piperidines and bretylium

Topics: Action Potentials; Adrenergic beta-Antagonists; Amiodarone; Anilides; Anti-Arrhythmia Agents; Bretylium Compounds; Calcium Channel Blockers; Cell Membrane; Disopyramide; Electrophysiology; Encainide; Flecainide; Humans; Lidocaine; Mexiletine; Piperidines; Procainamide; Quinidine; Tocainide

The frequency of ventricular arrhythmias increases with age. Several factors make elderly people more prone to antiarrhythmic drug toxicity. Familiarity with the changes in the pharmacokinetics and pharmacodynamics of antiarrhythmic agents may reduce or prevent adverse response in this patient population.

Topics: Aged; Amiodarone; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bretylium Compounds; Digoxin; Disopyramide; Encainide; Flecainide; Humans; Lidocaine; Mexiletine; Piperidines; Procainamide; Propranolol; Quinidine; Tocainide; Verapamil

The number of antiarrhythmic drugs available in the United States is increasing, with the discovery of antiarrhythmic properties of drugs previously marketed for other indications (phenytoin, imipramine) and the development of several new drugs, many of which are likely to become commercially available in the next 5 years. The currently available drugs and several promising investigational drugs are reviewed in this report. Their optimal use is dependent on an understanding of their electropharmacologic effects, pharmacokinetics, drug interactions, and clinical pharmacology. Such use may allow better attempts to reduce arrhythmia-related death and morbidity.

Topics: Adrenergic beta-Antagonists; Amiodarone; Anilides; Anti-Arrhythmia Agents; Benzeneacetamides; Biological Availability; Bretylium Compounds; Disopyramide; Encainide; Flecainide; Humans; Imipramine; Lidocaine; Mexiletine; Moricizine; Phenothiazines; Phenytoin; Piperidines; Procainamide; Propafenone; Propiophenones; Quinidine; Tocainide

Recently, a cholinergic neurogenic component of contraction has been characterised in the aganglionic mouse vas deferens. In this paper, a cholinergic component of contraction in the guinea-pig vas deferens is characterised pharmacologically. A residual, tetrodotoxin-sensitive (TTX, 0.3 microM), neurogenic contraction was revealed after prolonged exposure (5 h) to the adrenergic neurone blocker bretylium (20 microM) or in the presence of prazosin (100 nM) and alpha,beta-methylene ATP (1 microM), a purinergic agonist which desensitizes P2X receptors. The bretylium-resistant component was potentiated by the acetylcholinesterase (AChE) inhibitor neostigmine (10 microM) and inhibited by the muscarinic-receptor (mAChR) antagonist cyclopentolate (1 microM). Nicotine (30 microM) enhanced the bretylium-resistant component. Neostigmine increased the second component of contraction in the presence of prazosin and alpha,beta-methylene ATP, whilst yohimbine (1 microM), an alpha(2) adrenergic receptor antagonist, enhanced both the first and second components of the electrically evoked contraction. These enhanced contractions were blocked by cyclopentolate in both cases. Nicotine enhanced the cholinergic component of contraction revealed by neostigmine but failed to have any detectable effects in the presence of cyclopentolate. Neostigmine alone increased the slow component of contraction which was reversed by cyclopentolate to control levels. The M(3) receptor-antagonist 4-DAMP (10 nM) markedly inhibited the cholinergic component of contraction to a level comparable with cyclopentolate. Laser microscopy has shown that neostigmine also increased the frequency of spontaneous Ca(2+) transients remaining in smooth muscle cells after perfusion with prazosin and alpha,beta-methylene ATP, an effect blocked by 4-DAMP. These experimental data show that there is a functional cholinergic innervation in the guinea-pig vas deferens whose action is limited by acetylcholinesterase, blocked by cyclopentolate and mediated through M3 receptors. Moreover, by blocking the cholinesterase, the increased amount of ACh generates spontaneous Ca(2+) transients in smooth muscle cells.

