Cardiac actions in the dog of a new antagonist of adrenergic excitation which does not produce competitive blockade of adrenoceptors.
TL;DR: It is concluded that the cardiac actions of amiodarone are not produced by competitive blockade of β‐adrenoceptors.
Abstract: 1. The cardiac actions of amiodarone, a benzofuran derivative used in the treatment of angina pectoris, have been compared with those of (±)-propranolol in anaesthetized dogs.
2. After three successive intravenous injections of propranolol, 0·5 mg/kg, had reduced the heart rate by 25%, a fourth dose had no further negative chronotropic action, but amiodarone, 10 mg/kg intravenously, at this point reduced the heart rate by 23%.
3. Amiodarone, 10 mg/kg intravenously, reduced, but did not abolish, cardiac responses to isoprenaline, 2 μg/kg intravenously. Subsequent successive injections of 10 mg/kg of amiodarone did not further block the responses to isoprenaline, but propranolol, 1 mg/kg intravenously, abolished them.
4. Amiodarone reduced cardiac chronotropic and inotropic responses to glucagon, which were not affected by propranolol.
5. Cardiac output was increased 5 min after amiodarone, 10 mg/kg intravenously, but at 10 min and thereafter it did not differ from control values. Propranolol, 1 mg/kg intravenously, reduced cardiac output by 17% at 5 min, and by 30% after 30 min.
6. From this and other evidence which is discussed, it is concluded that the cardiac actions of amiodarone are not produced by competitive blockade of β-adrenoceptors.
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TL;DR: It is concluded that amiodarone is effective for long-term therapy of recurrent ventricular tachyarrhythmias, that induction of arrhythmia during therapy does not always predict efficacy, and that side effects are frequent but do not usually limit therapy.
Abstract: We evaluated the effects of amiodarone in 45 patients with recurrent ventricular tachycardia or ventricular fibrillation. At a mean follow-up time of 12.7 +/- 8.8 months (range, three to 36), amiodarone was successful in nine of 16 patients with recurrent ventricular fibrillation and 21 of 29 with recurrent ventricular tachycardia. During amiodarone therapy, ventricular tachycardia could be induced in 18 of 19 patients in whom it had been induced before therapy, but only six of these 19 had spontaneous recurrence during follow-up. Side effects included corneal microdeposits, hyperthyroidism, blue skin, nausea, and symptomatic bradycardia. Pulmonary fibrosis occurred in three patients. Doses of up to 2000 mg a day did not produce cardiac toxicity, but neurologic side effects precluded long-term therapy at this dose. We conclude that amiodarone is effective for long-term therapy of recurrent ventricular tachyarrhythmias, that induction of arrhythmia during therapy does not always predict efficacy, and that side effects are frequent but do not usually limit therapy.
545 citations
TL;DR: Amiodarone proved safe in patients with severe congestive heart failure and severe myocardial damage and liberates patients from a rigid hourly schedule and provides for continuous antiarrhythmic control, days and even weeks after treatment is discontinued.
Abstract: Amiodarone, administered orally in doses of 200 to 600 mg/day, was remarkably effective in the treatment and prevention of a wide variety of atrial and ventricular arrhythmias. Total suppression and control was provided in 98 (92.4 percent) of 106 patients with supraventricular arrhythmias and in 119 (82 percent) of 145 patients with ventricular arrhythmias. The rates of total control of the arrhythmia were: 96.6 percent in 30 patients with recurrent atrial flutter or fibrillation, 96.6 percent in 59 patients with repetitive supraventricular tachycardia, 100 percent in 27 patients with Wolff-Parkinson-White syndrome and 77.2 percent in 44 patients with recurrent ventricular tachycardia unsuccessfully treated with other drugs. Excellent results were obtained in 6 of 8 patients with repetitive ventricular tachycardia and ventricular fibrillation related to postinfarction ventricular aneurysm and in 12 of 14 patients with ventricular extrasystoles and ventricular tachycardia related to Chagasic myocarditis. Amiodarone proved safe in patients with severe congestive heart failure and severe myocardial damage. Its clinical efficacy was related to its electrophysiologic properties and to two unique properties: its wide safety margin and its cumulative effect. The latter liberates patients from a rigid hourly schedule and provides for continuous antiarrhythmic control, days and even weeks after treatment is discontinued.
534 citations
TL;DR: It was concluded that direct depression of depolarization could have contributed little to the protection against ouabain‐induced fibrillation, and it is suggested that this effect contributes to anti‐arrhythmic activity.
Abstract: 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.
403 citations
TL;DR: This trial demonstrated a significant reduction in cardiac mortality and ventricular arrhythmias with amiodarone treatment, however, given the wide confidence intervals and borderline statistical significance of the trial, larger trials are needed to confirm or refute this view.
283 citations
TL;DR: This review focuses on the arrhythmias most commonly requiring antiarrhythmic therapy—sustained ventricular tachycardia (VT), ventricular fibrillation (VF), and atrial fibrilation (AF)—because they are the most clinically significant and have been the focus of most studies published.
Abstract: Amiodarone was initially developed 3 decades ago for angina. On the basis of the number of prescriptions filled in retail pharmacies, amiodarone was the most-often-prescribed antiarrhythmic agent, accounting for 24.1% of the total antiarrhythmic prescriptions in 1998. Amiodarone accounted for 34.5% of prescriptions in Europe, 32.8% in North America, 73.8% in Latin America, and 0.3% in Japan and the Philippines. Amiodarone use has increased globally in 1998 at a rate greater than that of the whole antiarrhythmic market, with striking growth in North America, a 20.0% increase from 1997 to 1998 (according to International Medical Statistics, Medical Data Index, and Scott Levin drug and diagnosis audit, obtained with the assistance of J. Jones, Sanofi Pharma Inc, Paris, France). Amiodarone is used to manage virtually all forms of supraventricular and ventricular tachycardia. This review focuses on the arrhythmias most commonly requiring antiarrhythmic therapy—sustained ventricular tachycardia (VT), ventricular fibrillation (VF), and atrial fibrillation (AF)—because they are the most clinically significant and have been the focus of most studies published. This review will analyze the evidence that amiodarone is a safe and effective antiarrhythmic drug.
