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Conventional formulations of metoprolol have become well established in cardiovascular medicine and are particularly useful in the management of hypertension and ischaemic heart disease. Recently developed controlled release metoprolol delivery systems (metoprolol CR/ZOK and metoprolol OROS) were designed to overcome the drug delivery problems of matrix-based sustained release forms by releasing the drug at a relatively constant rate over a 24-hour period, and thus producing sustained and consistent metoprolol plasma concentrations and beta 1-blockade while retaining the convenience of once daily administration. Clinically and statistically significant reductions in blood pressure have been observed with metoprolol CR/ZOK and metoprolol OROS 24 hours after administration in mildly or moderately hypertensive patients. Studies in patients with mild to moderate hypertension have demonstrated that a similar or higher percentage of patients achieved a goal response with metoprolol CR/ZOK compared with matrix-based sustained release formulations of metoprolol, or conventional atenolol or bisoprolol, while metoprolol OROS achieved an equal or greater response rate compared with conventional or matrix-based sustained release metoprolol preparations. In patients with stable effort angina pectoris, once daily administration of metoprolol CR/ZOK provided at least equal antianginal efficacy as conventional metoprolol in divided doses, while metoprolol OROS reduced the mean number of anginal attacks by the same margin as atenolol. Controlled release metoprolol formulations have been well tolerated in clinical trials. Metoprolol CR/ZOK was associated with a similar or lesser degree of adverse effects related to the central nervous system compared with atenolol or long acting propranolol. Metoprolol CR/ZOK also demonstrated less pronounced beta 2-mediated bronchoconstrictor effects than atenolol in asthmatics, and less general fatigue and leg fatigue in healthy subjects. Metoprolol OROS produced less pronounced bronchoconstrictor effects than atenolol, matrix-based sustained release metoprolol or long acting propranolol in patients with asthma or obstructive airways disease, and healthy volunteers. These results are presumably due to the beta 1-selectivity of metoprolol in addition to the relatively low plasma concentrations maintained by metoprolol CR/ZOK and metoprolol OROS, and the avoidance of high peak plasma concentrations with these agents. Despite the relative safety of the controlled release forms of metoprolol, the use of all beta-adrenoceptor antagonists should be avoided in patients with a history of bronchospasm. Thus, controlled release metoprolol formulations offer the potential to maximise the confirmed benefits of this agent in the management of hypertension and angina, by maintaining clinically effective plasma concentrations within a narrow therapeutic range over a 24-hour dose interval.
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PMID:Controlled release metoprolol formulations. A review of their pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and ischaemic heart disease. 137 20

The quality of life has become an important element in assessment of medicinal treatment. As an independent expression, the quality of life covers the human disappointments which a medical disease may involve ("discomfort") whereas the clinical dysfunction caused by the disease is covered by the expression "disability". In the treatment of essential arterial hypertension, the clinical symptoms of the disease are few or none ("asymptomatic hypertension"). In an investigation of 303 patients in general practice for arterial hypertension, the significance of the frequency of dosage of metoprolol (Seloken) was assessed by means of measurement of the quality of life by the General Health Questionnaire (GHQ), a questionnaire which contains components such as fatigue, sleep, anxiety and depression. No advantages in the quality of life were found in administering antihypertensive drugs once or twice daily. From the methological point of view, the following conditions were found which should be taken into consideration in future investigations in this field: The GHQ was found to be easy for the patients to employ. This is important as the quality of life is a personally experienced dimension. The questionnaire correlated adequately with the visual analogue scales. Approximately 1/3 of the patients had reduced quality of life at the commencement of the investigation as assessed by GHQ. A multiple regression analysis revealed that the reduced well-being was due to social, life events and side effects. It is therefore recommended that these aspects should be described when patients commence a course of medicinal treatment i.e. the social life events and side effects of the medicine in connection with the actual subjective dimension of quality of life.
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PMID:[Measurement of the quality of life as a element in assessing therapeutic effects in essential arterial hypertension. Methodologic aspects]. 230 Oct 90

