Acute hemodynamic and antiischemic effects of intravenous amiodarone

The acute hemodynamic and antiischemic properties of amiodarone were investigated in 16 patients with more than 70% diameter reduction of a left coronary artery. Two successive atrial pacing stress tests (APST I and II) were performed, with an interval of 40 minutes in between, and amiodarone, 5 mg/kg/5 min, was infused 30 minutes after APST I. Hemodynamic changes during amiodarone administration consisted of a 20% decrease in left ventricular (LV) systolic pressure, a 13% decrease in systemic vascular resistance and an 18% decrease in stroke work. Coronary vascular resistance was reduced 19% and coronary sinus flow increased 23%. Despite a secondary 14% increase in heart rate, contractility decreased 21%, accompanied by a 45% increase in LV end-diastolic pressure, which persisted until APST II. Although most hemodynamic changes were observed only during the infusion, contractility and LV systolic pressure were still diminished at the beginning of APST II and remained so during pacing, resulting in a reduction in myocardial oxygen demand compared to APST I. Although overall myocardial oxygen consumption and coronary flow were equal during both pacing tests, amiodarone significantly reduced pacing-induced myocardial ischemia. Lactate metabolism remained normal during APST II (lactate extraction 12 +/- 3% vs -28 +/- 8% (APST I) at maximal pacing rates [p less than 0.05]), while ST-segment depression, LV end-diastolic pressure postpacing and angina were also significantly reduced during APST II. Thus, in humans, intravenous amiodarone reduces vascular resistance and contractility and inhibits pacing-induced myocardial ischemia, presumably by reducing myocardial oxygen demand.     

Acute antiarrhythmia treatment with amiodarone and blood levels of thyroid hormones

Amiodarone has a good antiarrhythmic effect administered either acutely or chronically. Since the antiarrhythmic effect of chronically administered amiodarone has been thought to be dependent on a depression of thyroid function, we studied the peripheral hormonal pattern of 10 euthyroid patients with ventricular arrhythmias who had been responsive to the acute intravenous administration of the drug (10 mg/Kg). During the first 12 hours following the drug administration, reverse T3, free T3 and free T4 values and QTc duration were unchanged. Therefore the antiarrhythmic effect of amiodarone when acutely administered has no correlation with thyroid hormone serum changes.     

The effects of amiodarone on serum thyroid hormones and hepatic thyroxine 5'-monodeiodination in rats

Amiodarone (2-n-butyl-3,4'-diethylaminoethoxy-3', 5'-diiodobenzoyl-benzofurane) is an antiarrhythmic drug which increases serum T4 and rT3 levels in patients and lowers serum T3 levels. To investigate its effects on T4 metabolism and its cardiac action, we fed amiodarone to male Fisher rats at doses of 5, 15, and 45 mg/kg BW X day; controls received potassium iodide for 4-7 weeks, and another group received sodium ipodate. At 4 weeks, amiodarone caused a dose-dependent increase in the serum T4 concentration and a slight reduction of serum TSH without a change in the serum T3 concentration. These changes were not present at 7 weeks. Sodium ipodate raised serum T4 concentrations at both times. Rats treated with T4 (150 micrograms/kg BW X day) to suppress thyroidal secretion of hormone and with amiodarone (15 mg/kg) had marked reduction of serum T3 concentrations compared with controls receiving T4 without amiodarone. Liver homogenates from rats treated with amiodarone showed marked reduction on T4 5'-monodeiodinase activity in a dose-related manner. Amiodarone added to liver homogenates in vitro at concentrations of 0.001-1 mM did not inhibit T3 production from T4, whereas ipodate added in vitro (0.01-1 mM) did inhibit T3 production. Rats treated with amiodarone showed a lowering of the resting heart rate and a reduction of the increment in heart rate after iv isoproterenol administration. The cardiac Ca++ myosin ATPase activity was reduced in rats receiving amiodarone (45 mg/kg) compared with that in controls. The data indicate that rats treated with amiodarone have reduced peripheral conversion of T4 to T3 owing to impaired hepatic T4 5'-monodeiodinase activity. In addition, these rats have slowing of heart rate and reduction of cardiac Ca++ myosin ATPase activity. These findings are consistent with the hypothesis that amiodarone blocks some effects of thyroid hormone on the heart, but additional studies are needed to test this hypothesis.     

