Myocardial Drug Concentrations Research Articles

Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake

Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium. Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before undergoing coronary surgery in the perhexiline arm of a randomized controlled trial. Perhexiline concentrations in plasma and heart tissue were determined by HPLC. Atrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24 mg l⁻¹ (IQR 0.12-0.44), the median atrial concentration was 6.02 mg kg⁻¹ (IQR 2.70-9.06) and median ventricular concentration was 10.0 mg kg⁻¹ (IQR 5.76-13.1). Atrial (r² = 0.76) and ventricular (r² = 0.73) perhexiline concentrations were closely and directly correlated with plasma concentrations (both P < 0.001). The median atrial : plasma ratio was 21.5 (IQR 18.1-27.1), ventricular : plasma ratio was 34.9 (IQR 24.5-55.2) and ventricular : atrial ratio was 1.67 (IQR 1.39-2.22). Using multiple regression, the best model for predicting steady-state atrial concentration included plasma perhexiline, heart rate and age (r² = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r² = 0.84). This study demonstrates that plasma perhexiline concentrations are predictive of myocardial drug concentrations, a major determinant of drug effect. However, net myocardial perhexiline uptake is significantly modulated by patient age, potentially via alteration of myocardial:extracardiac drug uptake.

Epicardial application of an amiodarone-releasing hydrogel to suppress atrial tachyarrhythmias

Background Amiodarone is currently the most effective antiarrhythmic drug for sinus rhythm maintenance. However, due to serious extracardiac adverse effects, prophylactic amiodarone therapy is only appropriate for patients at high risk for postoperative atrial fibrillation (AF). We hypothesized that epicardial application of an amiodarone-releasing hydrogel would produce therapeutic myocardial drug concentrations, while systemic levels would remain low. Methods Goats were fitted with right atrial epicardial patch electrodes. A poly(ethylene glycol)-based hydrogel with amiodarone (1 mg/kg bw) ( n = 10) or without drug ( n = 6) was applied to the right atrial epicardium. Atrial effective refractory period (AERP), conduction time and atrial response to burst pacing (rapid atrial response, RAR) were assessed up to 28 days in awake goats. Myocardial, plasma and extracardiac tissue amiodarone concentrations were analysed by high-performance liquid chromatography. Results The amiodarone-loaded hydrogel produced therapeutic drug concentrations in the right atrium up to 21 days after application. In this period, AERP and conduction time were prolonged, while RAR inducibility was reduced ( P < 0.05) compared to animals treated with drug-free hydrogel. Mean amiodarone concentrations in the right atrium were 1 order of magnitude higher than in other heart chambers and 2 orders of magnitude higher than in extracardiac tissues. Plasma amiodarone levels remained below the detection limit (< 10 ng/mL) during the 28-day follow-up. Conclusions Epicardial application of an amiodarone-releasing hydrogel reduces atrial vulnerability to tachyarrhythmias up to 3 weeks, while extracardiac drug levels remain low. Therefore, amiodarone-releasing hydrogel could be applied during cardiac surgery to prevent postoperative AF at minimal risk for extracardiac adverse side effects.

Abstract 4098: Epicardial Amiodarone-Releasing Hydrogel Reduces Inducibility of Atrial Fibrillation in Goats

