Dose-related effects of metoprolol on heart rate and pharmacokinetics in heart failure

BACKGROUND: The pharmacokinetics and pharmacodynamics of immediate-release (IR) metoprolol, 50 mg 3 times daily, were compared with those of different doses of controlled-release/extended-release metoprolol (CR/XL) given once daily. METHODS AND RESULTS: Fifteen patients with chronic heart failure were randomized to a 3-way crossover study to receive metoprolol IR 50 mg 3 times daily, CR/XL 100 mg once daily, and CR/XL 200 mg once daily for 7 days. On the seventh day of each treatment, serial plasma samples were drawn and standardized exercise tests and a 24-hour Holter recording were performed. Metoprolol IR 50 mg produced peak plasma levels comparable to those observed for CR/XL 200 mg (285 v 263 nmol/L). The difference in mean 24-hour heart rate between CR/XL 100 mg and IR 50 mg was 1.0 bpm (95% confidence interval [CI]), -2.9 to 4.9; NS) compared with -3.8 bpm (95% CI, -7.6 to -0.04; P = .048) between CR/XL 200 mg and IR 50 mg. Submaximal exercise heart rate was lower for patients receiving CR/XL 200 mg than those receiving IR 50 mg. No difference in tolerance or exercise performance was observed between treatment regimens. CONCLUSIONS: Peak plasma levels produced by metoprolol 200 mg CR/XL were similar to those of 50 mg IR. Metoprolol CR/XL 200 mg was associated with a more pronounced suppression of heart rate than metoprolol IR 50 mg. It is suggested that patients can safely be switched from multiple dosing of metoprolol IR 50 mg to a once-daily dose of metoprolol CR/XL.     

Achieving optimal beta1-blockade with metoprolol CR/Zok

The metoprolol CR/Zok is a multi-unit formulation containing metoprolol succinate controlled release (CR/Zok) in the form of individual drug delivery units (microcapsules). Each microcapsule acts as a diffusion cell and is designed to deliver metoprolol succinate at a near constant rate for about 20 hours independently of food intake, pH and other physiological variations. Taking the half-life of metoprolol into account this yields an even plasma concentration over 24 hours with a once daily dosage scheme. The formulation allows for once daily dosing, avoiding peaks and troughs in the plasma concentration of the drug. This leads to an even beta₁-blockade over 24 hours in dose ranges from 12.5 mg to 200 mg once daily. Plasma fluctuations are considerably decreased compared with immediate release formulations and cardioselectivity is well maintained also on 200 mg CR/Zok. Vital important beta₁-blockade is maintained for 24 hours. Metoprolol CR/Zok is well tolerated and well-being has been shown to be improved with metoprolol CR/Zok in patients with chronic heart failure as illustrated in the findings from the MERIT-HF study.     

Metabolic effects of controlled-release metoprolol in hypertensive men with impaired or diabetic glucose tolerance: a comparison with atenolol

In a double-blind, randomized, cross-over study with a single-blind placebo run-in period a new controlled-release (CR) formulation of metoprolol 200 mg once daily was compared with atenolol tablets 100 mg once daily in 22 patients (age 60.9 +/- 0.93 (SE) years) with primary hypertension and impaired or diabetic glucose tolerance. Each period lasted for three weeks. The two agents produced similar blood pressure 3 h as well as 24 h after drug intake. Three hours after drug intake, heart rate was lower on atenolol than metoprolol CR treatment, indicating a higher degree of beta-receptor blockade for atenolol at this point in time, when the plasma concentration of atenolol was most likely to be close to its peak. Concentrations of blood glucose, serum insulin, and serum C-peptide in the fasting state or after an oral glucose load did not differ between the active agents. HbA1c was marginally, but significantly, lower on atenolol than metoprolol CR treatment. No differences were found in serum levels of total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol or apoA-I, and apoB lipoproteins or triglycerides. In comparison to the placebo run-in period, both agents showed an unexpected improvement in glucose tolerance, a decrease in HDL cholesterol and for metoprolol CR a small, but significant decrease in LDL cholesterol. Thus, treatment with metoprolol CR tablets producing even plasma levels without high peak concentrations and conventional atenolol treatment had similar effects on metabolic control in hypertensive men and abnormal glucose tolerance.     

