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Propafenon
N-(carboxypheny)guanidine hydrochloride · C07381 · WZ-884-642 · WZ-884-643 · PROPAFENONE · AKOS 215-08 · Propafenonum · Propafenone-d
Identifikatoren & physikalische Daten
| CAS No. | 54063-53-5 |
|---|---|
| Summenformel | C21H27NO3 |
| Durchschnittliche Molmasse | 341,4 g/mol |
| Monoisotopische Masse | 341,19909372 g/mol |
| SMILES | CCCNCC(O)COc1ccccc1C(=O)CCc1ccccc1 |
| InChIKey | JWHAUXFOSRPERK-UHFFFAOYSA-N |
| PubChem CID | 4932 |
| ChEMBL | CHEMBL631 |
| ChEBI | CHEBI:63619 |
| EC No. | 258-955-6 |
| DTXSID | DTXSID9045184 |
| Lokaler Name | Propafenon |
Chemische & physikalische Eigenschaften
| XLogP | 3,3 |
|---|---|
| Polarare Oberfläche (TPSA) | 58,6 |
| H-Brücken-Donoren | 2 |
| H-Brücken-Akzeptoren | 4 |
| Frei drehbare Bindungen | 11 |
| Schwere Atome | 25 |
| Formalladung | 0 |
| Komplexität | 368 |
| Arzneimittel | PharmaceuticalsPharmaceuticals -> Used in Switzerland |
| LogP (Verteilungskoeffizient) | 3.23.83 |
| Löslichkeit | Slightly soluble7.58e-03 g/LDMSO: 68 mg/mL (199.16 mM)Ethanol: 41 mg/mL (120.08 mM)759.9ug/L(22.5 ºC) |
| Human Drugs | Breast FeedingLactationMilk, HumanAntiarrhythmicsPharmaceuticals |
| Decomposition | When heated to decomposition, material emits toxic fumes of NOx and HCl. |
| Physical Description | Solid |
| Dissociation Constants | 9.278.8 |
| Collision Cross Section | 176.48 Ų [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]178.5 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)] |
| Other Experimental Properties | MW: 377.90. Fine white crystalsslightly bitter taste. Soluble in basic lower aliphatic alcohols, carbon tetrachloride, hot waterslightly soluble in cold water. Insoluble in ether /Propafenone hydrochloride/ |
| Siedepunkt | 519.6±50.0 °C(Predicted) |
| Dichte | 1.096±0.06 g/cm3(Predicted) |
| Lagerbedingungen | 2-8°C |
| Aggregatzustand | Solid |
| pKa (Säurekonstante) | pKa 9.27 (Uncertain) |
| Farbe | White to Off-White |
| Kosmetik-Inhaltsstoffe Funktionen | SKIN PROTECTING |
| CAS Datenbank | 54063-53-5(CAS DataBase Reference) |
| NIST chemische Informationen | Propafenone(54063-53-5) |
Sicherheit & Vorschriften
| GHS-Einstufung | WarningH302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 2 reports by companies from 1 notifications to the ECHA C&L Inventory. |
|---|---|
| Regulatorische Informationen | REACH registered substance: Propafenone (EC: 258-955-6) |
| Brandpotenzial | This material is assumed to be combustible. |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including propafenone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Propafenone hydrochloride/ |
| Toxic Combustion Products | Emits toxic fumes under fire conditions. |
| Hazard Classes and Categories | Acute Tox. 4 (100%) |
| Brandbekämpfungsverfahren | Water spray, dry chemical, carbon dioxide, or foam as appropriate for surrounding fire and materials. ... As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing. |
| Lagerbedingungen | Store in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.Commercially available propafenone hydrochloride immediate-release tablets and extended-release capsules should be stored in tight containers at a controlled room temperature of 25 °C, but may be exposed to temperatures ranging from 15-30 °C. Propafenone hydrochloride immediate-release tablets should be stored in light-resistant containers. When stored under such conditions, the commercially available immediate-release tablets have an expiration date of 3 years following the date of manufacture. |
| Reinigungsverfahren | Wear approved respiratory protection, chemically compatible gloves, and protective clothing. Wipe up spillage or collect spillage using a high- efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labeled container for disposal. Wash spill site. |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash. |
| Preventive Measures | As a general rule, when handling USP Reference Standards, avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.As with all dry powders, it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.Engineering controls such as exhaust ventilation are recommended. |
| Personal Protective Equipment (PPE) | Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. If a respirator is not required, an approved dust mask should be used. |
