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Procainamid
C07401 · Procamide · Novocamid · Procainamide · Novocainamide · PROCAINEAMIDE · Novocaine amide · procainamide USP/EP/BP
Identifikatoren & physikalische Daten
| CAS No. | 51-06-9 |
|---|---|
| Summenformel | C13H21N3O |
| Durchschnittliche Molmasse | 235,33 g/mol |
| Monoisotopische Masse | 235,16846229 g/mol |
| SMILES | CCN(CC)CCNC(=O)c1ccc(N)cc1 |
| InChIKey | REQCZEXYDRLIBE-UHFFFAOYSA-N |
| PubChem CID | 4913 |
| ChEMBL | CHEMBL640 |
| ChEBI | CHEBI:8428 |
| EC No. | 200-078-8 |
| DTXSID | DTXSID7023512 |
| Lokaler Name | Procainamid |
Chemische & physikalische Eigenschaften
| XLogP | 0,9 |
|---|---|
| Polarare Oberfläche (TPSA) | 58,4 |
| H-Brücken-Donoren | 2 |
| H-Brücken-Akzeptoren | 3 |
| Frei drehbare Bindungen | 6 |
| Schwere Atome | 17 |
| Formalladung | 0 |
| Komplexität | 221 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | 1.30.82 |
| Löslichkeit | INSOL IN PETROLEUM ETHER /HYDROCHLORIDE SALT/3.02e+00 g/LChloroform (Slightly), Ethyl Acetate (Slightly) |
| Human Drugs | Breast FeedingMilk, HumanLactationAntiarrhythmicsPharmaceuticals |
| Schmelzpunkt | 165-169 °C165 - 169 °C47°C |
| Physical Description | Solid |
| Dissociation Constants | 9.249.359.32 |
| Collision Cross Section | 154.85 Ų [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards] |
| Other Experimental Properties | FREELY SOL IN WATERSOL IN ALCOHOLSLIGHTLY SOL IN CHLOROFORMVERY SPARINGLY SOL IN BENZENE, ETHERMP: 165-169 °CMAX ABSORPTION: 278 NMPH OF 10% AQ SOLN: 5.5 /HYDROCHLORIDE SALT/WHITE TO TAN, CRYSTALLINE POWDERODORLESS /HYDROCHLORIDE SALT/ |
| Siedepunkt | 377.72°C (rough estimate) |
| Dichte | 1.060 |
| Brechungsindex | 1.5700 (estimate) |
| Lagerbedingungen | Keep in dark place,Inert atmosphere,Room temperature |
| Aggregatzustand | Solid |
| pKa (Säurekonstante) | pKa 9.24±0.10 (Uncertain) |
| Farbe | Off-White to Light Brown |
Sicherheit & Vorschriften
| GHS-Einstufung | WarningH302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory. |
|---|---|
| Wechselwirkungen | STUDIES HAVE DEMONSTRATED THAT PROCAINAMIDE IN CATS...MAY PROLONG & INTENSIFY NEUROMUSCULAR BLOCKADE PRODUCED BY SUCCINYLCHOLINE. |
| Hepatotoxicity | In clinical trials, procainamide was associated with a low rate of serum aminotransferase and alkaline phosphatase elevations. Despite wide scale use, procainamide has only rarely been linked to cases of clinically apparent liver injury. In reported cases, fever and mild symptoms arose within 1 to 3 weeks of starting (or within 1 day of restarting) procainamide, associated with a cholestatic pattern of serum enzyme elevations with mild or no jaundice (Case 1). Immunoallergic features were usually present (fever, rash, leukocytosis). In reported cases, fever resolved immediately and evidence of liver injury within a few days to weeks of stopping procainamide. Liver biopsy may how granulomas in addition to mild nonspecific changes. Interestingly, the hepatotoxicity of procainamide closely resembles that of quinidine, but there is no apparent cross sensitivity to the hepatic injury. In addition, up to 20% of patients on long term procainamide therapy develop autoantibodies, including ANA and LE prep positivity and a proportion develop a “lupus-like” syndrome. These autoimmune conditions, however, typically occur without an accompanying hepatitis, serum enzyme elevations or jaundice. |
| Unerwünschte Wirkungen | The adverse effects of procainamide include cardiac toxicity, bradycardia, hypotension, drug-induced lupus erythematosus-like syndrome, and blood dyscrasias. QRS, QTc, and PR prolongation are the most potentially harmful cardiac side effects of procainamide and may become worse when levels of procainamide rise. Serial electrocardiograms are useful for monitoring these toxic effects during treatment with procainamide. Procainamide infusion may also increase the number of premature ventricular contractions in patients. |
