Administration time-dependent effects of amlodipine on ambulatory blood pressure in patients with essential hypertension

Amlodipine, a calcium antagonist of the 1,4-dihydropyridine type, has been shown to be effective in reducing blood pressure (BP) throughout the day and night when given once daily. However, the potential chronopharmacologic differing effects on BP of amlodipine have only been addressed occasionally. We investigated the administration-time dependent antihypertensive efficacy of amlodipine in patients with essential hypertension. We studied 194 patients with grade 1–2 essential hypertension (101 men and 93 women), 55.3±12.1 years of age, randomly assigned to receive a single daily dose of amlodipine (5 mg/day) either upon awakening or at bedtime. BP was measured by ambulatory monitoring at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 hours before and after 3 months of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate the diurnal and nocturnal means of BP on a per subject basis. The BP reduction after 12 weeks of therapy with amlodipine was slightly but not significantly larger after bedtime dosing (10.4 and 7.3 mm Hg reduction in the 24-hour mean of systolic and diastolic BP after amlodipine on awakening; 11.5 and 7.0 mm Hg after bedtime dosing; P>0.463 for treatment-time effect). This BP reduction was similar during both daytime activity and nighttime resting hours, independently of dosing time, indicating a full 24-hour therapeutic coverage of amlodipine administered either on awakening or at bedtime. The day/night BP ratio (calculated as the nocturnal decline of BP relative to the diurnal mean) was slightly reduced for diastolic BP after morning treatment (-1.6, P=0.037), but remained unchanged after bedtime dosing of amlodipine (increase of 0.2 and 0.7 in systolic and diastolic BP, P>0.337). Results from this trial demonstrate that amlodipine efficiently reduces BP for the entire 24 hours of the day independently of the time of its administration with respect to the rest-activity cycle of each individual patient. The similar BP reduction observed for the diurnal and nocturnal BP means indicates that amlodipine does not modify the circadian pattern of BP variability, even if administered at bedtime.