Reduction In Exercise-induced Tachycardia Research Articles

GRK5 Gln41Leu Polymorphism is not Associated with Sensitivity to β 1 -Adrenergic Blockade in Humans

A common, functionally significant polymorphism in GRK5 (Gln41Leu) encodes a gain-of-function enzyme that enhances desensitization of the beta(1)-adrenergic receptor. GRK5 Leu41 has been postulated to confer endogenous 'genetic beta-blockade' and contribute to an attenuated response to beta-blockers in black subjects. The effects of this GRK5 variant on sensitivity to a beta-blocker have not been studied in humans. We hypothesized that the GRK5 Gln41Leu variant contributes to interindividual variability in response to beta-blockade and to the ethnic difference in sensitivity between black and Caucasian individuals. We measured the heart rate at rest and during a graded incremental exercise in 154 healthy subjects (85 white and 69 black) before and after an oral administration of 25 mg atenolol. We determined the genotypes of GRK5 (Gln41Leu), beta(1)-adrenergic receptor (ADRB1 Ser49Gly and Arg389Gly) genotypes and plasma atenolol concentrations. The effects of genotype and covariates on sensitivity to atenolol, measured as the reduction in exercise-induced tachycardia, were determined using multiple regression analyses. The minor allele frequency of GRK5 Leu41 was 32.6% in blacks and 0% in whites. Black individuals were less sensitive to atenolol than white individuals (p < or = 0.011) but this was not explained by the GRK5 genotype. The GRK5 genotype had no effect on resting heart rate before (p = 0.61) and after adjustment for age, sex, ethnicity, atenolol concentrations, BMI and ADRB1 genotypes (p = 0.81). The decrease in heart rate after atenolol administration did not differ significantly according to the GRK5 genotype at rest or after exercise, before (all p > 0.14) and after statistical adjustment for covariates (all p > 0.17). The GRK5 Gln41Leu polymorphism does not affect sensitivity to the beta(1)-adrenergic blocker, atenolol, during acute physiological adrenergic stimulation, nor does it contribute to the ethnic differences in sensitivity to atenolol among black and Caucasian individuals.

Pharmacokinetic and Pharmacodynamic Evaluation During Coadministration of Nefazodone and Propranolol in Healthy Men

Potential interactions between nefazodone (200 mg every 12 hours) and propranolol (40 mg every 12 hours) were assessed in 18 healthy male volunteers in an open-label, randomized, three-way crossover study. The nature, frequency, and severity of adverse events during coadministration of nefazodone and propranolol were similar to those observed with either treatment alone. There were no clinically significant effects on vital signs, electrocardiographic results, or laboratory parameters. With coadministration, the maximum peak concentration (Cmax) and area under the concentration-time curve over the dosing interval (AUC tau) of propranolol decreased 29% and 14%, respectively; Cmax and AUC tau of 4-hydroxy-propranolol decreased 15% and 21%, respectively. Despite decreased plasma concentrations of the beta-antagonists, the reduction in exercise-induced tachycardia and post-exercise double product was slightly greater with coadministration than with propranolol alone. Administration of nefazodone alone did not significantly affect either pharmacologic parameter. The pharmacokinetics of nefazodone and its metabolites were largely unaffected during coadministration. Coadministration of propranolol and nefazodone results in modest pharmacokinetic inequivalencies, but no clinically significant alterations of the pharmacodynamics of propranolol.

Pharmacokinetics and pharmacodynamics of a new transdermal delivery system for bopindolol.

1. In two separate studies, each with 12 healthy male volunteers, the pharmacokinetic and dynamic properties of a transdermal delivery system for bopindolol were evaluated. 2. In study I it was shown that bopindolol absorption from a 14 mg patch occurred over the whole 7-day application period. No signs of a significant skin depot were found. 3. In study II, a linear pharmacokinetic behaviour but a non-linear kinetic/dynamic relationship was established for the patches over a dose range from 7 to 21 mg. Comparable peak effects of reduction in exercise-induced tachycardia were observed after different patch doses and an i.v. injection. However, the effect was significantly prolonged with the patches compared with the injection and was maintained over 7 days. 4. The patches showed a good local and systemic tolerability in both studies over a dosing interval of up to 7 days.

