Comparison of Withdrawal Phenomena After Propranolol, Metoprolol and Pindolol

Summary

Three groups of hypertensive patients were studied after they had received one of three pharmacologically different beta blockers for at least one month: PIND 10 mg bid (n=10), PROP 80 mg tid (n = 9), MET 150 mg bid (n = 8). After abrupt withdrawal of drug and replacement with placebo we measured the following on days zero (0) and about every 2nd day for up to 3 weeks: beta adrenergic sensitivity (βAS) by the chronotropic dose of isoproterenol required to increase heart rate (HR) by 25 beats/min (CD₂₅); resting HR, exercise HR (PIND only), resting blood pressure (BP), and symptoms. Values are medians. On day 0, beta blockade was evident from increased CD₂₅ values of 181 μg for PIND, 57 μg for PROP and 8.7 μg for MET, compared to 3,0 μg, 2,4 μg and 2,6 μg, respectively, at days 14–20. After PIND dayO, the CD ₂₅ slowly decreased to baseline by day 10 to 20. In contrast, after PROP dayO, the CD₂₅ decreased significantly 50% below baseline from day 4 to 14 (i.e. ↑ βAS) and after MET 52% below baseline from day 2 to 8. After PIND all patients had a gradual increase of BP to baseline. A significant rebound of BP occurred in 6/9 patients after PROP and 1/8 after MET all during the period of ↑ βAS (initial = 135/85, peak= 154/98, baseline = 139/86). After PIND a significant rebound of resting HR occurred in 9/10 patients (initial = 79, peak = 88, baseline = 75) and in exercise HR in 10/10 patients. After MET a rebound of resting HR occurred in 8/8 patients during the period of ↑ βAS (initial = 61, peak = 86, baseline = 75). After PROP the resting HR rapidly returned to baseline with a rebound of 10 beats/min in 4/9 patients. We also developed a gradual withdrawal schedule for PROP and MET aimed at preventing the changes described. Studies as described were performed on the last day of full dose, serially during gradual withdrawal and serially during placebo. Gradual withdrawal of PROP and MET either prevented or markedly diminished the changes in CD₂₅, HR, BP and symptoms observed after abrupt withdrawal. Conclusions: Withdrawal of PIND, PROP and MET produced differing evidence of increased cardiac responsiveness which may reflect their different effects on cardiac receptors influenced primarily by neuronal versus circulating catecholamine. The events after abrupt withdrawal of PROP and MET were prevented by gradual dose reduction.

Dr. Langlois is a recipient of a Canadian Heart Foundation Fellowship