The authors tested in an open, uncontrolled trial in a group of 23 patients with essential hypertension grade I-II (WHO classification) the effect of Metoprolol OROS. The OROS system is a new form of Metoprolol administration which makes it possible to maintain by a single dose per day a steady plasma concentration, while preserving the cardioselectivity and total 24-hour effectiveness during treatment of hypertension and angina pectoris. After eight weeks of Metoprolol OROS administration, in doses gradually adjusted to the therapeutic action, gradually a significant decrease of the heart rate (HR) occurred, of the systolic blood pressure (BPs) and diastolic blood pressure (BPd) (p less than 0.01 for all values) in a recumbent as well as upright position. A reduction of the BPd in an upright position by greater than or equal to 10 mm Hg was achieved in 85% of the patients, in 73.9% of the patients the BPd in an upright position dropped below 95 mm Hg. Four patients developed side-effects which were mild to medium severe (vertigo, palpitations, fatigue, sensation of tremor, tension in the lower extremities). Two patients discontinued treatment early, the main reason in both being palpitations which were under better conversely, in two patients palpitations which were not adequately controlled by previous metoprolol treatment, disappeared completely during Metoprolol OROS treatment. During the trial no significant changes in the investigated laboratory values incl. total cholesterol were recorded, Metoprolol OROS administered once per day is an effective, safe and well tolerated preparation in treatment of mild to medium severe essential hypertension.
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PMID:[The effect of OROS metoprolol in mild and moderately severe essential hypertension]. 239 74

1 Cardiovascular and sympatho-adrenal responsiveness to mental stress (CWT; a colour word test), orthostatic testing (ORT) and a cold pressor test (CPT) were examined in three groups of hypertensive patients (n = 14-16) before and after 6 months treatment with metoprolol (243 +/- 26 mg daily), propranolol (149 +/- 16 mg daily) or hydrochlorothiazide (50 +/- 8 mg daily) in an open trial design. 2 Treatment reduced outpatient blood pressures in the three groups similarly (from approximately 155/102 to 135/90 mm Hg). During treatment resting blood pressures in the laboratory were clearly reduced by beta-adrenoceptor blockade but not by thiazide treatment. Metoprolol and propranolol caused similar reductions of basal heart rates and plasma glycerol levels, whereas only propranolol reduced cyclic AMP concentrations in plasma. 3 Before treatment CWT and CPT increased systolic and diastolic blood pressures by about 30%. Heart rate increased by about 30 beats min-1 during CWT and 10-15 beats min-1 during CPT and ORT. Small venous plasma adrenaline responses were evoked by all tests, whereas noradrenaline was elevated mainly by CPT and ORT. Dopamine levels did not change. 4 Heart rate responses to all stressors were markedly and similarly reduced, whereas blood pressure responses were essentially unchanged during metoprolol or propranolol treatment. In the thiazide group circulatory responses to CWT were slightly attenuated, whereas responses to ORT and CPT were unchanged. 5 The systolic blood pressure levels were reduced throughout the test session in all three groups, although less so in the hydrochlorothiazide group. Both beta-adrenoceptor antagonists clearly reduced diastolic blood pressure and heart rate levels at rest and during stress, whereas thiazide treatment caused no significant changes in these respects. 6 The rate pressure product, which increased by 80-100% in response to CWT before treatment, was more markedly reduced by beta-adrenoceptor blockade than by thiazide treatment both at rest and during stress. 7 Self ratings (visual analogue scales) of stress and irritation were increased by CWT in a similar fashion before and during treatment in all groups. beta-adrenoceptor blockade was associated with higher subjective ratings of tiredness at rest, but not after CWT. Performance in the CWT increased slightly more in the thiazide group. The physiological responses to CWT were not correlated to the subjective responses.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Responses to mental stress and physical provocations before and during long term treatment of hypertensive patients with beta-adrenoceptor blockers or hydrochlorothiazide. 288 86

