Plasma Concentrations Of Amiodarone Research Articles

Pharmacokinetics of Amiodarone in hyperlipidemic and simulated high fat‐meal rat models

The objective of this study was to examine the effect of a high fat meal and hyperlipidemia on the pharmacokinetic behavior of amiodarone. To evaluate these effects, single doses of amiodarone were administered to rats i.v. (25 mg/kg) or orally (50 mg/kg). Some rats were rendered hyperlipidemic by intraperitoneal doses of poloxamer 407 followed by amiodarone i.v. In other normolipidemic rats, amiodarone was administered i.v. in a fasted state or after the administration of 1% cholesterol in peanut oil. Amiodarone plasma concentrations were considerably (>11-fold) increased in hyperlipidemia. Substantial decreases were noted in the clearance, volume of distribution and unbound fraction (11.6, 23 and 24.7-fold, respectively) in plasma of hyperlipidemic rats. Oral lipid caused a significant increase in plasma AUC(0-infinity) (1.38-fold) and a significant decrease in clearance (1.5-fold) of amiodarone after intravenous doses. Oral consumption of 1% cholesterol in peanut oil significantly increased the plasma AUC (1.83-fold) and bioavailability of amiodarone (1.31-fold) after oral doses. In determining oral bioavailability of lipophilic drugs such as amiodarone in food effect studies, in addition to the increase in absorption of drugs, other factors such as a decrease in clearance due to increases in lipoprotein levels should be taken into account.

Antiarrhythmic Properties of a Prior Oral Loading of Amiodarone in In Vivo Canine Coronary Ligation/Reperfusion-Induced Arrhythmia Model: Comparison With Other Class III Antiarrhythmic Drugs

Amiodarone, which is generally classified as class III antiarrhythmic drug in the Vaughan Williams classification, is widely used for the treatments of refractory arrhythmias. However, we previously reported that intravenous infusion of amiodarone (6.67 mg/kg per hour) did not suppress arrhythmias induced by coronary ligation/reperfusion in dogs. In this study, we examined effects of a prior oral loading of amiodarone on arrhythmias induced by coronary ligation/reperfusion. Sixteen female beagle dogs (8.5 – 12.5 kg) were divided into two groups; one group was given amiodarone (40 mg/kg, orally, n = 8), and the other was given empty gelatin capsules (n = 8) 2 h before the operation. Dogs were anesthetized with pentobarbital and artificially ventilated. The left chest was opened, and the left anterior descending coronary artery was ligated for 30 min and then reperfused. The mean plasma concentration of amiodarone was over 1.3 μg/ml. Although the prior oral loading of amiodarone did not change the QT interval, amiodarone suppressed the number of ectopic beats during coronary ligation and the incidence of ventricular fibrillation during coronary ligation and reperfusion periods (P<0.05 vs control group). In conclusion, a prior oral loading of amiodarone suppressed arrhythmias induced by coronary ligation/reperfusion with a dose that did not prolong the QT interval. This antiarrhythmic property of amiodarone is different from those of the other class III drugs in that antiarrhythmic effects were accompanied by QT prolongation in our all previous studies.

Phenylacetylglycine, a putative biomarker of phospholipidosis: Its origins and relevance to phospholipid accumulation using amiodarone treated rats as a model

Amiodarone was given to male Sprague–Dawley rats at a dose of 150 mg kg−1 day−1 for 7 consecutive days to induce phospholipidosis in the lungs of treated rats. Amiodarone was given alone or concurrently with phenobarbitone. Animals given amiodarone had raised total phospholipid in serum, lung and lymphocytes, and elevated lyso(bis)phosphatidic acid (LBPA) in all tissues. Urinary and plasma phenylacetylglycine (PAG) and hepatic portal:aortal phenylacetate (PA) ratio were increased, whereas hepatic phenylalanine hydroxylase (PAH) activity and plasma phenylalanine:tyrosine ratio were not affected. Phenobarbitone treatment increased hepatic total P450 content and induced 7-pentoxyres-orufin O-dealkylatian (PROD) activity, as expected, but had no effect on any other biochemical parameter. Plasma amiodarone concentration was reduced in rats co-administered both drugs and phospholipid accumulation in target tissues was attenuated compared with rats treated with amiodarone alone. However, phenobarbitone co-administration failed to alter the magnitude of response with regards to urinary PAG excretion and plasma concentration of its precursors after amiodarone treatment. Increased intestinal absorption of PAG precursors probably resulted in the raised urinary PAG after amiodarone treatment. Urinary PAG correlated weakly with serum, lymphocyte and lung phospholipids. However, urinary PAG excretion was similar in rats dosed solely with amiodarone or in combination with phenobarbitone, despite the fact that the degree of phospholipid accumulation was far less in rats given the combined treatment. Nevertheless, urinary PAG was raised only in animals exhibiting abnormal phospholipid accumulation in target tissues and may thus be useful as a surrogate biomarker for phospholipidosis.

