1-211

Timing for Administration of an

Antihypertensive Drug in the Treatment
of Essential Hypertension
Teruhisa Umeda, Shojiro Naomi, Taisuke Iwaoka, Junnosuke Inoue, Masato Sasaki,
Yasufumi Ideguchi, Tatsuo Sato

Abstract To find the best timing for administration of the morning surge was not completely suppressed by nitren-
long-acting antihypertensive drugs, we gave nitrendipine, a dipine given after breakfast, it was diminished by the drug
calcium antagonist of the dihydropyridine group, once a day to given on awakening or after supper, the latter brought a
six hospitalized and drug-free patients with essential hyper- deeper decline in blood pressure during sleep compared with
tension, changing the time of administration and studying the other times. The average of 24-hour blood pressure values
effects on the circadian rhythm of blood pressure. After obtained by nitrendipine given on awakening was the lowest
control values of 24-hour blood pressure variations were taken among the three occasions. Thus, administration of long-acting
with patients on placebo, a 10-mg tablet of nitrendipine was calcium antagonists with a rapid onset of action on awakening
given for 3 days on three occasions — at 6 AM on awakening, at in the early morning seems to be a more rational and beneficial
8:30 AM after breakfast, and at 6 PM after supper; 24-hour alternative than the conventional administration after break-
blood pressure values for each period were recorded on the fast. The earlier administration may prevent dangerous car-
third day. The 24-hour blood pressure values during the diovascular catastrophes, including stroke, myocardial infarc-
control period showed a biphasic circadian rhythm, with higher tion, and sudden death, known to occur often during the
values during wakefulness and lower values during sleep. The morning surge of blood pressure. (Hypertension. 1994;23 [suppl
control period was also characterized by a rapid rise in blood
pressure on awakening, the so-called morning surge of blood Key Words • antihypertensive agents • nitrendipine •
pressure, and a gradual decline during sleep at night. Although circadian rhythm • hypertension, essential • blood pressure
Downloaded from http://ahajournals.org by on November 21, 2022

C ircadian rhythm of blood pressure is known to be

biphasic, with blood pressure higher during
wakefulness and lower during sleep than the
average 24-hour blood pressure value.1-2 Especially in
patients with essential hypertension, an abrupt rise in
a day. Pharmacokinetic studies on dihydropyridine cal-
cium antagonists performed in hypertensive patients19'20
have also found a relatively straight correlation between
the logarithmic value of the plasma drug concentration
and the antihypertensive effect, suggesting that a higher
blood pressure after awakening in the early morning is plasma level will bring a more profound antihyperten-
commonly observed3; this is called the "morning surge" sive effect. We therefore sought to find out the best
of blood pressure and has been suggested to be a timing for administration of such drugs, especially in
dangerous trigger of cardiovascular catastrophes. Oc- those patients who suffer from remarkable morning
currences of stroke, 47 myocardial infarction,811 and surges of blood pressure even when they are taking
sudden death 9 1 2 1 4 have been shown to increase be-
antihypertensive drugs.
tween the hours of 6 and 9 AM compared with the rest of
In the present study, we used automatic noninvasive
the day. A number of precipitating factors may be
involved in these early morning catastrophes, but the blood pressure monitoring and performed chronophar-
marked rise in blood pressure almost certainly is a major macologic evaluation on the timing of administration of
factor, perhaps by causing a rupture of atherosclerotic a long-acting antihypertensive drug.
plaques whereby thrombus is formed.9
Methods
Antihypertensive drugs that are given once a day have Six patients with essential hypertension (World Health
come into common use in the treatment of essential Organization stages I or II) including three men and three
hypertension. Nitrendipine is one of the long-acting women aged 32 to 58 years were involved in this study. They
calcium antagonists of the dihydropyridine group whose were admitted for further examinations of hypertension with
clinical usefulness in the treatment of essential hyper- blood pressures greater than 160/95 mm Hg on at least two
tension has been established either as monotherapy 1517 consecutive visits in the outpatient clinic. After admission, any
or in combination with /J-blockers.18 Nitrendipine has a medication including antihypertensive drugs was discontinued
rapid onset of action and is usually given once or twice and a standard hospital diet was given. During the first 2
weeks, patients underwent clinical evaluations to exclude any
identifiable cause of hypertension and were diagnosed as
From the Department of Internal Medicine III, Kumamoto having essential hypertension. Details of the present study
(Japan) University Medical School. were explained, and informed consent was obtained.
Correspondence to Teruhisa Umeda, MD, Department of In- Patients were trained for 24-hour ambulatory blood pres-
ternal Medicine III, Kumamoto University Medical School, 1-1-1 sure monitoring with an automatic sphygmomanometer
Honjo, Kumamoto 860, Japan. (ABPM-203NP, Nippon Colin, Tokyo, Japan) in which the
 1-212 Supplement I Hypertension Vol 23, No 1 January 1994