Amiodarone (AM) is one of the most effective anti-arrhythmic drugs to prevent postoperative atrial fibrillation (AF). However, due to systemic side effects, prophylactic AM therapy is only appropriate for patients at high risk for postoperative AF. This study addressed the hypothesis that local epicardial delivery of AM produces therapeutic myocardial drug concentrations, while systemic levels remain low. Goats (n=14) were instrumented with right atrial epicardial patch electrodes, and a PEG-based hydrogel with AM (1 mg/kg bw) (n=9) or without drug (n=5) was applied to the right atrial epicardium. AF inducibility was assessed up to 28 days in awake goats by applying burst stimuli. Myocardial and plasma AM concentrations were analysed by HPLC. AM-hydrogel produced higher subepicardial than subendocardial drug concentrations, which both remained therapeutic up to 21 days after hydrogel application (fig. 1a ). In this period, AF inducibility was significantly lower in the AM-hydrogel group compared to hydrogel alone (fig. 1b ; p&lt;0.05). Plasma AM and metabolite levels were below detection limits (&lt;30 ng/L) during the 28-day follow-up. Epicardial AM-releasing hydrogel produces sufficient myocardial drug concentrations to reduce AF inducibility up to 3 weeks, whereas plasma drug levels remain undetectably low. This study demonstrates that local delivery of anti-arrhythmic drugs is a feasible approach to obtain therapeutically effective myocardial drug concentrations, while minimizing risk for systemic side effects. Locally applied AM-releasing hydrogel may be a novel strategy to prevent postoperative AF. Figure 1a. Amiodarone Distribution in Right Atrium (n=5) Figure 1b. AF Inducibility After Hydrogel Application (mean + SD)

Myocardial Effect Compartment Modeling of Metoprolol and Sotalol: Importance of Myocardial Subsite Drug Concentration

□ We have recently reported the time course of acute myocardial drug uptake and simultaneous pharmacodynamic effects for metoprolol (4mg; n=12) and sotalol (20mg; n=10) in patients with ischemic heart disease. The acute pharmacodynamic effects of the two drugs included reductions in both spontaneous heart rate and the contractile index peak positive rate of left ventricular pressure rise and prolongation of the electrocardiographic PR interval, all of which exhibited an equilibration delay compared with myocardial drug content. The objective of the current study was to analyze the relationship between myocardial drug content and effect for both metoprolol and sotalol using an effect compartment model, to examine the potential for the two drugs to share a common subsite of action in the myocardium. The time course of myocardial drug content was best described by a one-compartment model for metoprolol and a two-compartment model for sotalol. A linear pharmacodynamic model, relating the amount of drug at the effect-site (Ae) with each of the three effects, was used in the effect compartment modeling. The slope of each of these effects as a function of Ae was considerably flatter for sotalol than for metoprolol, reflecting the relative β-adrenoceptor antagonistic potencies of the two drugs. The exit rate constant from the effect compartment (Keo) did not differ significantly from each other or from the exit rate constant from the “peripheral” compartment (K21) for sotalol. The results suggest that the effect compartment within the myocardium for both drugs may correspond to a “peripheral” compartment, even though a “peripheral” pharmacokinetic compartment for myocardial metoprolol content was not apparent. Thus, the effect compartment for many cardioactive drugs may correspond to a pharmacokinetically “peripheral” compartment, irrespective of localization of effect to a small (e.g. sinoatrial node) or large (e.g. ventricular myocardium) region of the heart.

I.V. BOLUS ADMINISTRATION OF SUBCONVULSIVE DOSES OF LIGNOCAINE TO CONSCIOUS SHEEP: MYOCARDIAL PHARMACOKINETICS

Mass balance principles were used to study the myocardial pharmacokinetics of lignocaine in conscious sheep. After i.v. bolus doses of lignocaine 50, 75 or 100 mg, arterial lignocaine concentrations reached a peak in approximately 16 s and these increased linearly with dose. Coronary sinus concentrations reached a peak between 83 and 129 s and the values showed poor relationships with dose. Net myocardial lignocaine uptake lasted for approximately 60 s--this was much shorter than the reported initial distribution half-life of lignocaine. The maximum rate of uptake was proportional to both the dose and the peak arterial lignocaine concentrations. At 15 min, the myocardial lignocaine concentrations were 46 (SD 22)% of their peak values. Pseudo-equilibrium between blood and myocardial lignocaine concentrations was not observed. It is concluded that, despite the myocardium being very well perfused, lignocaine myocardial concentrations were not well represented by blood lignocaine concentrations for at least 15 min. A greater understanding of the determinants of myocardial drug concentrations is required.