Pharmacokinetics and bioavailability of digoxin capsules,solution and tablets after single and multiple doses

The bioavailability of single doses of digoxin capsules (0.4 mg), digoxin solution (0.4 mg) and reference tablets (0.5 mg) was compared with that of single intravenous doses (0.4 mg) of digoxin using measurement of 24 hour urinary excretion and area under the plasma concentration curve. The absolute systemic availability of all three oral preparations was significantly less than 100 percent. The bioavailability of capsules and solution was nearly identical (79 percent and 76 percent, respectively, as assessed with values for area under the concentration curve and 65 percent and 62 percent as assessed with urinary excretion values); both forms had greater systemic availability than the tablet, which had bioavailability values of 50 percent using area under the curve and 41 percent using urinary excretion. Capsules and solution also were similar in peak plasma digoxin levels achieved (3.7 and 3.1 ng/ml), time of peak concentration (0.8 and 0.6 hour after dosage) and apparent first order absorption half-life (11.3 and 10.2 minutes); both capsules and solution differed significantly from tablets (peak level 1.6 ng/ml, time of peak concentration 1.2 hours and absorption half-life 27.1 minutes). Single dose findings were substantiated when steady state plasma levels and 24 hour urinary excretion values were measured from days 11 through 16 of the period of once daily ingestion. Mean plasma levels (0.70 ng/ml) and urinary excretion values (45.1 percent of dose) for capsules were nearly identical to those for solution (0.69 ng/ml and 42.5 percent of the dose), and values for both capsules and solution were significantly greater than those for tablets. Within- and between-subject variation in bioavailability was similar for the three oral preparations. Thus the single dose bioavailability study was predictive of the steady state findings. The bioavailability of digoxin capsules is equivalent to that of a solution and significantly greater than that of a reference tablet formulation.     

Pharmacokinetic and pharmacodynamic comparison of an osmotic release oral metoprolol tablet and the metoprolol conventional tablet

Four double-blind, Latin-square studies were conducted to compare the pharmacokinetics and pharmacodynamic bioavailability of metoprolol OROS (oral osmotic) and the conventional tablet (CT) of metoprolol. Metoprolol OROS (7/95 mg or 14/190 mg) was administered once daily in doses equivalent to 100 mg of metoprolol CT given once, twice, thrice, and four times a day. In all four studies, lower peak plasma concentrations and longer times to peak were observed after metoprolol OROS than after metoprolol CT, indicating a controlled-release profile for metoprolol OROS. beta-Adrenergic blockade, as measured by reductions in exercise heart rate, was lower after metoprolol OROS than after metoprolol CT, but metoprolol OROS provided a smoother and more sustained beta-blockade. All four doses of metoprolol OROS at steady state produced relative pharmacodynamic bioavailability that ranged from 87% to 104% of that produced by equivalent doses of metoprolol CT.     

Oral administration of iron with vitamin C in haemodialyzed patients

One tablet of Sorbifer Durules contains 100 mg Fe2+ and 60 mg vitamin C. The authors examined in a short-term study 24 haemodialyzed patients with chronic renal failure of different etiology. The investigation was divided into three parts. During the first 4 weeks the patients did not receive Fe2+ nor vitamin C. During the subsequent four weeks the patients had Sorbifer Durules, one tablet/24 hours. This period was followed by another four weeks when the patients went again without Fe2+ and vitamin C treatment. At regular intervals, i.e. on days 0, 28, 56 and 84 the authors assessed the packed cell volume, blood haemoglobin and serum iron level, the total iron binding capacity, transferrin saturation, ferritin, and vitamin C in serum as well as the plasma oxalic acid level. Four weeks treatment using Sorbifer Durules led to a significant rise of the packed cell volume and haemoglobin in blood, iron and vitamin C in serum. This treatment did not affect the oxalic acid plasma level. Oral treatment with Sorbifer Durules, one tablet/24 hours, was adequate for maintaining the serum iron concentration in haemodialyzed patients during treatment with recombinant human erythropoietin. This treatment prevented at the same time the development of vitamin C deficiency in serum and a further rise of plasma oxalic acid in these patients.     

Comparative study of atenolol, metoprolol, metoprolol durules, and slow-release oxprenolol in essential hypertension.

