Pharmacodynamics of inotropic and chronotropic responses to oral therapy with propranolol. Studies in normal subjects and patients with angina.
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Administration, Oral↗
Biomedical subjects
R E Kates
Publications and source records attributed to R E Kates.
Rapid GLC determination of propranolol in human plasma samples.
A rapid GLC method for measuring plasma propranolol levels is reported. 4-Methylpropranolol was utilized as an internal standard. Pentafluoropropionate derivatives of propranolol and the internal standard eluted rapidly and gave good sensitivity under the conditions employed. The advantage of this procedure over previously reported methods is the speed of analysis, which is facilitated by rapid elution of contaminant peaks.
Chromatography, Gas↗
Negative inotropic effect of lidocaine in patients with coronary arterial disease and normal subjects.
The effect of administration of lidocaine on left ventricular performance was studied using systolic time intervals in nine normal subjects, eight patients with stable angina, and 15 patients with acute myocardial infarction. The greatest response in systolic time intervals occurred at three minutes after intravenous injection of lidocaine (100 mg), with values returning to baseline at 10 to 15 minutes. Administration of lidocaine produced a significant prolongation of the preejection period (PEP) corrected for heart rate in all groups and a prolongation of the ratio of PEP to left ventricular ejection time (PEP/LVET) in patients with angina. The group with acute myocardial infarction exhibited a hyperadrenergic state, as shown by a short baseline QS2I. The QS I was lengthened by administration of lidocaine in all groups, but this was more profound in those with acute myocardial infarction. These changes in systolic time intervals were still present at two hours after injection in six patients with acute myocardial infarction in whom an infusion of lidocaine followed the initial bolus. The effect of administering lidocaine after intravenous injection of propranolol (5 mg) was also studied in six normal subjects. Although propranolol therapy along prolonged the PEP/LVET, a further significant prolongation followed subsequent injection of lidocaine.
Acute Disease↗
Hypersensitivity to adrenergic stimulation after propranolol withdrawal in normal subjects.
The cardiac response to isoproterenol after propranolol withdrawal was studied in six normal persons. Serial isoproterenol infusions were done before and after oral propranolol administration, 160 mg daily for 2 days. Changes in electromechanical systole corrected for heart rate (QS2I) and pulse pressure were used to assess the inotropic response to isoproterenol, and changes in heart rate were used to assess the chronotropic response. As shown in previous studies, the negative inotropic effect of propranolol lasted only 12 to 15 h, while the negative chronotropic effect lasted 24 to 36 h. After the disappearance of blockade a hypersensitivity to isoproterenol was found 24 to 48 h after propranolol withdrawal in all three measured determinants. The explanation of this phenomenon most likely lies in the nature of adrenergic receptors that become activated during long-term blockade.
Administration, Oral↗
Absorption kinetics of sublingually administered propranolol.
The absorption of propranolol through the buccal cavity has been investigated in normal healthy male volunteers. Propranolol doses of 10 mg were retained in the mouth for varying lengths of time to investigate the absorption kinetics. Both plasma and oral contents were analyzed. Propranolol was found to be incompletely absorbed (about 40%) from the buccal cavity. The disappearance of propranolol from the oral cavity does not, however, reflect absorption of drug into the blood. Absorption onto or into the buccal mucosa followed first order kinetics with a half life of 1 to 17 minutes, variability being great between subjects. The appearance of drug into the blood was also first order characterized by a half life of 20 to 25 minutes. It was found that uptake from the oral cavity and appearance in the plasma are separate processes with transport into the plasma being the rate limiting step. This data is discussed in terms of previously presented models of buccal absorption.
Absorption↗
Increased methotrexate toxicity due to concurrent probenecid administration.
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Animals↗
Biliary secretion of methotrexate in rats and its inhibition by probenecid.
The biliary secretion of methotrexate was investigated in rats under steady-state conditions. The transport system involved was saturable and displayed Michaelis-Menten-type kinetics. Values for the maximal rate of transport and a transport constant analogous to the Michaelis constant were 12 mg/hr and 32 mg/liter (7 x 10-5 M), respectively. The inhibition of this transport mechanism by probenecid also was investigated, and the relationship between the plasma concentration of probenecid and the biliary clearance of methotrexate was elucidated. The value of Ki, the dissociation constant for the transport carrier-inhibitor complex, was 23 mug/ml (8 x10-5 M).