| Toxizitätsübersicht | IDENTIFICATION: Procainamide is an antiarrhythmic medication. Procainamide hydrochloride is a white to tan colored hygroscopic odorless crystalline powder. Soluble in water, alcohol, chloroform and practically insoluble in ether and benzene HUMAN EXPOSURE: Main risks and target organs: The heart is the main target organ. Procainamide is an antiarrhythmic agent used to suppress ventricular tachydysrhythmias. It increases the effective refractory period of the atria, and (to a lesser extent) that of the bundle of the His-Purkinje system and the ventricles. Toxic effects result from delay in conduction and depression of myocardial contractility, leading to cardiac dysrhythmia and cardiogenic shock. Its oral use is limited immunological adverse effects such as systemic lupus erythematosus in patients on chronic oral therapy. Summary of clinical effects: Cardiovascular System: Sinus or atrial tachycardias, atrioventricular and intraventricular block hypotension, cardiogenic shock, torsades de pointes and ventricular fibrillation. Central Nervous System: Lethargy, coma, respiratory arrest may result Gastrointestinal Tract: Nausea, vomiting, diarrhea and abdominal pain have been reported. Others: Anticholinergic effects, hypokalemia, metabolic acidosis and pulmonary edema. Indications: Suppression of ventricular arrhythmias. Treatment of automatic and reentrant supraventricular tachycardia. Supraventricular arrhythmias: Like quinidine, procainamide is only moderately effective in converting atrial flutter or chronic atrial fibrillation to sinus rhythm. The drug can be used to prevent recurrences of atrial flutter or atrial fibrillation after cardioversion. Procainamide is indicated in the treatment of ventricular premature contractions, and in preventing recurrence of ventricular tachycardia after conversion to sinus rhythm by intravenous drugs or by electrical cardioversion or by other antiarrhythmic therapyalso in preventing recurrence of paroxysmal supraventricular tachycardia, atrial fibrillation or flutter following conversion to sinus rhythm by initial vagotonic maneuvers, digitalis preparations, other pharmaceutical antiarrhythmic agents, or electrical cardioversion. The drug is useful in patients with severe ventricular arrhythmias who do not respond to lidocaine. Procainamide is useful for acute terminations of arrhythmias associated with the Wolff-Parkinson-White Syndrome. Procainamide is used in the treatment of cardiac arrhythmias occurring in patients during general anesthesia. The drug has been used in conjunction with hexamethonium bromide to produce controlled hypotension and, consequently, ischemia of sufficient degree for relatively bloodless field surgery. The injection of procainamide into painful soft tissues in fibrosis and radiculitis and into the periarticular tissues in degenerative arthritis provided relief for considerable periods. Contraindications: Complete heart block: because of its effects in suppressing nodal or ventricular pacemakers. Torsades de Pointes: administration of procainamide in such case may aggravate this special type of ventricular extrasystole or tachycardia instead of suppressing it. Idiosyncratic hypersensitivity: in patients sensitive to procaine or other ester-type local anesthetics, cross sensitivity to procainamide is unlikely. However, a previous allergic reaction to procainamide is a contraindication. Lupus erythematosus: aggravation of symptoms is highly likely. Precautions: Preferably, procainamide should not be used in patients with bronchial asthma or myasthenia gravis. Accumulation of the drug may occur in patients with heart, renal or liver failure. Procainamide may enhance the effects of antihypertensive agents, propranolol, and some skeletal muscle relaxants. Grave hypotension may follow intravenous administration of procainamideit should be injected slowly under monitoring of blood pressure and ECG. Although procainamide has been used effectively in the treatment of ventricular dysrhythmias caused by digitalis intoxication, its effects are unpredictable and fatalities have occurred. Procainamide should not be administered to nursing mothers. Routes of entry: Oral: Oral route is a common route of entry in cases of poisoning. Parenteral: Toxicity reactions can occur after intravenous injections. Absorption by route of exposure: Oral: Procainamide is almost completely and rapidly absorbed from the gastrointestinal tract. Peak levels are reached within 1 hr after ingestion of capsules, but somewhat later after administration of tablets. The bioavailability is approximately 85%. An overdose may significantly delay intestinal procainamide absorption and prolong poisoning symptoms. With the sustained-release formulations, bioavailability is decreased and the absorption is delayed. The duration of action exceeds 8 hours. Intramuscular: Plasma concentrations showed very large variations. Procainamide appears in the plasma within two minutes and peak concentrations are reached within 25 minutes. Intravenous: Procainamide acts almost immediately, the plasma level declines 10 to 15% hourly. Distribution by route of exposure: About 20% of the procainamide in plasma