Topics: Acetylcholine; Adrenergic alpha-Antagonists; Animals; Bretylium Compounds; Calcium; Cholinesterase Inhibitors; Cyclopentolate; Guinea Pigs; In Vitro Techniques; Male; Muscarinic Antagonists; Muscle Contraction; Myocytes, Smooth Muscle; Neostigmine; Nicotine; Nicotinic Agonists; Piperidines; Receptors, Muscarinic; Vas Deferens; Yohimbine

The antifibrillatory effects of flecainide 1 mg/kg + 0.05 mg/kg/min intravenously (i.v.), bretylium 6 mg/kg i.v., D-sotalol 2 mg/kg + 0.1 mg/kg/min i.v., and E-4031, a new class III drug, 50 micrograms/kg + 5 micrograms/kg/min i.v. were compared with three different methods of determining ventricular fibrillation threshold (VFT) in anesthetized open-chest dogs. In protocol 1, VFT was determined with 2-S, 50-Hz continuous pulses. Flecainide (n = 7) prolonged intraventricular conduction time (CT) and ventricular effective refractory period (ERP) and increased VFT significantly. Bretylium (n = 6) prolonged ERP slightly, but did not increase VFT significantly. Both D-sotalol (n = 6) and E-4031 (n = 6) prolonged ERP and increased VFT. In protocol 2, VFT was determined with the extrastimulus technique in dogs, with localized ventricular necrosis produced with protease. Flecainide (n = 10), D-sotalol (n = 8), and E-4031 (n = 8) restored VFT, which had been decreased by protease injection, to the baseline level, whereas bretylium (n = 8) did not. In protocol 3, the train pulse method with 100-Hz train pulses covering the vulnerable period was used in the same dogs used for protocol 2. Flecainide, bretylium, and D-sotalol increased VFT, but E-4031 did not. The antifibrillatory effects of class III drugs differ depending on the method of VFT determination. The present data suggest that the antifibrillatory effects of antiarrhythmic drugs should be assessed by different methods of VFT determination.

Topics: Analysis of Variance; Animals; Anti-Arrhythmia Agents; Bretylium Compounds; Dogs; Electric Stimulation; Flecainide; Heart Conduction System; Piperidines; Pyridines; Sotalol; Ventricular Fibrillation

MDL 11,939 (alpha-phenyl-1-[2-phenylethyl]-4-piperidine-methanol) is a new class III antiarrhythmic agent that was evaluated for antiarrhythmic activity in anesthetized dogs. Intravenous (i.v.) administration of MDL 11,939 (1, 3, and 10 mg/kg) increased left ventricular effective refractory periods. Q-T interval, and Q-Tc in a dose-related way. The effects of MDL 11,939 on ventricular refractoriness were similar to those observed with administration of identical doses of d-sotalol, with the exception that those produced by MDL 11,939 lasted longer. Intraduodenal administration of 10 mg/kg MDL 11,939 also increased left ventricular effective refractory period (LV ERP). The increase in left ventricular refractoriness produced by MDL 11,939 occurred without a significant increase in QRS duration. MDL 11,939 (10 mg/kg i.v.) also protected against induction of ventricular tachycardia (VT) and ventricular fibrillation (VF) induced with programmed electrical stimulation (PES) in anesthetized dogs with chronic 4- to 7-day myocardial infarctions. In comparison, antiarrhythmic effects of bretylium (10 mg/kg i.v.) against PES-induced ventricular arrhythmias were dependent on additional administration of propranolol (0.1 mg/kg i.v.), whereas propranolol alone (0.1 mg/kg i.v.) was ineffective. The results observed with MDL 11,939 are consistent with its in vitro class III antiarrhythmic action and suggest utility for this agent in treatment of VT and VF.

Topics: Animals; Anti-Arrhythmia Agents; Bretylium Compounds; Dogs; Drug Therapy, Combination; Electrocardiography; Electrophysiology; Female; Heart; Heart Ventricles; Male; Piperidines; Propranolol; Tachycardia; Ventricular Fibrillation