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词条 Flecainide
释义

  1. Medical uses

  2. Side effects

     Cardiac toxicity  Treatment  Lung toxicity 

  3. Mechanism of action

  4. Metabolism and drug interactions

  5. Long-term effects

  6. Overdose

  7. Brand names

  8. References

  9. External links

{{Drugbox
| Verifiedfields = changed
| verifiedrevid = 461100696
| IUPAC_name = (RS)-N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
| image = Flecainide structure.svg
| alt = Skeletal formula of flecainide
| width = 180
| chirality = Racemic mixture
| image2 = Flecainide 3D ball.png
| alt2 = Ball-and-stick model of the flecainide molecule
| width2 = 185
| pronounce = {{IPAc-en|f|l|ɛ|ˈ|k|eɪ|n|aɪ|d}} {{respell|flek|AY|nyde}}
| tradename = Tambocor, others
| Drugs.com = {{drugs.com|monograph|tambocor}}
| MedlinePlus = a608040
| pregnancy_category = C
| bioavailability = 95%
| protein_bound = 40%
| metabolism = CYP2D6 (limited)
| elimination_half-life = 20 hours (range 12–27 hours)
| excretion = Renal
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 54143-55-4
| ATC_prefix = C01
| ATC_suffix = BC04
| PubChem = 3356
| IUPHAR_ligand = 2560
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01195
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3239
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = K94FTS1806
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07962
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 75984
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 652
| C=17 | H=20 | F=6 | N=2 | O=3
| molecular_weight = 414.343 g/mol
| smiles = FC(F)(F)COc2cc(C(=O)NCC1NCCCC1)c(OCC(F)(F)F)cc2
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DJBNUMBKLMJRSA-UHFFFAOYSA-N
}}

Flecainide acetate 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|date=September 2014}} (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.

In 2016 it was the 273rd most prescribed medication in the United States with more than a million prescriptions.[1]

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[2] and in the suppression of arrhythmias in arrhythmogenic right ventricular dysplasia (ARVD).[3] 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.[4][5]

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.[6]

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

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.[7]

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, 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.[10]

As with all class I antiarrhythmic agents, Flecainide increases the capture thresholds of pacemakers.[10]

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,[11] 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,[11] and administration of a sodium load[11](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.[12][13]

Lung toxicity

Flecainide has a very high affinity for lung tissue [14] and is associated with drug-induced interstitial lung disease.[15][16][17][18][19]

Mechanism of action

Flecainide works by blocking the Nav1.5 sodium channel in the heart, slowing the upstroke of the cardiac action potential.[20] 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.[21]

Flecainide also inhibits ryanodine receptor 2 (RyR2),[22] a major regulator of sarcoplasmic release of stored calcium ions. It can reduce calcium sparks and thus arrhythmogenic calcium waves in the heart.[23] 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.[24]

Metabolism and drug interactions

Flecainide has high bioavailability after an oral dose,[25] 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.[26] 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.[27] 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,[28] 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|date=July 2011}}

  • 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

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]

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 suffered a flecainide intoxication.[30]

Brand names

Flecainide is sold under the trade name Tambocor (manufactured by 3M pharmaceuticals). Flecainide went off-patent on February{{nbsp}}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.