Animals↗
Separation of methotrexate and nonmethotrexate components in rat plasma.
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Animals↗
Time couse of the blockade effect of propranolol on sinus node and atrioventricular node.
The time course of the blockade effect of propranolol on the sinus node (SN) and the atrioventricular node (AVN) was studied in six normal volunteers. Serial isoproterenol infusions were done before and after oral propranolol administration, 160 mg daily for two days. The inhibition by propranolol of the heart rate increases due to isoproterenol was used to assess the blockade of the sinus node, and the diminution by propranolol of the shortening in the PR interval due to isoproterenol was used to assess the blockade of the atrioventricular node. The blockade effects on the sinus node and the atrioventricular node were identical and persisted more than 24 hours. There was no good relationship between plasma propranolol and blockade effect on sinus node and/or atrioventricular node as propranolol was no longer detectable in the plasma 24 hours after the last dose. A transient hypersensitivity to isoproterenol was present 36 to 48 hours after propranolol withdrawal. The explanation of these phenomena most likely lies in the peculiar nature of beta-adrenergic receptors.
Adult↗
Cyclosporine serum concentrations soon after heart or heart-lung transplantation.
The accumulation of cyclosporine was evaluated in 11 patients following either heart or heart-lung transplantation. Blood samples were drawn frequently for the first few postoperative days, and the plasma was analyzed by both radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC). The levels determined by RIA were higher than those assessed by HPLC, and it is hypothesized that the difference is due to antibody reactive metabolites of cyclosporine, which are measured by the RIA procedure. We did not find any consistent trends in the accumulation of these metabolites. Analysis of early clinical data did not suggest any relationship between levels of cyclosporine or its metabolites and clinical outcome.
Adult↗
Influence of hepatic dysfunction on the pharmacokinetics of propafenone.
Hepatic metabolism is the primary process of elimination of propafenone. It therefore is important to understand the effect of altered liver function on the disposition and elimination kinetics of this drug. Patients with abnormal liver function probably will require treatment with propafenone for cardiac arrhythmias; an understanding of the relationship between liver function and the pharmacokinetics of propafenone will provide a rational basis for optimal dosage adjustments in these individuals. Our results demonstrate that both systemic clearance and bioavailability of propafenone are sensitive to variability in liver function. The bioavailability of propafenone is inversely related to the clearance of indocyanine green (ICG), whereas a direct relationship exists between systemic clearance of propafenone and ICG clearance. Comparisons of clinical parameters with the propafenone data yielded interesting results. An overall clinical grading of severity of liver disease based on the presence or absence of portal hypertension (i.e., varices and/or splenomegaly), prior encephalopathy, and ascites did not correlate well with propafenone results. However, albumin, total bilirubin, serum glutamic oxaloacetic transaminase (SGOT) concentrations and prothrombin time values correlated strongly with the overall results. No definite relationships with subjects' age; weight; and hemoglobin, alkaline phosphatase, lactic acid dehydrogenose, cholesterol, blood urea nitrogen, or creatinine levels were detected. These results demonstrate that moderate to severe liver disease significantly affects the absorption and disposition of propafenone. In patients with cirrhosis, and presumably other forms of hepatic dysfunction, careful adjustments of propafenone doses are needed to optimize therapy.
Administration, Oral↗
Pharmacodynamics of intravenous amiodarone in the dog.
We have investigated the relationship between the myocardial disposition kinetics of amiodarone and the time course of its electrophysiologic effects in an open-chested anesthetized dog model. We observed that the maximal changes in both sinus cycle length and Wenkebach cycle length occurred about 30 min following a single intravenous dose of amiodarone or at the same time as the occurrence of the maximal myocardial concentration. The myocardial concentrations of amiodarone more closely reflect the electrophysiologic effects of amiodarone in the dog than do plasma concentrations. This difference is observable during the first 30 min following intravenous administration owing to the disequilibrium between plasma and myocardial disposition characteristics. Interanimal variability of electrophysiologic response is not accounted for by differences in myocardial concentrations.
Amiodarone↗
Myocardial uptake of encainide and its two major metabolites, O-demethyl encainide and 3-methoxy-O-demethyl encainide, in the dog.
