Ingestion-time – relative to circadian rhythms – differences in the pharmacokinetics and pharmacodynamics of hypertension medications

ABSTRACT

Introduction

Hypertension guidelines do not recommend the time to administer blood pressure (BP)-lowering medications, despite multiple prospective clinical trials reporting both improved normalization of BP 24 h patterning and reduced cardiovascular disease (CVD) events when ingested at bedtime rather than upon awakening.

Areas covered

We review: (i) circadian rhythm-dependent influences on the pharmacokinetics (PK) and pharmacodynamics (PD) of hypertension medications; (ii) reports of ingestion-time differences in PK and PD of such therapies; and (iii) (chrono)prevention of CVD morbidity and mortality achieved by the simple and low-cost bedtime hypertension chronotherapy strategy, i.e. scheduling at bedtime ≥1 conventional BP-lowering medications to target asleep BP control of ABPM-diagnosed true arterial hypertension patients.

Expert opinion

Proper management of hypertension requires awareness of known ingestion-time differences in both the PK of individual BP-lowering medications and their combinations, which arise from circadian rhythms affecting absorption, distribution, metabolism, and elimination, and their PD, which result from circadian rhythms in mechanisms that regulate the 24 h BP pattern. The vast majority of the multiple published trials document substantially enhanced lowering of asleep BP, increased sleep-time relative BP decline (dipping), and markedly better reduction of CVD morbidity and mortality when hypertension medications and their combinations are ingested at bedtime rather than upon waking.

KEYWORDS:

• Ambulatory blood pressure monitoring
• asleep blood pressure
• bedtime hypertension chronotherapy
• cardiovascular risk
• chronopharmacology
• chronopharmacokinetics
• chronopharmacodynamics
• hypertension medications

Article highlights

• Proper management of true arterial hypertension requires awareness of the demonstrated ingestion-time differences in the PK and PD of BP-lowering medications and their combinations that result from well-documented circadian rhythms influencing their absorption, distribution, metabolism, and elimination, plus other endogenous circadian rhythms that both regulate BP and influence response to hypertension therapy.

• Most studies on the chonopharmacokinetics of hypertension medications in humans consistently demonstrate, despite their limited sample sizes, morning versus evening ingestion-time differences in effects.

• The vast majority, i.e. 82.5%, of reported trials addressing the PD of hypertension medications and their combinations document with high consistency statistically and clinically significant ingestion-time differences, including enhanced asleep BP reduction, increased sleep-time relative BP decline with corresponding reduced prevalence of the non-dipper/riser pattern, decreased incidence of adverse events, and/or improvement in markers of target organ pathology for kidneys –– reduced albuminuria, increased estimated glomerular filtration rate – and heart – decreased left ventricular posterior diameter and left ventricular mass – when BP-lowering medications are ingested at bedtime than upon waking.

• Most importantly, no single reported trial documents enhanced BP-lowering or other benefits of the still conventional, although scientifically unjustified, morning/upon-awakening treatment-time scheme.

• Bedtime hypertension therapy that entails ingestion of the entire daily dose of ≥1 BP-lowering medications, especially when an ARB or ACEI, at bedtime, compared with the still usual therapeutic regimen that entails ingestion of all such medications upon awakening, significantly diminishes CVD morbidity and mortality.

• Findings of the Hygia Chronotherapy Trial additionally demonstrate the bedtime hypertension treatment strategy is safe; the risk for adverse effects is comparable to the more common morning-time treatment strategy, in agreement with other publications that report bedtime versus morning-time BP therapy significantly improves ambulatory BP reduction, mainly during sleep, and without increase in adverse effects.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.