|xi Sleeping ^IJgX | A waking m

120- Placebo

O)

E FIG 1. Line graph shows circadian rhythms of mean

blood pressure (MBP) in essential hypertensive pa-
100- tients. A prompt rise of MBP in early morning, the
Q_ so-called morning surge, was seen during placebo; it
was suppressed by administration of 10 mg of nltren-
m dipine on awakening (A) but not completely by admin-
90- istration after breakfast (B) and after supper (C). Each
hourly MBP value is the mean of six patients.

80-
t t t
12 18 24

TIME OF DAY
data on systolic, diastolic, and mean blood pressures (MBP) significantly to 105.2±7.0 mmHg (P<.01) by nitren-
and heart rate were stored in a memory block and printed out dipine given after supper at 6 PM, and the time of the
through an analyzer when required. Calibration was made early morning peak in blood pressure was delayed 1
against a mercury sphygmomanometer before each recording.
Accuracy of this device has been validated when it is used on
hour. When nitrendipine was given after breakfast at
the left arm to allow two microphones within the cuff to 8:30 AM, however, the peak height of the morning surge
differentiate between Korotkoff sounds and extraneous noises. at 7 AM was 103.0+12.4 mm Hg, which was not signifi-
Left forearm readings were taken every 30 minutes over 24 cantly lower than that during placebo. While patients
Downloaded from http://ahajournals.org by on November 21, 2022

hours using a standard-sized cuff with CO2 gas inflation. All were awake, few blood pressure variations were ob-
patients kept a diary of the times they awoke, took nitren- served in both the run-in and therapeutic periods, with
dipine or placebo tablets, ate, and went to sleep at night. a few small peaks at noon, 3, and 6 PM. After the onset
During a run-in period of 3 days, a placebo tablet was given of sleep, the fall in blood pressure was more profound
at 8:30 AM (after breakfast), and 24-hour blood pressure on the occasions when nitrendipine was given on awak-
variations were recorded on the third day as control values. ening and after supper compared with that after break-
During the therapeutic period of 9 days, a 10-mg tablet of
nitrendipine was given at 6 AM on awakening for 3 days, after fast or placebo. The lowest value in MBP during sleep at
breakfast (8:30 AM) for 3 days, and after supper (6:30 PM) for night was 87.6±5.4 mm Hg when nitrendipine was given
3 days. The order of changing the time of nitrendipine after supper.
administration was randomized among patients. Twenty-four-hour MBP in the run-in period was
The MBP of each hour was obtained from the mean of two 108.8±3.1 mm Hg, which was markedly lowered to
readings taken every 30 minutes. Data are expressed as
mean±SEM. Differences among the four occasions of placebo 95.0±2.5 mm Hg with administration of nitrendipine on
and drug administrations were evaluated by two-way ANOVA awakening (P<.01) and to 97.5±2.7 mm Hg with admin-
and Tukey's multiple comparison test. The relation between istration after supper (P<.05) but not significantly low-
the percent reduction in the morning MBP and that in the ered to 100.9 ±2.8 mm Hg with administration after
24-hour MBP was examined by correlation analysis and re- breakfast (Fig 2). When the mean of early morning
gression analysis. Values of P<.05 were defined as significant. blood pressures calculated from six readings during the
Results 3 hours from 6 to 9 AM was compared among the four
occasions including placebo and the three different
Hourly blood pressure during the placebo run-in
timings of nitrendipine administration, the value when
period fell progressively from the onset of sleep to its
lowest level of 101.7±4.2 mmHg at 2 hours before nitrendipine was given on awakening or after supper
awakening. When patients awoke at 6 AM, MBP ele- was significantly lower than that during placebo
vated slightly to 108.4±5.2 mm Hg and markedly to (95.1±3.2 [P<.001] or 101.0±3.2 mm Hg [P<.05] versus
117.6±7.2 mm Hg at 7 AM, which was the highest of the 109.7±2.8 mm Hg, respectively). Similarly, mean wak-
day, and then declined rapidly to 107.5±4.5 mm Hg at 8 ing blood pressures from 9 AM to 10 PM and mean
AM (Fig 1). This abrupt rise of blood pressure, with a sleeping blood pressures from 10 PM to 6 AM, were
sharp peak seen in the early morning, is the morning lowered significantly when nitrendipine was given on
surge. awakening in the early morning (P<.05). The mean of
When nitrendipine was given on awakening at 6 AM, sleeping blood pressures during nitrendipine adminis-
the peak height of this morning surge was markedly tration after supper was 89.4±3.8 mm Hg, which was
suppressed from 117.6±7.2 mm Hg during placebo to the lowest among the four occasions. Furthermore, a
98.2±4.9 mmHg (P-c.OOOl). It was also suppressed significant correlation was found between the percent
 Umeda et al Timing of Antihypertensive Drug Administration 1-213