Hemodynamic effects of intravenous amiodarone

Amiodarone is a potent antiarrhythmic agent that is effective in controlling both atrial and ventricular arrhythmias. Recently, intravenous administration was demonstrated to be effective in the acute management of rhythm disorders and, in addition, appeared to shorten the loading period normally required for oral drug administration. This investigation examined the hemodynamic effects of amiodarone after both acute intravenous bolus and continuous intravenous administration. Patients with a left ventricular ejection fraction greater than 0.35 experienced improved cardiac performance due to both acute and chronic peripheral vasodilation. However, patients with a lower ejection fraction developed a 20% decrease in cardiac index and clinically significant elevation of right heart pressures after acute bolus administration; these changes were variably compensated for by peripheral vasodilation when the drug was administered intravenously over 3 to 5 days continuously. Therefore, intravenous amiodarone can result in significant impairment of left ventricular performance in patients with preexisting left ventricular dysfunction.     

The effects of amiodarone on the thyroid

Amiodarone is a benzofuranic-derivative iodine-rich drug widely used for the treatment of tachyarrhythmias and, to a lesser extent, of ischemic heart disease. It often causes changes in thyroid function tests (typically an increase in serum T(4) and rT(3), and a decrease in serum T(3), concentrations), mainly related to the inhibition of 5'-deiodinase activity, resulting in a decrease in the generation of T(3) from T(4) and a decrease in the clearance of rT(3). In 14-18% of amiodarone-treated patients, there is overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH). Both AIT and AIH may develop either in apparently normal thyroid glands or in glands with preexisting, clinically silent abnormalities. Preexisting Hashimoto's thyroiditis is a definite risk factor for the occurrence of AIH. The pathogenesis of iodine-induced AIH is related to a failure to escape from the acute Wolff-Chaikoff effect due to defects in thyroid hormonogenesis, and, in patients with positive thyroid autoantibody tests, to concomitant Hashimoto's thyroiditis. AIT is primarily related to excess iodine-induced thyroid hormone synthesis in an abnormal thyroid gland (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), but mixed forms frequently exist. Treatment of AIH consists of L-T(4) replacement while continuing amiodarone therapy; alternatively, if feasible, amiodarone can be discontinued, especially in the absence of thyroid abnormalities, and the natural course toward euthyroidism can be accelerated by a short course of potassium perchlorate treatment. In type I AIT the main medical treatment consists of the simultaneous administration of thionamides and potassium perchlorate, while in type II AIT, glucocorticoids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. Radioiodine therapy is usually not feasible due to the low thyroidal radioiodine uptake, while thyroidectomy can be performed in cases resistant to medical therapy, with a slightly increased surgical risk.     

Hemodynamic effects of intravenous amiodarone in humans]

The haemodynamic action of I-V Cordarone have been studied in 20 subjects over a 15 minute period. Over the 15 minute period we studied variations in left pulmonary and ventricular pressures, in cardiac output, and in the paramaters of contraction VEC max, V max and Taylor's index. At a dose of 5 mg/kg there is a fall in peripheral resistance (1274 +/- 232 to 915 dynes/s/cm-5), and the measurements of contraction hardly vary. At a dose of 10 mg/kg, after an initial increase in output and a fall in peripheral resistance there occurs, after 4 minutes, an increase in left ventricular end-diastolic pressure (from 6 +/- 2 to 13 +/- 4 mmHg, P less than 0.01), and a lowering of contractility (VEC max reduced from 49.7 +/- 12.4 to 27.1 +/- 3.8, P less than 0.001). We have shown that the first phase of this response is due to the solvent (Tween 80), while the fall in contractility is due to the amiodarone. Doses above 10 mg/kg must be used with care, and only if there is no evidence of impaired cardiac function.     

