Effects Of Amiodarone In Patients Research Articles

Electrophysiological and therapeutic effects of amiodarone in patients with preexcited atrial fibrillation.

Atrial fibrillation (AF) with fast ventricular response over an overt accessory pathway (AP) (preexcited AF) with a short anterograde refractory period is a potentially malignant arrhythmia. This study aimed to evaluate the safety and efficacy of amiodarone for preexcited AF management. This study enrolled 103 patients with evidence of AP in electrocardiography. Patients with preexcited AF were included in the study. Intravenous amiodarone (300 mg) was infused for 30 min for all patients in the AF rhythm. Electrophysiological parameters were evaluated before amiodarone injection and 2 h after pharmacological or electrical cardioversion. Antegrade and retrograde refractory periods of the atrioventricular node (AVN) and AP, as well as antegrade and retrograde Wenckebach points of AVN, were increased significantly after amiodarone infusion. Furthermore, the mean of the shortest preexcited RR interval was increased during the monitoring period. Comparing the preexcited index at the beginning of the study and before cardioversion (2 h later) revealed that the QRS complexes changed to a wider pattern as the preexcitation index changed from 80.61 to 92.26 (P < 0.001). Nineteen (18.4%) patients converted to the sinus rhythm with amiodarone infusion. No ventricular arrhythmia was detected during monitoring. Amiodarone could be considered a safe drug in patients with preexcited AF for rate control despite its relatively low efficacy in conversion to the sinus rhythm.

Prediction of the dose range for adverse neurological effects of amiodarone in patients from an in vitro toxicity test by in vitro\u2013in vivo extrapolation

Amiodarone is an antiarrhythmic agent inducing adverse effects on the nervous system, among others. We applied physiologically based pharmacokinetic (PBPK) modeling combined with benchmark dose modeling to predict, based on published in vitro data, the in vivo dose of amiodarone which may lead to adverse neurological effects in patients. We performed in vitro–in vivo extrapolation (IVIVE) from concentrations measured in the cell lysate of a rat brain 3D cell model using a validated human PBPK model. Among the observed in vitro effects, inhibition of choline acetyl transferase (ChAT) was selected as a marker for neurotoxicity. By reverse dosimetry, we transformed the in vitro concentration–effect relationship into in vivo effective human doses, using the calculated in vitro area under the curve (AUC) of amiodarone as the pharmacokinetic metric. The upper benchmark dose (BMDU) was calculated and compared with clinical doses eliciting neurological adverse effects in patients. The AUCs in the in vitro brain cell culture after 14-day repeated dosing of nominal concentration equal to 1.25 and 2.5 µM amiodarone were 1.00 and 1.99 µg*h/mL, respectively. The BMDU was 385.4 mg for intravenous converted to 593 mg for oral application using the bioavailability factor of 0.65 as reported in the literature. The predicted dose compares well with neurotoxic doses in patients supporting the hypothesis that impaired ChAT activity may be related to the molecular/cellular mechanisms of amiodarone neurotoxicity. Our study shows that predicting effects from in vitro data together with IVIVE can be used at the initial stage for the evaluation of potential adverse drug reactions and safety assessment in humans.

Amiodarone for arrhythmia in patients with Chagas disease: A systematic review and individual patient data meta-analysis.