To exploit the antiarrhythmic properties of amiodarone fully, the clinician needs to be familiar with its pharmacokinetics, because they differ markedly from those of other cardiac drugs. Amiodarone is markedly lipophilic, which may account for some of its unusual pharmacokinetic features.1 It is incompletely absorbed (35% to 65%) after oral administration.2 3 4 It is taken up very extensively by tissue, with marked interindividual variation.5 Estimates of the elimination half-life of amiodarone vary, depending on how it has been measured. The relatively short half-life for disappearance of amiodarone from plasma after intravenous administration is likely a measure of drug redistribution from vascular space into tissue and not true body elimination.6 After long-term oral therapy, …
278 citations
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TL;DR: Experiments described in this paper indicate that although there are two kinds of adrenotropic receptors they cannot be classified simply as excitatory or inhibitory since each kind of receptor may have either action depending upon where it is found.
Abstract: T HE adrenotropic receptors are those hypothetical structures or systems located in, on or near the muscle or gland cells affected by epinephrine. The concept of a receptive mechanism was introduced by Langley (I, 2) to explain the action of curare on skeletal muscle. Dale was probably the first to make significant use of the receptor concept in connection with the sympathetic nervous system. In his classical paper (3) on the sympatholytic action of the ergot alkaloids, he recognized that what he called the sympathetic myoneural junction could also be called 'the receptive mechanism for adrenaline'; and he used this mechanism to explain the fact that the ergot alkaloids prevented only the motor (excitatory) actions of epinephrine and had no effect on the inhibitory actions of epinephrine or on the excitatory actions of barium or pituitrin. The adrenotropic receptors have been considered to be of two classes, those whose action results in excitation and those whose action results in inhibition of the eff ector cells. Experiments described in this paper indicate that although there are two kinds of adrenotropic receptors they cannot be classified simply as excitatory or inhibitory since each kind of receptor may have either action depending upon where it is found. The evidence for these conclusions is, in brief, that a series of six sympa-thomimetic amines has one order of potency-r, 2, 3, 4, 5, 6-on the following functions: vasoconstriction, excitation of the uterus and ureters, contraction of the nictitating membrane, dilation of the pupil and inhibition of the gut. In contrast, this same series of amines has an entirely different order of potency-z, 4, 6, 5, 3, Ion the following functions: vasodilation, inhibition of the uterus and myocardial stimulation. The variations in activity could be due to any or all of three factors: a) quantitative differences in potency, b) qualitatively different effects or c) differences due entirely to the experimental methods used. If the last Tao factors are controlled as much as possible by the selection of the amines and by using suitable experimental techniques, then the variations in activity are presumably due to actual differences in the receptors involved. Tentatively the first kind of receptor has been called the alpha adrenotropic receptor and the second kind the beta receptor. This concept of two fundamental types of receptors is directly opposed to the concept of two mediator substances (sympathin E and sympathin I) as propounded by …
2,544 citations
TL;DR: It was concluded that amiodarone had effects on cardiac action potentials similar to those which occur after thyroidectomy.
Abstract: 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.
550 citations
TL;DR: In the dog, myocardial performance was markedly augmented by the administration of glucagon, 50 μg/kg iv, as indicated by an average increase of 72.2±18.8% in force recorded by a strain gauge arch, despite an average decrease of 3.8±1.2 cm H2O (P < 0.02) in left ventricular end-diastolic pressure.
Abstract: The action of glucagon on cardiac performance was studied in 21 isolated cat papillary muscle preparations, in 13 spontaneously beating cat atria, in 15 intact dog hearts, and in 4 isolated perfused dog hindlimbs. In each papillary muscle preparation, addition of glucagon produced marked increases in maximal developed tension, averaging 36±4.2% (SEM) ( P P P P 2 O ( P P
238 citations
TL;DR: The results of these studies are discussed in reference to the known metabolic actions of glucagon and the catecholamines and the possibility that they both share a common mechanism of action mediated through an increase in the intracellular concentration of cyclic 3′,5′ AMP.
Abstract: Glucagon increased heart rate and contractile force in the anesthetized dog and increased isometric tension in the isolated dog papillary muscle. The positive inotropic and chronotropic responses were not abolished or reduced by previous administration of the beta-receptor blocking agent propranolol, in doses of 0.5 mg/kg. Glucagon increased the force and rate of cardiac contraction even when cardiac-depressant doses of propranolol, 2 mg/kg, had been given. Previous treatment with reserpine (1.0 mg/kg on each of 3 consecutive days) failed to diminish the positive inotropic and chronotropic effects of glucagon. However, previous administration of tyramine, 0.05 mg/kg, which resulted in a positive inotropic response in the dog, significantly reduced the glucagon-induced positive inotropic response. Theophylline, 10 mg/kg, likewise prevented the inotropic action of glucagon without preventing the positive inotropic effect of calcium chloride. The increase in isometric tension produced by glucagon in the isolated dog papillary muscle was prevented during simultaneous exposure of the muscles to acetylcholine. The results of these studies are discussed in reference to the known metabolic actions of glucagon and the catecholamines and the possibility that they both share a common mechanism of action mediated through an increase in the intracellular concentration of cyclic 39,59 AMP.
183 citations