Pharmacokinetics and pharmacodynamics of conventional and controlled-release formulations of metipranolol in man

The pharmacokinetics and beta-adrenoceptor blocking effects of conventional and sustained-release metipranolol have been studied in 6 healthy male volunteers given a single oral dose of 40 mg. Plasma drug concentrations determined by TLC and a radioreceptor assay, and the inhibition of exercise-induced tachycardia, were monitored for 48 h. Relevant amounts of active metabolites other than deacetylmetipranolol were not found. Compared to conventionally formulated metipranolol, the controlled-release product had a prolonged mean residence time (10.7 vs 5.5 h), the peak drug concentration was halved and the time to peak drug concentrations was delayed. Relatively constant plasma concentrations (cideal = 6.5 ng/ml) and a clinically significant reduction of exercise-induced tachycardia were maintained throughout a 24 h dosing interval. An individual deacetylmetipranolol plasma concentration-effect relationship was evaluated using the Emax model. Mean parameters were Emax 26% and C50 2.9 ng/ml.

Comparison of CNS‐Related Subjective Symptoms in Hypertensive Patients Treated with Either a New Controlled Release (CR/ZOK) Formulation of Metoprolol or Atenolol

The present study evaluated and compared subjective symptoms in hypertensive patients (N = 83) at therapeutically comparable dosages of a new controlled release (CR/ZOK) formulation of metoprolol (100 mg od) and atenolol (50 mg od). The trial was a 4-week randomized double-blind study preceded by a placebo run-in period. Blood pressure (BP) was recorded 24 hours after intake of last dose. In subpopulations, 24-hour ambulatory BP was recorded and exercise tests performed. Subjective symptoms were evaluated with a previously documented questionnaire (MSE-profile) which has been shown to be sensitive in detecting CNS-related symptoms caused by beta blockers. The MSE-profile includes three dimensions: Contentment, Vitality and Sleep. The results showed that there were no significant differences between the groups in BP reduction either at 24 hours or over the entire 24-hour dose interval. Furthermore, the degree of beta 1-blockade (reduction in exercise-induced tachycardia) 24 hours after last dose did not differ between the groups. There were no significant differences regarding subjective symptoms (Contentment, Vitality, Sleep) between the two treatment groups. An a posteriori power analysis showed that the power to detect a true difference was of an acceptable magnitude. In conclusion, there was no difference in CNS-related symptoms between metoprolol and atenolol at therapeutically comparable dosages indicating that the degree of lipophilicity may be of minor importance for the occurrence of such symptoms.

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The pharmacokinetic and pharmacodynamic interactions between diltiazem and propranolol, or atenolol were investigated in healthy volunteers. Diltiazem (30mg) or placebo was given three times daily for 3 days, and 30 min before administration of a β-adrenoceptor blocking drug given on the 4th day. A single dose of propranolol (20mg), or atenolol (50mg) was administered in a randomized, double-blind, crossover fashion. Exercise tests on a cycle ergometer were carried out before and after β-adrenoceptor blocking drug. Diltiazem significantly increased the AUC and elimination half-life of propranolol. The cardiac β-adrenoceptor blocking effect, as indicated by the percentage reduction in heart rate during exercise, tended to increase following diltiazem pretreatment, in comparison with placebo. In contrast, diltiazem did not significantly affect atenolol pharmacokinetics and pharmacodynamics. These results indicated that diltiazem impaired the total clearance of propranolol, which is principally metabolized by oxidative pathway in the liver. This kinetic interaction between diltiazem and propranolol may be partly related to the reduction in exercise-induced tachycardia.

Penbutolol: pharmacokinetics, effect on exercise tachycardia, and in vitro inhibition of radioligand binding.