BackgroundChagas disease is a neglected chronic condition caused by Trypanosoma cruzi, with high prevalence and burden in Latin America. Ventricular arrhythmias are common in patients with Chagas cardiomyopathy, and amiodarone has been widely used for this purpose. The aim of our study was to assess the effect of amiodarone in patients with Chagas cardiomyopathy.MethodologyWe searched MEDLINE, Embase and LILACS up to January 2018. Data from randomized and observational studies evaluating amiodarone use in Chagas cardiomyopathy were included. Two reviewers selected the studies, extracted data and assessed risk of bias. Overall quality of evidence was accessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE).Principal findingsWe included 9 studies (3 before-after studies, 5 case series and 1 randomized controlled trial). Two studies with a total of 38 patients had the full dataset, allowing individual patient data (IPD) analysis. In 24-hour Holter, amiodarone reduced the number of ventricular tachycardia episodes in 99.9% (95%CI 99.8%-100%), ventricular premature beats in 93.1% (95%CI 82%-97.4%) and the incidence of ventricular couplets in 79% (RR 0.21, 95%CI 0.11–0.39). Studies not included in the IPD analysis showed a reduction of ventricular premature beats (5 studies), ventricular tachycardia (6 studies) and ventricular couplets (1 study). We pooled the incidence of adverse side effects with random effects meta-analysis; amiodarone was associated with corneal microdeposits (61.1%, 95%CI 19.0–91.3, 5 studies), gastrointestinal events (16.1%, 95%CI 6.61–34.2, 3 studies), sinus bradycardia (12.7%, 95%CI 3.71–35.5, 6 studies), dermatological events (10.6%, 95%CI 4.77–21.9, 3 studies) and drug discontinuation (7.68%, 95%CI 4.17–13.7, 5 studies). Quality of evidence ranged from moderate to very low.ConclusionsAmiodarone is effective in reducing ventricular arrhythmias, but there is no evidence for hard endpoints (sudden death, hospitalization). Although our findings support the use of amiodarone, it is important to balance the potential benefits and harms at the individual level for decision-making.

Clinical aspects of treatment with amiodarone

Amiodarone has multiple and complex electrophysiological effects that render it avery effective antiarrhythmic drug for the treatment of both, supraventricular and ventricular arrhythmias. Proarrhythmic effects of amiodarone in patients with structural heart disease are rare. However, extracardiac adverse effects occurring in association with amiodarone treatment are frequent and feared. These adverse effects have usually been related to total amiodarone exposure (i. e., dose and duration of treatment). Parallel to amore frequent use of lower amiodarone maintenance doses (100-200 mg/day), the incidence of severe unwanted extracardiac side effects has decreased. High-dose maintenance regiments (daily dose ≥300 mg) are usually obsolete. This paper discusses recommendations regarding the monitoring of cardiac and extracardiac side effects of amiodarone. They need to be regarded by physicians using amiodarone to ensure long-term safety of amiodarone therapy.

216-28: Electrophysiological effects of amiodarone in patients with persistent atrial fibrillation

216-28: Electrophysiological effects of amiodarone in patients with persistent atrial fibrillation

Circadian changes in autonomic function in conscious rats with heart failure: Effects of amiodarone on sympathetic surge

Cardiovascular events are characterized by circadian periodicity with a peak prevalence during the awakening period, which suggests a morning surge in sympathetic activity. We developed an experimental system to determine circadian changes in heart rate (HR), blood pressure (BP), locomotor activity (Loc), respiratory rate and autonomic function in conscious, unrestrained rats. The effects of amiodarone on circadian variation of these variables were determined in rats with myocardial infarction and subsequent congestive heart failure (CHF). We continuously recorded BP, HR and Loc for 24 h in rats with CHF ( n = 16) or after a sham operation (Sham; n = 7). To determine circadian changes in sympathovagal balance, digitized BP and HR data throughout 24 h were analyzed based on maximum entropy. The study was repeated after 3 weeks of oral amiodarone (50 mg/kg/day) or saline administration. Baseline HR, mean BP, and Loc were higher in the dark period than in the light period (all p < 0.05) in both CHF and Sham rats, which is consistent with the circadian periodicity of nocturnal animals. Low-frequency components of diastolic BP variability (LFdp), an index of sympathetic tone, were significantly higher during the awakening period (16:00–20:00) than during the sleeping period (08:00–14:00), a finding analogous to the sympathetic morning surge in men. Amiodarone suppressed this transient increase in LFdp power during the awakening period. Our experimental system could detect sympathetic surge in conscious rats. Amiodarone suppressed the sympathetic surge, which could explain, at least in part, beneficial effects of amiodarone in patients with CHF.

