HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Flecainide
Flecainide-d4 · Flecaine · Flecanide · FLECAINIDE · rac Flecainide · FLECAINTDE BASE · Flecainide USP/EP/BP · (±)-Flecainide solution
Identifikatoren & physikalische Daten
| CAS No. | 54143-55-4 |
|---|---|
| Summenformel | C17H20F6N2O3 |
| Durchschnittliche Molmasse | 414,34 g/mol |
| Monoisotopische Masse | 414,13781148 g/mol |
| SMILES | O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F |
| InChIKey | DJBNUMBKLMJRSA-UHFFFAOYSA-N |
| PubChem CID | 3356 |
| ChEMBL | CHEMBL652 |
| ChEBI | CHEBI:75984 |
| EC No. | 685-650-9 |
| DTXSID | DTXSID8023054 |
Chemische & physikalische Eigenschaften
| XLogP | 3,8 |
|---|---|
| Polarare Oberfläche (TPSA) | 59,6 |
| H-Brücken-Donoren | 2 |
| H-Brücken-Akzeptoren | 10 |
| Frei drehbare Bindungen | 7 |
| Schwere Atome | 28 |
| Formalladung | 0 |
| Komplexität | 500 |
| LogP (Verteilungskoeffizient) | 3.784.6 |
| Löslichkeit | 48.43.24e-02 g/LChloroform (Slightly), Methanol (Slightly) |
| Schmelzpunkt | 228-229105-1070C |
| Physical Description | Solid |
| Dissociation Constants | 9.3 |
| Kovats Retention Index | 22712211.32230.5 |
| Collision Cross Section | 192.2 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)] |
| Siedepunkt | 434.9±45.0 °C(Predicted) |
| Dichte | 1.286±0.06 g/cm3(Predicted) |
| Flammpunkt | 9℃ |
| Lagerbedingungen | Keep in dark place,Inert atmosphere,Room temperature |
| Aggregatzustand | Solid |
| pKa (Säurekonstante) | pKa 9.3 (Uncertain) |
| Farbe | White to Off-White |
| BCS Class | 1 or 2 |
| Hauptanwendungen | clinical testing |
| 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) |
| InChIKey | DJBNUMBKLMJRSA-UHFFFAOYSA-N |
| SMILES | O=C(NCC1CCCCN1)C2=CC(OCC(F)(F)F)=CC=C2OCC(F)(F)F |
| CAS Datenbank | 54143-55-4(CAS DataBase Reference) |
| NIST chemische Informationen | Benzamide, n-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)-(54143-55-4) |
Sicherheit & Vorschriften
| GHS-Einstufung | WarningH302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]H336 (50%): May cause drowsiness or dizziness [Warning Specific target organ toxicity, single exposureNarcotic effects]H361 (50%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]H361d (50%): Suspected of damaging the unborn child [Warning Reproductive toxicity]P203, P261, P264, P270, P271, P280, P301+P317, P304+P340, P318, P319, P330, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website. |
|---|---|
| Regulatorische Informationen | Status: Active Update: 10-05-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/24769 |
| Hazard Classes and Categories | Acute Tox. 4 (100%)STOT SE 3 (50%)Repr. 2 (50%) |
| Treatment | 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. (L1129) |
| Gesundheitliche Auswirkungen | 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 (L1129). |
| Hepatotoxicity | In clinical trials, flecainide was associated with a low rate of serum aminotransferase and alkaline phosphatase elevations. Despite wide scale use, flecainide has only rarely been linked to cases of clinically apparent liver injury. The typical presentation is with a cholestatic hepatitis arising within 1 to 6 weeks of starting flecainide. In addition, instances of acute hepatic injury arising within 1 to 3 days of starting flecainide with marked, but short lived elevations in serum aminotransferase levels and minimal increases in alkaline phosphatase have been published, but may actually represent acute worsening of congestive heart failure and ischemic hepatitis due to the proarrhythmic effects of flecainide. In all instances, the liver injury was self limited. Immunoallergic and autoimmune features were not present.Likelihood score: C (probable rare cause of clinically apparent liver injury). |