Twenty-five patients with moderate essential hypertension (standing diastolic blood pressure 100-125 mmHg, phase 5) completed a single-blind placebo-controlled cross-over study comparing four week periods of treatment with atenolol 100 mg, metoprolol 100 mg, metoprolol durules 200 mg, slow-release oxprenolol 160 mg, and slow-release oxprenolol 320 mg respectively. All the drugs were significantly better than placebo at reducing resting blood pressure at 24 hours. Atenolol produced the greatest mean reduction of pressure and was the most effective drug for most patients, though the differences between atenolol and metoprolol durules were not statistically significant. These two drugs, however, were significantly more effective than the remainder. A similar ranking was seen with respect to the reduction of the blood pressure and heart rate response to exercise. None of the treatments had any significant effect on the patients' rating of perceived exertion during the exercise test.     

Pharmacokinetics of sustained release and conventional tablets of theophylline plus hydroxyethyltheophylline and its comparison with tablet aminophylline.

Pharmacokinetics of a sustained release (SR) and conventional formulations of theophylline plus hydroxyethyltheophylline was compared with tablet aminophylline. Time concentration curve of serum theophylline with the three formulations after single and multiple dosage schedules revealed significantly retarded absorption with the SR preparation. SR tablet was also seen to produce uniform steady state levels with fluctuation of serum concentrations within the therapeutic range for a duration of over 12 hours. In comparison, aminophylline and conventional theophylline hydroxyethyltheophylline tablets produced sharp swings in steady state levels with trough levels dipping to subtherapeutic concentrations within 4-6 hours. SR formulation, therefore, is likely provide consistent serum levels and better therapeutic control in comparison to the other two conventional tablets.     

A comparison of once and twice daily atenolol for angina pectoris

We have studied the effects of four doses of atenolol in 11 patients with stable angina pectoris using a symptom-limited exercise test and angina diaries. The doses 100 mg twice daily and 50 mg, 100 mg and 200 mg once daily were given double-blind and randomised within patients following run-in on placebo. Measurements were made 12 hours after the last twice daily dose and 24 hours after the last once daily dose. Exercise tolerance was improved by 40-74% and exercise duration before the onset of angina by 61-94% (P less than 0.01). Maximal heart rate was reduced further by a total daily dose of 200 mg than by lower doses, but no extra benefit was derived by giving the drug twice daily. The largest increase in exercise tolerance was obtained during treatment with 50 mg once daily. Atenolol was shown to be an effective anti-anginal agent when given once daily, and there were no major differences between the doses studied.     

Differing beta-blocking effects of carvedilol and metoprolol

BACKGROUND: Metoprolol is a beta(1)-selective beta-adrenergic antagonist while carvedilol is a non-selective beta-blocker with additional blockades of alpha(1)-adrenoceptors. Administration of metoprolol has been shown to cause up-regulation of beta-adrenoceptor density and to decrease nocturnal melatonin release, whereas carvedilol lacks these typical effects of beta-blocking drugs. AIMS: To compare beta-blocking effects of metoprolol and carvedilol when applied orally in healthy subjects. Methods: We investigated the effects of single oral doses of clinically recommended amounts of metoprolol (50, 100 and 200 mg) and carvedilol (25, 50 and 100 mg) to those of a placebo in a randomised, double-blind, cross-over study in 12 healthy male volunteers. Two hours after oral administration of the drugs heart rate and blood pressure were measured at rest, after 10 min of exercise, and after 15 min of recovery. RESULTS: Metoprolol tended to decrease heart rate during exercise (-21%, -25% and -24%) to a greater extent than carvedilol (-16%, -16% and -18%). At rest, increasing doses of metoprolol caused decreasing heart rates (62, 60 and 58 beats/min) whereas increasing doses of carvedilol caused increasing heart rates (62, 66 and 69 beats/min), 50 and 100 mg carvedilol failed to differ significantly from the placebo (71 beats/min). CONCLUSIONS: We conclude that clinically recommended doses of carvedilol cause a clinically relevant beta-blockade in humans predominantly during exercise where it appears to be slightly (although not significantly) less effective than metoprolol. On the other hand, the effects of carvedilol on heart rate at rest appear rather weak, particularly in subjects with a low sympathetic tone. This might be caused by a reflex increase on sympathetic drive secondary to peripheral vasodilation resulting from the alpha-blocking effects of the drug. These results might be helpful in explaining why carvedilol, in contrast to metoprolol, may fail to cause up-regulation of beta-adrenoceptor density and does not decrease nocturnal melatonin release. This, in turn, may be a reason for the weak side-effects of carvedilol resulting from the beta-blockade. In addition, our data might be of interest in the interpretation of the forthcoming results of the COMET trial, although it has to be emphasised that they were derived from healthy subjects and, therefore, cannot be directly extrapolated to patients with heart failure.     