N-Nitrosylation potential of mono- N-desethylamiodarone at physiological pH

Amiodarone (AMI) is frequently used for the treatment of supraventricular arrhythmias. The parent drug is rapidly dealkylated to mono- N-desethylamiodarone (MDEA) and the plasma concentrations of AMI and MDEA are comparable. MDEA is a secondary amine and may thus undergo formation to the corresponding N-nitrosamine in combination with coadministered nitrovasodilators. Previous studies have shown that nitrovasodilators release the vasoactive NO which may nitrosylate thiol or secondary amine groups in aqueous solutions. Therefore, the nitrosylation potential of MDEA at physiological pH was investigated. N-Nitroso-monodesethylamiodarone (NO-MDEA) was synthesized, characterized and used as a reference product for the detection of the corresponding N-nitrosamine. HPLC and NMR results have shown that the NO-MDEA product is an equilibrium of two configurational isomers ( syn and anti). NO-release was generated by sodium nitroprusside (SNP) which was exposed to light. The formation to NO-MDEA was assayed by HPLC-UV. It has been found that MDEA is nitrosylated in the higher nanomolar range and that varying oxygenation of the reaction mixture did not significantly affect the reaction yields. The addition of thiols such as serum albumin (0.6 mM), l-cysteine (2.5 mM) or N-acetylcysteine (2.5 mM) inhibited the NO-MDEA formation indicating that they may prevent N-nitrosamine formation in vivo. However, as S-nitrosothiols may also release NO , in long term exposure to elevated levels of nitric oxide the nitrosylation of secondary amines may be taken into account.

Comparison of Plasma Concentrations for Two Amiodarone Products

BACKGROUND:A generic formulation of amiodarone was recently approved by the Food and Drug Administration based on single-dose equivalence data. Because amiodarone has complex pharmacokinetic properties, a narrow therapeutic range, and a significant adverse effect profile, concern about equivalency persists.OBJECTIVE:To compare steady-state plasma concentrations of the brand-name reference product Cordarone with the AB-rated generic formulation, Pacerone, in patients exposed to both products.METHODS:A retrospective analysis was performed at the Minneapolis Veterans Affairs Medical Center on 138 patients who were taking a stable dose of amiodarone before and after an amiodarone generic product substitution.RESULTS:Seventy-seven patients had steady-state plasma concentrations documented for each product at the same dose. The mean steady-state plasma concentrations of amiodarone were not significantly different for Cordarone compared with Pacerone (1.07 ± 0.48 vs. 1.19 ± 0.66 μg/mL, respectively); similarly, the concentrations of the active metabolite (desethylamiodarone) did not differ (0.95 ± 0.30 vs. 0.96 ± 0.49 μg/mL, respectively). However, the variability in plasma drug concentrations between products was increased as compared to variability within each product.CONCLUSIONS:This study indicates that comparable steady-state concentrations can be achieved with a change in formulation from Cordarone to Pacerone. However, individual responses vary, suggesting that monitoring of plasma concentrations is prudent 1–3 months after any change from one product to another.