The pharmacokinetics of penbutolol 40 mg, its reduction in exercise-induced tachycardia, and the in vitro inhibition of radioligand binding to beta-adrenoceptors by plasma have been investigated in 7 healthy volunteers. The peak penbutolol concentration of 285 ng/ml was observed 1.2 h after administration, and the maximum of 4'-OH-penbutolol of 4.76 ng/ml was found after 1.64 h. Penbutolol was detected for up to 48 h, and 4'-OH-penbutolol dropped below the limit of detection after about 10 h. The terminal plasma concentration of penbutolol declined with an average half-life of 19 h. The maximum reduction in exercise-induced tachycardia was 33 beats/min 2.6 h after taking penbutolol. There was still a significant reduction of about 7 beats/min after 48 h. This effect could be adequately explained by the concentration-time course of penbutolol in combination with Clark's model of the concentration-effect relationship. Antagonist activity in plasma caused 91% inhibition of radioligand binding in vitro to beta 2-adrenoceptors on rat reticulocyte membranes 1.6 h after intake of penbutolol. By 48 h after intake, radioligand binding was still significantly inhibited (23%). The in vitro inhibition of radioligand binding by plasma showed a linear correlation with the reduction in exercise-induced tachycardia for all phases of the workload. The time course of the reduction in heart rate was completely explained by the in vitro inhibition of radioligand binding. However, it was not possible to explain the in vitro inhibition of radioligand binding by the concentration-time course of penbutolol using a simple competition model, although both variables were based on the same sampling site. When the in vitro inhibition of radioligand binding was plotted against the penbutolol concentration at the same sampling times (with both variables transformed to multiples of the apparent inhibition constant) the discrepancy became even more apparent as time-related counterclockwise hysteresis. None of the known metabolites of penbutolol can explain the discrepancy between the penbutolol concentration and the inhibition of radioligand binding in vitro. It appears that an other active metabolite is formed, which contributes to the effect in vitro and in vivo and so can explain the observed discrepancy.

The effect of propranolol on exercise induced tachycardia is determined by plasma concentration and the density of adrenergic receptors on leukocytes.

The chronotropic response to a single oral dose of propranolol in 23 healthy subjects has been related to the plasma propranolol concentration and the density of beta-adrenoceptors on peripheral polymorphonuclear leucocytes. The percentage reduction in exercise-induced tachycardia was significantly correlated with the log plasma propranolol concentration within subjects but not between subjects. Taking the concentration of the active metabolite 4-hydroxypropranolol into account did not improve the interindividual correlation. The reduction in exercise-induced tachycardia was significantly correlated with the maximum binding density of (125I)-hydroxybenzylpindolol on polymorphonuclear leucocyte membrane fragments measured before medication. A response index (% reduction in exercise-induced tachycardia/plasma propranolol concentration) was correlated with the maximum binding density of (125I)-hydroxybenzylpindolol (pre-drug) at 2 h (rs = 0.72), 4 h (rs = 0.84) and 6 h (rs = 0.73) after dosing. The data suggest that interindividual variation in the response to propranolol after a single oral dose is determined by interindividual differences both in plasma propranolol and adrenoceptor density.

Antiarrhythmic efficacy of propranolol: Comparison of low and high serum concentrations

Propranolol has been effective in suppressing ventricular arrhythmias in up to 70% of patients in some series; however, a wide range of concentrations was required to produce this degree of efficacy. In one series, 40% of responders required high serum concentrations (greater than 500 ng/ml) in excess of those required for physiologic beta-receptor blockade (25 to 150 ng/ml). To assess the relative contribution of high concentration electrophysiologic effects to antiarrhythmic efficacy the results of programmed electrical stimulation were compared at high and low (beta-blocking) concentrations in 28 patients with inducible sustained ventricular tachycardia. Propranolol was given as a series of loading and maintenance infusions producing first a mean concentration of 130 +/- 72 ng/ml (beta-blocking) and then a mean concentration of 743 +/- 523 ng/ml (high). Beta-blockade was assessed by the percent reduction in exercise-induced tachycardia. Near maximal beta-blockade was achieved by a concentration of 150 ng/ml. At a low concentration, 6 of 28 patients had a response to propranolol (complete in 5 and partial in 1). At a high concentration, one additional patient had a complete response while three had a partial antiarrhythmic response. At high concentrations of propranolol there was a significant shortening of the QTc interval relative to that seen during the low dose infusion. No other significant electrophysiologic changes occurred at high versus low concentration. In summary, an antiarrhythmic response to propranolol occurs most frequently at a beta-blocking concentration. High concentration electrophysiologic effects occur and these appear to contribute to antiarrhythmic efficacy in some patients.