precipitating factors may be involved in these early

morning catastrophes, the marked rise in blood pressure
is one of the major factors, causing the rupture of
24hra atherosclerotic plaques whereby thrombus is formed.5
Accordingly, attenuation of the morning surge of blood
pressure may be one of the most important targets in
the treatment of essential hypertension.
In this decade, a major part of antihypertensive
therapy has been changed from the use of relatively
short-acting drugs usually given two or three times a day
Earty
morning
to the long-acting drugs given once a day; nevertheless,
(6.00-9:00) the mechanism of action is variable. The purpose of this
E change might be to improve patient compliance with
therapy and/or achieve a more stable control of 24-hour
0_ blood pressure variations. However, little attention has
CD
been paid on the timing of administration of long-acting
drugs, because in principle, the antihypertensive effects
Awaking of such drugs have been proved to last for 24 hours.
(9.00-22:00) Currently, patients usually are advised to take long-
acting drugs after breakfast, without any particular
considerations, perhaps because of simple convention
or an expectation of better absorption from the intes-
tine. This also might be true in most clinical trials on
long-acting antihypertensive drugs, because any partic-
ular description of the timing of drug administration has
Sleeping
(22 0 0 - 6 - 0 0 )
not been found.
Nitrendipine is one of the long-acting calcium antag-
onists whose antihypertensive effect is characterized by
Placebo A B C a rapid onset of action similar to that of other dihydro-
FIG 2. Bar graphs show comparison of mean Wood pressure
pyridine calcium antagonists including nifedipine, nisol-
(MBP) during 24 hours, early morning, wakefulness, and sleep at dipine, and manidipine. Although the clinical useful-
night. Administration of 10 mg of nitrendlplne on awakening (A) ness of nitrendipine in the treatment of essential
Downloaded from http://ahajournals.org by on November 21, 2022