| Wechselwirkungen | Although specific pharmacokinetic drug interaction studies are not available, the manufacturer of propafenone states that the drug should not be used concomitantly with other drugs that prolong the QT interval, including certain phenothiazines, cisapride, bepridil (not currently commercially available in the US), tricyclic antidepressant agents, or macrolides.Although specific pharmacokinetic drug interaction studies are not available, the manufacturer of ritonavir states that ritonavir should not be used concomitantly with certain cardiovascular agents, including propafenone, because of the potential for substantially increased plasma concentrations of these cardiovascular drugs and potentially serious and/or life-threatening adverse effects. This pharmacokinetic interaction may occur because ritonavir has high affinity for several cytochrome P-450 (CYP) isoenzymes (e.g., CYP3A, CYP2D6, CYP1A2) involved in propafenone metabolism.Increased serum theophylline concentrations have been reported in patients receiving theophylline concomitantly with propafenone and some clinicians suggest that serum theophylline concentrations and ECGs be monitored closely in patients receiving such combined therapy.The manufacturer states that concomitant use of propafenone and local anesthetic agents (i.e., during pacemaker implantation, surgery, or dental procedures) may increase the risk of adverse nervous system effects.For more Interactions (Complete) data for Propafenone (24 total), please visit the HSDB record page. |
| Hepatotoxicity | In clinical trials, propafenone was associated with a low rate of serum aminotransferase and alkaline phosphatase elevations. Since its approval and more widescale use, propafenone has been linked to rare instances of clinically apparent liver injury, at least a dozen cases of which have been reported in the literature. Patients usually present with symptoms of jaundice and pruritus 2 to 8 weeks after starting propafenone, and the pattern of serum enzyme elevations are typically mixed (Case 1) or cholestatic (Case 2). Immunoallergic and autoimmune features are uncommon. While the jaundice can be prolonged, patients typically recover in 1 to 3 months and there have been no instances of acute liver failure, chronic hepatitis or vanishing bile duct syndrome attributed to its use. |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ In general, overdosage of propafenone may be expected to produce effects that are extensions of the drug's pharmacologic effects, particularly those involving cardiac conduction and function and the CNS. Overdosage of propafenone may result in nausea and/or vomiting, hypotension, somnolence, bradycardia, intra-atrial and intraventricular conduction disturbances, and in rare cases, seizures and high-grade ventricular arrhythmiasfatalities also have occurred. Cardiac manifestations may occur within 30-120 minutes after ingestion. Manifestations of overdosage generally are most severe during the 3 hours following the overdose. Nausea generally is the first manifestation of toxicity and may occur within 30 minutes of ingestion of the drug./CASE REPORTS/ A 71-year-old woman with atrial fibrillation developed elevations of greater than two times the upper limit of normal in alkaline phosphatase (ALK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyltransferase (GGT) after initiation of propafenone therapy. The patient developed elevations of greater than two times the upper limit of normal in ALK, ALT, and AST, one month after initiating propafenone therapy. The propafenone dose was decreased from 900 to 675 mg/day and, ten days later, the ALK, ALT, and AST were decreased slightly, but still above the upper limit of normal. One month later, serum transaminases had returned to baseline, but propafenone therapy was discontinued because of recurrent atrial fibrillation, persistent elevation in ALK, and elevation in GGT. Two months after discontinuing propafenone, serum aminotransaminase and ALK concentrations had normalized and GGT had decreased and remained only slightly elevated. The occurrence of liver injury secondary to propafenone therapy is rare. Reported cases appear to be secondary to hepatocellular injury, cholestasis, or a combination of the two. In this case, the pattern demonstrated by elevations in liver enzymes may be classified as acute cholestatic liver injury. Because the reported incidence is 0.1-0.2 percent and there are no known fatalities secondary to propafenone liver injury, routine monitoring of liver function tests in all patients receiving propafenone cannot be recommended at this time. Baseline liver function tests prior to initiating propafenone therapy with follow-up laboratory studies one month later are recommended in patients with known liver dysfunction. If elevations are noted, a reduction in dose may result in lower liver enzyme concentrations, although discontinuation of therapy may be required in some cases./CASE REPORTS/ ... A patient with episodic jabbing and crushing pain in his hands and feet, aching in his forearms, and hyperesthesias