treat tachyarrhythmias (abnormal fast rhythms of the heart). It is used to treat a variety of cardiac arrhythmias including paroxysmal atrial fibrillation (episodic irregular heartbeat originating in the upper chamber of the heart), paroxysmal supraventricular tachycardia (episodic rapid but regular heartbeat originating in the atrium), and ventricular tachycardia (rapid rhythms of the lower chambers of the heart). Flecainide works by regulating the flow of sodium in the heart, causing prolongation of the cardiac action potential.
Flecainide acetate (Tambocor) is the focus of the book Deadly Medicine by Thomos J. Moore (Simon and Schuster 1995) which chronicles the drug's development, approval by the US Food and Drug Administration and marketing history from 1972 to 1994. It asserts that neglect and cover-ups on the part of the pharmaceuticals, academics and FDA officials involved in its approval and marketing led to the deaths of 50,000 - 200,000 people who took the drug.
Flecainide was originally sold under the trade name Tambocor (manufactured by 3M pharmaceuticals). Flecainide went off-patent on February 10th, 2004, and is now available in generic version and under the trade names Almarytm, Apocard, Ecrinal, and Flécaine.
Flecainide is used in the treatment of many types of supraventricular tachycardias, including AV nodal reciprocating tachycardia (AVNRT) and Wolff-Parkinson-White syndrome (WPW). This is because of the action of flecainide on the His-Purkinje system.
It also has limited use in the treatment of certain forms of ventricular tachycardia (VT). In particular, flecainide has been useful in the treatment of ventricular tachycardias that are not in the setting of an acute ischemic event. It has use in the treatment of right ventricular outflow tract (RVOT) tachycardia and in the suppression of arrhythmias in arrhythmogenic right ventricular dysplasia (ARVD). However, studies have shown an increased mortality when flecainide is used to suppress ventricular extrasystoles in the setting of acute myocardial infarction.
In individuals suspected of having the Brugada syndrome, the administration of flecainide may help reveal the ECG findings that are characteristic of the disease process. This may help make the diagnosis of the disease in equivocal cases.
Flecainide has been introduced into the treatment of arrhythmias in the pediatric population.
According to recent research published in Nature Medicine, flecainide inhibits the release of the cardiac ryanodine receptor–mediated Ca2+, and is therefore believed to medicate the underlying molecular cause of catecholaminergic polymorphic ventricular tachycardia in both mice and humans.
The dosing of flecainide is varied, with consideration made to the individual's other medications and comorbid conditions and how they may affect the metabolism of flecainide. Individuals with significant renal impairment may require measurement of the plasma level of flecainide to ensure that the drug level remains within the therapeutic range (i.e.: that toxic levels do not occur). In addition, lower drug levels may be sought for the treatment of benign arrhythmias, to lower the chance of inducing a toxic effect of the drug. When used in the pediatric population, the dose of flecainide may be adjusted to the individual's body surface area. Since food digestion can alter the absorption of the drug, Flecainide should be taken one hour before meals.
Given the variable half life of flecainide and the characteristic QRS prolongation on ECG elicited in flecainide toxicity, especially at rapid heart rates , starting flecainide or changing the level of the drug is done under telemetry monitoring (preferably in a hospital telemetry unit) until a steady state plasma level has been achieved, typically three to five days after the dose has been increased.
For the treatment of supraventricular tachycardias and paroxysmal atrial fibrillation or flutter in individuals without significant structural heart disease, a starting dose of 50 mg twice a day may be appropriate. The dose may be increased (once a steady state level has been reached) if breakthrough dysrhythmias occur.
For the treatment of life-threatening ventricular arrhythmias (i.e.: ventricular tachycardia), a starting dose of 100 mg twice a day may be appropriate. As with the treatment of benign arrhythmias, the dose of flecainide given for the treatment of life-threatening ventricular dysrhythmias should not be increased until a steady state has been achieved.
Mechanism of action
Flecainide works by blocking the Nav1.5 sodium channel in the heart, causing prolongation of the cardiac action potential. This thereby slows conduction of the electrical impulse within the heart. The greatest effect is on the His-Purkinje system and ventricular myocardium. The effect of flecainide on the ventricular myocardium causes decreased contractility of the muscle, which leads to a decrease in the ejection fraction.