Bioavailability of amiodarone tablets administered with and without food in healthy subjects

The tablet form of amiodarone is indicated for the treatment of recurrent ventricular fibrillation or hemodynamically unstable ventricular tachycardia. It is recommended that the tablet be taken with meals in cases of gastrointestinal intolerance. However, the effect of food on its bioavailability is unknown. The primary objective of this study was to determine the effect of food on the bioavailability of amiodarone. This was a 2-period crossover study conducted in 30 healthy male subjects. Subjects were randomly assigned to 1 of 2 sequences in which the following 2 treatments were administered: (1) a single-dose of amiodarone (three 200-mg Cordarone tablets) after an overnight fast, and (2) the same dose immediately after a standard high-fat breakfast. Plasma concentrations of amiodarone and desethylamiodarone (DEA) were measured for 6 weeks after each dose. Food enhanced the extent of absorption, resulting in a peak concentration (Cmax) and area under the curve (AUCT) 3.8 and 2.4 times the respective values under fasting conditions. Food also significantly increased the rate of absorption, reducing the time (tmax) to Cmax from 7.1 to 4.5 hours. The effect of food on DEA levels was significant but less pronounced. An in vitro dissolution study confirmed a marked difference between amiodarone release under simulated fed and fasting conditions. Thus, food significantly enhances both the rate and extent of absorption of amiodarone, which is attributed partially to the effect of food on drug release from its formulation. Therefore, it is recommended that amiodarone tablets be taken consistently with meals.

Amiodarone-Induced thyroid dysfunction and ventricular tachyarrhythmias during long-term therapy in Japan.

In 232 Japanese patients receiving long-term amiodarone therapy for life-threatening ventricular tachyarrhythmias, hyperthyroidism and hypothyroidism developed in 29 patients (12.5%) and 25 patients (10.8%), respectively. In patients with hyperthyroidism, the recurrence of sustained ventricular tachycardia was significantly higher with thyrotoxicosis than in the euthyroid period (31% vs 3%, p<0.01). Holter monitoring showed that the average heart rate and ventricular premature complexes significantly increased with hyperthyroidism. On the other hand, there was no increase in the recurrence of ventricular tachyarrhythmia with hypothyroidism. There was no change in the dose or the plasma concentration of amiodarone or desethylamiodarone in the euthyroid period or when hyperthyroidism or hypothyroidism manifested. It is important to monitor for arrhythmia when hyperthyroidism develops during amiodarone therapy.

Influence of CYP3A Metabolizer Status on the Pharmacokinetics and Pharmacodynamics of Amiodarone

The present work was designed to determine whether the individual differences in pharmacokinetics and pharmacodynamics of amiodarone and its N-desethyl metabolite are related to cytochrome CYP3A metabolizer status. 12 cardiac patients with inducible ventricular tachyarrhythmias during the baseline electrophysiologic study were enrolled in this study. Urinary 24-hour excretion of 6 beta-hydroxycortisol (6 beta-OHC and the ratio of 6 beta-hydroxycortisol to urinary free cortisol (6 beta-OHC/UFC) were measured before the first amiodarone administration. Trough plasma concentrations of amiodarone and N-desethylamiodarone (N-DEA) were measured after 79 +/- 11 days (2nd period) and after 182 +/- 25 days (3rd period). Electrophysiologic effects of amiodarone therapy were established with serial electrophysiologic studies in 9 of these patients at the baseline and after 79 +/- 11 days (during the second period). Both the 6 beta-OHC excretion and 6 beta-OHC/UFC ratio varied approximately 6-fold between the patients. We found significant inverse correlation between the 6 beta-OHC excretion and the trough plasma concentrations of amiodarone at the time of the 3rd period (rs = -0.58, p < 0.05). Similarly, there was correlation between the 24-hour urinary 6 beta-OHC excretion and trough plasma concentrations of amiodarone during the 3rd period (rs = -0.64, p < 0.025). We were unable to detect any association between CYP3A activity and amiodarone pharmacodynamics. This study points toward important information value of CYP3A metabolizer status in the context of therapeutic drug monitoring of amiodarone.

Amiodarone concentration in human myocardium after rapid intravenous administration.

