Flecainide

Last updated
Flecainide
Flecainide structure.svg
Flecainide 3D ball.png
Clinical data
Pronunciation /flɛˈkeɪnaɪd/ fleh-KAY-nyde
Trade names Tambocor, others
AHFS/Drugs.com Monograph
MedlinePlus a608040
Drug class Ic antiarrhythmic [1]
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: WARNING [2] Rx-only
Pharmacokinetic data
Bioavailability 95%
Protein binding 40%
Metabolism CYP2D6 (limited)
Elimination half-life 20 hours (range 12–27 hours)
Excretion Kidney
Identifiers
  • (RS)-N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.211.334 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H20F6N2O3
Molar mass 414.348 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • 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) Yes check.svgY
  • Key:DJBNUMBKLMJRSA-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Flecainide is a medication used to prevent and treat abnormally fast heart rates. [1] This includes ventricular and supraventricular tachycardias. [1] Its use is only recommended in those with dangerous arrhythmias or when significant symptoms cannot be managed with other treatments. [1] Its use does not decrease a person's risk of death. [1] It is taken by mouth or injection into a vein. [1] [3]

Contents

Common side effects include dizziness, problems seeing, shortness of breath, chest pain, and tiredness. [1] Serious side effects may include cardiac arrest, arrhythmias, and heart failure. [1] It may be used in pregnancy, but has not been well studied in this population. [3] [4] Use is not recommended in those with structural heart disease or ischemic heart disease. [1] Flecainide is a class Ic antiarrhythmic agent. [1] It works by decreasing the entry of sodium in heart cells, causing prolongation of the cardiac action potential. [1]

Flecainide was approved for medical use in the United States in 1985. [1] It is available as a generic medication. [3] In 2021, it was the 205th most commonly prescribed medication in the United States, with more than 2 million prescriptions. [5] [6]

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).

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 [7] and in the suppression of arrhythmias in arrhythmogenic right ventricular dysplasia (ARVD). [8] 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. [9] [10]

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. [11]

Flecainide has been introduced into the treatment of arrhythmias in children.

In the long-term, flecainide seems to be safe in people with a healthy heart with no signs of left ventricular hypertrophy, ischemic heart disease, or heart failure. [12]

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, should not take this drug. The results were so significant that the trial was stopped early and preliminary results were published. [13]

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. [14] 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. [15] 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 kidney 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. [16]

As with all class I antiarrhythmic agents, flecainide increases the capture thresholds of pacemakers. [17] [18]

Heart

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, [19] 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, [19] and administration of a sodium load [19] (often in the form of hypertonic sodium bicarbonate). Placing the individual on cardiopulmonary bypass support may be necessary in order to temporarily remove the need for a beating heart and to increase blood flow to the liver. [20] [21]

Lungs

Flecainide has a very high affinity for lung tissue [22] and is associated with drug-induced interstitial lung disease. [23] [24] [25] [26] [27]

Interactions

Flecainide has high bioavailability after an oral dose, [28] 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. [29] 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. [30] 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, [16] 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 ]

Overdose

Flecainide intoxication is rare but serious due to the cardiogenic shock that it provokes. Its diagnosis can be difficult in the lack of contributing anamnestic elements. Clinical and paraclinical signs are not specific. Treatment is primarily symptomatic, which gives good results thanks to the hypertonic solution of sodium salts. Organ donation is possible in the case of braindead patients who had a flecainide intoxication. [31]

Mechanism of action

Flecainide works by blocking the Nav1.5 sodium channel in the heart, slowing the upstroke of the cardiac action potential. [32] 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. [33]

Flecainide also inhibits ryanodine receptor 2 (RyR2), [34] a major regulator of sarcoplasmic release of stored calcium ions. It can reduce calcium sparks and thus arrhythmogenic calcium waves in the heart. [35] 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. [36]

Society and culture

Brand names

Flecainide is sold under the trade name Tambocor (manufactured by 3M pharmaceuticals). Flecainide went off-patent in February 2004. In addition to being marketed as Tambocor, it is available in generic version and under the brand names Almarytm, Apocard, Ecrinal, and Flécaine.