静脉联合应用美托洛尔和胺碘酮对缺血再灌注大鼠心律失常和心肌梗死范围的影响

目的观察静脉联合应用美托洛尔、胺碘酮对缺血/再灌注大鼠快速室性心律失常和心肌梗死范围的影响。方法Sprague-Dawley(SD)大鼠40只麻醉后,依缺血前所用药物不同,随机分为对照组、美托洛尔组、胺碘酮组、胺碘酮+美托洛尔组,复制缺血/再灌注模型,给药20min后,行缺血7min后,再灌注10min,观察再灌注期间室性心动过速和心室颤动的发生;然后再缺血30min,再灌注120min,观察心肌梗死/缺血区域面积比值,并经颈内动脉监测血压和心率。结果在观察过程中,各用药组血压、心率改变没有显著性差异。大鼠缺血/再灌注前静脉注射美托洛尔、胺碘酮显著减少缺血再灌注的室性心动过速,而胺碘酮+美托洛尔组进一步减少(P<0.01);同样,胺碘酮+美托洛尔组显著减少了再灌注诱发的总的心室颤动的发生(P<0.05),美托洛尔组、胺碘酮组没有统计学差异;不可逆心室颤动的发生,与胺碘酮组比较,美托洛尔组显著下降,胺碘酮+美托洛尔组较美托洛尔组进一步降低,但没有显著差异。美托洛尔组、胺碘酮组均减少了心肌梗死/缺血区域面积比率(P<0.05),胺碘酮+美托洛尔组则进一步降低(P<0.01)。结论联合应用美托洛尔和胺碘酮静脉注射可以进一步减少缺血/再灌注快速室性心律失常发生率,减少心肌梗死范围。     

The various effects of amiodarone on thyroid function.

Amiodarone, a benzofuranic-derivative iodine-rich drug used mostly for tachyarrhythmias, often causes changes in the peripheral metabolism of thyroid hormones mainly due to the inhibition of 5'-deiodinase activity: an increase in serum thyroxine and reverse triiodothyronine, and a decrease in serum triiodothyronine concentrations. Overt thyroid dysfunction, either amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH), occurring in 14% to 18% of patients receiving long-term treatment, may develop both in apparently normal thyroid glands and in glands with preexisting abnormalities. AIH is mainly due to the failure to escape from the acute Wolff-Chaikoff effect, and, in patients with thyroid autoimmune phenomena, to concomitant Hashimoto's thyroiditis. AIT is due to excess iodine-induced thyroid hormone synthesis (type I AIT) or to amiodarone-related destructive thyroiditis (type II AIT), although mixed forms often occur. Treatment of AIH consists of levothyroxine replacement therapy while continuing amiodarone therapy; alternatively, amiodarone can be discontinued, if possible, and the natural course toward euthyroidism can be accelerated by a short trial of potassium perchlorate. In type I AIT, the simultaneous administration of thionamides and potassium perchlorate is the treatment of choice, while in type II AIT steroids are the most useful therapeutic option. Mixed forms are best treated with a combination of thionamides, potassium perchlorate, and glucocorticoids. The low thyroidal 131I uptake usually makes radioiodine therapy not feasible, while thyroidectomy is a valid alternative in cases resistant to medical therapy.     

静脉胺碘酮的主要不良反应分析

目的了解静脉胺碘酮在实际应用中出现的主要不良反应情况,探讨如何进一步规范使用胺碘酮,减少其副作用。方法对本院在2003年10月到2005年9月的静脉使用胺碘酮的全部住院病历进行回顾性研究,对出现不良反应的病例进行统计与分析。结果静脉胺碘酮后出现肝功能异常的发生率为12.6%,男性比女性更容易发生肝功能异常。重度肝功能异常的病例9例,需干预的严重心动过缓7例,需干预的低血压4例,过敏反应1例。结论尽管静脉胺碘酮有可能导致一些副作用,但只要密切监测,早期发现,早期处理,其使用是安全有效的。     

静脉胺碘酮的主要不良反应分析

目的了解静脉胺碘酮在实际应用中出现的主要不良反应情况，探讨如何进一步规范使用胺碘酮，减少其副作用。方法对本院在2003年10月到2005年9月的静脉使用胺碘酮的全部住院病历进行回顾性研究，对出现不良反应的病例进行统计与分析。结果静脉胺碘酮后出现肝功能异常的发生率为12．6％，男性比女性更容易发生肝功能异常。重度肝功能异常的病例9例，需干预的严重心动过缓7例，需干预的低血压4例，过敏反应1例。结论尽管静脉胺碘酮有可能导致一些副作用，但只要密切监测，早期发现，早期处理，其使用是安全有效的。     

Effect of intravenous amiodarone in patients with intraventricular conduction disorders