Exercise during therapeutic beta-blockade: a two-year study in hypertensive patients.

The use of beta-adrenoceptor blocking drugs has been thought to impair physical performance. To test this statement, 12 patients with mild to moderate hypertension performed a submaximal exercise test during treatment with placebo and after 3 and 24 months of monotherapy with betaxolol, 20 to 40 mg daily. The resting heart rate and systolic and diastolic blood pressures were reduced after 3 months of treatment and the reduction was maintained 24 hours after the last dose at the 2-year visit. A 12% to 14% reduction of exercise-induced tachycardia was found, but blood pressure during exercise was reduced only in the patients with mild hypertension. However, in no patient did the working capacity decrease.

Relationship between plasma concentrations and cardiac beta‐ adrenoceptor blockade‐a study with oral and intravenous bopindolol.

Bopindolol, an esterified beta-adrenoceptor blocking drug, was administered to nine healthy male volunteers in oral (1 mg and 4 mg) and intravenous (1 mg) doses. Plasma concentrations determined using a radio-receptor assay (RRA) and high pressure liquid chromatography (h.p.l.c.) yielded almost identical results, indicating that hydrolysed bopindolol, the major metabolite, is responsible for the pharmacological activity of the drug. After intravenous administration the half-life for the formation of the hydrolysis product was about 0.3 h. The elimination of hydrolysed bopindolol from the plasma, determined with a one-compartment model occurred with a half-life of about 4 h. There were indications for a longer beta phase of elimination with a half-life of about 8 h, which, owing to the relative insensitivity of the method for concentrations present after more than 24 h, could not be determined exactly. The absolute bioavailability of the active compound is about 70%. Cardiac beta-adrenoceptor blockade was determined as the reduction in exercise-induced tachycardia. With oral doses the maximum effect was reached after 3 h (-29 beats min-1 after 1 mg, -40 beats min-1 after 4 mg). After intravenous administration most of the effect was present after 0.5 h but the maximum effect (-33 beats min-1) was only reached at 3 h. Bopindolol possesses a long duration of action: after 48 h 33% of the maximum effect of the oral dose of 4 mg was still present.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamics of beta-adrenoceptor blockade with cetamolol.

Cetamolol is a new beta-adrenoceptor blocking agent shown in animals to have moderate beta 1-adrenoceptor selectivity and partial agonist activity. In healthy normal volunteers, beta 1-adrenoceptor blockade was measured as the reduction of exercise-induced tachycardia, systolic blood pressure, and double product at 2, 8, and 24 h after a single oral dose of 10, 25, and 50 mg cetamolol. beta 1-adrenoceptor blockade was significantly linearly related to log serum cetamolol level, was maximal at 2 h, and was still clinically significant at 24 h. A crossover study of single 0, 10, and 25 mg doses confirmed these findings.

Simultaneous modeling of bopindolol kinetics and dynamics.

Bopindolol has beta-blocking effects for 96 hr despite a 4-hr t1/2. To investigate the concentration-effect relationship after single and repeated doses. 2-mg oral doses were given once and then daily for 13 days to six healthy subjects. In plasma, no unchanged drug, only the hydrolysis product of bopindolol (referred to as bopindolol concentration) was detectable or could be measured up to 24 hr. Chemical assay by HPLC and determination of total active beta-adrenoceptor blocking material by radioreceptor assay gave identical results. The t1/2 was 4 to 5 hr. Effects, measured as reduction in exercise-induced tachycardia (REIT) and as the isoproterenol dose ratio (DR - 1), were followed for 96 hr. The concentration of bopindolol in plasma (predicted with a one-compartment body model) could be related to the measured effects by classic effect models for 20 t1/2s. Parameter estimates for kinetic end effect models did not differ after single and repeated doses. With the parameters from the single-dose experiment, the time course of the plasma concentration and the effects after the multiple-dose experiment could be adequately predicted for 24 and 96 hr. A deep compartment, an active metabolite, or irreversible destruction of the receptor (accounting for the persistence of the effect) could be excluded. The "dissociation constant" of 100 pmol/l (from DR -1/concentration) and the minimal effective plasma concentration (from REIT/log concentration) of 1 pmol/l suggest that enough receptors are occupied at chemically unmeasurable levels in plasma to induce an effect. The "dissociation constant" determined in vivo is of the same order as that from in vitro radioligand studies.