is bound to proteins. Procainamide is rapidly distributed into most body tissues except the brain. In patients with cardiac failure or shock the volume of distribution may decrease. Procainamide crosses the placental barrier and has been reported to accumulate in the fetus. Biological half-life by route of exposure: Peak plasma levels: Oral: one to 2 hours after ingestion. Intramuscular: eighty minutes after administration. Intravenous: Within several minutes. The plasma half life after therapeutic doses is 3 to 4 hours. However, in one patient the overdose plasma half life was 8.8 hours. Congestive heart failure increases the plasma procainamide half life to 5 to 8 hours. The half-life is reduced in children and is prolonged in patients with renal insufficiency. Its major active metabolite, N-acetylprocainamide (NAPA), has a longer half-life than procainamide, from 6 hours up to 36 hours in overdoses. Metabolism: The major metabolic pathway of procainamide is hepatic N-acetylation. The rate of acetylation is determined genetically and shows a bimodal distribution into slow and fast acetylators. The major active metabolite, NAPA, has antiarrhythmic properties. Other urinary metabolites include desethyl-NAPA and desethyl-procainamide, which account for 8 to 15% of a dose of procainamide. The exact relationship between antiarrhythmic activity and plasma levels of NAPA has not been established. Up to 15% of the intravenous procainamide therapeutic dose is metabolized to NAPA, and 81% of the NAPA dose is excreted unchanged in urine. In fast acetylators or in renal insufficiency, 40% or more of a dose of procainamide may be excreted as NAPA, and its concentrations in plasma may equal or exceed those of the parent drug. Procainamide hydrochloride is only slightly hydrolyzed by plasma enzymes (to p-amino benzoic acid and diethylaminoethylamine). Elimination by route of exposure: Procainamide is excreted in the urine with about 50% as unchanged procainamide, and up to about 30% as NAPA (less in slow acetylators). Since the elimination of both the parent drug and metabolites is almost entirely by renal excretion, they can accumulate to dangerous levels when renal failure or congestive heart failure is present. After an overdose, hepatic biotransformation probably is a more important elimination pathway than renal excretion. Following an overdose, the elimination half-life (in the presence of a serum creatinine of 5.8 mg/dL) of NAPA increased from 6 to 35.9 hours while the procainamide elimination increased from 3 to 10.5 hours. Mode of action: Toxicodynamics: Toxic effects result from quinidine-like effect with delay of conduction and depression of myocardial contractility. Contractility of the undamaged heart is usually not affected by therapeutic concentrations, although slight reduction of cardiac output may occur, and may be significant in the presence of myocardial damage. High toxic concentrations may prolong atrioventricular conduction time or induce atrioventricular block or even cause abnormal automaticity and spontaneous firing, by unknown mechanisms. The toxic mechanism of the drug is dose dependent and is related to depression of contractility, decreased vascular resistance secondary to direct vasodilatation and some alpha adrenergic blocking. Besides the cardiovascular effects, procainamide produces CNS depression and has anticholinergic effects. Pharmacodynamics: Procainamide is an antiarrhythmic agent with electrophysiological properties similar to that of quinidine. Procainamide increases the effective refractory period of the atria, of the bundle of His-Purkinje system and of the ventricles. It reduces impulse conduction velocity in atria, His-Purkinje fibers, and ventricular muscle. But it has also variable effects on the atrioventricular node, a direct slowing action and a weaker vagolytic effect which may speed atrio-conduction slightly. Myocardial excitability is reduced in the atria, Purkinje fibers, papillary muscles, and ventricles by an increase in the threshold for excitation. NAPA is less potent than procainamide, and some of its cardiac actions are qualitatively different. Procainamide does not produce alpha-adrenergic blockade, but, in the dog, it can block autonomic ganglia weakly and cause a measurable impairment of cardiovascular reflexes. Human data: Adults: A single oral dose may produce symptoms of toxicity. Ingestion of 3 gm may be dangerous, especially if patient is slow acetylator or has renal impairment or underlying heart disease. Death was reported from intravenous administration. Interactions: