To achieve perfect 24‐hour blood pressure (BP) control, selection of long‐acting antihypertensive agents is essential. The BP‐lowering effect of short‐acting drugs is attenuated from midnight through the early morning hours, while that of long‐acting agents persist until the next morning drug dosage (Figure 5.1) [314] . In masked uncontrolled hypertension, reduction of morning home BP decreased important markers of target organ damage, including the urinary albumin‐creatinine ratio (UACR), pulse wave velocity (PWV), and left ventricular hypertrophy (LVH) even though office BP did not change (Figure 5.2) [315] . Use of long‐acting antihypertensive agents is required for perfect 24‐hour BP control of morning and nocturnal hypertension (Table 5.1) [37] . Longer‐acting antihypertensives are better at controlling nighttime and morning BP levels. These drugs are usually administered once daily in the morning, and provide continuous BP reduction over a 24‐hour period to attenuate the exaggerated morning BP surge (MBPS). Specific chronological treatment is based on the timing of antihypertensive dosing and selection of antihypertensive agent drug class(es). Specific treatment of the MBPS can be achieved using antihypertensive medication that reduces the pressor effect of neurohumoral factors potentiated in the morning (Figure 1.58) [106] , such as agents that inhibit sympathetic activity or the renin‐angiotensin‐aldosterone system (RAAS) (Table 5.1) [37] . Bedtime dosing of antihypertensive drugs, especially calcium channel blockers (CCBs), alpha‐blockers, and RAAS inhibitors, suppresses the exaggerated MBPS without excessive nocturnal hypotension during sleep. These treatments are also effective for nocturnal hypertension. On the other hand, specific drugs for reducing nighttime BP are those that reduce circulating volume, such as diuretics (including thiazide‐type diuretics), indapamide, mineralocorticoid receptor blockers, sacubitril/valsartan, and sodium‐glucose cotransporter (SGLT2) inhibitors. Figure 5.1 Twenty‐four‐hour blood pressure (BP)‐lowering profiles of different antihypertensive agents. Although both may appear to have similar antihypertensive effects based on office BP, the two have very different profiles over 24 hours, as measured by ambulatory BP monitoring, with Drug A showing a more consist effect throughout the 24‐hour dosing interval. Source: Based on Elliott et al. J Hypertens Suppl. 1996; 14: S15–S19 [314] . In addition to BP‐lower efficacy, selection of the appropriate antihypertensive drug(s) needs to take into account any concomitant conditions (Table 5.2) [253] . With respect to the effects of antihypertensive drug classes on cardiovascular event rates, beta‐blockers provide less‐effective prophylaxis of major cardiovascular events and stroke compared with other antihypertensive agents, while CCBs and angiotensin receptor blockers (ARBs) are the most effective agents for reducing the risk of stroke (Figure 5.3) [285] . However, diuretics appear to be superior to CCBs for preventing the development of heart failure (Figure 5.3) [285] . However, it is important to note that beta‐blocker studies included in the meta‐analysis used conventional agents that were available from the 1980s through to the early 2000s, such as propranolol and atenolol. Therefore, the effects of newer beta‐blockers such as carvedilol and bisoprolol also need to be investigated. CCBs have potent BP‐lowering effects on morning BP when their antihypertensive effect persists for 24 hours. The most important characteristic of the BP‐lowering effects of CCBs is that the extent of BP reduction almost always depends on pretreatment baseline BP. The higher the baseline BP, the greater the BP reduction achieved. The fact that CCBs do not lower BP extensively when baseline levels are lower means that these agents are ideally suited to reducing BP variability. In patients with a morning surge‐type of morning