Clinical pharmacology of pindolol

Beta-adrenoceptor blockade is responsible for the therapeutic actions of beta-adrenoceptor-blocking drugs in the treatment of hypertension and angina pectoris. Many aspects of their effects can therefore be studied in relatively simple clinical pharmacologic experiments. Cardiac beta-adrenoceptor blockade can be measured in terms of the reduction of isoprenaline-induced and exercise-induced tachycardia. Base on these experimental procedures pindolol is, on a weight-for-weight basis, about 20 times more potent than propranolol. The duration of action of pindolol, measured by the reduction in exercise-induced tachycardia, is longer than that of many other beta-adrenoceptor-blocking drugs such as propranolol, alprenolol, and slow-release oxprenolol tested at equipotent beta-adrenoceptor-blocking doses. Pindolol is a beta-adrenoceptor-blocking drug with partial agonist activity (intrinsic sympathomimetic activity [ISA]). Drugs of this type are as effective in inhibiting beta-adrenoceptor stimulation as drugs devoid of this property, but unlike the latter they produce some stimulation of beta adrenoceptors. The ISA of pindolol is sufficient to counterbalance the diminution in resting sympathetic tone that results from beta-adrenoceptor blockade. In hemodynamic studies pindolol does not alter or only slightly reduces normal cardiac output. This is in contrast to drugs lacking ISA, which consistently depress cardiac output. In addition, propranolol has been shown to markedly reduce blood flow in the calf, whereas pindolol and placebo do not differ from one another in their effect on this parameter. A linear correlation exists between the logarithm of plasma concentrations of pindolol and cardiac beta-adrenoceptor blockade expressed as a reduction of exercise-induced tachycardia. The high systemic availability of pindolol after oral administration, due to good oral absorption and low first-pass effect, is revealed not only in pharmacokinetic studies but also in pharmacodynamic experiments; beta-adrenoceptor blockade 75 minutes after intravenous administration was equivalent to that observed 2 hours after the same doses given orally.

Adrenergic beta receptor blockade: hemodynamic importance of intrinsic sympathomimetic activity at rest.

Dose-response curves for heart rate, cardiac output, arterial blood pressure, and pulmonary artery pressure were obtained in 37 patients with ischemic heart disease after intravenous administration of six increasing doses of propranolol, atenolol, practolol, pindolol, CPEP (1 -[2-cyanophenoxy]-3β-[3-phenylureido]-ethylamino-2-propanol), and BMMP (1-t-butylamino-3-[2-N-methylcarbamoyl-methoxyphenoxy]propan-2-ol-hydrochloride). The doses were equipotent, as indicated by reduction in exercise-induced tachycardia. The dose-response curves for cardiac output and heart rate can be divided into three groups according to the degree of intrinsic sympathomimetic activity. One group without intrinsic sympathomimetic activity included propranolol and atenolol, which reduced cardiac output (about 26% to 28%) and heart rate (about 15% to 17%). A second group with moderate intrinsic sympathomimetic activity, represented by practolol and BMMP, induced less reduction in cardiac output (about 12% to 17%) and heart rate (about 7% to 10%). A third group with pronounced intrinsic sympathomimetic activity, represented by pindolol and CPEP, did not reduce cardiac output and heart rate. Mean systemic blood pressure was essentially unchanged even after the largest dose of any of the drugs. Mean pulmonary artery pressure rose after atenolol, propranolol, and BMMP but not after pindolol, CPEP, and practolol. Atenolol, BMMP, and practolol are beta-1–selective drugs, it is concluded that the acute hemodynamic response to adrenergic beta receptor blocking drugs at rest is determined primarily by the degree of intrinsic sympathomimetic activity, whereas beta-1 selectivity did not modify the central hemodynamic responses to beta adrenoceptor blockade. Clinical Pharmacology and Therapeutics (1981) 29, 711–718; doi:10.1038/clpt.1981.100

A pharmacodynamic and pharmacokinetic comparison of pindolol 20 mg retard and a conventional tablet.