Intravenous amiodarone has been found useful in the emergent management of life-threatening arrhythmias. Experimental studies have shown that its electrophysiologic effects are proportional to its myocardial concentration. However, early after its intravenous administration, the extent of the concentration of amiodarone in the human myocardium, the site of its action, is not well known. This study was performed to measure the myocardial concentration of amiodarone shortly after rapid intravenous injection. Amiodarone, 150 mg, was injected over 15 seconds intravenously into 9 patients, 52 +/- 9 years of age, weighing between 65 and 98 kg (mean = 81 +/- 15.6). All patients suffered from idiopathic dilated cardiomyopathy, were in NYHA functional class II, and the mean left ventricular ejection fraction was 21 +/- 6%. Right ventricular endomyocardial biopsy, required for the establishment of the diagnosis, was performed 2-5 minutes after drug administration for measurements of its myocardial concentration. Plasma concentrations of amiodarone were also measured at 2, 5, 10, and 60 minutes, and measurements of right heart hemodynamics were made 2 and 10 minutes after the injection. At 2.5 +/- 1.2 minutes after amiodarone administration, the mean myocardial concentration was 95.7 +/- 67.4 micrograms/g (range, 16-175), and the myocardial/plasma amiodarone ratio was 5.05 +/- 5.01. Heart rate increased from 82 +/- 17 to 90 +/- 13 beats/min (P < 0.05), and systolic blood pressure decreased from 132 +/- 19 to 118 +/- 17 mmHg (P < 0.03). The extent of myocardial fibrosis was 5.13 +/- 6.55% (range, 0.3-17.5%). Intravenous amiodarone (150 mg) accumulates rapidly in the human myocardium. This pharmacokinetic characteristic probably explains its acute efficacy in the treatment of life-threatening arrhythmias.

Myocardial amiodarone concentrations after short- and long-term treatment in patients with end-stage heart failure.

Pharmacokinetics and tissue concentrations of amiodarone may vary considerably in end-stage heart failure, but may be crucial for treatment efficiency and antiarrhythmic drug therapy. This study was undertaken to determine plasma amiodarone and desethylamiodarone concentrations and to determine whether they correlate with myocardial concentrations in explanted hearts from patients with end-stage heart failure. Eight patients with idiopathic dilated cardiomyopathy and normal coronary arteries were included in the present study. Myocardial tissue samples (seven sites) and epicardial fat were taken from each explanted heart, and drug concentrations of amiodarone and desethylamiodarone were determined. In addition, plasma drug levels were measured and compared with the myocardial amiodarone/desethylamiodarone concentrations. The mean cumulative amiodarone dose was 91 g and the mean plasma concentrations of amiodarone and desethylamiodarone were 0.68 and 0.84 microg.ml(-1), respectively. The tissue concentrations of amiodarone amounted to 13.2 and 28.3 microg.g(-1), respectively, in the atria and to 13.0 and 40.8 microg.g(-1), respectively, in the ventricles. The distribution of the drug and its metabolite were similar in the right and left ventricles. There was a good correlation between myocardial concentration of amiodarone and desethylamiodarone and the cumulative ingested dose of amiodarone. Tissue drug concentrations correlated only poorly with plasma amiodarone or desethylamiodarone levels. The highest drug levels were measured in the epicardial fat tissue, where the ratio of amiodarone 105 microg.g(-1) to desethylamiodarone 32 microg.g(-1) was reversed (3.3 compared with 0.29 in the ventricles). Thus, amiodarone concentrations in epicardial fat were approximately 10 times higher than myocardial and 150 times higher than plasma levels. Our data confirm the slow equilibrium of amiodarone and desethylamiodarone concentrations between plasma and myocardium. Myocardial tissue concentrations of desethylamiodarone and, to a lesser degree, amiodarone correlate with the cumulative ingested dose of amiodarone. Monitoring of the total cumulative dose may be more relevant clinically than monitoring plasma levels. These results support the clinical practice of reducing the maintenance dose of amiodarone in patients who are on long-term treatment.

Relation Between Amiodarone and Desethylamiodarone Plasma Concentrations and Ventricular Defibrillation Energy Requirements

The main finding of this prospective, controlled study is that amiodarone and desethylamiodarone plasma concentrations < 1 mg/L are associated with a 23% increase in the acute defibrillation energy requirement and with a 31% increase in the requirement for a subcutaneous patch or array. The defibrillation energy requirement does not correlate with the plasma concentrations of amiodarone, desethylamiodarone, amiodarone plus desethylamiodarone, or with the duration or daily dosage of amiodarone therapy.