brought the lowest MBP in every period of the day when hypertension has been widely accepted when it is given
compared with placebo and administration of drug after break- once a day,1517 Maclean et al18 pointed out that the
fast (B) and after supper (C). Each value is the mean of six duration of its antihypertensive effect is less than 24
patients. Vertical bars indicate standard errors. ***P<.001,
**P<.01, *P<.05, by two-way ANOVA and Tukey's multiple hours and recommended twice-a-day administration. In
comparison test. fact, some patients receiving nitrendipine once a day
and measuring their home blood pressures often com-
plain of insufficient control of blood pressure in the
reduction in the mean of morning blood pressures and early morning. Especially in the cold season, their early
that of 24-hour MBP (r=.616, P<.001). morning blood pressures are extremely high even when
Discussion they are taking the drug every day after breakfast. This
is somewhat reasonable because plasma concentrations
This study on a small group of essential hypertensive of the drug might be near minimum at that time. There
patients clearly demonstrated a prompt rise in blood is a relatively straight correlation between the antihy-
pressure after awakening in the early morning as well as pertensive effect of calcium antagonists and logarithmic
a biphasic circadian rhythm of ambulatory blood pres- value of plasma concentrations,19'20 so antihypertensive
sure. The exact mechanism of either the morning surge effects in the early morning should be at a minimum
or circadian rhythm of blood pressure is still unknown. when such drugs are taken after breakfast.
Linsell et al21 found either a similar prompt rise in the The chronopharmacologic aspect of the present study
early morning or a circadian rhythm in plasma catechol- clearly demonstrated that the morning rise in blood
amine levels in humans; the marked increase of plasma pressure can be attenuated by administration of antihy-
norepinephrine started abruptly around 6 AM on awak- pertensive drugs on awakening instead of after break-
ening and reached a peak at 8 AM, followed by a gradual fast. Another alternative for attenuating the early morn-
decline. Panza et al22 also reported a similar circadian ing surge in blood pressure is the administration of
rhythm in basal vascular tone, either partly or entirely drugs after supper. However, this seems to be somewhat
due to increased a-sympathetic vasoconstrictor activity problematic, because blood pressures can become too
during the morning. These findings suggest that the low during sleep, which can be unfavorable especially in
prompt rise in sympathetic nerve activity after awaken- patients with atherosclerotic changes on the cerebral
ing may have a central role in the morning surge of arteries because of induction of thrombosis. However,
blood pressure. Thus, sudden increased firing in the evidence that cerebral infarction is a nocturnal illness is
sympathetic nervous system seems to be a dangerous not convincing.23'24 In this context, an abrupt rise in
trigger of cardiovascular catastrophes, including blood pressure in the early morning may be more
stroke, 47 myocardial infarction,811 ischemic heart at- harmful than blood pressures that are too low during
tack,14 and sudden death. 1214 Although a number of sleep.
 1-214 Supplement I Hypertension Vol 23, No 1 January 1994

It is difficult to explain why the most profound 8. Muller JE, Stone PH, Turi ZG, Rutherford JD, Czeisler CA,
depressor effect on 24-hour blood pressure was ob- Parker C, Poole WK, Passamani E, Roberts R, Robertson T, Sobel
BE, Willerson JT, Braunwald E, the MILIS Study Group. Cir-
served by administration of nitrendipine on awakening cadian variation in the frequency of onset of acute myocardial
compared with the other two occasions (see Fig 2). An infarction. N Engl J Med. 1985;313:1315-1322.
extraneous factor such as an order effect is not likely 9. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers
because the order of the three occasions was randomly of onset of acute cardiovascular disease. Circulation. 1989;79:
assigned. One can speculate that the more appropri- 733-743.
ately controlled morning blood pressure may bring 10. Pepine CJ. Circadian variations in myocardial ischemia. JAMA.
better control of 24-hour blood pressure because ex- 1991;265:386-390.
11. Willich SN, Linderer T, Wegscheider K. Increased morning
traordinary stimuli during the morning surge may acti- incidence of myocardial infarction in the ISAM Study: absence
vate the sympathetic nervous system, the renin-angio- with prior 0-adrenergic blockade. Circulation. 1989;80:853-858.
tensin system, or other pressor mechanisms—all factors 12. Willich SN, Levy D, Rocco MB. Circadian variation in the
that can affect blood pressure variation during 24 hours. incidence of sudden cardiac death in Framingham Heart Study
This hypothesis may be supported by the finding in this population. Am J CardioL 1987;60:801-806.
study that there was a significant correlation between 13. Muller JE, Ludmer PL, Willich SN, Tofler GH, Aylmer G, Klangos
the percent reduction in morning MBP and in 24-hour I, Stone PH. Circadian variation in the frequency of sudden cardiac
death. Circulation. 1987;75:131-138.
MBP during nitrendipine administration. 14. Mulcahy D, Keegan J, Cunningham D, Quyyumi A, Crean P,
In conclusion, administration of dihydropyridine cal- Park A, Wright C, Fox K. Circadian variation of total ischemic
cium antagonists with a rapid onset of action on awak- burden and its alteration with anti-anginal agents. Lancet. 1988;
ening in the early morning instead of after breakfast can 2:755-758.
reduce not only morning blood pressure but also 24- 15. DiSalvo MM, Finocchiaro PM, Bonaccorso M, Attanasio L.
Nitrendipine efficacy and safety in patients with mild to moderate
hour MBP. It is also worth noting that patients taking essential hypertension. / Cardiovasc Pharmacol 1991;18(suppl
such drugs on awakening appear to show a better 1):S45-S47.
compliance with treatment and fewer symptoms of 16. Braun H, Weber F. Antihypertensive monotherapy with nitren-
flushing and palpitation, especially during daytime dipine in general practice. / Cardiovasc Pharmacol 1991;18(suppl
working hours, compared with patients taking such 1):S59-S62.
drugs after breakfast. These observations require fur- 17. Mele D, Manfredini R, Amadei G, Vaccari M, Sgobino P, Fersini
C, Longhini C. Acute and chronic nitrendipine administration in
ther chronopharmacologic studies on other long-acting essential hypertension. J Cardiovasc Pharmacol 1992;19(suppl
antihypertensive drugs to find the best timing of admin- 2):S49-S52.
istration while considering effectiveness or even lifestyle 18. Maclean D, Mitchell ET, Lewis R, Irvine N, McLay JS, McEwen J,
of each patient. Further large studies are necessary to Coulson RR, Slater ND, Fitzsimons TJ, McDevitt DG. Com-
answer the most important question of whether these parison of once daily atenolol, nitrendipine and their combination
Downloaded from http://ahajournals.org by on November 21, 2022