Prediction of Acute Myocardial Disposition of Antiarrhythmic Drugs

Using peripheral blood concentration and myocardial content data (from coronary sinus catheterization and serial determination of transmyocardial drug concentration gradients) from a previous clinical study of the antiarrhythmic drugs lidocaine and mexiletine, we tested the hypothesis that two prospectively defined models of myocardial drug disposition could be used to predict myocardial drug content, in the first 30 min following bolus iv injection, from peripheral blood concentrations alone. Compartmental analysis of peripheral blood concentration data from prolonged blood sampling (three-compartment model) and from the first 30 min after drug injection (two-compartment model) was used to calculate drug content, during the first 30 min, in the second compartment of each of the models. The time course of calculated compartmental content was similar to that of the measured myocardial content in 16 of the 18 patients studied, although there were some differences in the time of peak content. This relatively noninvasive method may therefore be useful in predicting the time course of myocardial drug content after acute iv drug administration.

The antiarrhythmic efficacy of amiodarone and desethylamiodarone, alone and in combination, in dogs with acute myocardial infarction.

Antiarrhythmic activity of amiodarone's desethyl metabolite, which accumulates during oral amiodarone therapy, has been postulated to explain the delayed onset of antiarrhythmic effects during long-term amiodarone therapy. To determine their relative antiarrhythmic efficacy, amiodarone and its desethyl metabolite, desethylamiodarone, were administered to mongrel dogs with ventricular tachycardia 24 hr after ligation of the left anterior descending coronary artery. Cumulative doses of amiodarone, desethylamiodarone, a combination of amiodarone and desethylamiodarone, or the vehicle for drug administration were given at 1 hr intervals. Both amiodarone and desethylamiodarone suppressed ventricular arrhythmias in a dose-dependent fashion. The metabolite, however, was more potent with a 50% effective concentration for suppression of premature ventricular complexes of 1.4 mg/liter compared with 4.6 mg/liter for the parent compound. Plasma and myocardial drug concentrations were similar to those measured during long-term amiodarone therapy in man, with desethylamiodarone producing greater myocardial concentrations than amiodarone for a given plasma concentration. Coadministration of the metabolite along with the parent drug resulted in suppression of arrhythmias at lower doses of amiodarone than when the latter was administered alone, and concentration-response analysis indicated an additive antiarrhythmic effect. These experiments suggest that the accumulation of desethylamiodarone that occurs with long-term oral amiodarone therapy contributes importantly to the antiarrhythmic effects of the drug, and may account for the gradual increase in antiarrhythmic action during the course of amiodarone therapy.

Effects of Amiodarone and Desethylamiodarone on Rabbit Myocardial β-Adrenoceptors and Serum Thyroid Hormones—Absence of Relationship to Serum and Myocardial Drug Concentrations

The antiadrenergic actions of amiodarone (Am) are well known but its effect and that of its metabolite, desethylamiodarone (DAm), on beta-receptor density (Bmax) and affinity (KD) are poorly defined. Thus, the acute and chronic effects of Am and DAm on myocardial beta-receptors in rabbits were determined relative to changes in thyroid hormones and serum and tissue drug concentrations. Bmax and KD were measured by radio-ligand binding, thyroid hormones by RIA, and drug levels by HPLC. Compared with controls, intravenous Am (20 mg/kg) reduced Bmax by 23% (p less than 0.05) and DAm (20 mg/kg) by 32% (p less than 0.05). After 3 weeks of chronic drug, the corresponding value for Am was 24% (p less than 0.05) versus 45% (p less than 0.05) for DAm. The effect of DAm was significantly greater (p less than 0.05) than that of Am, being comparable to that of Am (-44%) after 6 weeks. In the case of Am, doubling the dose (and myocardial level) led to no further decrease in Bmax. DAm also reduced Bmax more following chronic treatment than after acute administration (-45 versus -32%), a difference of borderline significance. Following 3 weeks of p.o. Am, T3 decreased 3% (NS) and reverse T3 (rT3) increased 90% (p less than 0.05); after 6 weeks, the corresponding values were 25% (p less than 0.05) and 181% (p less than 0.01). After 1 week of p.o. DAm, T3 did not change but rT3 increased by 34% (p less than 0.05); after 3 weeks the corresponding values were 21% (p less than 0.01) and 64% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term myocardial uptake of lidocaine and mexiletine in patients with ischemic heart disease.

