Time of Administration Ofanti-Hypertensives - Effect of Chronotherapy

What is the best time to take my B.P. medications (antihypertensives)? It depends on the medication, and the number of medications. If is a water pill (diuretic such as Bendrofluazide) it is better to take it in the morning because you will be passing a lot of urine. There are some that can make you a bit dizzy, especially for first-timers (e.g. Doxazocin, Lisinopril, Losartan) and are therefore better taken at night. There is another aspect, which needs to be considered. It is referred to as Chronotherapy- that is using the body's circadian rhythm patterns to increase the efficiency of medication.

There is a paper by Carter et al titled "Efficacy and Safety of Nighttime Dosing of Antihypertensives:Review of the Literature and Design of a Pragmatic Clinical Trial" published in J Clin Hypertens (Greenwich). 2014 February ; 16(2): 115-121. doi:10.1111/jch.12238.It notes that a common strategy to improve medication adherence and improve blood pressure control is to give antihypertensives as a single daily dose. However, many antihypertensive agents do not adequately control blood pressure throughout the entire 24 hour dosing interval.

There is now renewed interest in treating hypertension with divided doses or giving some antihypertensives in the evening. It has been known for several years that blood pressure exhibits circadian variability with a rapid increase on arising in the morning. A circadian rhythm is a natural, internal process that regulates the sleep-wake cycle and repeats roughly every 24 hours. In the case of blood pressure the effect is referred to as the early morning surge in blood pressure. Blood pressure plateaus throughout the afternoon and declines dramatically in most individuals during sleep. The drop during sleep is called nighttime dipping and is defined as a drop in systolic blood pressure of greater or equal to (≥) 10%. Normal nighttime blood pressures are less than(<) 120/70 mm Hg while they are less than (<) 135/85 mm Hg for daytime pressures and less than (<) 130/80 mm Hg for the entire 24-hour period.

Target organ damage (on the kidney, heart, brain) and cardiovascular (CV) events are predicted more reliably by 24-hour ambulatory blood pressure monitoring (ABPM) than office measurements.ABPM provides measurements during the critical nighttime period. Studies show that sleep time blood pressure is a better predictor of CV events than daytime pressures or full 24-hour results.

The lack of a drop in blood pressure at night (non-dippers) increases CV risk. In a study comparing patients with only white coat hypertension to those with ambulatory hypertension, patients with daytime hypertension who had a nocturnal dipping pattern had a relative risk of 3.70 and those with a non-dipping pattern had a relative risk of CV events of 6.26 when compared to those with white coat hypertension.Studies have found that a non-dipping pattern may be the best predictor of risk for increased CV events. Patients with resistant hypertension, diabetes or chronic kidney disease are much more likely to be non-dippers than patients without these conditions. Administration of antihypertensives at night has been shown to convert many patients from non-dippers to dippers.

Several biological events exhibit circadian patterns and trigger acute CV events. Myocardial infarction and sudden death are known to occur more frequently in the early morning hours (7:00-9:00 AM). Platelet aggregation, plasma catecholamines, coronary resistance, and vascular resistance increase in the early morning hours, which, along with the surge in blood pressure, contribute to the greater CV risk in the morning.

Most antihypertensives are taken in the morning at about 6:00-7:00 AM and achieve peak concentrations in 60-90 minutes. Therefore, when blood pressure is measured in the usual clinical setting, the antihypertensive effect is at its maximum. However, since the early morning surge in blood pressure will occur before most of the drugs are absorbed, these patients may go unprotected unless the drug has a duration of action of at least 24 hours. Many agents (e.g. Hydrochlorothiazide, Atenolol, Enalapril, Nifedipine) have relatively short half-lives and often do not reduce blood pressure during the early morning surge in blood pressure when given as a single morning dose.In the past many antihypertensives were given twice dailybecause of these pharmacokinetic features. The need for adherence may have changed this practice and may have affected 24-hour blood pressure control for many patients. It is important to add that there are newer molecules with better pharmacokinetic profiles. Notwithstanding this, several authors and the recent American Diabetes Association (ADA) guidelines suggest that one approach to achieve good 24-hour control, improve the dipping pattern and prevent the early morning surge in blood pressure is to give some of the antihypertensives in the evening.

It is commonly thought that drug absorption, distribution and elimination are constant processes in a given individual. There are circadian patterns to gastric acid secretion, gastric emptying, gastric transit time, hepatic blood flow and enzyme activity. These changes can influence drug pharmacokinetics in a circadian pattern and have been termed chronokinetics. Beta-blockers (e.g. Atenolol, Propranolol) and ACE inhibitors (e.g. Lisinopril, Ramipril) are known to have time-dependent pharmacokinetics. The drug pharmacokinetics may therefore change with night-time dosing.

A bedtime dose will lower the blood pressure during the critical night-time period. This strategy should also help protect patients with hypertension during the vulnerable early morning period when blood pressure increases rapidly and has been associated with increased CV events (the early morning surge).

The MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares [Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events]) study was designed to investigate whether bedtime treatment with more than or equal to (≥) 1 antihypertensives reduced blood pressure and cardiovascular disease (CVD) risk significantly better than conventional therapy, in which all medications were ingested upon waking. The study was a prospective, randomized, open-label, blinded endpoint (PROBE) trial in 2,156 individuals with hypertension from one center in Spain. Subjects were randomized to take all of their antihypertensives on awakening or one or more agents at bedtime. The subjects were followed for a median of 5.6 years. The sleep time systolic blood pressure was significantly lower with bedtime dosing (110.9 ±13.9 versus 116.1 ± 17.9 mm Hg, p<0.001). Ambulatory blood pressure was controlled in 62.2% of subjects with dosing at bedtime versus 52.8% with dosing on awakening. There were significantly fewer major events (CVD deaths, acute myocardial infarction and stroke) with bedtime dosing than in those who took all medications on awakening.

The results of this 5.6-yr median follow-up study establish that bedtime chronotherapy more effectively improves BP control, better decreases prevalence of non-dipping, and, most importantly, best reduces CVD morbidity and mortality. This chronotherapeutic approach to hypertension is justified by the fact that BP is usually lowest at night as is sodium excretion, but when sodium intake is excessive or its daytime excretion hampered, nocturnal BP is adjusted higher, to a level required for compensation overnight, via the pressure/natriuresis mechanism, resulting in non-dipping 24-h BP patterning. In diurnally active persons, the entire circadian BP pattern may be reset to a lower mean level and to a "more normal" day-night variation, simply by enhancing natriuresis during the night-the time-of-day when it can be most effective. A modification as simple and inexpensive as switching one or more hypertension medications from morning to evening may be all that is needed to normalize nighttime BP, exerting an effect exactly like sodium restriction.

DR. EDWARD O. AMPORFUL

CHIEF PHARMACIST

COCOA CLINIC.

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