Absence of change of signal-averaged electrocardiogram identifies patients with ventricular arrhythmias who are non-responders to amiodarone

Objectives: The aim of this study was to assess the ability of a non-invasive study, the signal-averaged ECG (SAECG), to predict the effect of amiodarone at ventricular level. Background: Amiodarone is the main drug drug used in the treatment of ventricular arrhythmias. Standard ECG does not detect any change in QRS complex resulting from amiodarone therapy. SAECG is more sensitive than ECG for detecting changes in QRS complex. Methods: The study examined the effects of amiodarone on SAECG in relation to the results of programmed ventricular stimulation in 68 patients with old myocardial infarction, spontaneous and inducible sustained ventricular tachycardia (VT). Results: Amiodarone prolonged the total QRS duration (dur) (129±28 vs. 140±30 ms, P<0.05) and low amplitude signal (LAS) dur (45±20 vs. 51±20 ms, P<0.1), whereas the root-mean-square voltage of the last 40 ms of QRS complex (RMS 40) was significantly reduced (20±16 vs. 14±9 μV, P<0.05). Changes in SAECG parameters did not differ significantly in patients in whom amiodarone prevented the inducibility of VT ( n=15) and those in whom VT remained inducible with amiodarone ( n=53), but in baseline QRS duration was significantly shorter in patients in whom amiodarone prevented the VT induction (118±26 vs. 133±28 ms, P<0.05). In patients in whom amiodarone did not prolong the cycle length of VT ( n=15), SAECG did not change significantly (QRS dur 131±29 vs. 132±27 ms, LAS 42±20 vs. 42±19 ms, RMS 40 22±14 vs. 19±11 μV). Comparison of the SAECG data in patients with no inducible VT and those with slowed VT differed significantly ( P<0.05) between the control state and the recording with amiodarone. Conclusions: The effects of amiodarone on VT inducibility are predicted by a shorter baseline QRS duration and the degree of drug-induced prolongation of filtered QRS duration. Amiodarone prolonged the QRS duration, LAS duration and decreased RMS 40; this effect was more important in patients with no inducible VT and in those with only slowed VT, than in patients with unchanged or accelerated VT. The absence of changes of QRS duration predicted the induction of a more rapid or not slowed VT with amiodarone with a sensitivity of 87% and a specificity of 83%. Therefore, SAECG appears as an useful and simple means to predict the effects of amiodarone in patients with myocardial infarction and VT.

Pulmonary Effect of Amiodarone in Patients With Heart Failure

Objectives. The purpose of this study was to evaluate the pulmonary effects of amiodarone in patients with heart failure, in those with chronic obstructive pulmonary disease (COPD) and in those undergoing a surgical procedure.Background. Amiodarone has been known to cause pulmonary complications, especially in those with COPD and in those undergoing a surgical procedure.Methods. Patients receiving vasodilator therapy for congestive heart failure were prospectively randomized to placebo or amiodarone at 800 mg/day for 14 days, 400 mg/day for 50 weeks and then 300 mg/day thereafter. Chest X-ray film and pulmonary function tests with diffuse capacity of carbon monoxide (DLCO) were obtained at baseline and annually. The power to detect a 20% difference in DLCO at 1 year exceeded 90% in all patients and in those with COPD (two-sided alpha = 0.05). The sample allowed a 75% power to detect pulmonary complications (1% vs. 5%) between the two treatment groups.Results. There was no difference in baseline characteristics between patients randomized to amiodarone (n = 269) or placebo (n = 250). The DLCO measurements at randomization were 18.3 ± 6.9 and 17.7 ± 7.6 ml/min per mm Hg for the amiodarone and placebo groups, respectively (p = 0.3). At 1 and 2 years, DLCO measurements were 17.7 ± 7.0 and 18.3 ± 7.7 ml/min per mm Hg for the amiodarone group and 17.9 ± 7.2 and 18.2 ± 7.2 for the placebo group, respectively. There were no significant differences between the groups, with corresponding p values of 0.73 and 0.96 at years 1 and 2, respectively. Among patients with COPD, DLCO measurements at randomization were 17.9 ± 6.7 and 15.8 ± 6.8 ml/min per mm Hg for the amiodarone and placebo groups, respectively. At years 1 and 2, DLCO measurements were 16.6 ± 7.8 and 17.8 ± 9.5 ml/min per mm Hg for the amiodarone group and 16.5 ± 6.6 and 16.3 ± 7.0 ml/min per mm Hg for the placebo group, with corresponding p values of 0.95 and 0.48, respectively. There was no difference in survival free of noncardiac or perioperative deaths between patients assigned to amiodarone or placebo. Pulmonary fibrosis was diagnosed in four patients (1.1%) treated with amiodarone and in three patients (0.8%) receiving placebo.Conclusions. Our study shows that amiodarone can be safely used, with an acceptable pulmonary toxicity, in patients with heart failure.