Related Research Articles

<span class="mw-page-title-main">Premature ventricular contraction</span> Skipped beat with ventricular origin

A premature ventricular contraction (PVC) is a common event where the heartbeat is initiated by Purkinje fibers in the ventricles rather than by the sinoatrial node. PVCs may cause no symptoms or may be perceived as a "skipped beat" or felt as palpitations in the chest. PVCs do not usually pose any danger.

<span class="mw-page-title-main">Propafenone</span> Anti-arrhythmic medication

Propafenone, sold under the brand name Rythmol among others, is a class 1c anti-arrhythmic medication, which is used to treat illnesses associated with rapid heart beat such as atrial and ventricular arrhythmias.

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Quinidine</span> Antiarrythmic medication

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of antimalarial agent quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.

<span class="mw-page-title-main">Amiodarone</span> Antiarrhythmic medication used for various types of irregular heartbeats

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia (VT), ventricular fibrillation (VF), and wide complex tachycardia, as well as atrial fibrillation and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.

<span class="mw-page-title-main">Torsades de pointes</span> Type of abnormal heart rhythm

Torsades de pointes, torsade de pointes or torsades des pointes is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). It was described by French physician François Dessertenne in 1966. Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm, occurring in between 1% and 10% of patients who receive QT-prolonging antiarrhythmic drugs.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

<span class="mw-page-title-main">Procainamide</span> Medication to treat cardiac arrhythmias

Procainamide (PCA) is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is a sodium channel blocker of cardiomyocytes; thus it is classified by the Vaughan Williams classification system as class Ia. In addition to blocking the INa current, it inhibits the IKr rectifier K+ current. Procainamide is also known to induce a voltage-dependent open channel block on the batrachotoxin (BTX)-activated sodium channels in cardiomyocytes.

<span class="mw-page-title-main">Disopyramide</span> Chemical compound

Disopyramide is an antiarrhythmic medication used in the treatment of ventricular tachycardia. It is a sodium channel blocker and is classified as a Class 1a anti-arrhythmic agent. Disopyramide has a negative inotropic effect on the ventricular myocardium, significantly decreasing the contractility. Disopyramide also has an anticholinergic effect on the heart which accounts for many adverse side effects. Disopyramide is available in both oral and intravenous forms, and has a low degree of toxicity.

<span class="mw-page-title-main">Acecainide</span> Antiarrythmic drug

Acecainide is an antiarrhythmic drug. Chemically, it is the N-acetylated metabolite of procainamide. It is a Class III antiarrhythmic agent, whereas procainamide is a Class Ia antiarrhythmic drug. It is only partially as active as procainamide; when checking levels, both must be included in the final calculation.

<span class="mw-page-title-main">Prajmaline</span> Chemical compound

Prajmaline (Neo-gilurythmal) is a class Ia antiarrhythmic agent which has been available since the 1970s. Class Ia drugs increase the time one action potential lasts in the heart. Prajmaline is a semi-synthetic propyl derivative of ajmaline, with a higher bioavailability than its predecessor. It acts to stop arrhythmias of the heart through a frequency-dependent block of cardiac sodium channels.

<span class="mw-page-title-main">Lorcainide</span> Antiarrythmic agent

Lorcainide is a Class 1c antiarrhythmic agent that is used to help restore normal heart rhythm and conduction in patients with premature ventricular contractions, ventricular tachycardiac and Wolff–Parkinson–White syndrome. Lorcainide was developed by Janssen Pharmaceutica (Belgium) in 1968 under the commercial name Remivox and is designated by code numbers R-15889 or Ro 13-1042/001. It has a half-life of 8.9 +- 2.3 hrs which may be prolonged to 66 hrs in people with cardiac disease.