Antianginal efficacy of the combination of felodipine-metoprolol 10/100 mg compared with each drug alone in patients with stable effort-induced angina pectoris: a multicenter parallel group study. The TRAFFIC Study Group

OBJECTIVE: The primary objective of this randomized, double-blind, parallel group trial was to compare the antianginal and antiischemic efficacy of a combination tablet of felodipine-metoprolol 10/100 mg once daily with both drugs given separately once daily in patients with stable effort-induced angina pectoris. The secondary objective was to compare the tolerability of the 3 treatments. METHODS: The main criteria for inclusion were stable effort-induced angina pectoris for at least 2 months before the enrollment and a positive bicycle exercise test result. Patients were allocated to once-daily treatment with either felodipine-metoprolol 10/100 mg, felodipine 10 mg, or metoprolol 100 mg. The duration of active double-blind treatment was 4 weeks. There were 3 primary efficacy variables in the study; time until end of exercise, time until onset of chest discomfort, and time until 1-mm ST depression during a standardized exercise test. RESULTS: The number of patients randomized was 397. There was a statistically significant improvement in time until end of exercise with felodipine-metoprolol 10/100 mg compared with metoprolol 100 mg (P =.04) and felodipine 10 mg compared with metoprolol 100 mg ( P =.03). However, for time until onset of pain or time until 1-mm ST-depression there were no significant differences among the treatment groups. At highest comparable workload, ST depression was less pronounced with felodipine-metoprolol than with metoprolol alone (P =.04), and the rate-pressure product was significantly lower in the groups receiving felodipine-metoprolol and metoprolol than in the group receiving felodipine alone. The combination and metoprolol were better tolerated than felodipine alone. CONCLUSIONS: In stable angina pectoris, the combination felodipine-metoprolol 10/100 mg and felodipine 10 mg alone increased exercise time compared with metoprolol 100 mg. The combination tablet and metoprolol 100 mg alone showed a more favorable tolerability profile than felodipine 10 mg alone.     

Effects of felodipine on plasma digoxin levels and haemodynamics in patients with heart failure

The interaction between felodipine and digoxin was studied after a single oral dose and at steady state in 14 patients with congestive heart failure. Felodipine (10 mg) was randomly given as an extended release (FER) tablet in a double-blind, placebo-controlled, cross-over fashion. In addition, felodipine (10 mg) was given openly as a plain tablet, following the double-blind period. Each period lasted for 7 d. Felodipine ER did not alter the pharmacokinetics of digoxin when given as a single dose or at steady state compared with placebo. At steady state the felodipine plain tablet resulted in an 11% increase (P less than 0.05) in peak plasma concentrations of digoxin. Systolic time intervals as noninvasively measured haemodynamic parameters were not significantly altered following the felodipine ER period, while the felodipine plain tablet significantly decreased the pre-ejection/left ventricular ejection time ratio compared to placebo.     

MERIT-HF - description of the trial

The MERIT-HF study was a randomized, double-blind, placebo-controlled trial with a single-blind, two-week placebo run-in period. There were two primary objectives: total mortality; and the combined endpoint of total mortality or all-cause hospitalizations (time to first event). Several other combined endpoints were also predefined, as were number of hospitalizations due to heart failure and other cardiovascular causes, withdrawal of study medicine due to all causes, and due to worsening heart failure, and change in NYHA class. The effect on Quality of Life was assessed in a substudy. The major inclusion criteria were symptomatic heart failure for at least 3 months corresponding to NYHA class II-IV; and a left ventricular ejection fraction of 0.40 or less in 40 to 80 year old men and women. The patients had to be on optimal treatment for at least 2 weeks prior to randomization, defined in principle as any combination of diuretics and an ACE inhibitor. The recommended starting dose was half a 25 mg tablet of metoprolol CR/Zok once daily in patients in NYHA functional class III-IV, and one 25 mg tablet once daily in patients in NYHA class II. It was recommended to double the dose after each 2-week period in order to reach the highest tolerated dose aiming for a target dose level of 200 mg once daily of metoprolol CR/Zok or placebo. This dosage regimen could be modified according to the judgement of the investigator. Randomization began on February 14, 1997, and the last patient was randomized April 14, 1998. 1990 patients were randomized to metoprolol CR/Zok and 2001 to placebo. The International Steering Committee stopped the study by October 31, 1998, upon recommendation from the Independent Safety Committee. The second pre-planned interim analysis (50% point) had shown that the pre-defined criterion for termination of the study was met and exceeded. The mean follow-up time was 1 year.     

