Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels.

Synopsis: Verapamil is a novel antiarrhythmic and antianginal agent which, although introduced in 1962, has only recently gained prominence not only as a significant agent in cardiovascular therapeutics but also as a powerful tool to examine the nature of some of the biophysical phenomena at the membrane of cardiac and other excitable tissues. Verapamil is the prototype of those agents which selectively inhibit membrane transport of calcium, an action which accounts for the drug’s peripheral and coronary vasodilator properties, its effect on excitation-contraction coupling and hence its negative inotropic propensity, as well as its depressant effects on the sinus node and atrioventricular conduction. Its pharmacological effects are largely independent of the autonomic nervous system. The main therapeutic uses of the drug are in the management of atrial tachyarrhythmias, angina, and possibly hypertension. The overall experimental and clinical data suggest that verapamil will become an important and safe addition to existing drug regimens, especially as an agent of choice for the short-term treatment of most cases of paroxysmal supraventricular tachycardias. The initial experience in other arrhythmias, angina and hypertension, is also sufficiently encouraging to justify further detailed clinical trials to define its potential role in cardiovascular therapeutics.

Verapamil: A Review of its Pharmacological Properties and Therapeutic Use

The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis.

The past decade has seen the introduction of many new class 1 drugs, restricting fast inward current. Confirmative evidence has been obtained that the antiarrthymic action of lidocaine and diphenylhydantoin is indeed due to their effect as class 1 agents depressing conduction. The original class 3 drug, amiodarone, is increasingly in use as an antiarrhythmic of first choice for WPW and for arrhythmias associated with hypertrophic myopathy, and as a reserve drug in resistant arrhythmias of other types. Other compounds delaying repolarization have proved to be clinically effective as antiarrhythmics. In addition to their class 2 antiarrhythymic action exhibited acutely, on long-term treatment beta blockers have a class 3 action, which might be, at least in part, responsible for the protection of postinfarction patients against sudden death. Recent research suggests that inhibition of slow inward current may lead, as a secondary consequence of lowered [Ca]i, to improved cell-to-cell conduction. Finally, all but one of the new antiarrhythmic drugs, none of which existed in 1972, have turned out to possess one or more of the four classes of action originally described. This can hardly be a coincidence. The single exception, alinidine, a selective bradycardic agent, may restrict anionic currents, which would constitute a fifth class of action, but this is far from proved.

https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/j.1552-4604.1984.tb01822.x

A Classification of Antiarrhythmic Actions Reassessed After a Decade of New Drugs

background The optimal pharmacologic means to restore and maintain sinus rhythm in patients with atrial fibrillation remains controversial. methods In this double-blind, placebo-controlled trial, we randomly assigned 665 patients who were receiving anticoagulants and had persistent atrial fibrillation to receive amiodarone (267 patients), sotalol (261 patients), or placebo (137 patients) and monitored them for 1 to 4.5 years. The primary end point was the time to recurrence of atrial fibrillation beginning on day 28, determined by means of weekly transtelephonic monitoring. results Spontaneous conversion occurred in 27.1 percent of the amiodarone group, 24.2 percent of the sotalol group, and 0.8 percent of the placebo group, and direct-current cardioversion failed in 27.7 percent, 26.5 percent, and 32.1 percent, respectively. The median times to a recurrence of atrial f ibrillation were 487 days in the amiodarone group, 74 days in the sotalol group, and 6 days in the placebo group according to intention to treat and 809, 209, and 13 days, respectively, according to treatment received. Amiodarone was superior to sotalol (P<0.001) and to placebo (P<0.001), and sotalol was superior to placebo (P<0.001). In patients with ischemic heart disease, the median time to a recurrence of atrial fibrillation was 569 days with amiodarone therapy and 428 days with sotalol therapy (P=0.53). Restoration and maintenance of sinus rhythm significantly improved the quality of life and exercise capacity. There were no significant differences in major adverse events among the three groups. conclusions Amiodarone and sotalol are equally efficacious in converting atrial fibrillation to sinus rhythm. Amiodarone is superior for maintaining sinus rhythm, but both drugs have similar efficacy in patients with ischemic heart disease. Sustained sinus rhythm is associated with an improved quality of life and improved exercise performance.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa041705

Amiodarone versus sotalol for atrial fibrillation.

1. Amiodarone (2-butyl, 3-(4-diethylaminoethoxy, 3,5-diiodo, benzoyl) benzofuran hydrochloride), an anti-anginal drug which causes coronary dilatation and depresses myocardial oxygen consumption, was found to protect anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation.

2. A 5% (73·4 mM) solution of amiodarone had no local anaesthetic action on guinea-pig skin.

3. Amiodarone, 20 mg/kg (29·4 μmol/kg) given daily for 6 weeks intraperitoneally, had no effect on the resting potential or action potential height, and only a small effect on the maximum rate of depolarization, of isolated rabbit atrial or ventricular muscle fibres as shown by intracellular recording. It caused a considerable prolongation of the action potential in both tissues.

4. Simultaneous administration of thyroxine (5 μg; 6·26 nmol), given daily for 3 weeks intraperitoneally, prevented the prolongation by amiodarone of the duration of the action potential.