<span class="mw-page-title-main">Catecholaminergic polymorphic ventricular tachycardia</span> Medical condition

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death.

Afterdepolarizations are abnormal depolarizations of cardiac myocytes that interrupt phase 2, phase 3, or phase 4 of the cardiac action potential in the electrical conduction system of the heart. Afterdepolarizations may lead to cardiac arrhythmias. Afterdepolarization is commonly a consequence of myocardial infarction, cardiac hypertrophy, or heart failure. It may also result from congenital mutations associated with calcium channels and sequestration.

<span class="mw-page-title-main">Pilsicainide</span> Chemical compound

Pilsicainide (INN) is an antiarrhythmic agent. It is marketed in Japan as サンリズム (Sunrythm). It was developed by Suntory Holdings Limited and first released in 1991. The JAN applies to the hydrochloride salt, pilsicainide hydrochloride.

Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels.

<span class="mw-page-title-main">Moracizine</span> Chemical compound

Moracizine or moricizine, sold under the trade name Ethmozine, is an antiarrhythmic of class IC. It was used for the prophylaxis and treatment of serious and life-threatening ventricular arrhythmias, but was withdrawn in 2007 for commercial reasons.

<span class="mw-page-title-main">Arrhythmia</span> Group of medical conditions characterized by irregular heartbeat

Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adults – is called tachycardia, and a resting heart rate that is too slow – below 60 beats per minute – is called bradycardia. Some types of arrhythmias have no symptoms. Symptoms, when present, may include palpitations or feeling a pause between heartbeats. In more serious cases, there may be lightheadedness, passing out, shortness of breath, chest pain, or decreased level of consciousness. While most cases of arrhythmia are not serious, some predispose a person to complications such as stroke or heart failure. Others may result in sudden death.

The Cardiac Arrhythmia Suppression Trial (CAST) was a double-blind, randomized, controlled study designed to test the hypothesis that suppression of premature ventricular complexes (PVC) with class I antiarrhythmic agents after a myocardial infarction (MI) would reduce mortality. It was conducted between 1986 and 1989 and included over 1700 patients in 27 centres. The study found that the tested drugs increased mortality instead of lowering it as was expected. The publication of these results in 1991/92, in combination with large follow-up studies for drugs that had not been tested in CAST, led to a paradigm shift in the treatment of MI patients. Class I and III antiarrhythmics are now only used with extreme caution after MI, or they are contraindicated completely. Heart Rhythm Society Distinguished Scientist D. George Wyse was a member of the CAST trial's steering and executive committees.

QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (ECG). Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP). QT prolongation is an established side effect of antiarrhythmics, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antidepressants, antihistamines, opioids, and complementary medicines. On an ECG, the QT interval represents the summation of action potentials in cardiac muscle cells, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, resulting in QT prolongation.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "Flecainide Acetate Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 7 April 2019.
  2. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  3. 1 2 3 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 103. ISBN   9780857113382.
  4. ↑ "Flecainide (Tambocor) Use During Pregnancy". Drugs.com. Retrieved 7 April 2019.
  5. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  6. ↑ "Flecainide - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  7. ↑ Gill JS, Mehta D, Ward DE, Camm AJ (October 1992). "Efficacy of flecainide, sotalol, and verapamil in the treatment of right ventricular tachycardia in patients without overt cardiac abnormality". British Heart Journal. 68 (4): 392–397. doi:10.1136/hrt.68.10.392. PMC   1025139 . PMID   1449923.
  8. ↑ Sakurada H, Hiyoshi Y, Tejima T, Yanase O, Tokuyasu Y, Watanabe K, et al. (May 1990). "[Effects of oral flecainide treatment of refractory tachyarrhythmias]". Kokyu to Junkan. Respiration & Circulation. 38 (5): 471–476. PMID   2115193.
  9. ↑ Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. (March 1991). "Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial". The New England Journal of Medicine. 324 (12): 781–788. doi: 10.1056/NEJM199103213241201 . PMID   1900101.
  10. ↑ Greenberg HM, Dwyer EM, Hochman JS, Steinberg JS, Echt DS, Peters RW (December 1995). "Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I". British Heart Journal. 74 (6): 631–635. doi:10.1136/hrt.74.6.631. PMC   484119 . PMID   8541168.
  11. ↑ Gasparini M, Priori SG, Mantica M, Napolitano C, Galimberti P, Ceriotti C, Simonini S (January 2003). "Flecainide test in Brugada syndrome: a reproducible but risky tool". Pacing and Clinical Electrophysiology. 26 (1P2): 338–341. doi:10.1046/j.1460-9592.2003.00045.x. PMID   12687841. S2CID   555793.
  12. ↑ Aliot E, Capucci A, Crijns HJ, Goette A, Tamargo J (February 2011). "Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation". Europace. 13 (2): 161–173. doi:10.1093/europace/euq382. PMC   3024037 . PMID   21138930.
  13. ↑ Cardiac Arrhythmia Suppression Trial (CAST) Investigators (August 1989). "Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction". The New England Journal of Medicine. 321 (6): 406–412. doi:10.1056/NEJM198908103210629. PMID   2473403.
  14. ↑ Ohki R, Takahashi M, Mizuno O, Fujikawa H, Mitsuhashi T, Katsuki T, et al. (January 2001). "Torsades de pointes ventricular tachycardia induced by mosapride and flecainide in the presence of hypokalemia". Pacing and Clinical Electrophysiology. 24 (1): 119–121. doi:10.1046/j.1460-9592.2001.00119.x. PMID   11227957. S2CID   41090195.
  15. ↑ Morganroth J (February 1992). "Early and late proarrhythmia from antiarrhythmic drug therapy". Cardiovascular Drugs and Therapy. 6 (1): 11–14. doi:10.1007/BF00050910. PMID   1533532. S2CID   22653784.
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  17. ↑ Fornieles-Pérez H, Montoya-García M, Levine PA, Sanz O (May 2002). "Documentation of acute rise in ventricular capture thresholds associated with flecainide acetate". Pacing and Clinical Electrophysiology. 25 (5): 871–872. doi:10.1046/j.1460-9592.2002.00871.x. PMID   12049386. S2CID   7180036.
  18. ↑ Suffredini JM, Rutland J, Akpunonu P, Baum R, Catanzaro J, Elayi CS (August 2019). "Flecainide Toxicity Resulting in Pacemaker Latency and Intermittent Failure to Capture". The American Journal of Case Reports. 20: 1279–1283. doi:10.12659/AJCR.916370. PMC   6735620 . PMID   31467262.