| Unerwünschte Wirkungen | Cardiac ToxicityFlecainide has proarrhythmic effects with an increased incidence of mortality and nonfatal cardiac arrest in patients with a history of myocardial infarction and asymptomatic premature ventricular contractions/non-sustained ventricular tachycardia. Flecainide prolongs depolarization and can slow conduction in the atrioventricular node and the His-Purkinje system. These changes can result in prolonged PR intervals and first-degree and second-degree heart blocks. Preexisting sinus node disease can result in profound bradycardia. It does not affect repolarization, exerting a mild effect on the QT interval.Flecainide has a negative inotropic effect on cardiac muscles. Therefore, its use is contraindicated in patients with heart failure. Flecainide can convert atrial fibrillation to atrial flutter with 1:1 conduction or provoke ventricular tachyarrhythmiastherefore, a beta-blocker or a calcium channel blocker should be used concurrently.Common reactions to flecainide include dizziness, arrhythmias, dyspnea, visual disturbances, palpitations, chest pain, tremor, asthenia, abdominal pain, and constipation.Drug-Drug InteractionsSignificant drug interactions include ritonavir, cisapride, desipramine, dronedarone, quinidine, saquinavir, and tipranavir. Concurrent use with these agents should be avoided. Flecainide interacts with many other drugs, and therapy modification may be necessarytherefore, thorough medication reconciliation is important, as with all medications.* Digoxin: Flecainide has been administered to patients receiving digoxin without significant adverse effectshowever, during multiple-dose administration, plasma digoxin concentrations may increase, requiring additional monitoring.* Amiodarone: When amiodarone is added to ongoing flecainide therapy, plasma flecainide levels may increase twofold or more. Therefore, reducing the flecainide dose and carefully monitoring for toxicity are advised.* Disopyramide/verapamil: The combined use of disopyramide or verapamil with flecainide should be approached cautiously. Since all three medications have negative inotropic effects, they should be used together only if the benefits clearly outweigh the risks.* Calcium channel blockers: The combination of nifedipine or diltiazem with flecainide has not been studied, and concurrent use is not routinely recommended until further data are available.* CYP450 enzyme inducers:Enzyme inducers, such as phenytoin, phenobarbital, and carbamazepine, modestly increase flecainide elimination by approximately 30%, potentially necessitating minor dosage adjustments in chronic therapy.* CYP2D6 inhibitors: CYP2D6 inhibitors such as quinidine may increase plasma flecainide levels by inhibiting its metabolism. Antidepressants such as fluoxetine, paroxetine, and duloxetine are potent CYP2D6 inhibitors, and their coadministration with flecainide has been shown to increase plasma flecainide concentrations by 16% to 28%. |
| Expositionspfade | Ingestion (MSDS, A308). Nearly complete following oral administration. |
| Toxizitätsübersicht | Signs and Symptoms of OverdoseThere is no specific antidote for flecainide overdose. Ingestion of doses up to 8000 mg has been survived, with reported plasma concentrations as high as 5.3 mcg/mL. Clinical features may include nausea, vomiting, seizures, hypotension, bradycardia, syncope, and pronounced ECG abnormalities such as marked QRS widening, QT and PR prolongation, ventricular tachycardia, atrioventricular block, asystole, bundle branch block, heart failure, or cardiac arrest. Fatal outcomes have occurred following ingestion of as little as 1000 mg, often in the context of co-ingestion with other medications or alcohol. Flecainide plasma levels should be obtained to confirm toxicity.The therapeutic window for flecainide is narrow, ranging from 0.2 to 1.0 mcg/mL. A patient with atrial tachyarrhythmia and pacemaker therapy developed a wide-QRS tachycardia that mimicked ventricular tachycardia. Pacemaker interrogation confirmed atrial flutter with pacemaker-mediated ventricular pacing, consistent with flecainide toxicity. Infrequent cases of suicide by intentional flecainide overdose have been reported in the literature.Management of OverdoseManagement of an overdose is mainly supportive, and there is no antidote for flecainide overdose. According to the review of literature, the documented mortality rate from overdose of Class Ic Vaughan Williams antiarrhythmics stands at 22.5%. Standard treatments include aggressive fluid resuscitation, administration of hypertonic sodium bicarbonate, and intravenous magnesium. The initial management of toxicity involves administering a sodium bicarbonate infusion to promptly counteract the effects of flecainide, thereby preventing potentially life-threatening arrhythmias. Case reports indicate that sodium bicarbonate can be used as monotherapy and is commonly given as first-line treatment for a