Sleep blood pressure (BP) is a powerful predictor of cardiovascular complications, and there is suggestive evidence that controlling BP during sleep has beneficial outcomes. When drugs are given in the morning, the drug concentration may be lowest at the time when good BP control is desirable. This has led to the idea that it may be preferable to give medication in the evening.
The study by Zappe et al. is an important contribution to the question when should drugs that act on the renin–angiotensin system (RAS) be administered. Is there an advantage of night-time over morning administration as some studies have suggested? [2,3] Their study  clearly shows that when an angiotensin-receptor blocking (ARB) drug is administered in a dose that has a full 24-h duration of effect (valsartan 320 mg), the time of administration has little influence on the 24 h, day or sleep BP reduction. This was true in people who were on monotherapy and also in people in whom addition of a diuretic was needed. Hermida and Ayala, and their group [2–4] have written extensively on this subject, and come down in favour of nocturnal dosing independent of the dose and the agent. The present study would appear to be in conflict with their results with valsartan 160 mg . This difference is more apparent than real. In the study with valsartan 160 mg, Hermida et al. claim superiority of nocturnal dosing over awakening dosage. However, there were similar falls in 24-h ambulatory blood pressure and night-time (sleep) BP. The superiority was based on an increase in the diurnal nocturnal BP ratio which, in their study, was due to a greater fall in daytime BP with the morning dose as compared to the nocturnal dose. Their studies [2–4] and the present study  compared fixed doses of medication taken in the morning and evening. Whereas the conclusions are important, they do not address the real-life problem. When therapy is started and titrated according to clinic BP response, is it better to take a medication that blocks the RAS in the morning or evening?
There are a variety of factors that impinge on this matter: relationship of time of administration to time of measuring BP; importance of sleep BP as a predictor of outcome; possible different rates of drug metabolism during sleep and awake; different BP responses to RAS inhibition at different periods of the day.
The most critical is the relationship between the time of taking medication and BP measurement. If a person takes the medication in the morning and BP is measured sometime after, there may be a false sense of achievement. Many angiotensin-converting enzyme (ACE) inhibitors, in particular, and some ARBs also have a half-life much less than 24 h, and depending on the dose, the BP-lowering effect may not last for 24 h. The dose range for such drugs is wide. Enalapril's dose is 5–40 mg/day. The response to these doses of enalapril, 4 h after administration, is similar, but only 20 and 40 mg have an effect that endures for 24 h. When enalapril was initially studied in trials in which titration was decided on BP measured before taking medication in the morning, the average dose was greater than 20 mg. However, survey of medication use, in general practice, revealed that the average dose used was less than 15 mg/day. Valsartan has been used to treat hypertension in a range of doses from 80 to 320 mg/day. Studies comparing telmisartan 80 mg with valsartan 160 mg indicate that between 18 and 24 h after dosing in the morning, valsartan has a reduced BP-lowering effect compared with telmisartan . Thus, if BP is measured after medication had been taken, it is likely that the drug will not be titrated to a dose that gives optimal 24-h BP control. If, however, medication is taken at night, BP will be measured at least 12 h after medication and it is more likely that the correct dose will be reached. This was the rationale behind a study by Morgan et al. in 1997 in which perindopril was given in a crossover design study in the morning or at night. This was a fixed-dose study. Perindopril, given in the morning, had full 24-h duration of action, and night-time and morning BP was controlled to a similar extent to that when the same dose was taken in the evening. However, perindopril, given in the evening, did not have a full 24-h duration of action. The reason for this will be discussed later.
Trandolapril for ACE inhibitors and telmisartan for ARBs have the longest half-lives and in some ways are the preferred drugs. If a shorter-acting drug is used, it should be titrated to a dose that is known to have full 24-h duration of action. Alternatively, once control appears to have been achieved, the clinic BP should be measured on a day when the person is told not to take any medication. Home BP measurement in the morning may be a way to achieve this readily.