Gastric mucosal damage caused by plain and microencapsulated acetylsalicylic acid tablets in healthy subjects: a gastrocamera study.

In a randomized, cross-over study plain acetylsalicylic acid (ASA) tablet and microencapsulated ASA tablets were given in doses of 1 gram 3 times a day for 3 days to 8 healthy subjects with no previous gastrointestinal disturbances. Gastrocamera examinations were performed before the ASA treatment and 1--2 hours after the last dose of ASA. The gastric mucosa appeared macroscopically normal at all the control examinations; whereas musocal bleeding was evident in all the subjects after the ASA treatment. There was no statistically significant difference between the plain ASA and the microencapsulated ASA preparations. No correlation could be found between the ASA concentration in plasma and the gastric mucosal damage.     

A Comparison of 100 mg Atenolol and 100 mg Metoprolol Once a Day at Rest and during Exercise in Hypertensives

Abstract The effects of once daily dosage of the two cardioselective β-adrenoceptor blocking agents, atenolol and metoprolol, were studied in 26 patients with primary hypertension. The study was a randomized double-blind cross-over trial with placebo run-in and wash-out. Assessment of effect was performed about 1 and 25 hours after dosing. At rest, both atenolol and metoprolol lowered the blood pressure (BP) and heart rate (HR) compared to placebo. Atenolol induced a more effective BP reduction than metoprolol, especially 25 hours after drug intake. During exercise 1 hour after dosing both drugs reduced BP and HR to a similar extent, whereas 25 hours after dosing atenolol gave a more efficient BP and HR reduction than metoprolol. Our data show that both 100 mg atenolol and 100 mg metoprolol are effective antihypertensive β-blockers at rest and during exercise, 1 hour after intake. Metoprolol was less effective than atenolol 25 hours after dosing probably due to its shorter plasma half-life, thus implying a twice daily regimen for metoprolol in standard preparation.     

Pulmonary effects of long-term beta 2-blockade in healthy subjects: comparative study of metoprolol OROS

The effects on airway response of metoprolol OROS (oral osmotic) and three other long-acting beta-adrenoceptor blockers were studied. This was a placebo-controlled, randomized, five-period, single-blind, crossover trial in 15 healthy volunteers. Bronchial beta-blockade was estimated as the displacement of the salbutamol bronchodilator response of specific airway conductance (SGAW) measured by whole-body plethysmography. Metoprolol OROS (14/190 mg), slow-release (SR) metoprolol (200 mg), atenolol (100 mg), long-acting (LA) propranolol (160 mg), and placebo were given once daily for 7 days. Inhaled salbutamol was administered at peak drug levels in cumulative doses of 12.5 to 800 micrograms on day 5 and in a single dose of 400 micrograms on day 7. On day 5, salbutamol induced significant increases in SGAW in each treatment group. SGAW increased after the single dose of salbutamol on day 7 in all groups and then declined steadily. The highest values were found after placebo and metoprolol OROS, with smaller increases after SR metoprolol, atenolol, and LA propranolol, the latter showing the smallest increase. Therefore, it would appear that under steady-state conditions, beta 2-bronchial receptors are least blocked by metoprolol OROS, followed by SR metoprolol, atenolol, and LA propranolol.     

