What is documented concerning effects and side-effects of controlled release metoprolol (Seloken ZO

Fråga: What is documented concerning effects and side-effects of controlled release metoprolol (Seloken ZOC), as compared to ordinary metoprolol (Seloken) or other betablockers, such as atenolol, in the treatment of hypertension?

Sammanfattning: A smoother plasma concentration profile of metoprolol in a controlled release formulation allows for lower dosage and seems beneficial with respect to tolerability compared to ordinary metoprolol. No conclusive differences in effect or tolerability have been shown between atenolol and controlled release metoprolol in equal doses.

Svar: The literature concerning effects and side-effects of different betablockers for different indications is extensive. The following answer focuses on controlled clinical trials comparing the two in Sweden currently available oral formulations of metoprolol and/or atenolol in the treatment of hypertension.

Metoprolol is a lipophilic selective beta-1-receptor antagonist used for the treatment of hypertension, angina pectoris and (supraventricular) arrhythmia. The tablet form is well absorbed with a maximal plasma concentration peak within 1-2 hours. The bioavailability is 40-50 percent due to first pass metabolism. The plasma half-life is 3-5 hours. Metoprolol is metabolised before urinary excretion, mainly by the polymorphic CYP2D6 enzyme. The controlled release formulation contains coated microgranulae, resulting in approximately zero-order absorption over a 24-hour interval. The bioavailability of the controlled release formulation is 30-40 per cent, ie somewhat lower compared to the tablets. The controlled release metoprolol formulation is claimed to give a 24-hour control of blood pressure and enhanced beta-1-selectivity, due to a constant, low plasma concentration profile (3).

Atenolol is a hydrophilic beta-1-selective antagonist. It has a varying and approximately 50 per cent bioavailabilty, and a maximal plasma concentration after 2-4 hours and a half-life of 6-9 hours. It is mainly excreted renally as unchanged drug. A low frequency of CNS-related side-effects, in comparison with (ordinary) metoprolol and the highly lipophilic substance propanolol, has been attributed to the low degree of passage over the blood-brain barrier of atenolol (1-2).

In comparative studies, 50 mg controlled release metoprolol has been shown to be as effective as 100 mg ordinary metoprolol or 50 mg atenolol in the treatment of moderate hypertension (3, 4). This may be explained by the fact that more pharmacological effect per dose of drug is obtained when the plasma concentration time curve is flat as common receptor theory predicts this profile to be more efficient than profiles with great fluctuations. The controlled release metoprolol formulation also seemed to be better tolerated than ordinary metoprolol. The total number of adverse events differed significantly between the two treatment groups. The plasma concentration varied between approximately 50-100 nmol/l over 24 hours after intake of 50 mg controlled release metoprolol, whereas a peak concentration between 600-700 nmol/l was seen after intake of 100 mg metoprolol (3). In 12 healthy volunteers, a lesser effect on terbutaline induced hyperglycemia and hypokalemia in healthy volunteers, as a sign of higher beta-1-selectivity, was seen with 100 mg metoprolol controlled release compared to 100 mg metoprolol and 100 mg atenolol (5). Whether this difference is true for the usually recommended doses of 50 mg for both controlled release metoprolol and atenolol is uncertain. In a patient study, no difference in side-effect frequency was seen when 100 mg controlled release metoprolol was compared to 100 mg atenolol (6).

The above mentioned studies are in agreement with data retrieved from the files of the Swedish Adverse Drug Reactions Advisory Committee (SADRAC). A total of 226 side-effects have been reported for atenolol and 466 reports for metoprolol, 344 of which concern Seloken and 94 Seloken ZOC. For metoprolol, one third of the reports concern psychiatric effects with nightmares being the single most common side-effect. Seloken and Seloken ZOC have similar side-effect profiles, only with overall fewer reports for Seloken ZOC. Both drugs have a total prescription in Sweden of approximately 370000 defined daily doses (DDD). For atenolol, with a total of 690000 DDD prescribed in Sweden, psychiatric effects constitute one fifth of the reports, with depression as the most common diagnosis. The profile and amount of side-effect reports, when related to the amount of prescribed daily doses, are very similar for Seloken ZOC and atenolol, whereas significantly more side-effects have been reported for Seloken. 1 Cove-Smith JR, Kirk CA: CNS-related side-effects with metoprolol and atenolol. Eur J Clin Pharmacol 1985; 28(suppl): 69-72 2 Westerlund A: Central nervous system side-effects with hydrophilic and lipophilic beta-blockers. Eur J Clin Pharmacol 1985; 28(suppl): 73-76 3 Omvik P, Leer J, Istad H, Westergren G: Equal efficacy and improved tolerability with 50 mg controlled-release metoprolol compared with 100 mg conventional metoprolol in hypertensive patients. Am J Therap 1994; 1: 65-73 4 Klein G, Berger J, Olsson G, Menzel T: A double-blind comparison of metoprolol CR/ZOK 50 mg and atenolol 50 mg once daily for uncomplicated hypertension. J Clin Pharmacol 1990; 30: S72-S77 5 Kendall M, Akhlaghi S, Hughes B, Lewis H: Is metoprolol CR/ZOK more selective than conventional metoprolol and atenolol. J Clin Pharmacol 1990; 30: S98-S102 6 Walle P-O, Westergren G, Dimenäs E, Olofsson B, Albrektsen T: Effects of 100 mg of controlled-release metoprolol and 100 mg of atenolol on blood pressure, central nervous system-related symptoms, and general well being. J Clin Pharmacol 1994; 34: 742-747