Comparative evaluation of amiodarone-induced phospholipidosis and drug accumulation in Fischer-344 and Sprague-Dawley rats

Amiodarone (AD) and its major metabolite, desethylamiodarone (desethylAD), are both phospholipogenic. The present study was undertaken to evaluate the comparative susceptibilities of male Fischer-344 and Sprague-Dawley rats to AD-induced phospholipidosis in alveolar macrophages (AMs), liver and kidney tissue and the concomitant accumulation of AD and desethylAD in these cells, tissues and plasma. Rats were administered AD (100 mg/kg/day, p.o.) for 1 week. Plasma concentrations of AD and desethylAD were approximately 4- and 12-fold higher, respectively, in Fischer-344s compared to Sprague-Dawleys 24 h after the last dose. AD and desethylAD levels in AMs were approximately 12- and 25-fold higher, respectively, in Fischer-344s than Sprague-Dawleys. In the liver and kidney, levels of both compounds were also significantly higher in Fischer-344s than Sprague-Dawleys. Ultrastructural features indicative of phospholipidosis were not observed consistently in any tissue except AMs from treated Fischer-344s. AM total phospholipid increased nearly 5-fold in Fischer-344s, while Sprague-Dawleys showed no increase over control. AMs from both strains incubated with 10 μM AD or desethylAD in vitro were not significantly different in their accumulation of the compounds. When incubated with AD or desethylAD, the lysosomal phospholipases A 1 partially purified from AMs of both strains were equally sensitive to inhibition as measured by the drug concentration giving 50% inhibition in activity (IC 50). The results of this study indicate that at the same administered dose, AD and desethylAD, accumulate to higher tissue levels and are more phospholipogenic in male Fischer-344 rats than in male Sprague-Dawley rats. The basis for the high susceptibility of Fischer-344 rats to AM-induced phospholipidosis is unknown at present but appears not to be related to biochemical or cellular features of the AMs.

Acute antiarrhythmic effects of intravenously administered amiodarone on canine ventricular arrhythmia.

We investigated antiarrhythmic effects of intravenously (i.v.) administered amiodarone using four canine ventricular arrhythmia models. Bolus injections of amiodarone 3 mg/kg suppressed epinephrine (EPI)-induced arrhythmia and 5-mg/kg bolus injections of amiodarone suppressed digitalis- and two-stage coronary ligation-induced arrhythmia models, but the antiarrhythmic effects did not correlate with the amiodarone plasma concentrations. The infusion of amiodarone 6.67 mg/kg/h did not prolong the QTc interval or produce antiarrhythmic effects in coronary ligation and reperfusion experiments. Amiodarone significantly decreased the mean blood pressure (MAP), and this effect lasted throughout the observation period. The results indicate that the antiarrhythmic effects of intravenously administered amiodarone may not be due to its class III action, but to other actions, such as class I, II and IV actions.

Serial pulmonary function tests in patients treated with low-dose amiodarone

Problems with pulmonary toxicity have emerged as a potentially limiting factor for amiodarone use. We studied 24 consecutive patients receiving low-dose (i.e., ≤400 mg/day) amiodarone for refractory tachyarrhythmias. Serial pulmonary function test results were correlated with daily dose, serum concentration, cumulated dose, and duration of amiodarone treatment to determine the effect of the drug on pulmonary function. The mean follow-up period for the 24 patients, who completed baseline and follow-up evaluations, was 47 months (range 31 to 75 months). In 22 of the 24 patients a reduction in total diffusion capacity (T LCO) was noted after treatment; for all 24 patients the mean reduction in T LCO was 12.9% of the predicted value (SD 9.6% predicted) ( p < 0.02). The decrease in T LCO was found to be significantly related to an increasing cumulated dose of amiodarone ( p = 0.007), whereas the reduction in T LCO was found to be unrelated to sex, age, underlying heart disease, arrhythmia, daily dose of amiodarone, duration of treatment, plasma concentration of amiodarone and desethylamiodarone, and pretreatment pulmonary function abnormalities. Seven (29%) of the patients had asymptomatic pulmonary toxicity with a decrease in T LCO ≥ 20% of the predicted value. In conclusion, long-term treatment with low-dose amiodarone was associated with a substantial decrease in T LCO, a higher cumulative dose of the drug was related to an increasing reduction in T LCO, and protreatment pulmonary function abnormalities were not predictive for development of subclinical pulmonary toxicity.

