Flecainide

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Flecainide
Skeletal formula of flecainide
Space-filling model of the flecainide molecule
Systematic (IUPAC) name
(RS)-N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
Clinical data
Trade names Tambocor
AHFS/Drugs.com monograph
MedlinePlus a608040
Pregnancy
category
  • C
Pharmacokinetic data
Bioavailability 95%
Protein binding 40%
Metabolism CYP2D6 (limited)
Biological half-life 20 hours (range 12-27 hours)
Excretion Renal
Identifiers
CAS Number 54143-55-4 YesY
ATC code C01BC04 (WHO)
PubChem CID: 3356
IUPHAR/BPS 2560
DrugBank DB01195 YesY
ChemSpider 3239 YesY
UNII K94FTS1806 YesY
KEGG D07962 YesY
ChEBI CHEBI:75984 N
ChEMBL CHEMBL652 YesY
Chemical data
Formula C17H20F6N2O3
Molecular mass 414.343 g/mol
  • FC(F)(F)COc2cc(C(=O)NCC1NCCCC1)c(OCC(F)(F)F)cc2
  • InChI=1S/C17H20F6N2O3/c18-16(19,20)9-27-12-4-5-14(28-10-17(21,22)23)13(7-12)15(26)25-8-11-3-1-2-6-24-11/h4-5,7,11,24H,1-3,6,8-10H2,(H,25,26) YesY
  • Key:DJBNUMBKLMJRSA-UHFFFAOYSA-N YesY
 NYesY (what is this?)  (verify)

Flecainide acetate (/flɛˈkeɪnaɪd/ US dict: fle·kā′·nīd) 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[citation needed] (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 is sold under the trade name Tambocor (manufactured by 3M pharmaceuticals). Flecainide went off-patent on February 10, 2004. In addition to being marketed as Tambocor, it is also available in generic version and under the trade names Almarytm, Apocard, Ecrinal, and Flécaine.

Medical uses

Flecainide is used in the treatment of many types of supraventricular tachycardias, including AV nodal re-entrant 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[1] and in the suppression of arrhythmias in arrhythmogenic right ventricular dysplasia (ARVD).[2] Studies (notably the Cardiac Arrhythmia Suppression Trial) have shown an increased mortality when flecainide is used to suppress ventricular extrasystoles in the setting of acute myocardial infarction.[3][4]

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.[5]

Flecainide has been introduced into the treatment of arrhythmias in the pediatric population.

Dosing

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.

Given the variable half-life of flecainide and the characteristic QRS prolongation on ECG elicited in flecainide toxicity, especially at rapid heart rates,[6] 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 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.

Side effects

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[which?], should not take this drug. The results were so significant that the trial was stopped early and preliminary results were published.[7] 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.[8] 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.[9] 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,[10] 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.[11] Therefore, capture thresholds should be remeasured in individuals with pacemakers after the steady-state flecainide dose is changed.

Cardiac toxicity

Due to the narrow therapeutic index of flecainide, physicians should be alert for signs of toxicity before life-threatening arrhythmias occur like torsades de pointes. While the toxic effects of flecainide are closely related to the plasma levels of the drug,[12] it is unfeasible 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

Treatment of flecainide cardiac 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,[12] and administration of a sodium load[12](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.[13][14]

Lung toxicity

Flecainide has a very high affinity for lung tissue [15] and is associated with drug-induced interstitial lung disease.[16][17][18][19][20]

Mechanism of action

Flecainide works by blocking the Nav1.5 sodium channel in the heart, slowing the upstroke of the cardiac action potential.[21] This thereby slows conduction of the electrical impulse within the heart, i.e. it "reduces excitability". 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 and is why that flecainide is useful to break a tachyarrhythmia.[22]

Flecainide also inhibits ryanodine receptor 2 (RyR2), [23] a major regulator of sarcoplasmic release of stored calcium ions. It can reduce calcium sparks and thus arrhythmogenic calcium waves in the heart.[24] While Flecainide therapy has been shown to suppress ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and mouse models of this disease, the relative contribution from the inhibition of sodium channels and of RyR2 in this effect on CPVT is unclear.[25]

Metabolism and drug interactions

Flecainide has high bioavailability after an oral dose,[26] 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.[27] 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 metabolized by the cytochrome P450 2D6 isoenzyme in the liver.[28] Therefore, alterations in renal function or urine pH will greatly affect the elimination of flecainide, as more is eliminated by the kidney than by the hepatic route.

Because of the dual elimination routes of flecainide and its tendency to decrease myocardial contractility,[10] 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:[citation needed]

Long-term effects

In the long term, flecainide seems to be safe in patients with a healthy heart with no signs of left ventricular hypertrophy, ischemic heart disease or heart failure.[29]

References

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  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ 10.0 10.1 Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ 12.0 12.1 12.2 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ P Camus, A Fanton, P Bonniaud, C Camus et al. "Interstitial lung disease induced by drugs and radiation. Respiration 2004; 71:301–326 doi:10.1159/000079633 PMID 15316202
  18. ↑ S Pesenti, D Lauque, G Daste, V Boulay et al. "Diffuse Infiltrative Lung Disease Associated with Flecainide. Respiration 2002; 69:182–185 doi:10.1159/000056325 PMID 11961436
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  26. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  27. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  28. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  29. ↑ Aliot E, Capucci A, Crijns HJ, Goette A, Tamargo J. Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation. Eurospace 2011 13:161-173

External links

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