References

1. ^{{cite web |title=The Top 300 of 2019 |url=https://clincalc.com/DrugStats/Top300Drugs.aspx |website=clincalc.com |accessdate=22 December 2018}}
2. ^{{cite journal |vauthors=Gill J, Mehta D, Ward D, Camm A | title = Efficacy of flecainide, sotalol, and verapamil in the treatment of right ventricular tachycardia in patients without overt cardiac abnormality | journal = Br Heart J | volume = 68 | issue = 4 | pages = 392–97 | year = 1992 | pmid = 1449923 | doi = 10.1136/hrt.68.10.392 | pmc = 1025139}}
3. ^{{cite journal |vauthors=Sakurada H, Hiyoshi Y, Tejima T, Yanase O, Tokuyasu Y, Watanabe K, Motomiya T, Sugiura M, Hiraoka M | title = [Effects of oral flecainide treatment of refractory tachyarrhythmias] | journal = Kokyu to Junkan | volume = 38 | issue = 5 | pages = 471–76 | year = 1990 | pmid = 2115193}}
4. ^{{cite journal | doi = 10.1056/NEJM199103213241201 |vauthors=Echt D, Liebson P, Mitchell L, Peters R, Obias-Manno D, Barker A, Arensberg D, Baker A, Friedman L, Greene H | title = Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial | journal = N Engl J Med | volume = 324 | issue = 12 | pages = 781–88 | year = 1991 | pmid = 1900101}}
5. ^{{cite journal |vauthors=Greenberg H, Dwyer E, Hochman J, Steinberg J, Echt D, Peters R | title = Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST I | journal = Br Heart J | volume = 74 | issue = 6 | pages = 631–35 | year = 1995 | pmid = 8541168 | doi = 10.1136/hrt.74.6.631 | pmc = 484119}}
6. ^{{cite journal |vauthors=Gasparini M, Priori S, Mantica M, Napolitano C, Galimberti P, Ceriotti C, Simonini S | title = Flecainide test in Brugada syndrome: a reproducible but risky tool | journal = Pacing Clin Electrophysiol | volume = 26 | issue = 1 Pt 2 | pages = 338–41 | year = 2003 | pmid = 12687841 | doi = 10.1046/j.1460-9592.2003.00045.x}}
7. ^{{cite journal | author = Cardiac Arrhythmia Suppression Trial (CAST) Investigators | title = Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. | journal = N Engl J Med | volume = 321 | issue = 6| pages = 406–12 | year = 1989 | pmid = 2473403| doi =10.1056/NEJM198908103210629 }}
8. ^{{cite journal |vauthors=Ohki R, Takahashi M, Mizuno O, Fujikawa H, Mitsuhashi T, Katsuki T, Ikeda U, Shimada K | title = Torsades de pointes ventricular tachycardia induced by mosapride and flecainide in the presence of hypokalemia | journal = Pacing Clin Electrophysiol | volume = 24 | issue = 1 | pages = 119–21 | year = 2001 | pmid = 11227957 | doi = 10.1046/j.1460-9592.2001.00119.x}}
9. ^{{cite journal | author = Morganroth J | title = Early and late proarrhythmia from antiarrhythmic drug therapy | journal = Cardiovasc Drugs Ther | volume = 6 | issue = 1 | pages = 11–14 | year = 1992 | pmid = 1533532 | doi = 10.1007/BF00050910}}
10. ^{{cite journal |vauthors=Fornieles-Pérez H, Montoya-García M, Levine P, Sanz O | title = Documentation of acute rise in ventricular capture thresholds associated with flecainide acetate | journal = Pacing Clin Electrophysiol | volume = 25 | issue = 5 | pages = 871–72 | year = 2002 | pmid = 12049386 | doi = 10.1046/j.1460-9592.2002.00871.x}}
11. ^1 2 {{cite journal |vauthors=Winkelmann B, Leinberger H | title = Life-threatening flecainide toxicity. A pharmacodynamic approach | journal = Annals of Internal Medicine | volume = 106 | issue = 6 | pages = 807–14 | year = 1987 | pmid = 3107447 | doi=10.7326/0003-4819-106-6-807}}
12. ^{{cite journal |vauthors=Corkeron M, van Heerden P, Newman S, Dusci L | title = Extracorporeal circulatory support in near-fatal flecainide overdose | journal = Anaesth Intensive Care | volume = 27 | issue = 4 | pages = 405–08 | year = 1999 | pmid = 10470398}}
13. ^{{cite journal |vauthors=Yasui R, Culclasure T, Kaufman D, Freed C | title = Flecainide overdose: is cardiopulmonary support the treatment? | journal = Annals of Emergency Medicine | volume = 29 | issue = 5 | pages = 680–82 | year = 1997 | pmid = 9140253 | doi = 10.1016/S0196-0644(97)70257-9}}
14. ^{{cite journal |pmid=3125854 | volume=24 | issue=6 | title=Flecainide distribution in human tissues | pmc=1386410 |date=December 1987 | pages=820–22 |vauthors=Latini R, Cavalli A, Maggioni AP, Volpi A | doi=10.1111/j.1365-2125.1987.tb03252.x | journal=British Journal of Clinical Pharmacology}}
15. ^{{cite journal |pmid=11563482 | volume=68 | issue=9 | title=Drug-induced lung disease |date=September 2001 | pages=782–85, 789–95 |vauthors=Ozkan M, Dweik RA, Ahmad M | doi=10.3949/ccjm.68.9.782 | journal=Cleve Clin J Med}}
16. ^{{cite journal | vauthors = Camus P, Fanton A, Bonniaud P, Camus C et al | year = 2004 | title = Interstitial lung disease induced by drugs and radiation | url = | journal = Respiration | volume = 71 | issue = 4| pages = 301–26 | doi = 10.1159/000079633 | pmid = 15316202 }}