Using His bundle recordings and stimulation techniques, theelectrical effects of amiodarone (5 mg/kg intravenously) wereassessed in 12 patients aged 34–80 years (mean 65) exhibitingin sinus rhythm, intraventricular conduction disturbances. Bundlebranch block was present in 10 patients: left bundle branchblock in three patients, right bundle branch block in three,bilateral bundle branch block in four. All the patients hada long H-V interval (65–80 ms; mean 71). As has been previouslyreported, amiodarone slowed the sinus rate, prolonged the QTinterval, increased the atrial effective refractory period anddepressed A-V nodal conduction. Despite the presence of advancedconduction disturbances within the His-Purkinje system, amiodaronedid not alter the H-V interval in 11 patients and increasedit in one by only 5 ms. Thus, clinically, the use of amiodaronein patients with bundle branch block should be safe.     

Pharmacokinetics of intravenous amiodarone and its electrocardiographic effects on healthy Japanese subjects

The aim of this phase I, dose-escalating study was to evaluate the pharmacokinetics, electrocardiographic effect and safety of amiodarone after a single intravenous administration in Japanese subjects. Thirty-two healthy Japanese male volunteers (20–32 years) were randomized to three single-dose groups (1.25, 2.5 and 5.0 mg/kg). In each group, six (1.25 mg/kg) or ten (2.5 and 5.0 mg/kg) subjects received a single 15-min infusion of intravenous amiodarone, and two subjects received glucose solution as control. The pharmacokinetic profile, blood pressure and electrocardiographic analyses were obtained on a timely basis after up to 77 days. The maximum plasma concentration (C _max) and area under the concentration-time curve (AUC_0–96) for amiodarone 1.25, 2.5 and 5.0 mg/kg displayed dose-dependent characteristics: mean C _max was 2,920 ± 610, 7,140 ± 1,480 and 13,660 ± 3,410 ng/ml, respectively; the mean AUC_0-96 was 3,600 ± 700, 8,100 ± 1,600 and 16,600 ± 4,300 ng h/ml, respectively. A long serum half-life (>14 days) was observed for amiodarone and desethylamiodarone. PR intervals were prolonged at 15 min (0.16 ± 0.0.1 vs. 0.15 ± 0.01 s, p = 0.03) and 18 min (0.17 ± 0.01 vs. 0.15 ± 0.01 s, p = 0.03) with the 5.0 mg/kg dose compared with baseline. No other significant changes in electrocardiographic parameters, pulse rate or blood pressure were observed. A needle-pain-induced vasovagal effect appeared in a volunteer, and three volunteers experienced pain at the drug infusion site. After a single infusion of amiodarone at doses of 1.25–5.0 mg/kg, serum concentrations increased in a dose-dependent manner. A single intravenous amiodarone dose barely affected the electrocardiographic parameters and was well tolerated.     

Rate-dependent effects of intravenous lidocaine, procainamide and amiodarone on intraventricular conduction

In this study, the duration of the QRS complex during ventricular pacing was used as an index of intraventricular conduction to quantitate the rate-dependent effects of intravenous lidocaine, procainamide and amiodarone. Right ventricular apical pacing (15 to 20 beats) was performed at cycle lengths of 600, 500, 400, 350, 300, 275 and 250 ms, before and 5 minutes after the intravenous administration of lidocaine in 11 patients (serum level 3.2 +/- 0.8 micrograms/ml [mean +/- SD] ), procainamide in 14 patients (serum level 8.2 +/- 1.9 micrograms/ml) and amiodarone in 12 patients (serum level 3.9 +/- 1.2 micrograms/ml). Electrocardiographic recordings were made at a paper speed of 150 mm/s. QRS duration was measured in a blinded fashion, with reproducibility within 5%. In the control state, QRS duration was the same at all paced cycle lengths. After lidocaine, procainamide and amiodarone administration, the shortest paced cycle length with complete ventricular capture was 250 +/- 0, 275 +/- 38 and 264 +/- 20 ms, respectively. At a paced cycle length of 600 ms, the increase in QRS duration compared with the control state was 1 +/- 2% with lidocaine (p greater than 0.05), 21 +/- 7% with procainamide (p less than 0.001) and 6 +/- 6% with amiodarone (p less than 0.05). At the shortest paced cycle length with complete capture, the increase in QRS duration compared with the control state was 20 +/- 6% with lidocaine (p less than 0.001), 42 +/- 11% with procainamide (p less than 0.001) and 26 +/- 4% with amiodarone (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)