During the intervening years since metoprolol was first reviewed in the Journal (1977), it has become widely used in the treatment of mild to moderate hypertension and angina pectoris. Although much data have accumulated, its precise mechanisms of action in these diseases remain largely uncertain. Optimum treatment of hypertension and angina pectoris with metoprolol is achieved through dose titration within the therapeutic range. It has been clearly demonstrated that metoprolol is at least as effective as other beta-blockers, diuretics and certain calcium antagonists in the majority of patients. Although a twice daily dosage regimen is normally used, satisfactory control can be maintained in many patients with single daily doses of conventional or, more frequently, slow release formulations. Addition of a diuretic may improve the overall response rate in hypertension. Several controlled trials have studied the effects of metoprolol administered during the acute phase and after myocardial infarction. In early intervention trials a reduction in total mortality was achieved in one moderately large trial of prolonged treatment, but in another, which excluded patients already being treated with beta-blockers or certain calcium antagonists and where treatment was only short term, mortality was significantly reduced only in 'high risk' patients. Overall results with metoprolol have not demonstrated that early intervention treatment in all patients produces clinically important improvement in short term mortality. Thus, the use of metoprolol during the early stages of myocardial infarction is controversial, largely because of the requirement to treat all patients to save a small number at 'high risk'. This blanket coverage approach to treatment may be more justified during the post-infarction follow-up phase since it has been shown that metoprolol slightly, but significantly, reduces the mortality rate for periods of up to 3 years. Metoprolol is generally well tolerated and its beta 1-selectivity may facilitate its administration to certain patients (e.g. asthmatics and diabetics) in whom non-selective beta-blockers are contraindicated. Temporary fatigue, dizziness and headache are among the most frequently reported side effects. After a decade of use, metoprolol is well established as a first choice drug in mild to moderate hypertension and stable angina, and is beneficial in post-infarction patients. Further study is needed in less well established areas of treatment such as cardiac arrhythmias, idiopathic dilated cardiomyopathy and hypertensive cardiomegaly.
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PMID:Metoprolol. An updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in hypertension, ischaemic heart disease and related cardiovascular disorders. 294 80

Various publications have described a beta 2-receptor regulated potassium transport system in the cellular membrane of human skeletal muscle. To examine the suggestion that serum potassium alterations are among the causes of premature muscular fatigue during physical exercise under pharmacological blockade of beta-receptors, we have compared the influence of sustained blockade with a beta 1-selective blocker and a nonselective beta-blocker on the levels of serum potassium before, during and after a physical exercise test. 63 healthy physical education students received in random order and under double blind conditions either 100 mg Metoprolol (beta 1-selective) or 80 mg Propranolol (non-selective), or placebo daily for 3 months. Serum potassium was measured before, during (at 150 Watt and at the end of exercise) and after a bicycle exercise with a stepwise increase in work loads. After three months of beta-blocker treatment serum potassium levels during exercise were significantly higher than in control subjects receiving the placebo, and it took longer for the serum potassium levels to return to the resting level in the beta-blocker treated subjects. At rest, however, the levels were not found to be statistically different. In the subjects receiving Propranolol the post-exercise serum potassium levels were higher than in the subjects receiving Metoprolol. Three days after cessation of the medication these differences were no longer perceptible. Our findings confirm the existence of a beta-receptor regulated potassium transport system in human skeletal muscle and indicate that the transmembranous potassium transport in human skeletal muscle is predominantly regulated via beta 2-receptors, although beta 1-receptors seem also to be involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Physical performance and serum potassium under chronic beta-blockade. 299 86

Pharmacokinetic and pharmacodynamic properties of a new controlled-release (CR) formulation of metoprolol have been compared with those of atenolol. Metoprolol CR (100 mg and 200 mg), atenolol (50 mg and 100 mg) and placebo were each given once daily for four days in a double-blind, cross-over study to ten healthy men. The plasma concentration-time profiles were more even with metoprolol CR than with atenolol over the 24-h dose interval, shown by the lower fluctuation ratio and the longer time period during which the plasma concentration exceeded 50% of the maximum concentration. All four active treatment regimens reduced exercise heart rate over the 24-h period compared with placebo. However, the reduction in both exercise heart rate and systolic blood pressure (SBP) was more even with metoprolol CR than with atenolol. The remaining beta 1-blockade after 24 h, expressed as the percentage reduction in exercise heart rate in relation to placebo, was significantly greater after the administration of metoprolol CR, 200 mg, than after either dose of atenolol. At this time the beta 1-blockade with metoprolol CR, 100 mg, was similar to that with atenolol, 100 mg. At peak plasma concentrations, 4 h after the dose, the subjects experienced less fatigue during exercise with metoprolol CR than with atenolol.
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PMID:Pharmacokinetics and pharmacodynamics of controlled-release metoprolol: a comparison with atenolol. 337 90