17. ^{{cite journal | vauthors = Pesenti S, Lauque D, Daste G, Boulay V et al | year = 2002 | title = Diffuse Infiltrative Lung Disease Associated with Flecainide | url = | journal = Respiration | volume = 69 | issue = 2| pages = 182–85 | doi = 10.1159/000056325 | pmid = 11961436 }}
18. ^{{cite journal |pmid=11471279 | volume=30 | issue=21 | title=[Interstitial pneumopathy due to flecainide] | year=2001 | page=1062 |vauthors=Haas M, Pérault MC, Bonnefoy P, Rodeau F, Caron F | journal=Presse Med}}
19. ^{{cite journal |pmid=10707759 | volume=55 | issue=1 | title=Flecainide-associated pneumonitis with acute respiratory failure in a patient with the LEOPARD syndrome |date=February 2000 | pages=45–57 |vauthors=Robain A, Perchet H, Fuhrman C | doi=10.2143/ac.55.1.2005718 | journal=Acta Cardiol}}
20. ^{{cite journal |vauthors=Ramos E, O'leary M | title = State-dependent trapping of flecainide in the cardiac sodium channel | journal = J Physiol | volume = 560 | issue = Pt 1 | pages = 37–49 | year = 2004 | pmid = 15272045 | doi = 10.1113/jphysiol.2004.065003 | pmc = 1665201}}
21. ^{{cite journal |vauthors=Wang Z, Fermini B, Nattel S | title = Mechanism of flecainide's rate-dependent actions on action potential duration in canine atrial tissue | journal = J Pharmacol Exp Ther | volume = 267 | issue = 2 | pages = 575–81 | year = 1993 | pmid = 8246130}}
22. ^{{cite journal |vauthors=Mehra D, Imtiaz MS, van Helden DF, Knollmann BC, Laver DR |title=Multiple modes of ryanodine receptor 2 inhibition by flecainide |journal=Molecular Pharmacology |volume=86 |issue=6 |pages=696–706 |year=2014 |pmid=25274603 |doi=10.1124/mol.114.094623 |url=http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=25274603 |issn= |pmc=4244595}}
23. ^{{cite journal |vauthors=Hilliard FA, Steele DS, Laver D, Yang Z, Le Marchand SJ, Chopra N, Piston DW, Huke S, Knollmann BC |title=Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass |journal=Journal of Molecular and Cellular Cardiology |volume=48 |issue=2 |pages=293–301 |year=2010 |pmid=19835880 |pmc=2813417 |doi=10.1016/j.yjmcc.2009.10.005 |url=http://linkinghub.elsevier.com/retrieve/pii/S0022-2828(09)00428-3 |issn=}}
24. ^{{cite journal |vauthors=Smith GL, MacQuaide N |title=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 |journal=Circulation Research |volume=116 |issue=8 |pages=1284–86 |year=2015 |pmid=25858058 |doi=10.1161/CIRCRESAHA.115.306298 |url=http://circres.ahajournals.org/content/116/8/1284.extract}}
25. ^{{cite journal | author = Smith G | title = Flecainide: a new class Ic antidysrhythmic | journal = Drug Intell Clin Pharm | volume = 19 | issue = 10 | pages = 703–07 | year = 1985 | pmid = 3902429}}
26. ^{{cite journal | doi = 10.1038/clpt.1993.9 |vauthors=Padrini R, Piovan D, Busa M, al-Bunni M, Maiolino P, Ferrari M | title = Pharmacodynamic variability of flecainide assessed by QRS changes | journal = Clin Pharmacol Ther | volume = 53 | issue = 1 | pages = 59–64 | year = 1993 | pmid = 8422742}}
27. ^{{cite journal |vauthors=Haefeli W, Bargetzi M, Follath F, Meyer U | title = Potent inhibition of cytochrome P450IID6 (debrisoquin 4-hydroxylase) by flecainide in vitro and in vivo | journal = J Cardiovasc Pharmacol | volume = 15 | issue = 5 | pages = 776–79 | year = 1990 | pmid = 1692938 | doi = 10.1097/00005344-199005000-00013}}
28. ^1 {{cite journal |vauthors=Santinelli V, Arnese M, Oppo I, Matarazzi C, Maione S, Palma M, Giunta A | title = Effects of flecainide and propafenone on systolic performance in subjects with normal cardiac function | journal = Chest | volume = 103 | issue = 4 | pages = 1068–73 | year = 1993 | pmid = 8131440 | doi = 10.1378/chest.103.4.1068}}
29. ^{{cite journal | vauthors = Aliot E, Capucci A, Crijns HJ, Goette A, Tamargo J | year = 2011 | title = Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation | url = | journal = Eurospace | volume = 13 | issue = 2| pages = 161–73 | doi=10.1093/europace/euq382| pmc = 3024037}}
30. ^{{cite journal |last1=Abdelilah |first1=Ghannam et. al |last2= |first2= |date=2014 |title=Non-Accidental Flecainide Overdose, A Case Report |journal=International Journal of Medicine and Surgery |volume=1 |issue=1 |page= 53|doi=10.15342/ijms.v1i2.18 }}

External links

  • [https://web.archive.org/web/20041001082738/http://www.rxlist.com/cgi/generic2/flecainide.htm RxList: Tambocor (Flecainide)]
{{Antiarrhythmic agents}}{{Ion channel modulators}}

7 : Antiarrhythmic agents|Benzamides|Organofluorides|Phenol ethers|Piperidines|Sodium channel blockers|Trifluoromethyl compounds
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