Antiadrenergic cardiovascular adverse effects of high-dose amiodarone loading regimen

A 55-year-old patient with inferior wall infarction was treated effectively for ventricular tachycardia with high-dose oral amiodarone loading regimen (5 g within 16 hours). Serial pharmacokinetic studies demonstrated a rapid temporary increase in amiodarone plasma concentration to a maximum of 3.40 μg/ml 17 hours after initiation of therapy followed by a return to normal plasma concentration within 8 hours. During fast drug evasion the patient developed acute low-output syndrome with syncope successfully controlled with intravenous catecholamine administration. Our findings suggest that the cardiovascular collapse was caused by the non-competitive adrenoceptor antagonism of amiodarone resulting in secondary autonomic insufficiency.

Efficacy and safety of short intravenous amiodarone in supraventricular tachyarrhythmias

The safety and efficacy of short intravenous therapy with amiodarone were evaluated in 44 patients (24 males, 20 females), aged 21–84 years, with supraventricular tachyarrhythmias newly arisen in less than 24 hours. The study group consisted of 15 patients with paroxysmal supraventricular tachycardia, 8 patients with atrial flutter and 21 patients with atrial fibrillation. They were treated with a single infusion of amiodarone up to 2 hours after the restoration of a stable sinus rhythm, or up to a maximum dose of 2400 mg in 24 hours. Our study shows that 88.6% of all supraventricular tachyarrhythmias reverts to sinus rhythm in less than 24 hours: 100% of paroxysmal supraventricular tachycardia, 75% of atrial flutter, and 85.7% of atrial fibrillation. Intravenously administered amiodarone proves to take effect rapidly (0.5 to 22 hours). The plasma amiodarone concentrations at sinus rhythm restoration showed a wide range (405–3800 ng/ml). Piecewise analysis suggested that the probability of sinus rhythm was 14.4-fold greater in paroxysmal supraventricular tachycardia. No linear statistical relationship was detectable between the log-dose-body mass index and log-QTc. Total amiodarone dose and left atrial volume are inversely correlated with a statistically significant difference. The toxicity in our short intravenous course with amiodarone was not relevant. We conclude that short high-dose intravenous amiodarone shows efficacy and safety in all newly occurring supraventricular tachyarrhythmias.

Chylous Transport of Amiodarone

A patient receiving amiodarone for longstanding ventricular dysrhythmias presented with idiopathic chylothorax. During drainage of chylothorax for pleurodesis, serial plasma amiodarone concentrations declined while pleural fluid concentrations remained stable. Chylous transport of amiodarone and other lipid-bound drugs should be recognized to avert complications during chylothorax drainage.

Influence of amiodarone on genetically determined drug metabolism in humans

Amiodarone has been shown to interact with the nongenetically determined hepatic elimination of several drugs, including phenytoin and digoxin. Its influence on genetically determined metabolic pathways has not been studied in humans. We examined the effects of oral amiodarone therapy on the genetically determined metabolism of isoniazid (N-acetyltransferase), mephenytoin (cytochrome P450MEPH), and dextromethorphan (CYP2D6). Eight patients with arrhythmias were studied before and 76 +/- 16 days after amiodarone (loading dose of 1000 mg/day for 10 days followed by a maintenance dose of 200 to 400 mg/day). Genetically determined enzyme activity was assessed indirectly by calculating the metabolic ratio (parent drug/metabolite in 8-hour urine for CYP2D6 and P450MEPH and N-acetylisoniazid/isoniazid in plasma for N-acetyltransferase) after oral administration of the parent compounds. At the time of phenotyping, plasma concentrations of amiodarone and N-desethylamiodarone were 0.66 +/- 0.35 micrograms/ml and 0.65 +/- 0.26 micrograms/ml, respectively. Amiodarone increased the log(metabolic ratio) of dextromethorphan from a median of -2.5 (range, -2.9 to -2.0) to a median of -1.9 (range, -2.5 to -1.5; p less than 0.02) but did not alter the metabolic ratio of mephenytoin or isoniazid. The amount of dextromethorphan excreted in urine increased from a median of 0.084 mumol/8 hours (range, 0.041 to 0.161 mumol/8 hours) to a median of 0.205 mumol/8 hours (range, 0.064 to 0.288 mumol/8 hours; p less than 0.02) and the amount of its metabolite (dextrorphan) tended to decrease from a median of 26 mumol/8 hours (range, 15 to 37 mumol/8 hours) to a median of 20 mumol/8 hours (range, 7 to 27 mumol/8 hours; p less than 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between myocardial amiodarone concentration and antiarrhythmic effect in dogs with myocardial infarction and electrically induced ventricular arrhythmias