The effect of flecainide on the sodium channels of the heart increases as the heart rate increases. This is known as use-dependence. This means that flecainide is potentially more useful to break a tachyarrhythmia (because it has increased effect during the fast heart rate) than to prevent a bradyarrhythmia from occurring (because of its lowered effectiveness during slower heart rates).
Metabolism and drug interactions
Flecainide has high bioavailability after an oral dose, meaning that most of the drug that is ingested will enter the systemic blood stream. Peak serum concentrations can be seen 1 to 6 hours after ingestion of an oral dose. While the plasma half life is about 20 hours, it is quite variable, and can range from 12 to 27 hours. During oral loading with flecainide, a steady state equilibrium is typically achieved in 3 to 5 days.
The majority of flecainide is eliminated by the kidneys, with the remainder metabolised by the cytochrome P450 2D6 isoenzyme in the liver. Therefore, alterations in renal function or urine pH will greatly affect the elimination of flecainide, as more is eliminated by the hepatic route.
Because of the dual elimination routes of flecainide and its tendency to decrease myocardial contractility, flecainide interacts with numerous pharmaceuticals and can potentiate the effects of other myocardial depressants and AV node blocking agents. In addition, flecainide can decrease the metabolism or elimination of many (but not all) agents that use the cytochrome P450 enzyme system.
A full list of drug interactions with flecainide can be obtained from the manufacturer. Some important drug interactions with flecainide include:
- Alcohol - may further depress normal heart function.
- Amiodarone - inhibits cytochrome P450 2D6 and may increase flecainide levels
- Cimetidine - increases flecainide levels by 30% and half-life by 10%
- Digoxin - may increase digoxin levels
- Paroxetine - increased effect of both drugs.
- Propafenone - increased effect of both drugs and increased risk of toxicity.
- Quinidine - inhibits cytochrome P450 2D6 and may increase flecainide levels
Serious adverse reactions
Results of a medical study known as the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that patients with structural heart disease (such as a history of MI (heart attack), or left ventricular dysfunction) and also patients with ventricular arrhythmias, should not take this drug. In patients with these kinds of heart diseases, flecainide actually increases the chance of suffering a fatal arrhythmia.
The dose may need to be adjusted in certain clinical scenarios. As with all other antiarrhythmic agents, there is a risk of proarrhythmia associated with the use of flecainide. This risk is probably increased when flecainide is co-administered with other class Ic antiarrhythmics, such as encainide. The risk of proarrhythmia may also be increased by hypokalemia. The risk of proarrhythmia is not necessarily associated with the length of time an individual is taking flecainide, and cases of late proarrhythmia have been reported. Because of the role of both the liver and the kidneys in the elimination of flecainide, the dosing of flecainide may need to be adjusted in individuals who develop either liver failure or renal failure.
Because of the negative inotropic effects of flecainide, it should be used with caution in individuals with depressed ejection fraction, and may worsen congestive heart failure in these individuals. It should be avoided in people with ischaemic heart disease and the elderly.
As with all class I antiarrhythmic agents, Flecainide increases the capture thresholds of pacemakers. Therefore, capture thresholds should be remeasured in individuals with pacemakers after the steady-state flecainide dose is changed.
Due to the narrow therapeutic index of flecainide, physicians should be alert for signs of toxicity before life-threatening arrhythmias occur like torsade de pointes. While the toxic effects of flecainide are closely related to the plasma levels of the drug, it is infeasible to check the plasma concentration in an individual on a regular basis.
Signs of flecainide toxicity include marked prolongation of the PR interval and widening of the QRS duration on the surface ECG. There may be signs and symptoms attributable to overt heart failure secondary to sudden decreased myocardial contractility.
Treatment of flecainide toxicity involves increasing the excretion of flecainide, blocking its effects in the heart, and (rarely) institution of cardiovascular support to avoid impending lethal arrhythmias. Modalities that have had success include administration of a beta-sympathomimetic agent, and administration of a sodium load(often in the form of hypertonic sodium bicarbonate). Placing the individual on cardiopulmonary bypass support may be necessary in order to temporarily obviate the need for a beating heart and to increase blood flow to the liver.
Long term effects
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- Family Practice Notebook
- Medline Plus
- Atrial Fibrillation Foundation
- Cleveland Clinic
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