General

Metoprolol is a beta₁-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta₂-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction.

Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.

The relative beta₁-selectivity of metoprolol has been confirmed by the following: (1) In normal subjects, metoprolol is unable to reverse the beta₂-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces FEV₁ and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta₁-receptor blocking doses.

In five controlled studies in normal healthy subjects, the same daily doses of TOPROL-XL and immediate release metoprolol were compared in terms of the extent and duration of beta₁-blockade produced. Both formulations were given in a dose range equivalent to 100-400 mg of immediate release metoprolol per day. In these studies, TOPROL-XL was administered once a day and immediate release metoprolol was administered once to four times a day. A sixth controlled study compared the beta₁-blocking effects of a 50 mg daily dose of the two formulations. In each study, beta₁-blockade was expressed as the percent change from baseline in exercise heart rate following standardized submaximal exercise tolerance tests at steady state. TOPROL-XL administered once a day, and immediate release metoprolol administered once to four times a day, provided comparable total beta₁-blockade over 24 hours (area under the beta₁-blockade versus time curve) in the dose range 100–400 mg. At a dosage of 50 mg once daily, TOPROL-XL produced significantly higher total beta₁-blockade over 24 hours than immediate release metoprolol. For TOPROL-XL, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta₁-blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/trough (ie, at 24-hours post-dosing) were: 14/9, 16/10, 24/14, 27/22 and 27/20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg TOPROL-XL once a day, respectively. In contrast to TOPROL-XL, immediate release metoprolol given at a dose of 50–100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with TOPROL-XL over the dosing range of 200 to 400 mg, a t.i.d. to q.i.d. divided dosing regimen was required for immediate release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta₁-blocking effects of 50 mg immediate release metoprolol administered t.i.d., 100 mg and 200 mg TOPROL-XL once daily. A 50 mg dose of immediate release metoprolol t.i.d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of TOPROL-XL. A 200 mg dose of TOPROL-XL produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate release metoprolol.

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