If other antiarrhythmic drugs are being used, additive effects on the heart may occur with procainamide administration, and dosage reduction may be necessary. Anticholinergic drugs administered concurrently with procainamide may produce additive antivagal effects on A-V nodal conduction. Patients taking procainamide who require neuromuscular blocking agents such as succinylcholine may require less than usual doses of the latter, due to procainamide effect on reducing acetylcholine release. The neuromuscular blocking activity of an antibiotic having such action may be accentuated by procainamide. The hypotensive action of antihypertensive agents, including thiazide diuretics, may be potentiated by procainamide. Cimetidine therapy given to older male patients taking procainamide may increase steady-state concentrations of procainamide. Main adverse effects: The side-effects most frequently reported after high dosage of procainamide include anorexia, diarrhea, nausea, and vomiting. Intravenous administration may cause hypotension, ventricular fibrillation or asystole if the injection is too rapid. Following chronic administration, systemic lupus erythematosus-like syndrome may develop. Other side effects which have been reported include mental depression, dizziness, psychosis with hallucinations, joint and muscle pain, muscular weakness, a bitter taste, flushing, skin rashes, pruritus, angioneurotic edema and hypersensitivity leading to chills, fever and urticaria. Leucopenia and agranulocytosis have followed repeated use of procainamide. Neutropenia, thrombocytopenia, or hemolytic anemia may rarely be encountered. High concentrations of procainamide in plasma can produce ventricular premature depolarization, ventricular tachycardia, or ventricular fibrillation. Hepatomegaly with increased serum aminotransferase level has been reported after a single oral dose. Mild hypovolemia, hypokalemia, metabolic acidosis may occur. Increased QT interval and prolonged QRS together with hypotension are sensitive indexes of serious poisoning. Parenteral administration of procainamide should be monitored electrocardiographically to give evidence of impending heart block. Acute poisoning: Ingestion: Serious toxic effects include conduction disturbances (QRS, QT prolongations), ventricular arrhythmias and cardiogenic shock. Increased ventricular extrasystoles, ventricular tachycardia (especially of the "torsades de pointes" type) or fibrillation may occur. The threshold of cardiac pacing is increased and the heart may even be nonresponsive. Lethargy, confusion and coma may occur. Other toxic manifestations are pulmonary edema, respiratory depression, urticaria, pruritus, nausea, vomiting, diarrhea and abdominal pain. Psychosis with hallucinations have been reported occasionally. Parenteral exposure: Intravenous administration may cause hypotension, ventricular fibrillation or asystole if the injection is too rapid. Chronic poisoning: Ingestion: A lupus erythematosus like syndrome of arthralgia, pleural or abdominal pain, and sometimes arthritis, pleural effusion, pericarditis, fever, chills, myalgia, and possibly related hematologic or skin lesions is fairly common after prolonged procainamide administration. Neutropenia, thrombocytopenia, or hemolytic anemia may rarely be encountered. Agranulocytosis has occurred after repeated use of procainamide. Course, prognosis, cause of death: Presence of PVCs and runs of ventricular tachycardia that are almost always successfully treated. Prognosis is usually good if there is not progress to ventricular fibrillation or asystole. Death is due to ventricular fibrillation or asystole. Long-term effects are agranulocytosis from hypersensitivity reaction, which is associated with 90% recovery rate. Systematic description of clinical effects: Cardiovascular: Acute: Sinus or atrial tachycardia due to the vagolytic effects. Conduction disturbances such as atrioventricular block, intraventricular block. Ventricular arrhythmias, including torsades de pointes, ventricular tachycardia and fibrillation. Hypotension and cardiogenic shock. ECG may show widening QRS, atrioventricular block, prolongation of QT interval and ventricular arrhythmia. Chronic: Chronic exposure may also produce arrhythmias. Cardiac tamponade due to pericarditis has been reported in a case of procainamide induced systemic lupus syndrome. Respiratory: Acute: Respiratory arrest and pulmonary edema. Neurological: Central nervous system (CNS): Acute: Dizziness or giddiness, weakness, mental depression, and psychosis with hallucinations