Blood pressure is not a static parameter and alters throughout the day. During the morning hours, the sympathetic nervous system is the predominant controller of BP . With sleep, the sympathetic nervous system usually turns off and BP falls. Associated with this fall in BP, plasma renin rises  and becomes the main controller of BP during the sleep hours. In patients in whom there is no sleep-induced fall in BP, the sympathetic system may maintain activity, and in these people, an alpha-blocking drug induces large falls in BP . In a person at bed rest, plasma renin is higher during sleep than in the awake period . However, in normal life, during the awake hours, plasma renin alters with posture and, together with the sympathetic system, controls BP. The study by Morgan et al. demonstrated that when perindopril was given in the evening, the response did not last for 24 h, whereas the morning dose reduced BP during the sleep hours at a similar time after dosing. A study by Smith et al. with trandolopril had similar observations. In that study , over 48 h, the BP-lowering response after a morning dose disappeared in the second afternoon (i.e. about 30–36 h after the dose), but reappeared during the sleep hours. Thus, it appears that people are more responsive to blockade of the RAS when asleep and that a lower concentration of the drug may be effective. In the present study , the numerical falls in sleep (night-time) SBP and DBP at all time periods presented were greater than the daytime fall on both the morning, and night-time dose of valsartan and on lisinopril, though there is no statistical analysis of this effect. These data are summarized in Table 1. The excess fall in SBP at night time in the six periods was 0.58 (SD 0.40) mmHg, with a P value less than 0.05. Similar changes were seen in DBP. A similar result has been shown by Morgan and Anderson . Calcium channel blockers and diuretics which act independent of the hormonal and autonomic nervous system had similar falls in BP during the awake and sleep hours. Beta blockers had no significant response during the sleep hours, whereas the fall with ACE inhibitors was greater when asleep than when awake. An equal or similar fall in BP almost certainly indicates a greater response, as the baseline BP was lower during the sleep period and it is one of the most powerful predictors of the magnitude of the response. The percentage changes in SBP relative to the initial SBP are indicated in Table 1. A mean fall of 9.21% at night was observed as compared to 7.85% during the day. An extra SBP fall of 17.5% was also seen.
The results of the study by Morgan et al., indicating a lesser duration of action when given at night, could be explained by a greater rate of metabolism or elimination during the sleep period, but a difference in pharmacokinetics would not explain the confirmatory results seen with trandolopril . Thus, it appears that BP is more responsive to blockade of the RAS during sleep.
Sleep BP, both experimentally and in humans, has been shown to be a powerful predictor of cardiovascular outcome [12–15]. Sleep BP at baseline and during treatment had a greater predictor effect than awake BP. Thus, an argument can be made to take medication in the evening. However, it is possible that more doses would be missed by evening administration than by morning ingestion. The important lesson to be learnt is to ensure that drugs that act on the RAS are administered in doses that are known to have complete 24-h duration of action. If doses are used that are lower than those with complete 24-h effect, it is important to check control with either a 24-h monitor or morning BP prior to administration of the drug.
The study that is required to clarify the advice to give to the treating physician is one in which the medication is given when awake or in the evening, and medication is titrated by usual clinic BP. The result needs to be monitored by 24-h BP measurements to determine which strategy is most effective in achieving optimal control. To resolve some of the above mentioned problems, it would be ideal to also assess the pharmacokinetics of the drug given at the different times to determine whether BP responds differently to the same plasma level of drug during sleep and awake.
Conflicts of interest
There are no conflicts of interest.
1. Zappe DH, Crikelair N, Kandra A, Palatini P. Time of administration important? Morning versus evening dosing of valsartan. J Hypertens
2. Hermida RC, Ayala DE, Fernández JR, Calvo C. Comparison of the efficacy of morning versus evening administration of telmisartan in essential hypertension. Hypertension
3. Hermida RC, Ayala DE. Chronotherapy with the angiotensin-converting enzyme inhibitor ramipril in essential hypertension: improved blood pressure control with bedtime dosing. Hypertension
4. Hermida RC, Calvo C, Ayala DE, Domínguez MJ, Covelo M, Fernández JR, et al. Administration time-dependent effects of valsartan on ambulatory blood pressure in hypertensive subjects. Hypertension
5. Lacourcière Y1, Krzesinski JM, White WB, Davidai G, Schumacher H. Sustained antihypertensive activity of telmisartan compared with valsartan. Blood Press Monit
6. Morgan T, Anderson A, Jones E. The effect on 24 h blood pressure control of an angiotensin converting enzyme inhibitor (perindopril) administered in the morning or at night. J Hypertens
7. Somers VK, Dyken ME, Mark AL, Abboud FM. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med
8. Brandenberger G, Follenius M, Goichot B, Saini J, Ehrhart J, Simon C. Twenty-four-hour profiles of plasma renin activity in relation to the sleep awake cycle. J Hypertens
9. Kario K1, Schwartz JE, Pickering TG. Changes of nocturnal blood pressure dipping status in hypertensives by nighttime dosing of alpha-adrenergic blocker, doxazosin: results from the HALT study. Hypertension
10. Smith DHG, Neutel JM, Black HR, Schoenberger JA, Weber MA. Once daily therapy with trandolapril in the treatment of hypertension. J Hum Hypertens
11. Morgan TO, Anderson A. Different drug classes have variable effects on blood pressure depending on the time of day. Am J Hypertens
12. Morgan TO, Brunner HR, Aubert J-F, Wang Q, Griffiths C, Delbridge L. Cardiac hypertrophy depends upon sleep blood pressure: a study in rats. J Hypertens
13. Kikuya M, Ohkubo T, Asayama K, Metoki H, Obara T, Saito S, et al. Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality: the Ohasama Study. Hypertension
14. Staessen JA, Thijs L, Fagard R. Predicting cardiovascular risk using conventional versus ambulatory blood pressure in older patients with systolic hypertension. JAMA
15. Morgan TO. The importance of sleep blood pressure. Expert Rev Cardiovasc Ther