Acute electrophysiologic effects of amiodarone in patients with congestive heart failure

Patients with severe congestive heart failure (CHF) are at increased risk for atrial and ventricular arrhythmias and sudden cardiac death. Amiodarone is generally well tolerated by this population and has a low proarrhythmic potential. Because of its peculiar kinetics, amiodarone requires a prolonged loading period, necessitating lengthy hospitalizations in a monitored setting. This study was planned prospectively to assess the electrophysiologic effects of an abbreviated high-dose oral load of amiodarone in patients with severe CHF and known or suspected life-threatening ventricular arrhythmias. Fifteen patients with stable CHF and known or suspected life-threatening ventricular arrhythmias underwent baseline electrophysiologic study. The study was repeated after administration of oral amiodarone, 50 mg/kg/day for 2 days in 8 divided doses (mean dose 6.9 ± 0.4 g). After amiodarone administration, there was prolongation in virtually all conduction times and refractory periods. The prolongation of refractoriness was most pronounced in the atrium. Ventricular effective refractory periods demonstrated reverse frequency dependence. We conclude that a brief high-dose oral load of amiodarone is well tolerated by patients with CHF. It has marked and diffuse electrophysiologic actions suggestive of class I and III effects in addition to antiadrenergic and calcium blocking action. These effects are especially pronounced in the atrium.

Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia.

To assess the incidence of amiodarone-mediated aggravation of ventricular tachyarrhythmias or the development of new arrhythmias, such as torsade de pointes, in patients with cardiac disease. A MEDLINE literature search was done to identify articles published during the last 20 years that presented data on amiodarone-associated proarrhythmic events. The articles were divided into three categories: case reports, uncontrolled retrospective studies, and prospective controlled trials. In addition, articles were identified that examined the effects of amiodarone in patients with previously documented drug-induced torsade de pointes. 65 English-language case reports dealing with torsade de pointes during amiodarone therapy were found in the literature. In many of these cases, other predisposing factors for the development of torsade de pointes were reported. Seventeen studies each reported data from at least 50 patients who were treated with amiodarone for at least 6 months. Of 2878 patients included in these trials, 57 were reported to have a proarrhythmic event while exposed to the drug (an overall incidence of 2%). Torsade de pointes was observed in one third of these patients (an overall incidence of 0.7%). In seven placebo-controlled trials in which the drug was given as monotherapy, amiodarone was not associated with the development of a proarrhythmic event in any patient. Finally, in three reports, 31 patients with previous drug-mediated torsade de pointes were exposed to amiodarone during short- and long-term therapy. In none of these patients did a recurrent episode of torsade de pointes develop, despite the amiodarone-induced prolongation of the QTc interval, which was equivalent to that observed at the time of torsade de pointes during exposure to previous drugs. Amiodarone appears to be associated with a remarkably low frequency of proarrhythmic events and an incidence of torsade de pointes of less than 1.0%. This low arrhythmogenicity and the negligible negative inotropic effect of the compound constitute properties that make amiodarone particularly useful in treating high-risk patients prone to sudden cardiac death. Its potential to reduce this risk is currently being evaluated in several large prospective trials.