The relationship between the antiarrhythmic effect of amiodarone and its myocardial concentration was studied in dogs with 1-week-old myocardial infarction and reproducibly inducible sustained ventricular tachycardia or ventricular fibrillation. Three groups of animals (n = 10/group) received amiodarone, 40 mg.kg-1.day-1 (low-dose amiodarone), amiodarone 60 mg.kg-1.day-1 (high-dose amiodarone), or no amiodarone (control group). After 1 week of treatment, programmed electrical stimulation was repeated, and plasma and myocardial amiodarone and desethylamiodarone concentrations were measured. In the control group, sustained ventricular tachycardia or ventricular fibrillation was induced in six dogs (p = NS) when compared with baseline data. In the low-dose amiodarone group, sustained ventricular tachycardia or ventricular fibrillation was induced only in two dogs after 1 week of treatment (p less than 0.01 vs. baseline data). Sustained ventricular tachycardia or ventricular fibrillation was induced in seven dogs after treatment with high-dose amiodarone (p = NS vs. baseline data). Plasma amiodarone concentration in the low-dose amiodarone group (2.54 +/- 1.95 micrograms/mL) was significantly less (p less than 0.01) than that in the high-dose amiodarone group (4.64 +/- 1.66 micrograms/mL). Similarly, the plasma desethylamiodarone in the low-dose amiodarone group (0.32 +/- 0.16 microgram/mL) was significantly less (p less than 0.001) than that in the high-amiodarone dose group (0.56 +/- 0.23 microgram/mL). The myocardial amiodarone concentration in the low-dose amiodarone group (49.7 +/- 23.1 micrograms/g) was significantly lower (p less than 0.001) than that in the high-dose group (98.4 +/- 32.1 micrograms/g).(ABSTRACT TRUNCATED AT 250 WORDS)

An Increase in Plasma Cholesterol Independent of Thyroid Function during Long-Term Amiodarone Therapy

To determine whether long-term amiodarone treatment is associated with a rise in plasma cholesterol, and, if so, to analyze its relation with thyroid function. Consecutive entry trial, including cardiac patients who initiated amiodarone medication but excluding those with abnormal thyroid function (defined as peak thyroid-stimulating hormone [TSH] response to thyrotropin-releasing hormone [TRH] less than 2.8 or greater than 22.0 mU/L) either before or during amiodarone treatment. Twenty-three patients who remained euthyroid were studied. Oral administration of amiodarone (mean duration of treatment, 17 months; range, 6 to 30 months). Fasting plasma lipids, thyroid hormones, and peak TSH to TRH values were recorded before and every 6 months during amiodarone treatment. Plasma cholesterol gradually increased from 5.1 +/- 0.2 mmol/L before treatment to 6.9 +/- 0.8 mmol/L after 30 months of amiodarone medication (P less than 0.001); the peak TSH response to TRH did not change. When age- and sex-specific reference values were applied, 30% of the patients had cholesterol values above the 75th percentile before treatment; this number rose to 69% after 2 years of treatment. The rise in plasma cholesterol was associated with an equal increase in apoprotein B. Plasma cholesterol was not related to the daily dose of amiodarone or to plasma concentrations of amiodarone, desethylamiodarone, thyroxine (T4), triiodothyronine (T3), or reverse triiodothyronine (rT3). Linear regression analysis indicated a positive relation between plasma cholesterol and the cumulative dose of amiodarone (r = 0.25, P less than 0.05). Long-term amiodarone treatment is associated with a dose-dependent increase in plasma cholesterol that is independent of thyroid function.