hypertension, higher morning BP is reduced to a greater extent while lower nighttime BP is not reduced, resulting in an improved circadian BP pattern. In patients with nocturnal hypertension (non‐dipper/riser type of nighttime BP), both higher nighttime BP and daytime BP could be similarly reduced by CCBs. Figure 5.2 Changes in office systolic blood pressure (SBP) (a), home morning SBP (b), and the extent of subclinical CVD (c–e) during antihypertensive therapy in patients with sustained uncontrolled hypertension (HT) or masked uncontrolled HT. BP, blood pressure; CVD, cardiovascular disease; LVMI, left ventricular mass index; PWV, pulse wave velocity; SBP, systolic blood pressure; UACR, urinary albumin‐creatinine ratio. Office SBP decreased only in the sustained uncontrolled HT group (p < 0.001 vs. baseline). Morning home SBP decreased significantly from baseline in both groups (p < 0.001). All indices of subclinical CVD were reduced during the study period in both groups (all p < 0.001). Source: Reprinted from Hoshide et al. J Am Coll Cardiol. 2018; 71: 2858–2859 [315] . Copyright (2015), with permission from Elsevier. Table 5.1 Antihypertensive treatment to target morning and nocturnal hypertension. Source: Modified from Kario. Essential Manual of 24‐Hour Blood Pressure Management from Morning to Nocturnal Hypertension. UK: Wiley Blackwell; 2015:1–138 [37] . BP, blood pressure; RAS, renin‐angiotensin system; SGLT2, sodium glucose cotransporter 2. Table 5.2 Indications for specific antihypertensive therapies based on the presence of comorbidities (based on 2019 recommendations from the Japanese Society of Hypertension). Source: Umemura et al. Hypertens Res. 2019;42:1235–1481 [253] . a Start with low doses, increase gradually with due care and attention. b Watch for coronary vasospastic angina. ACEi, angiotensin converting‐enzyme inhibitor; ARB, angiotensin receptor blocker; CCBs, calcium channel blockers; CKD, chronic kidney disease. Figure 5.3 Event‐controlling effect by antihypertensive drug class. ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CI, confidence interval; RR, relative risk. Source: Reprinted from Ettehad et al. Lancet. 2016; 387: 957–967 [285] , with permission from Elsevier. There are several types of calcium channel in the body (Table 5.3) [316] , and CCBs predominantly block L‐type channels to antagonize vascular smooth muscle contraction, resulting in BP reduction. Cilnidipine and azelnidipine also have activity at N‐type and L‐type channels, respectively, resulting in a unique profile of 24‐hour BP‐lowering effect. Table 5.3 Properties of calcium channels. Source: Created based on data from Triggle. Biochemical Pharmacology. 2007 30;74:1–9 [316]. Amlodipine, the CCB with the longest half‐life, is the best drug for facilitating morning BP control when it is administered once daily in the morning. Amlodipine monotherapy was more effective than valsartan, a short‐acting renin‐angiotensin system (RAS) inhibitor, in controlling 24‐hour ambulatory BP and morning BP in patients with hypertension (Figure 5.4) [317] . In addition, the prevalence of nonreactor patients (showing no reduction in morning BP) was reduced to a greater extent in the amlodipine group than in the valsartan group. The higher the baseline morning BP, the greater the difference between the two agents in morning BP‐lowering effect. In a titration study of amlodipine, 10 mg/day in a patient with uncontrolled hypertension treated with amlodipine 5 mg/day, similar characteristics of amlodipine were found even when the dosage was increased [318] . The BP‐lowering effect of amlodipine titration from 5 to 10 mg/day is highly dependent on baseline BP both for office BP and home BP (Figure 5.5) [318] . This office‐ and home BP‐lowering effect of amlodipine titration has been shown to be comparable in patients previously treated with amlodipine 5 mg monotherapy, amlodipine 5 mg in combination with an ARB, and amlodipine 5 mg combined with both an ARB and diuretics (Figure 5.6) [318] . Figure 5.4 Ambulatory morning blood pressure (BP)‐lowering effects of amlodipine vs. valsartan. Source: Created based on data from Eguchi et al. Am J Hypertens. 