The reversal of amiodarone-induced perioperative reduction in cardiac systolic reserve in dogs

There is controversy about the myocardial depressant effects of amiodarone in patients with decreased cardiac function undergoing surgery. Some surgeons believe that these effects complicate the discontinuation of cardiopulmonary bypass. Accordingly, the hemodynamic effects of amiodarone were evaluated in two groups of anesthetized mongrel dogs that had undergone a median sternotomy. A control group of 10 dogs and an amiodarone-treated group (15 mg/kg per day for 3 weeks) of 10 dogs were studied, and serum (0.26 to 1.09 μg/ml) and tissue (cardiac 2.97 to 11.60 μg/ml) levels of amiodarone were measured by liquid chromatography.Hemodynamic measurements were made at baseline and after administration of routine therapeutic intravenous doses of dobutamine (10 μg/kg per min), isoproterenol (0.06 μg/kg per min) and epinephrine (2 μg/min). The amiodarone-treated dogs had a smaller increase in cardiac output compared with baseline than did control dogs. For each drug when the amiodarone-treated group was compared with the control group, increases in cardiac output (liters/min) were: dobutamine, 1.32 ± 0.24 versus 1.73 ± 0.31; isoproterenol, 0.84 ± 0.26 versus 1.43 ± 0.28; epinephrine, 0.25 ± 0.15 versus 0.44 ± 0.53. Amiodarone-treated dogs were also given higher doses of drugs, dobutamine (50 μg/kg per min), isoproterenol (1.2 μg/kg per min) and epinephrine (20 μg/min). Increases in cardiac output were 1.24 ± 0.24, 1.62 ± 0.25 and 2.82 ± 0.64, respectively. All cardiac outputs were significantly increased from the baseline values (p < 0.05) except those measured in the amiodarone group receiving the lower dose of epinephrine.Thus, amiodarone-treated dogs bave a relative reduction of perioperative cardiac systolic reserve. Reversal of this myocardial depression may require the use of drugs in excess of standard doses. Epinephrine was the most effective drug in this study. It produced improvements in cardiac output by increasing stroke volume, whereas changes secondary to dobutamine or isoproterenol were more closely related to changes in heart rate. These findings have implications for amiodarone-treated patients during and after cardiopulmonary bypass.

Clinical and electrophysiologic effects of amiodarone in patients with atrial fibrillation complicating the Wolff-Parkinson-White syndrome

The clinical and electrophysiologic effects of oral amiodarone were evaluated in 10 patients with a history of spontaneous atrial fibrillation and a rapid ventricular response, complicating the Wolff-Parkinson-White syndrome. Five patients developed ventricular fibrillation during an episode of atrial fibrillation. Seven patients underwent electrophysiology study and arrhythmia induction, both before and during chronic amiodarone treatment. During a mean 30 months of follow-up (range 8 to 59 months), no recurrences of atrial fibrillation or ventricular fibrillation were noted. One patient had recurrent supraventricular tachycardia and underwent surgery. One had serious and five had minor side effects. Arrhythmia suppression was assoclated with prolongation of the anterograde accessory pathway (+38%, p < 0.01) and atrial (+34%, p < 0.01) effective refeactory periods. Amiodarone also slowed the ventricular response to induced atrial fibrillation, prolonging the mean (+90%, p < 0.01) and minimum (+104%, p = 0.01) R-R intervals. Thus, amiodarone is a safe and effective alternative for arrhythmia prevention if surgery is inadvisable or is not desired by the patient.