have been reported occasionally. Lethargy may progress to coma. Skeletal and smooth muscle: Chronic: Skeletal muscular weakness and diaphragmatic paralysis has been reported in a case. Gastrointestinal: Acute: Anorexia, nausea, vomiting, abdominal pain, bitter taste, or diarrhea may occur in 3 to 4% of patients taking oral procainamide. Chronic: Nausea, vomiting may be seen. Hepatic: Acute: Hepatomegaly with increased serum aminotransferase level has been reported after a single oral dose. Dermatological: Chronic: Angioneurotic edema, urticaria, pruritus, flushing, and maculopapular rashes. Eye, ear, nose, throat: local effects: Acute: Blurred vision has been reported. Hematological: Chronic: Neutropenia, thrombocytopenia, or hemolytic anemia and agranulocytosis may rarely be encountered. Immunological: Chronic: Systemic lupus erythematosus like syndrome has been reported. Metabolic: Acid-base disturbances: Acute: Metabolic acidosis has been reported. Fluid and electrolyte disturbances: Acute: Hypokalemia may occur. Angioneurotic edema and maculopapular rashes have been reported. Special risks: Pregnancy: It is not known whether procainamide cause fetal harm when administered to a pregnant woman. Procainamide should be given to a pregnant woman only if clearly needed. Breast feeding: Both procainamide and NAPA are excreted in human milk. Therefore, procainamide should be given to a nursing mother only if clearly needed. Pediatric use: Safety and effectiveness in children have not been established. Plasma levels of NAPA may rise disproportionately in patients with renal impairment, because it is more dependent than procainamide on renal excretion for elimination. Elimination: Renal elimination of procainamide appears not to be affected by urinary pH or by urinary flow rate. However, because procainamide and NAPA are substantially eliminated by the kidney, it is important to maintain adequate renal functions.Toxicity from procainamide overdose is rare as it is usually given IV in a monitored setting. However, it is plausible to administer a toxic dose accidentally or when a patient with renal impairment receives an inaccurate dose. Consultation of a medical toxicologist and regional poison control center is necessary in cases of oral procainamide overdose. Treatment would theoretically be similar to an overdose of other Class 1A antiarrhythmics, including quinidine and disopyramide, in which the patient receives hypertonic sodium bicarbonate to block sodium channels. |
| Human Toxicity Excerpts | ...IT HAS OCCASIONALLY CAUSED SERIOUS SIDE EFFECTS, & DEATHS HAVE RESULTED. WHEN...GIVEN ORALLY, MOST FREQUENTLY OBSERVED...EFFECTS ARE ANOREXIA, NAUSEA, & VOMITING. FLUSHING, BITTER TASTE, DIARRHEA, WEAKNESS, MENTAL DEPRESSION, GIDDINESS, & PSYCHOSIS WITH HALLUCINATIONS...ALSO...REPORTED.HYPERSENSITIVITY TO DRUG, CHILLS, FEVER, JOINT & MUSCLE PAIN, MALAISE, ITCHING, ANGIOEDEMA, & URTICARIAL OR MACULOPAPULAR SKIN RASH HAVE...OCCURRED. ... FATAL AGRANULOCYTOSIS...REPORTED... /ORAL ADMIN/...IV ADMIN... HYPOTENSION COMMONLY OCCURS & CAN RESULT IN CARDIOVASCULAR COLLAPSE, CONVULSIONS, & CORONARY INSUFFICIENCY. SERIOUS DISTURBANCES OF CARDIAC RHYTHM, SUCH AS VENTRICULAR ASYSTOLE OR FIBRILLATION... HYPOTENSION MAY OCCUR AFTER IM /ADMIN/, BUT IT IS USUALLY NOT SEVERE. |
| Drug Induced Liver Injury | Drug-Induced Liver Injury Severity and Toxicity (DILIst)procainamideDILI PositiveIntravenousDOI:10.1016/j.drudis.2019.09.022 |
| Non-Human Toxicity Excerpts | ...RAPID IV INJECTION OF LARGE DOSES IN ANIMALS CAUSES TREMORS & DEATH MAY RESULT FROM RESP DEPRESSION. |
| Effects During Pregnancy and Lactation | ◉ Summary of Use during Lactation |
| UN-Transportnummer | 2811 |
| Gefahrenklasse | 6.1 |
| Verpackungsgruppe | Ⅲ |
| Gefahrstoffdaten | 51-06-9(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Procainamide and its analogs were employed by Dr Claude Beck in a series of cardiac surgeries during the early 1930s. The compound was used to alleviate arrhythmias that present during the procedures, and was selected for its favorable tissue absorption properties. Procainamide’s central amide provides it protection from inactivating esterase action and allows oral administration of the compound. Procainamide was approved for use in the United States in 1950.
Verwenden
Procainamide is intended for treating paroxysmal atrial tachycardia, atrial fibrillation, premature ventricular contraction, and ventricular tachycardia. For quickly reaching therapeutic concentrations, parenternal introduction of procainamide is preferred over cynidine.