of his extremities /is described/. He had been taking propafenone for 1 year because of ventricular arrhythmias. Results of a nerve conduction velocity test were abnormal. Electron microscopic findings on a sural nerve biopsy specimen represented distal small fiber neuropathy. Findings on a thermoregulatory sweat test and on autonomic tests were abnormal, compatible with a distal small fiber neuropathy. ... . In this patient, propafenone seemed to be responsible for the development of peripheral neuropathy, which resolved after use of the drug had been discontinued./CASE REPORTS/ A case of acute liver injury associated with the use of the antiarrhythmic drug propafenone in a 62-year-old woman undergoing clinical observation for recurrent atrial fibrillation is reported. Propafenone hydrochloride, a class 1C antiarrhythmic drug widely used in the clinical practice for the treatment of supraventricular and ventricular arrhythmias, rarely (0.1-0.2% of incidence) causes liver injury characterized by a rise in hepatic cell enzymes or cholestatic enzymes or both. Within 2 months of the discontinuation of therapy the liver function tests return to normal, therefore there are no known fatalities secondary to propafenone liver injury including fulminant hepatitis and death. The close temporal relationship between the administration of the drug and the acute onset of signs of liver injury, the marked rise in liver function tests following the increase of the drug dosage and their gradual normalization after its withdrawal strongly suggest that propafenone is involved in the pathogenesis of this syndrome. Although rare, hepatotoxicity due to this widely used antiarrhythmic drug should be borne in mind in the differential diagnosis of sudden hepatocellular or cholestatic syndrome of obscure origin. It seems prudent to obtain baseline liver function before starting therapy with propafenone and then follow up laboratory tests some months later at least in patients with known liver disease.For more Human Toxicity Excerpts (Complete) data for Propafenone (26 total), please visit the HSDB record page. |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)propafenoneDILI PositiveOralDOI:10.1016/j.drudis.2019.09.022 |
| Non-Human Toxicity Excerpts | /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Renal changes have been observed in the rat following 6 months of oral administration of propafenone hydrochloride at doses of 180 and 360 mg/kg/day (about 2 and 4 times, respectively, the maximum recommended human daily dose (MRHD) on a mg/sq m basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for 6 weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone hydrochloride at a dose of 270 mg/kg/day (about 3 times the MRHD on a mg/sq m basis). There were no renal or hepatic changes at 90 mg/kg/day (equivalent to the MRHD on a mg/sq m basis)./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Decreases in neonatal survival, weight gain, and physiologic development were observed in rats receiving oral propafenone hydrochloride dosages of 360 mg/kg or more daily (4 or more times the maximum recommended human daily dosage) from mid-gestation through weaning./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Increased maternal death was observed in rats receiving oral propafenone hydrochloride dosages as low as 90 mg/kg daily (equivalent to the maximum recommended human daily dosage) from mid-gestation through weaning./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Administration of large IV doses of propafenone in monkeys, dogs, and rabbits has caused transient, reversible decreases in spermatogenesisthis effect was observed only at lethal or sublethal dosages and was not seen in rats receiving oral or IV propafenone.For more Non-Human Toxicity Excerpts (Complete) data for Propafenone (6 total), please visit the HSDB record page. |
| Populations at Special Risk | Propafenone is extensively metabolized in the liver, and dosage should be reduced substantially in patients with impaired hepatic function. The drug also should be used with caution in patients with renal dysfunction since a considerable portion of the dose is excreted in urine as active metabolites.Propafenone (immediate-release formulation) is contraindicated in patients with uncontrolled congestive heart failurethe extended-release formulation of the drug is contraindicated in patients with congestive heart failure. Propafenone is contraindicated in patients with cardiogenic shock, atrioventricular or intraventricular disorders of impulse generation and/or conduction (e.g., sick sinus node syndrome, atrioventricular block) unless an artificial pacemaker is present, bradycardia, severe hypotension, marked electrolyte imbalance.Propafenone has been reported to exacerbate myasthenia gravis, and it has been suggested that use of the drug be avoided in patients with this condition.Propafenone, like other agents with nonselective beta-adrenergic blocking activity, generally should not be used in patients with asthma/bronchospastic disease or nonallergic bronchospastic disease (e.g., chronic bronchitis, emphysema) since the drugs may inhibit bronchodilation produced by endogenous catecholamines. |