Important differences between short- and long-term hemodynamic effects of amiodarone in patients with chronic ischemic heart disease at rest and during ischemia-induced left ventricular dysfunction

To assess and compare the hemodynamic profile of short-and long-term amiodarone administration in the same set of patients and to investigate hemodynamic mechanisms responsible for the antianginal effect of this drug, 10 patients with documented coronary artery disease and stable angina pectoris were studied. Simultaneous right heart catheterization and equilibrium radionuclide angiocardiography were performed at rest and during exercise before therapy (control), after a 5 minute intravenous infusion of 7.5 mg/kg of amiodarone and after 21.0 +/- 4.3 days of peroral therapy (10 days 800 mg/day, 7 days 400 mg/day and then 200 mg/day). After acute drug administration, ejection fraction, stroke index and systolic blood pressure decreased, whereas heart rate, left and right ventricular filling pressures and systemic vascular resistance increased. These effects were reversed after long-term therapy; all measured values returned to control levels except for heart rate, which decreased below the control value, and right atrial pressure, which remained slightly elevated. Amiodarone drug levels decreased from 4.8 +/- 1.8 after intravenous infusion to 1.2 +/- 0.6 mg/liter after long-term therapy. After adjustment for hemodynamic changes at rest, there were still significant reductions in heart rate, mean arterial pressure and rate-pressure product during exercise. It is concluded that the marked negative inotropic effect of amiodarone administered acutely in the dose applied calls for cautious use of this drug when administered intravenously. In contrast, long-term oral amiodarone therapy seems hemodynamically safe, even in patients with moderately depressed left ventricular function.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic effects of amiodarone in patients with refractory ventricular tachycardia

We examined the chronic electrophysiologic, systemic, and pharmacologic effects of chronic oral amiodarone therapy in 24 patients with refractory ventricular tachycardia and organic heart disease. Chronic amiodarone therapy resulted in significant increases in R-R interval (from 798 ± 182 msec to 912 ± 100 msec; P < 0.01), P-R interval (from 205 ± 66 msec to 221 ± 87 msec; P < 0.02), QRS duration (from 103 ± 24 msec to 115 ± 28 msec; P < 0.001), and Q-Tc interval (from 413 ± 48 msec to 470 ± 46 msec; P < 0.001). Significant increases were also noted in P-A interval (from 36 ± 14 msec to 45 ± 13 msec; P < 0.05), A-H interval (from 119 ± 61 msec to 141 ± 87 msec; P < 0.02), and H-V interval (from 52 ± 12 msec to 64 ± 11 msec; P < 0.001). Electrophysiologic parameters showing changes included corrected sinus node recovery time (from 271 ± 140 msec to 425 ± 122 msec; P < 0.01), the effective refractory period of the atrium (from 263 ± 32 msec to 321 ± 47 msec; P < 0.01), the effective refractory period of the atrioventricular node (from 348 ± 109 msec to 478 ± 157 msec; P < 0.001), the effective refractory period of the ventricle (from 253 ± 21 msec to 291 ± 28 msec; P < 0.001), the atrial pacing cycle length producing A-V nodal Wenckebach (from 436 ± 109 msec to 531 ± 95 msec; P < 0.001), and the functional refractory period of the A-V node (from 422 ± 68 msec to 499 ± 95 msec; P < 0.001). Programmed electrical stimulation performed after 21–88 (mean 31) days of treatment was highly predictive of long-term results if suppression of arrhythmia induction was demonstrated (12 patients) or if the spontaneous arrhythmia was reinduced (5 patients). Induction of morphologically new ventricular tachyarrhythmias was frequent (42%) but had a low spontaneous recurrence rate (10%) during follow-up. Systemic parameters on chronic amiodarone therapy showed significant increases in total T 4 and reverse T 3, with no change in pulmonary function tests or left ventricular ejection fraction. Serum amiodarone levels at chronic electrophysiologic study ranged from 0.44–4.10 (mean 1.3) μg/ml. Long-term follow-up (2.5 to 20 months) demonstrated a marked improvement in clinical symptoms and mortality, but a significant recurrence rate of a well-tolerated slower arrhythmia persisted. Adverse effects on chronic amiodarone therapy were frequent (10 patients) and often disabling but required drug discontinuation in only 1 patient.