In 10 healthy volunteers the time course of cardiac beta-adrenoceptor blocking activity, plasma levels and cumulative urinary excretion of pindolol were compared during a 4-day course of pindolol 5 mg (Visken) t. d. s., and one tablet of pindolol 20 mg retard (Visken retard) once a day. After oral administration of the 20 mg retard tablet, plasma concentrations of pindolol higher than half the maximum value (1/2 Cp (tmax)) were maintained about 2.5 times as long as after administration of the conventional 5 mg tablet. This is evidence for an important and marked retardation of drug release. During treatment with pindolol 20 mg retard once daily, cardiac beta-adrenoceptor blockade, measured by the reduction in exercise-induced tachycardia and in the exercise-induced rise in systolic blood pressure, at almost all times throughout the 24 h period was at least as great as during treatment with pindolol 5 mg t. d. s. This suggests that patients successfully treated with pindolol 5 mg t. d. s. can be maintained with the same beta-adrenoceptor blockade by a single tablet of pindolol 20 mg retard once daily.

Beta blockade with pindolol: Differential cardiac and renal effects despite similar plasma kinetics in normal and uremic man

Cardiac and renal effects (measured as the reduction in exercise-induced tachycardia and PRA, respectively) and circulating drug concentrations after acute beta blockade with intravenous pindolol were compared between seven normal volunteers and six patients with terminal renal failure. Kinetic parameters were similar in both groups (total body clearance, 450 mg/min), indicating enhanced extrarenal elimination in patients. For any given drug concentration, however, the uremic patients responded to beta blockade with a greater decrease in pulse rate than did normal volunteers (P less than 0.001). Moreover, in the same group, the decrease of PRA was more marked (from 13.3 to 5.7 vs. 3.3 to 1.9 ng/ml/hr) and lasted longer (8 hours and more vs. 2 hours). Plasma aldosterone remained unchanged. These data reveal an increased dependency of both heart rate and renin release on beta adrenergic-mediated mechanisms in uremic man. They also show that kinetic findings in normal subjects cannot always be extrapolated to predict kinetic behavior in disease, and that similar kinetics do not imply similar effectiveness.

Plasma levels and negative chronotropic effect of metoprolol following single doses of a conventional and sustained-release formulation

Plasma levels and associated reduction in exercise-induced tachycardia have been examined following the administration of single doses of metoprolol in conventional and slow-release tablets at different times to six healthy male subjects. The study was carried out in two parts. Initially, the tablets were given at 9 a.m. and the subjects were studied up to 14 h and then at 24 h. Subsequently, the same doses were given at 9 p.m. and the subjects were studied 12-24 h after drug administration (i.e. 9 a.m.-9 p.m. the next day). After giving the slow-release tablets the peak plasma levels were significantly lower but the drug persisted in the plasma at higher levels than after the conventional tablet. However, the beta-blocking effect was comparable from the two dosages. The results obtained for the period 12-24 h after the evening dose differed from the corresponding values after morning administration in that the plasma levels were higher and the beta-blocking effects more marked. Furthermore, the half-life values calculated from these data were significantly longer.

Assessment of perhexiline maleate in angiographically proven intractable angina: A double-blind trial

We report a randomized double-blind placebo controlled trial on perhexiline. Twenty-eight patients with beta-blocker resistant intractable angina were included but only 20 of these completed the 12 week period of the trial. Perhexiline was effective in 14 patients (70 per cent) as shown by a significant (P < 0.01) decrease in glyceryl trinitrate consumption and in anginal crises. Exercise tests on a bicycle ergometer showed a significant (P < 0.01) increase in exercise tolerance and a reduction in exercise-induced tachycardia. Three patients experienced profound relief from angina and declined to have aortocoronary bypass surgery. The main side effects were tremor, dizziness, and nausea but these did not seriously incapacitate the patients. We conclude that perhexiline is a valuable drug for treating intractable angina, especially when surgery is not feasible.