QRS duration of greater than 100 ms, in increments of 1 to 2 mEq/kg. Sodium bicarbonate raises serum pH and increases extracellular sodium levels, enabling it to compete with flecainide for sodium channel binding and strengthening the electrochemical gradient across cell membranes. Consult a medical toxicologist and contact the national poison control center for up-to-date information.Lipid emulsion therapy can also be used in conjunction with sodium bicarbonate for flecainide toxicity. The "lipid sink" theory suggests that it removes lipophilic flecainide from toxicity sites by increasing blood lipid levels. Management is mainly supportive. Prompt gastrointestinal decontamination should be considered to limit absorption. Hemodynamic instability may respond to inotropic or chronotropic agents. Mechanical ventilation may be required in patients with severe cardiac and respiratory depression. Advanced supportive measures, including intra-aortic balloon counterpulsation or transvenous pacing, may be indicated in cases of refractory conduction block or profound hemodynamic compromise. Due to flecainide's prolonged elimination half-life (approximately 12–27 hours) and potential for nonlinear kinetics at toxic concentrations, extended monitoring and supportive care are essential. Hemodialysis does not enhance clearance.Flecainide acts on sodium channels on the neuronal cell membrane, limiting the spread of seizure activity and reducing seizure propagation. The antiarrhythmic actions are mediated through effects on sodium channels in Purkinje fibers. Flecainide is a sodium channel blocker, binding to voltage gated sodium channels. It stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses. Ventricular excitability is depressed and the stimulation threshold of the ventricle is increased during diastole. |
| Signs and Symptoms | Symptoms of overdose include nausea and vomiting, convulsions, hypotension, bradycardia, syncope, extreme widening of the QRS complex, widening of the QT interval, widening of the PR interval, ventricular tachycardia, AV nodal block, asystole, bundle branch block, cardiac failure, and cardiac arrest. |
| Carcinogen Classification | No indication of carcinogenicity to humans (not listed by IARC). |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)flecainideDILI PositiveOralDOI:10.1016/j.drudis.2019.09.022 |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during LactationMaternal doses of flecainide up to 200 mg daily produce low levels in milk and undetectable infant serum levels. Flecainide is not expected to cause any adverse effects in breastfed infants, especially if the infant is older than 2 months.◉ Effects in Breastfed InfantsA woman with ventricular arrhythmia was treated with flecainide 87.3 mg twice daily during pregnancy and postpartum and exclusively breastfed her infant. Her infant was followed weekly with electrocardiograms until about 6 months of age. All were normal.Eight breastfed infants of mothers taking flecainide were followed after inquiries by their mothers. The extent of breastfeeding was exclusive in 2 infants, mixed in 5 and unknown in 1. The median maternal flecainide dose was 150 mg (IQR 100 to 175 mg). Clinical examination at day 15 of life was normal in all infants, electrocardiograms in 2 were normal, and none of the 8 infants had an adverse effect. Two children who breastfed for 5 and 8 months, were healthy and developed normally at 1 and 2 years of age, respectively.◉ Effects on Lactation and BreastmilkRelevant published information was not found as of the revision date. |
| Toxicity Data | LD50: 50-498 mg/kg (Oral, Rat) (A308) |
| Wassergefährdungsklasse (WGK) | 1 |
| UN-Transportnummer | 3249 |
| R-Sätze (R) | 11-23/24/25-39/23/24/25 |
| Gefahrensymbole | F,T |
| Sicherheitshinweise (S) | 7-16-36/37-45 |
| Gefahrenklasse | 6.1(b)Acute Tox. 3 DermalAcute Tox. 3 InhalationAcute Tox. 3 OralFlam. Liq. 2STOT SE 1 |
| Verpackungsgruppe | III |
| Lagerklasse | 3 - Flammable liquids |
Anwendungen & Verwendung
Beschreibung
From the chemical point, flecainide is an analog of procainamide, to which a 2.2.2-trifluoroethoxyl group was added at C2 and C3 of the benzene ring, and a diaminoethyl side chain is ended in the piperidine ring.
Verwenden
Flecainide, as with other local anesthetics, is used for naturally occurring ventricular arrhythmia.