The antihypertensive effects of oral labetalol, a new alpha- and beta-adrenergic blocking agent, and metoprolol, a relatively beta1 selective adrenergic blocker, were evaluated in 91 patients with mild to moderate hypertension (standing diastolic blood pressure of 90 to 115 mm Hg) in a double-blind parallel group multicenter clinical trial. The effects of the two drugs on plasma lipids and lipoprotein fractions were also assessed. Following a four-week placebo phase, 44 patients were randomized to receive labetalol and 47 metoprolol. During a four-week titration phase, the labetalol dose was increased from 100 mg twice daily to a maximum of 600 mg twice daily to achieve a standing diastolic blood pressure of 90 mm Hg that was decreased by 10 mm Hg or more. Metoprolol was titrated from 50 mg to 200 mg twice daily. An eight-week maintenance period followed during which hydrochlorothiazide could be added. At the end of the maintenance phase, the doses of labetalol and metoprolol were tapered over a two to four day period after which patients received a placebo for one week. Blood pressure in the supine and standing position was measured at each visit. Labetalol and metoprolol both significantly (p less than 0.01) lowered the supine and standing blood pressure from baseline with no significant difference found between the two treatment groups. Both drugs lowered the heart rate; however, the rate-lowering effect was significantly greater with metoprolol (p less than 0.01). There were no significant effects of either drug on plasma lipids or lipoprotein fractions. Fatigue was the most frequently reported complaint with both drugs. Dizziness, dyspepsia, and nausea were more common with labetalol; bradycardia was more common with metoprolol. There was no blood pressure "overshoot" after withdrawing drug treatment; however, a heart rate "overshoot" was seen after metoprolol was tapered off and stopped. Labetalol is as safe and effective as metoprolol in the treatment of patients with mild to moderate hypertension.
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PMID:Multiclinic comparison of labetalol to metoprolol in treatment of mild to moderate systemic hypertension. 635

The effect of metoprolol, a beta1-selective receptor blocking agent without intrinsic stimulating activity, on blood pressure, pulse and plasma concentration 2 and 24 h after dose intake and on working capacity and perceived exertion 2 h after dose intake was investigated when given as 100 mg and 200 mg conventional tablets or 200 mg slow-release tablets (Durules) once daily, long-term, to 20 patients with primary (essential) hypertension. Metoprolol 100 mg and 200 mg once daily effectively lowers blood pressure over a 24-h period, and 200 mg Durules once daily gives beta-receptor blockade for 24 h. Peak plasma concentration 2 h after dose intake and individual variations in plasma concentrations are reduced on 200 mg Durules compared with 200 mg conventional tablets. Working capacity is not reduced, though perceived exertion and leg fatigue seem to be slightly increased with metoprolol, especially 200 mg conventional tablets.
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PMID:Metoprolol administered once daily in the treatment of hypertension. A double-blind crossover comparison between conventional tablets and metoprolol Durules. 702 91

The cardioselective betablocking agent metoprolol was used to treat 21 outpatients with essential arterial hypertension graded 1 and 2 of the OMS scale. The treatment was given orally for a mean duration of nine weeks at doses of 100 mg/day for two weeks and 200 mg/day for the remaining time. The treatment caused a significant reduction of systolic and diastolic arterial pressure (p less than 0.001), both in the erect and the lying down position. The heart rate was also significantly reduced both in the lying down (p less than 0.01) and the erect (p less than 0.05) positions. Metoprolol was shown to be effective and well tolerated as an antihypertensive agent; the treatment had to be interrupted in a single case because of dizziness, tiredness and dullness.
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PMID:[Metoprolol in the treatment of essential hypertension (author's transl)]. 720 75


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