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  20. ↑ Corkeron MA, van Heerden PV, Newman SM, Dusci L (August 1999). "Extracorporeal circulatory support in near-fatal flecainide overdose". Anaesthesia and Intensive Care. 27 (4): 405–408. doi: 10.1177/0310057x9902700413 . PMID   10470398.
  21. ↑ Yasui RK, Culclasure TF, Kaufman D, Freed CR (May 1997). "Flecainide overdose: is cardiopulmonary support the treatment?". Annals of Emergency Medicine. 29 (5): 680–682. doi:10.1016/S0196-0644(97)70257-9. PMID   9140253.
  22. ↑ Latini R, Cavalli A, Maggioni AP, Volpi A (December 1987). "Flecainide distribution in human tissues". British Journal of Clinical Pharmacology. 24 (6): 820–822. doi:10.1111/j.1365-2125.1987.tb03252.x. PMC   1386410 . PMID   3125854.
  23. ↑ Ozkan M, Dweik RA, Ahmad M (September 2001). "Drug-induced lung disease". Cleveland Clinic Journal of Medicine. 68 (9): 782–785, 789–795. doi:10.3949/ccjm.68.9.782. PMID   11563482. S2CID   45036873.
  24. ↑ Camus P, Fanton A, Bonniaud P, Camus C, Foucher P (2004). "Interstitial lung disease induced by drugs and radiation". Respiration; International Review of Thoracic Diseases. 71 (4): 301–326. doi:10.1159/000079633. PMID   15316202. S2CID   16315007.
  25. ↑ Pesenti S, Lauque D, Daste G, Boulay V, Pujazon MC, Carles P (2002). "Diffuse infiltrative lung disease associated with flecainide. Report of two cases". Respiration; International Review of Thoracic Diseases. 69 (2): 182–185. doi:10.1159/000056325. PMID   11961436. S2CID   72367121.
  26. ↑ Haas M, Pérault MC, Bonnefoy P, Rodeau F, Caron F (2001). "[Interstitial pneumopathy due to flecainide]". Presse Médicale. 30 (21): 1062. PMID   11471279.
  27. ↑ Robain A, Perchet H, Fuhrman C (February 2000). "Flecainide-associated pneumonitis with acute respiratory failure in a patient with the LEOPARD syndrome". Acta Cardiologica. 55 (1): 45–47. doi:10.2143/ac.55.1.2005718. PMID   10707759. S2CID   20721407.
  28. ↑ Smith GH (October 1985). "Flecainide: a new class Ic antidysrhythmic". Drug Intelligence & Clinical Pharmacy. 19 (10): 703–707. doi:10.1177/106002808501901001. PMID   3902429. S2CID   1086493.
  29. ↑ Padrini R, Piovan D, Busa M, al-Bunni M, Maiolino P, Ferrari M (January 1993). "Pharmacodynamic variability of flecainide assessed by QRS changes". Clinical Pharmacology and Therapeutics. 53 (1): 59–64. doi:10.1038/clpt.1993.9. PMID   8422742. S2CID   23471140.
  30. ↑ Haefeli WE, Bargetzi MJ, Follath F, Meyer UA (May 1990). "Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo". Journal of Cardiovascular Pharmacology. 15 (5): 776–779. doi: 10.1097/00005344-199005000-00013 . PMID   1692938. S2CID   25544471.
  31. ↑ Ghannam A, Tazi A, Kettani A, Faroudy M (2014). "Non-Accidental Flecainide Overdose, A Case Report". International Journal of Medicine and Surgery. 1 (2): 53. doi: 10.15342/ijms.v1i2.18 .
  32. ↑ Ramos E, O'leary ME (October 2004). "State-dependent trapping of flecainide in the cardiac sodium channel". The Journal of Physiology. 560 (Pt 1): 37–49. doi:10.1113/jphysiol.2004.065003. PMC   1665201 . PMID   15272045.
  33. ↑ Wang Z, Fermini B, Nattel S (November 1993). "Mechanism of flecainide's rate-dependent actions on action potential duration in canine atrial tissue". The Journal of Pharmacology and Experimental Therapeutics. 267 (2): 575–581. PMID   8246130.
  34. ↑ Mehra D, Imtiaz MS, van Helden DF, Knollmann BC, Laver DR (December 2014). "Multiple modes of ryanodine receptor 2 inhibition by flecainide". Molecular Pharmacology. 86 (6): 696–706. doi:10.1124/mol.114.094623. PMC   4244595 . PMID   25274603.
  35. ↑ Hilliard FA, Steele DS, Laver D, Yang Z, Le Marchand SJ, Chopra N, et al. (February 2010). "Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass". Journal of Molecular and Cellular Cardiology. 48 (2): 293–301. doi:10.1016/j.yjmcc.2009.10.005. PMC   2813417 . PMID   19835880.
  36. ↑ Smith GL, MacQuaide N (April 2015). "The direct actions of flecainide on the human cardiac ryanodine receptor: keeping open the debate on the mechanism of action of local anesthetics in CPVT". Circulation Research. 116 (8): 1284–1286. doi: 10.1161/CIRCRESAHA.115.306298 . PMID   25858058.
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