Determination of short-term myocardial drug uptake and subsequent redistribution was performed in 27 patients with ischemic heart disease for the antiarrhythmic agents lidocaine and mexiletine, using frequent simultaneous measurements of drug concentration in aortic and coronary sinus blood, combined with measurement of coronary sinus blood flow after intravenous bolus injection of the drug. Maximal myocardial drug content per unit resting coronary sinus blood flow (MDC:F) was significantly greater in patients in whom coronary sinus pacing at 100 beat/min was performed during the initial period of drug uptake. Maximal myocardial drug content occurred after 2.4 +/- 0.2 (SEM) for lidocaine and after 5.5 +/- 0.6 min for mexiletine (p less than .001), and pacing did not affect time to maximum myocardial drug content. In nonpaced, but not paced, patients maximal MDC:F was greater in the lidocaine group than that in the mexiletine group. The subsequent efflux of lidocaine from the myocardium was more rapid that that of mexiletine in both paced and nonpaced groups.

Myocardial uptake of drugs and clinical effects.

The process of uptake of cardioactive drugs into the myocardium is a major determinant of the efficacy and potential toxicity of such agents. Evaluation of responses to anti-arrhythmic and positive inotropic agents is best performed with reference to their concentration in the myocardium, and the potential toxicity of drugs such as tricyclic antidepressants and anthracycline antineoplastics is likely to be related to peak myocardial drug concentrations. Although it has been appreciated for many years that even during long term drug administration the myocardial drug content may not be readily predictable on the basis of estimation of plasma drug concentrations, methodology for direct assessment of myocardial drug content has remained limited. The results of in vitro experiments, utilising tissue culture preparations of myocardial cells or isolated atria, have shed some light on the role of local factors as determinants of myocardial drug uptake. For many agents, attainment of maximal cardiac drug content in vitro is a very slow process (taking up to 3 hours), although maximal inotropic and electrophysiological effects may occur more rapidly. The prolonged time course of drug washout from these preparations also reflects their extensive and slow intracellular accumulation. Mechanical activity of the myocardium appears to accelerate drug uptake, particularly for otherwise slowly equilibrating agents, but the major determinant of the extent of drug uptake into isolated myocardial preparations is lipophilicity, perhaps reflecting the passage of drugs through the sarcolemma. In intact animals, assessment of myocardial drug content after acute drug administration has been performed utilising serial myocardial biopsy or sacrifice of animals. Studies in open-chested dogs suggest that acute accumulation of agents may be most closely predicted from the second compartment of a 3-compartment pharmacokinetic model, and that there is a variable correlation between changes in plasma and myocardial drug concentrations. For example, bretylium concentrations within the myocardium continue to increase for up to 6 hours after drug administration. Factors which may influence drug uptake into the myocardium in intact animals include ischaemia, which usually results in a delay in both drug uptake and subsequent clearance. This change can also be inferred from the time course of onset of antiarrhythmic drug effects in some models of myocardial ischaemia. Anoxia may also inhibit myocardial drug uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

Myocardial Bethanidine Kinetics After Single-Dose Intravenous Infusion: Correlation with Plasma Kinetics in Closed-Chest Dogs

Myocardial and plasma bethanidine kinetics were determined in five dogs after an intravenous dose of 6 mg/kg/10 min. Serial myocardial drug concentrations were determined from endomyocardial samples obtained by transvenous biopsies between 15 min and 72 h. Tissue and plasma samples were assayed by gas-liquid chromatography. Bethanidine was rapidly concentrated in myocardium within 15 min. Tissue/plasma drug ratios averaged 131 +/- 35 between 15 min and 2 h and 53 +/- 10 between 6 and 48 h. Parallel biexponential decay then occurred for both tissue and plasma compartments; the terminal half-life approximated 16 h. Based on differences in rates of myocardial drug kinetics, the cardiac antifibrillatory effects of bethanidine may occur more rapidly than those of bretylium.

