ABSTRACT
Thirty-two alpha-amino anilides with various substituents in the aromatic ring and in the alpha position are described. Their abilities to protect mice against chloroform-induced fibrillation and to elicit toxicity were determined. Substitution of an alkyl or aryl group in the alpha position enhanced the antifibrillatory activity. In most cases, increased potency was accompanied by increased toxicity. Eleven compounds were tested in dogs with surgically induced myocardial infarction; most showed antiarrhythmic activity. 2-Aminopropiono-2',6'-xylidide, tocainide, was chosen for clinical investigation.
Subject(s)
Anilides/chemical synthesis , Anti-Arrhythmia Agents/chemical synthesis , Anilides/pharmacology , Animals , Atrial Fibrillation/prevention & control , Chloroform/toxicity , Coronary Vessels/drug effects , Dogs , Female , MiceABSTRACT
Tocainide, a primary amine analogue of lidocaine, is effective against some experimental and clinical arrhythmias. Its pharmacokinetic behavior was studied in 6 healthy male subjects. Peak blood levels (CB max) and area under the blood concentration-time curve (AUC) were linearly related to dose with slopes of 0.0067 mcg/ml and 6 min mcg/ml per milligram of dose, respectively. Renal clearance of tocainide averaged 59 ml/min when urinary pH was uncontrolled or acidified, while it was reduced to 13 ml/min during intense sodium bicarbonate loading. Blood levels following intravenous infusion were well described by a 2-compartment open model with a volume of the central compartment of 0.92 L/kg. The t 1/2 beta was 11 hr and total body clearance was 166 ml/min. Loo-Riegelman analysis of the absorption rate did not allow unequivocal assignment of an "order" to the absorption process. Bioavailability approached 100%. Administration of drug 5 min after a test meal suppressed CB max 40% but minimally affected AUC. Approximately 50% of the drug was found to be plasma protein bound at clinically effective concentrations.
Subject(s)
Anilides/metabolism , Anti-Arrhythmia Agents/metabolism , Administration, Oral , Adult , Bicarbonates/pharmacology , Biological Availability , Drug Administration Schedule , Ethylamines/metabolism , Food , Half-Life , Humans , Infusions, Parenteral , Intestinal Absorption/drug effects , Kidney/metabolism , Kinetics , Lidocaine/administration & dosage , Lidocaine/analogs & derivatives , Male , Middle Aged , Time FactorsSubject(s)
Fatty Acids, Nonesterified/blood , Heart Rate/drug effects , Myocardial Infarction/blood , Pyridines/pharmacology , Administration, Oral , Analysis of Variance , Animals , Blood Pressure/drug effects , Chemical Phenomena , Chemistry , Coronary Vessels , Depression, Chemical , Dogs , Electrocardiography , Female , Fluorine/administration & dosage , Fluorine/blood , Fluorine/pharmacology , Injections, Intravenous , Ligation , Male , Methanol/administration & dosage , Methanol/blood , Methanol/pharmacology , Pyridines/administration & dosage , Pyridines/blood , Time FactorsSubject(s)
Anti-Arrhythmia Agents/pharmacology , Heart/drug effects , Tetrodotoxin/pharmacology , Animals , Arrhythmias, Cardiac/drug therapy , Blood Pressure/drug effects , Body Temperature/drug effects , Cardiac Output/drug effects , Central Venous Pressure/drug effects , Dogs , Electrocardiography , Female , Heart Rate/drug effects , Heart Ventricles/drug effects , Tetrodotoxin/administration & dosage , Tetrodotoxin/therapeutic use , Tetrodotoxin/toxicitySubject(s)
Arrhythmias, Cardiac/drug therapy , Lidocaine/administration & dosage , Administration, Oral , Animals , Blood Pressure/drug effects , Coronary Vessels , Disease Models, Animal , Dogs , Electrocardiography , Female , Heart Rate/drug effects , Heart Ventricles , Injections, Intravenous , Lidocaine/blood , Lidocaine/pharmacology , Lidocaine/toxicity , Ligation , Male , Time FactorsSubject(s)
Acetanilides/pharmacology , Acetanilides/toxicity , Lidocaine/metabolism , Administration, Oral , Animals , Arrhythmias, Cardiac/drug therapy , Blood Pressure/drug effects , Chloroform/adverse effects , Dogs , Electrocardiography , Ethylamines/pharmacology , Ethylamines/toxicity , Female , Lethal Dose 50 , Lidocaine/therapeutic use , Lidocaine/toxicity , Male , Mice , Mice, Inbred Strains , Respiratory Insufficiency/chemically induced , Seizures/chemically induced , Vomiting/chemically induced , Xylenes/pharmacology , Xylenes/toxicityABSTRACT
1. The effects of (+/-)-propranolol, (+/-)-, (+)- and (-)-alprenolol were studied in unanaesthetized dogs with ventricular arrhythmias produced by ligation of the left coronary artery. The responses were compared with those of similar control dogs which were given only isotonic saline.2. The ventricular arrhythmias were abolished by cumulative doses of 3.5 mg/kg of (+/-)-alprenolol, 7.5 mg/kg of (-)-alprenolol and (+/-)-propranolol and by 15.5 mg/kg of (+)-alprenolol.3. At the time of maximum antiarrhythmic activity none of the drugs produced significant alterations in mean arterial pressure or atrial rate.4. Cumulative doses of 7.5 mg/kg and 15.5 mg/kg of the four drugs resulted in some instances of lip licking, emesis and/or head tremors while 31.5 mg/kg was invariably lethal.5. Since the beta-adrenoceptor blocking activity of (-)-alprenolol is 100 times greater than that of (+)-alprenolol, suppression of these ventricular arrhythmias was apparently unrelated to antagonism of sympathetic influences.6. Alprenolol and propranolol have myocardial depressant properties apart from their effects on beta-adrenoceptors which could account for the anti-arrhythmic activity observed.