Encainide is a new antiarrhythmic agent which is currently undergoing clinical evaluation. Two metabolites, O-demethyl encainide (ODE) and 3-methoxy-O-demethyl encainide (MODE), have been identified. We have investigated the myocardial accumulation of these three compounds in an anesthetized open-chested dog model. We also considered the degree of plasma protein binding and the oil/water partitioning characteristics of these three compounds to see if they explained differences in myocardial accumulation. Each compound was administered by intravenous infusion to a group of five dogs. Blood and myocardial biopsy samplings were carried out under steady-state conditions. The myocardial/plasma concentration ratios for encainide, ODE, and MODE were 8.4, 5.4, and 4.8, respectively. The ratios were compared with a completely randomized analysis of variance followed by multiple comparisons. The myocardial/plasma concentration ratio for encainide was significantly greater (p less than .05) than the ratios of the metabolites; however, the difference between ODE and MODE was not significant. Myocardial uptake of encainide, ODE, and MODE was quite rapid, and the myocardial concentration-time course of each compound followed its time course in plasma closely. Encainide and its two metabolites are only moderately bound to plasma proteins. The mean (+/- SD) percent bound for encainide, ODE, and MODE are 49 +/- 10, 55 +/- 19, 44 +/- 18, respectively. The whole blood/plasma concentration ratios are 1.04 +/- 0.16, 1.08 +/- 0.23, and 1.06 +/- 0.08 for encainide, ODE, and MODE, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Anilides↗
Comparative electrophysiology of lorcainide and norlorcainide in the dog.
Electrophysiologic effects of intravenous lorcainide and its major metabolite, norlorcainide, were examined in 18 anesthetized dogs, using intracardiac electrophysiologic measurements and programmed stimulation. Lorcainide and norlorcainide were studied separately, using six dogs for each experiment. Each compound was administered by a series of 5 one-h graded infusions each involving a loading dose over 15 min followed by a 45-min maintenance infusion. Plasma concentrations ranged from 94 +/- 34 to 1345 +/- 471 ng/ml for lorcainide and 81 +/- 22 to 1344 +/- 458 ng/ml for norlorcainide. Six additional dogs were studied, using a combination of a constant lorcainide infusion and four progressively increasing doses of norlorcainide. Both lorcainide and norlorcainide caused concentration-dependent prolongation of PR interval, QRS duration, AH and HV intervals, atrial and ventricular effective refractory periods, and the atrioventricular nodal functional refractory period. For each electrophysiologic parameter, plots of percent change as a function of log plasma concentration were nearly superimposable for lorcainide and norlorcainide. Plots for the combined treatment group using the total plasma concentration of lorcainide and norlorcainide were similar to those for each compound alone. We conclude that in dogs norlorcainide has considerable electrophysiologic activity, and is approximately equieffective and equipotent when compared with lorcainide, and that the electrophysiologic effects of the two compounds appear additive.
Animals↗
Evaluation of combined administration of verapamil and disopyramide in dogs.
The electrophysiologic and hemodynamic effects of concurrent administration of verapamil and disopyramide were studied in morphine-chloralose-anesthetized dogs. Twenty-one dogs were studied; seven received verapamil alone, seven received disopyramide alone, and seven received the two drugs in combination. Both drugs were administered by intravenous infusion, resulting in sustained plasma levels within the therapeutic range. Effects were measured every 30 min and compared with baseline (pretreatment) values. In all three groups heart rate and cardiac output decreased slightly; however, the effect produced by the combination was not significantly different from that produced by either drug alone. Most of the electrophysiologic changes observed in the combined-treatment dogs could be attributed to the individual effects of either verapamil or disopyramide and were not suggestive of any interaction between these two drugs. In the combined-treatment dogs the atrial and ventricular refractoriness increased in the same way as with disopyramide alone, and the spontaneous discharge rate of the sinus node and the conduction through the atrioventricular node were slowed as with verapamil alone. However, a significant prolongation of the sinus node recovery time occurred in the combined-treatment dogs. Five of the seven dogs experienced at least one episode of sinus arrest following pacing. The profile of effects observed may be dependent, in part, on the model we utilized. However, our data suggest that the combination of verapamil and disopyramide may produce severe sinus node depression.
Animals↗
Influence of protein binding on the myocardial uptake and pharmacodynamics of propafenone.