2004;17:112–117 [317] . Figure 5.5 Systolic blood pressure (SBP)‐lowering effect of increasing the dose of amlodipine from 5 to 10 mg once daily in 583 patients with uncontrolled hypertension in the Amlodipine Cohort study by Internet‐based research for Evaluation of Efficacy (ACHIEVE) study. Source: Kario et al. Curr Hypertens Rev. 2011;7:102–110 [318] . Republished with permission of Bentham Science Publishers Ltd. Amlodipine has been shown to significantly reduce higher daytime BP, but not lower nighttime BP in extreme dippers, while in non‐dippers, amlodipine reduced higher nighttime BP as well as higher daytime BP (Figure 5.7) [319] . In a meta‐analysis of Asian studies (two crossover and nine parallel controlled studies), where ten studies used amlodipine and one used nifedipine gastrointestinal therapeutic system (GITS), the ambulatory BP‐lowering effect of CCBs was greater than that of RAS inhibitors, and the slope of the regression lines was comparable for both nighttime and daytime BP measurements (Figure 5.8) [320] . Nifedipine is a potent vasodilating drug that reduces nighttime BP and morning BP in patients with hypertension. In the recent prospective, randomized, multicenter, open‐label Calcium Antagonist Controlled‐Release High‐Dose Therapy in Uncontrolled Refractory Hypertensive Patients (CARILLON) study, the ambulatory BP‐lowering of nifedipine controlled release (CR) (80 mg)/candesartan (8 mg) vs. amlodipine (10 mg)/candesartan (8 mg) was investigated in patients with uncontrolled hypertension (n = 51). Changes in 24‐hour BP were comparable between the groups. The nifedipine group demonstrated a significant decrease in the UACR, whereas the amlodipine group demonstrated a significant decrease in N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) level. Patients with higher daytime and morning surge in systolic blood pressure (SBP) at baseline had greater reductions in ambulatory BP when treated with the nifedipine combination compared with the amlodipine combination (Figure 5.9) [321] . Figure 5.6 Effect of increasing the dosage of once‐daily amlodipine from 5 to 10 mg in patient subgroups based on baseline medication status in 583 patients with uncontrolled hypertension in the Amlodipine Cohort study by Internet‐based research for Evaluation of Efficacy (ACHIEVE) study. ARB, angiotensin receptor blocker; SBP, systolic blood pressure. Source: Kario et al. Curr Hypertens Rev. 2011;7:102–110 [318] . Republished with permission of Bentham Science Publishers Ltd. Figure 5.7 Differential blood pressure (BP)‐lowering effect of amlodipine on nighttime BP in patient subgroups based on dipping status. Source: Kario and Shimada Am J Hypertens. 1997; 10: 261–268 [319] . Figure 5.8 Effect of dihydropyridine calcium channel blockers on 24‐hour systolic blood pressure (SBP) in Eastern Asians. BP, blood pressure; RAS, renin‐angiotensin system. Source: Wang et al. Hypertens Res. 2011; 34: 423–430 [320] . The prospective, randomized, parallel‐group, crossover effects of vasodilating vs. sympatholytic antihypertensives on sleep blood pressure in hypertensive patients with sleep apnea syndrome (VASSPS) study [231] , evaluated the effects of a nighttime dose of vasodilating (nifedipine CR 40 mg) vs. sympatholytic (carvedilol 20 mg) antihypertensive agents on nighttime BP using a recently developed trigger nighttime home BP monitor (TNP) with an oxygen‐triggered function that initiates BP measurement when oxygen saturation falls. The BP‐lowering effects of nifedipine on the mean (p < 0.05) and minimum (p < 0.01) nighttime SBP readings, and morning SBP (p < 0.001) were greater than those of carvedilol (Figure 2.73 and Table 2.6) [231] . Nighttime SBP surge (difference between the