The pharmacokinetics of digoxin in newborn and adult sheep.

The pharmacokinetics of digoxin were determined in 12 ewes and 13 newborn sheep after bolus drug administration and under steady state drug conditions. After death, tissue distribution of digoxin was determined and normalized to plasma drug concentrations at steady state. Volume of distribution and total drug clearance were lower at steady state than the comparable variables calculated from bolus drug administration. No significant difference between ewes and newborns was shown for drug distribution half-life (0.72 vs. 0.76 hr), drug elimination half-life (15.2 vs. 13.7), or renal drug clearance (0.86 vs. 0.89 liters/kg/hr). Total drug clearance as well as the area derived and steady state volumes of distribution were higher in newborns than in ewes. Digoxin secretion into the urine was limited in newborns, as evidenced by a lower renal digoxin clearance to creatinine clearance ratio in newborns than in ewes (371 vs. 600%). The plasma concentration of digoxin at steady state correlated well with myocardial drug concentrations. Drug distribution was similar in both age groups; however, the tissue to plasma digoxin ratio in kidney was higher in newborns than in ewes (mean 469 vs. 263, respectively). Although age-related differences in drug clearance and distribution volume existed, intersubject variation was substantial, and the demonstrated variations were not large enough to account for the high doses of digoxin used to treat congestive heart failure in immature subjects.

Kinetics of antifibrillatory effects of bretylium: Correlation with myocardial drug concentrations

To determine the kinetics of the antifibrillatory effects of bretylium tosylate and to assess the relative importance of myocardial versus serum drug concentrations, studies were performed in 32 dogs after they received bolus injections of bretylium tosylate (6 mg/kg or 2 mg/kg body weight) or saline solution. Parallel determinations were made of drug concentrations in serum and myocardium, together with antifibrillatory and electrophysiologic effects, both with and without 2 minutes of coronary ischemia produced by temporary coronary ligation. Serum bretylium concentration decreased rapidly after intravenous injection, whereas myocardial concentrations increased gradually, peaking at 1.5 to 6 hours in both open and closed chest dogs. The ratio of myocardial to serum drug concentration increased to 6.4 to 12.6 at 12 hours. Parallel elimination of the drug in serum and myocardium occurred thereafter, with elimination half-life of 10.5 hours (closed chest dogs). Electrophysiologic and antifibrillatory effects paralleled myocardial rather than serum drug kinetics with peak effects at 3 to 6 hours. The ventricular effective refractory period was 24 to 26 ms greater at 3 hours in dogs treated with the drug than in those receiving saline solution. The ventricular fibrillation threshold increased 6 to 10-fold after 2 mg/kg of the drug was given at 3 to 6 hours in dogs both with and without ischemia in comparison with that in control animals treated with saline solution. The average increase in threshold exceeded 12-fold after administration of 6 mg/kg of the drug (2 minutes to 12 hours). The repetitive ventricular response threshold 3 hours after drug administration increased 5-fold after 2 mg/kg and 18-fold after 6 mg/kg of the drug was administered in dogs with or without ischemia. These studies elucidate canine serum and myocardial drug kinetics of bretylium, quantify the prolonged antifibrillatory effect of this drug with its delayed maximal effect and emphasize the importance of tissue levels of bretylium in determining drug action.

Kinetics of antiarrhythmic effects of bretylium: Correlation with myocardial drug concentrations

Kinetics of antiarrhythmic effects of bretylium: Correlation with myocardial drug concentrations