Administration-Time-Dependent Effects of Spirapril on Ambulatory Blood Pressure in Uncomplicated Essential Hypertension

Abstract

The administration of most angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) at bedtime results in a greater reduction of nighttime blood pressure (BP) than dosing upon awakening. It has been proposed that this effect may be a consequence of a short half-life and duration of action. However, those findings were also documented for long-acting medications, such as the ARB telmisartan. Accordingly, we investigated the administration-time-dependent effects on ambulatory BP of spirapril, an ACEI with an elimination half-life of about 40 h. We studied 165 previously untreated hypertensive subjects, 42.5 +/- 13.9 yrs of age, treated with spirapril (6 mg/day) as monotherapy for 12 weeks either upon awakening or at bedtime. BP was measured by ambulatory monitoring for 48 h before and after treatment. The BP reduction during diurnal activity was similar for both treatment times. Bedtime spirapril administration, however, was significantly more efficient than morning administration in reducing asleep BP. The awake/asleep BP ratio was decreased with the upon-awakening spirapril treatment schedule but significantly increased toward a more dipping pattern with the bedtime treatment schedule. The proportion of patients with controlled ambulatory BP increased from 23 to 59% (p < 0.001) with bedtime treatment. Sleep-time BP regulation is significantly better achieved with bedtime spirapril administration. This might be clinically important, as the sleep-time BP mean has been shown to be a more relevant marker of cardiovascular risk than the awake mean values. These administration-time-dependent effects of spirapril seem to be a class-related feature, and may be associated with the nocturnal activation of the renin-angiotensin-aldosterone system.

Effect of bedtime administration of blood-pressure lowering agents on ambulatory blood pressure monitoring results: A meta-analysis

“…The mechanisms for these observed treatment-time differences remain unclear, but it has been generally agreed that the pharmacokinetics (PK) -the study of what the body does to a drug, absorption, distribution, metabolism, and elimination -and pharmacodynamics (PD) -the study of what a drug does to the body -of the medications occurring in relation to the 24 h cyclic processes were involved in BP regulation [11,31]. Circadian rhythms in gastric pH and emptying, gastrointestinal motility, biliary function and circulation, liver enzyme activity, and blood flow to the duodenum, kidney, and other organs, among other factors can lead to ingestion-time differences in the PK of conventional antihypertensive medications [8,11].…”

“…Circadian rhythms in gastric pH and emptying, gastrointestinal motility, biliary function and circulation, liver enzyme activity, and blood flow to the duodenum, kidney, and other organs, among other factors can lead to ingestion-time differences in the PK of conventional antihypertensive medications [8,11]. In particular, the circadian pattern of the glomerular filtration rate, with a maximum during the day and a minimum at night, played a significant role [8,11,32]. Consequently, antihypertensive drugs were cleared more slowly overnight, potentially prolonging their duration of action when ingested at bedtime as compared to taken at awakening.…”

“…Decreasing nighttime BP and bedtime administration of antihypertensive drugs have already been taken into account for the treatment strategy aiming to improve BP management, but no clear consensus has been reached on the BP-lowering effect of this strategy. Recent researches have documented that ingesting at least one antihypertensive medication at bedtime, compared with treatment with all medications upon awakening, showed a significant reduction in the 24-h mean systolic BP (SBP)/diastolic BP (DBP) and the reduction was much more prominent during nighttime, decreasing the prevalence of nondipping [8,11,12], however, the similar 24-h mean SBP/DBP reduction for both treatment times was also reported [13][14][15]. Therefore, we conducted this meta-analysis to investigate the effects of bedtime administration of BP-lowering agents on ambulatory BP monitoring (ABPM) results.…”

“…The mean nocturnal BP value has been suggested as the most sensitive predictor of cardio-and cerebrovascular morbidity and mortality, in other words, insufficient BP fall at night compared to daytime level or a non-dipping pattern is associated with elevated risk of end-organ injury, particularly to heart (left ventricular hypertrophy, congestive heart failure and myocardial infarction), brain (stroke), and kidneys (albuminuria and progression to end-stage renal failure), as well as poor prognosis [9][10][11]. Decreasing nighttime BP and bedtime administration of antihypertensive drugs have already been taken into account for the treatment strategy aiming to improve BP management, but no clear consensus has been reached on the BP-lowering effect of this strategy.…”

Fixed-combination of amlodipine and diuretic chronotherapy in the treatment of essential hypertension: improved blood pressure control with bedtime dosing—a multicenter, open-label randomized study

“…The SBP, DBP and HR of each participant were automatically measured every 20 min during the day (0600-2200 hours) and every 30 min during the night for 24 consecutive hours 14,15 with an ABPM device (Wuxi Zhongjian, Wuxi City, China). All subjects were examined by ABPM under baseline conditions when they were free of medication (after the 2-week washout for previously treated subjects) both before and after the 12 weeks of timed therapy.…”