A clinical evaluation of sustained release metoprolol durules in the treatment of angina pectoris

Summary: A clinical comparison of the sustained release form of metoprolol, consisting of a 200 mg metoprolol durule, with 100 mg conventional metoprolol twice daily, has been carried out to assess the therapeutic control of ten patients with stable angina pectoris. Objective measurements of heart rate, blood pressure, and ECG recordings were assessed during exercise on a bicycle ergometer. Ten patients completed the 8-week double-blind study. There were similar changes in heart rate and blood pressure at rest and during exercise, both at 2h and at 12 and 24 h postdose. Although similar exercise tolerance was achieved on both regimes, there was significantly less ST-segment depression at 24h post durule, in comparison with the 12h post conventional metoprolol reading, suggesting that metoprolol durules produce a more effective reduction in the degree of myocardial ischemia.     

Duration of effects and tolerance of slow-release isosorbide-5-mononitrate for angina pectoris

Isosorbide-5-mononitrate (IS-5MN) is an active metabolite of isosorbide dinitrate, but unlike its parent compound, is nearly 100% bioavailable after oral administration. Once-a-day therapy with a slow-release formulation of IS-5MN is used widely in Europe for 24-hour prophylaxis of angina pectoris. In a randomized, crossover, double-blind, placebo-controlled study, the duration of effects of 50 and 100 mg of slow-release IS-5MN were evaluated after the first dose and after once-a-day therapy for 1 week in 9 patients with stable angina pectoris. Compared with placebo values, standing blood pressure decreased (p less than 0.001) and exercise time to the onset of angina and total exercise duration increased (p less than 0.008 and p less than 0.003) at 4 hours, but not at 20 or 24 hours after first dose of 50 and 100 mg of slow-release IS-5MN. After once-a-day therapy for 1 week, no improvement in exercise duration or reduction in ST-segment depression was seen after 50 or 100 mg of slow-release IS-5MN at 4, 20 or 24 hours despite high plasma IS-5MN concentrations. Thus, despite therapeutic plasma concentrations, 50 and 100 mg of slow-release IS-5MN did not exert antianginal or anti-ischemic effects at 20 and 24 hours after the first dose and at 4, 20 and 24 hours after sustained once-a-day therapy for 1 week.     

Controlled release levodopa/carbidopa (Sinemet CR4) in Parkinson's disease – an open evaluation of efficacy and safety

Abstract Twenty patients with moderately severe Parkinson's disease entered an open study of the efficacy and safety of a slow release preparation containing levodopa 200mg and carbidopa 50mg per tablet (‘Sinemet CR4’). Following an initial four week baseline stabilisation period on conventional ‘Sinemet’ tablets, the patients were transferred to ‘Sinemet CR4’ and observed at intervals over the next 12 months. Fifteen patients completed the full year observation period. When compared with the baseline period, treatment with ‘Sinemet CR4’ was associated with longer periods of functional improvement and less fluctuation of response following each dose. The median (range) dose frequency was reduced from three (three-12) to two (two-seven) times daily (p< 0.001) on ‘Sinemet CR4’ although median (range) total daily dose of levodopa was increased from 700 (375–2525) to 800 (400–2800) mg without any increase in adverse effects. Three patients developed peripheral neuropathy while receiving Sinemet CR4, but the association with this therapy is unclear. Overall ‘Sinemet CR4’ allowed a longer dosage interval and provided more stable control of disease manifestations than conventional ‘Sinemet’. (Aust NZ J Med 1991; 21: 397–400.)     

Study of hemodynamic effects of allapinin and metoprolol using continuous wave Doppler echocardiography at rest and during physical exercise in patients with paroxysmal supraventricular tachycardia]

Doppler echocardiography is an excellent tool to study the hemodynamic effects of cardiac drugs. Resting and exercise effects produced by metoprolol and allapinin on Doppler-derived measures of left ventricular (LV) performance were examined in patients with paroxysmal supraventricular tachycardias. Seventeen patients underwent continuous wave Doppler examination from the suprasternal notch at rest and during each stage of a standard exercise protocol. The study was repeated following 3-4 days of treatment with metoprolol given in a daily dose of 200 mg. The hemodynamic effects of allapinin, 100 mg daily, were evaluated in the same manner in 8 patients. With metoprolol, all resting Doppler measurements were altered insignificantly and all Doppler--derived parameters of aortic flow (peak, velocity, mean acceleration, cardiac index and LV ejection force) were much lower at the maximum exercise. Allapinin failed to alter any Doppler measurements of aortic blood flow at rest or during the peak exercise.