5. Treatment of rabbits with 20 mg/kg of amiodarone daily intraperitoneally for 6 weeks had no effect on the weight of the thyroid gland, but was associated with a reduction in body growth rate.

6. Treatment of rabbits with 10 mg/kg (60·3 μmol/kg) of potassium iodide (equal in its iodine content to that of 20 mg/kg of amiodarone), given daily for 6 weeks intraperitoneally, had no effect on body growth rate or the duration of cardiac action potentials.

7. It was concluded that amiodarone had effects on cardiac action potentials similar to those which occur after thyroidectomy.

/pdf/the-effect-of-amiodarone-a-new-anti-anginal-drug-on-cardiac-10uvx2th06.pdf

The effect of amiodarone, a new anti‐anginal drug, on cardiac muscle

Summary

1
Both MJ 1999 and AH 3474 protected guinea-pigs anaesthetized with urethane against ouabain-induced ventricular fibrillation.

2
MJ 1999 had 1/90, and AH 3474 1/30, of the activity of procaine in reducing the height of the action potential of frog sciatic nerve.

3
MJ 1999 and AH 3474 reduced the rate of rise of intracellularly recorded action potentials at concentrations in excess of 160 × 10−6m (50 mg/l.). It was concluded that direct depression of depolarization could have contributed little to the protection against ouabain-induced fibrillation.

4
MJ 1999, but not AH 3474, greatly prolonged the duration of the action potential in acute experiments on isolated atrial and ventricular muscle, and prolonged the Q-Tc interval of the electrocardiogram in anaesthetized guinea-pigs. It is suggested that this effect contributes to anti-arrhythmic activity.

5
At concentrations up to 80 × 10−6m AH 3474 had positive chronotropic and inotropic effects on isolated rabbit atrial muscle, but at higher concentrations these were superseded by negative effects. MJ 1999 was depressant at all concentrations studied, the threshold concentrations being 19 × 10−6m for chronotropic, and 162 × 10−6m for inotropic effects.

A third class of anti-arrhythmic action: Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474

All previously studied antiarrhythmic drugs which also have local anaesthetic properties reduce the maximum rate of depolarization (MRD) of cardiac muscle. Recent evidence suggested that lidocaine and diphenylhydantoin (DPH) might have a different mode of action, because they did not reduce MRD except at high concentration. The latter evidence, however, was obtained from tissues nourished by solutions containing 2.7-3 mM potassium. In the present experiments, the effects of lidocaine and DPH were studied in solutions with 5.6 and 3 mM KCl. In the former, both drugs reduced MRD at concentrations similar to those found in the blood of treated patients, but in low [KCl] higher concentrations were necessary. It was concluded that there was no reason to suppose that the mode of action of lidocaine and DPH on the cardiac membrane is fundamentally different from that of quinidine, procaine, procainamide and other compounds which interfere directly with depolarization.

Effect of Altering Potassium Concentration on the Action of Lidocaine and Diphenylhydantoin on Rabbit Atrial and Ventricular Muscle

1. Ko 1173, 1-(2',6'-dimethyl-phenoxy)-2-amino-propane, was equal to lignocaine in potency as a local anaesthetic on stripped frog sciatic nerve at pH 7·5.

2. In anaesthetized guinea-pigs in which ventricular fibrillation had been produced by an intravenous infusion of ouabain, intravenous administration of Ko 1173 caused reversion to sinus rhythm in ten out of ten animals. The mean dose of Ko 1173 required was 3·3 mg (15·3 μmol)/kg. When the ouabain infusion was continued, ventricular fibrillation did not recur, and the lethal dose of ouabain was greater than in controls.

3. Pretreatment with Ko 1173, however, did not influence the toxicity of ouabain infusion, implying great brevity of action.

4. Ko 1173 given intravenously caused a bradycardia which was maximal in 2-3 min, and which did not last more than 5 minutes.

5. Ko 1173 reduced the maximum driven frequency of isolated rabbit atria, raised electrical threshold, slowed conduction velocity and depressed contractions.

6. Ko 1173 reduced the maximum rate of depolarization of intracellularly recorded rabbit atrial and ventricular potentials, but did not affect the resting potential or the duration of the action potential.

Investigations of the mode of action of a new antidysrhythmic drug, Kö 1173.

Fundamental concepts in cardiovascular drug action and therapy principal classes of therapeutic agents - present and future myocardial ischemia and infarction acute myocardial infarction antithrombotic therapy in the prophylaxis of arterial thromboembolism disorders of cardiac rhythm congestive heart failure hypertension drug therapy of dyslipidemias and of atherosclerosis cardiac transplantation pharmacology and therapeutics deserving special consideration.

B. N. Singh

Papers

The effect of amiodarone, a new anti‐anginal drug, on cardiac muscle

A third class of anti-arrhythmic action: Effects on atrial and ventricular intracellular potentials, and other pharmacological actions on cardiac muscle, of MJ 1999 and AH 3474

Effect of Altering Potassium Concentration on the Action of Lidocaine and Diphenylhydantoin on Rabbit Atrial and Ventricular Muscle

Investigations of the mode of action of a new antidysrhythmic drug, Kö 1173.

Cardiovascular pharmacology and therapeutics