The relationship between plasma protein binding, myocardial uptake, and cardiac pharmacodynamics of propafenone was studied in an isolated perfused rabbit heart model. Hearts were perfused with buffer which contained varied concentrations of alpha 1-acid glycoprotein (alpha 1AGP). The rate and extent of myocardial uptake was assessed, as was the time course and magnitude of the change in QRS duration. The addition of alpha 1AGP has significant influence on both the rate and extent of myocardial accumulation as well as the resultant changes in QRS duration. The steady-state changes in QRS duration were linearly related to the free perfusate propafenone concentration. At times of disequilibrium, the relationship between free concentration and effect was not evident. However, at all times, a linear relationship between the myocardial concentration of propafenone and the resultant effect was observed. This relationship was not influenced by addition of alpha 1AGP protein to the perfusate; however, the amount of drug which was able to partition into the myocardium was greatly affected. These studies demonstrate that protein binding does influence the partitioning of drug into the myocardium and subsequently modulates the cardiac effect.
Animals↗
Pharmacodynamic modeling of antiarrhythmic drug effects--application to 3-methoxy-O-demethyl encainide.
The pharmacodynamic characteristics of 3-methoxy-O-demethyl encainide (MODE) were studied in instrumented, chloralose-anesthetized dogs. The HIS Purkinje conduction times (HV) were utilized to assess drug effect. Two protocols were conducted; the first protocol involved multiple pairs of loading and maintenance infusions to achieve several steady-state plasma drug concentrations. The second protocol involved a single short infusion. The data from both protocols supported a linear concentration-effect relationship for the concentration range studied. The slopes and intercepts were similar for both data sets. The data from the second protocol were also analyzed to assess the temporal aspects of the pharmacodynamics of MODE. Data analysis indicated that there is significant hysteresis in the plasma concentration-effect relationship that is characterized by a first-order rate constant corresponding to a half-life (t1/2) of approximately 10 min. These study results also demonstrated the advantages of single-infusion protocols over multiple-infusion studies for evaluating the concentration-effect relationship of antiarrhythmic drugs.
Anilides↗
Clinical pharmacokinetics of N-acetylprocainamide.
Since N-acetylprocainamide was identified in the urine of patients receiving procainamide, this compound has been studied both as a metabolite of procainamide and as a separate antiarrhythmic agent. N-acetylprocainamide absorption following oral administration is more than 8-% complete. 59 to 89% of N-acetylprocainamide is excreted unchanged in the urine in subjects with normal renal function. Deacetylation of N-acetylprocainamide to procainamide is a minor route of N-acetylprocainamide elimination. The half-life of N-acetylprocainamide in patients with normal renal function has been reported to vary between 4.3 and 15.1 hours. Total body clearance (mean +/- SD) of N-acetylprocainamide in patients with normal renal function has been reported to range from 2.08 +/- 0.36 ml/min/kg to 3.28 +/- 0.52 ml/min/kg. There is a linear relationship between N-acetylprocainamide clearance and creatinine clearance. The half-life of N-acetylprocainamide in functionally anephric patients may be as long as 42 hours; however, it can be effectively cleared from plasma by haemodialysis. N-acetylprocainamide is 10% protein-bound. There is an age-related decline in N-acetylprocainamide clearance, mostly due to the decrease in creatinine clearance that occurs with ageing. In the neonate, the half-life of acetylprocainamide is prolonged. Several therapeutic trials carried out to assess the effectiveness of N-acetylprocainamide in suppressing chronic ventricular premature beats have now been reported. If there is a therapeutic response to N-acetylprocainamide it will probably occur at a plasma concentration between 15 and 25 micrograms/ml. A high degree of overlap has been reported between the concentration range associated with arrhythmic suppression and the range of concentrations where intolerable side effects begin to occur. No severe cardiac toxicity has been reported with oral therapy despite plasma concentrations as high as 40 micrograms/ml. However, hypotension has been reported in association with a rapid intravenous bolus of N-acetylprocainamide. A maximum intravenous infusion rate of 50 mg/min has been recommended. N-acetylprocainamide in patients receiving procainamide; however, N-acetylprocainamide concentrations remain below the therapeutic range in patients with normal renal function. In patients with renal failure receiving procainamide, N-acetylprocainamide concentrations rise dramatically. The dose of N-acetylprocainamide must be adjusted in patients with renal insufficiency, and it should be used more cautiously in the very old and very young. N-acetylprocainamide plasma concentration monitoring would be valuable clinically in patients with renal insufficiency receiving either N-acetylprocainamide or procainamide, and in the very young and the aged.
Acecainide↗