Administration-time differences in effects of hypertension medications on ambulatory blood pressure regulation

Chronobiol Int. 2013 Mar;30(1-2):280-314. doi: 10.3109/07420528.2012.709448. Epub 2012 Oct 19.


Specific features of the 24-h blood pressure (BP) pattern are linked to progressive injury of target tissues and risk of cardiovascular disease (CVD) events. Several studies have consistently shown an association between blunted asleep BP decline and risk of fatal and nonfatal CVD events. Thus, there is growing focus on ways to properly control BP during nighttime sleep as well as during daytime activity. One strategy, termed chronotherapy, entails the timing of hypertension medications to endogenous circadian rhythm determinants of the 24-h BP pattern. Significant and clinically meaningful treatment-time differences in the beneficial and/or adverse effects of at least six different classes of hypertension medications, and their combinations, are now known. Generally, calcium channel blockers (CCBs) are more effective with bedtime than morning dosing, and for dihydropyridine derivatives bedtime dosing significantly reduces risk of peripheral edema. The renin-angiotensin-aldosterone system is highly circadian rhythmic and activates during nighttime sleep. Accordingly, evening/bedtime ingestion of the angiotensin-converting enzyme inhibitors (ACEIs) benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril exerts more marked effect on the asleep than awake systolic (SBP) and diastolic (DBP) BP means. Likewise, the bedtime, in comparison with morning, ingestion schedule of the angiotensin-II receptor blockers (ARBs irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with the additional benefit, independent of drug terminal half-life, of converting the 24-h BP profile into a more normal dipping pattern. This is the case also for the bedtime versus upon-awakening regimen of combination ARB-CCB, ACEI-CCB, and ARB-diuretic medications. The chronotherapy of conventional hypertension medications constitutes a new and cost-effective strategy for enhancing the control of daytime and nighttime SBP and DBP levels, normalizing the dipping status of their 24-h patterning, and potentially reducing the risk of CVD events and end-organ injury, for example, of the blood vessels and tissues of the heart, brain, kidney, and retina.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adrenergic Antagonists / administration & dosage
  • Adrenergic Antagonists / therapeutic use
  • Angiotensin Receptor Antagonists / administration & dosage
  • Angiotensin Receptor Antagonists / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / administration & dosage
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Antihypertensive Agents / administration & dosage*
  • Antihypertensive Agents / therapeutic use
  • Blood Pressure / drug effects
  • Blood Pressure Monitoring, Ambulatory / methods*
  • Circadian Rhythm
  • Diuretics / administration & dosage
  • Diuretics / therapeutic use
  • Drug Administration Schedule
  • Female
  • Humans
  • Hypertension / drug therapy*
  • Male
  • Risk Factors
  • Time Factors


  • Adrenergic Antagonists
  • Angiotensin Receptor Antagonists
  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Diuretics