in mild to moderate essential hypertension. Br J Clin Pharmacol

approaches can prevent cardiovascular catastrophes in 1990;29:455-463.
patients with essential hypertension. 19. Umeda T, Naomi S, Iwaoka T, Inoue J, Ohno M, Hamasaki S,
Miura F, Sato T. The antihypertensive effect and pharmacokinetics
References of nitvadipine (FK235) in essential hypertension. Jpn J Clin
1. Miller-Craig MW, Bishop CN, Raftery EB. Orcadian variation of Pharmacol Ther. 1986;17:735-748.
blood pressure. Lancet. 1978; 1:795 -797. 20. Umeda T, Iwaoka T, Miura F, Naomi S, Ohno M, Sasaki M, Sato
2. Broadhurst P, Brigden G, Dasgupta P. Ambulatory intra-arterial T, Inoue J, Hamasaki S. Pharmacokinetic study of nitrendipine in
blood pressure in normal subjects. Am Heart J. 1990;120-.161-166. patients with essential hypertension: relation between antihyper-
3. Khoury AF, Sunderajan P, Kaplan N. The early morning rise in tensive effect and plasma concentration. Jpn J Clin Exp Med, 1989;
blood pressure is related mainly to ambulation. Am J Hypertens. 66:615-620.
1992;5:339-344. 21. Iinsell CR, Lightman SL, Mullen PE, Brown MJ, Causon RC.
4. Marshall J. Diurnal variation in occurrence of stroke. Stroke. 1977; Circadian rhythm of epinephrine and norepinephrine in man.
8:230-231. J Clin Endocrinol Metab. 1985;«hl210-1215.
5. T»ementzis SA, Gill JS, Hitchcock ER, Gill SK, Beevers BG. 22. Panza JA, Epstein SE, Quyyumi AA. Circadian variation in
Diumal variation of and activity during onset of stroke. Ncuro- vascular tone and its relation to a-sympathetic vasoconstrictor
surgery. 1985;17:901-904. activity. N Engl J Med. 1991;325:986-990.
6. Arboix A, Mart-Vilalta JL. Acute stroke and circadian rhythm. 23. Windt C, Van Gijn J. Cerebral infarction does not occur typically
Stroke. 1990;21:826. at night. / Neurol Neuroswg Psychiatry. 1988;51:109-lll.
7. Wroe SJ, Sandercock P, Bamford J, Dennis M, Slattery J, Wartow 24. Marler JR, Price TR, Clark GL, Muller JE, Robertson T, Mohr JP.
C Diurnal variation in incidence of stroke: Oxfordshire com- Morning increase in onset of ischemic stroke. Stroke. 1989;20:
munity stroke project. BMJ. 1992;304:155-157. 473-476.