| Antidote and Emergency Treatment | Intoxication caused by propafenone is very rare, and there are no known detailed epidemiological studies. We present the clinical manifestation of severe propafenone intoxication successfully treated in a 17 year-old male. He was brought to the Intensive Care Unit after he had taken 3.0 g propafenone. The main clinical findings included: sudden cardiac arrest, coma, hypotension, left ventricular failure, bradycardia, sinoatrial block, atrioventricular junctional or/and ventricular tachycardia. During the treatment, transient heart pacing was performed and catecholamines were administered by means of continuous intravenous infusion of pressure doses as well as of infusion liquids. Cessation of toxic signs four hours after admission to hospital was observed. This relatively rare, fully symptomatic intoxication with propafenone deserved to be presented due to the drug's common usage in the treatment of dysrhythmia and life-threatening symptoms of overdosing. The course of the disease was dramatic and the patient survived only thanks to quick resuscitation, artificial ventilation, transient heart pacing, acidosis treatment and administration of pressure doses of catecholamines.Propafenone is an anti-arrhythmic drug used in the management of supraventricular and ventricular arrhythmias. It is metabolised through cytochrome P450 2D6 pathwaysthe major metabolites possess anti-arrhythmic activity. The cytochrome P450 CYP2D6 is coded by more than 70 alleles resulting in great genetic polymorphism of CYP2D6 isoenzymes, and up to 7% of Caucasian population are poor metabolisers. This case report describes a patient with severe overdose of propafenone who presented with coma, seizures and cardiotoxicity. The patient was managed with intravenous glucagon, hypertonic sodium bicarbonate, hypertonic saline and inotropic support. The propafenone and its 5-hydroxypropafenone (5-OHP) metabolite were measured by high-performance liquid chromatography with ultraviolet detection (no assay was available at the time to measure N-despropyl propafenone concentrations). Toxicological screen showed propafenone concentrations at a maximum of 1.26 mg/L at 9-10 hr post-presentation, falling to 0.25 mg/L at 27-28 hr post-presentation. No propafenone metabolite 5-OHP was detected in any sample analyzed. No antidepressant or analgesic drugs were detected in toxicological screen. Propafenone overdose has been reported to be associated with features of severe cardiovascular and CNS toxicity. Aggressive treatment, meticulous monitoring and supportive care was associated with a good outcome in this case.Emergency and supportive measures. Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Continuously monitor vital signs and ECG for a minimum of 6 hours after exposure, and admit the patient for 24 hours of intensive monitoring if there is evidence of toxicity. /Antiarrhythmic drugs/Specific drugs and antidotes. In patients with intoxication by type 1a or type 1c drugs, QRS prolongation, bradyarrhythmias, and hypoentsion may respond to sodium bicarbonate ... . The sodium bicarbonate reverses cardiac-depressant effects caused by inhibition of the fast sodium channel. /Antiarrhythmic drugs/For more Antidote and Emergency Treatment (Complete) data for Propafenone (8 total), please visit the HSDB record page. |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| Non-Human Toxicity Values | LD50 Dogt iv 10 mg/kg /Propafenone hydrochloride/LD50 Rat iv 18,800 ug/kg /Propafenone hydrochloride/LD50 Rat oral 700 mg/kg /Propafenone hydrochloride/ |
| EPA Human Health Benchmarks for Pharmaceuticals | Propafenone10.544.4Initiate therapy with propafenone hydrochloride tablets 150 mg given every eight hours (450 mg/day).Data used to generate the benchmarks include the following: Lowest Daily Dose (LDD): 450 mg/day, Lowest Therapeutic Dose (LTD): 5.6 mg/kg-day, and Screening Dose: 0.002 mg/kg-day.28-Feb-19 |
| Wassergefährdungsklasse (WGK) | 3 |
| RTECS-Nr. | UH2833000 |
| R-Sätze (R) | 46-22 |
| Gefahrensymbole | T |
| Sicherheitshinweise (S) | 53-36/37/39-45 |
| Gefahrstoffdaten | 54063-53-5(Hazardous Substances Data) |
Anwendungen & Verwendung
Verwenden
Cardiac depressant (anti-arrhythmic).