hypoxia‐peak SBP measured by the oxygen‐triggered function and SBP readings within 30 minutes before and after the peak SBP) was only significantly reduced by carvedilol (p < 0.05). Cilnidipine, a unique lipophilic L‐/N‐type CCB, suppresses sympathetic activity by inhibiting N‐type calcium channel‐associated norepinephrine release from peripheral sympathetic nerve endings. The Ambulatory Blood Pressure Control and Home Blood Pressure (Morning and Evening) Lowering by N‐Channel Blocker Cilnidipine (ACHIEVE‐ONE) trial was a large‐scale clinical study of 2319 patients with hypertension treated with cilnidipine. After 12 weeks’ therapy, both morning SBP and pulse rate (PR) self‐measured at home reduced to a greater extent in patients with higher baseline morning SBP (−3.2 mmHg and −1.3 beats per minute [bpm] in patients with morning SBP in the first quartile; −30.9 mmHg and −3.2 bpm for those with morning SBP in the fourth quartile), and also reduced home morning PR and SBP to a greater extent in those with a higher baseline morning PR (by 0.6 bpm and −15.6 mmHg when PR was <70 bpm, and −9.7 bpm and −20.2 mmHg when PR was ≥85 bpm). When the study subjects were separated into two groups based on higher (≥70 bpm) and lower (<70 bpm) PR within each quartile of morning SBP, the highest quartile, higher PR groups had a greater reduction in morning SBP than the lower PR group (by 4.6 mmHg) (Figure 5.10) [322] . These results suggest that cilnidipine significantly reduced BP and PR in patients with morning hypertension and increased sympathetic activity. Figure 5.9 Comparison of ambulatory systolic blood pressure (SBP)‐lowering effects during treatment with higher dosages of different calcium channel blockers in patients with uncontrolled hypertension in the Calcium Antagonist Controlled‐Release High‐Dose Therapy in Uncontrolled Refractory Hypertensive Patients (CARILLON) study. AML, amlodipine 10 mg + candesartan 8 mg; NCR, nifedipine 80 mg + candesartan 8 mg. Source: Mizuno et al. Blood Press. 2017; 26: 284–293 [321] . Copyright Skandinaviska Stiftelsen för Hjärt‐och Kärlforskning, reprinted by permission of Taylor & Francis Ltd. www.tandfonline on behalf of Skandinaviska Stiftelsen för Hjärt‐och Kärlforskning. Figure 5.10 Changes in home morning systolic blood pressure (MSBP) during treatment with cilnidipine in patient subgroups based on baseline morning blood pressure and pulse rate (PR). MSBP quartile (Q) 1: <142.7 mmHg; MSBP Q2: ≥142.7 to <151.7 mmHg; MSBP Q3; ≥151.7 to ≤161.2 mmHg; MSBP Q4 ≥161.3 mmHg; low morning PR: <70 beats/min; high morning PR ≥70 beats/min. Source: Kario et al. J Clin Hypertens. 2013; 15: 133–142 [322] . In another study, ambulatory BP monitoring (ABPM) data were obtained from 615 patients and classified according to their nighttime dipping status as extreme dippers, dippers, non‐dippers, or risers. Twelve weeks’ treatment with cilnidipine significantly reduced 24‐hour BP in all groups (p < 0.001 vs. baseline). Changes in nighttime SBP from baseline (with baseline values) were −17.9 (154.6), −11.9 (142.1), −6.6 (128.5), and 0.1 mmHg (115.8 mmHg), respectively, in risers, non‐dippers, dippers, and extreme dippers. Changes from baseline in nighttime SBP reduction rate were 8.2% in risers (p < 0.001), but −7.0% in extreme dippers (p < 0.001), while no change was observed in the overall rate of nighttime SBP reduction (Figure 5.11) [323] . These results show that cilnidipine partially, but significantly, restored abnormal nighttime dipping status toward a normal dipping pattern in patients with hypertension. Azelnidipine, another lipophilic L‐/T‐type CCB, restored baroreflex sensitivity and significantly lowered the heart rate to reduce morning BP compared with amlodipine [324, 325]. In a comparative ABPM study of azelnidipine 16 mg and amlodipine 5 mg, the 24‐hour BP‐lowering effect, including nighttime and morning BP, was comparable between the two groups (Figure 5.12) [326] . However, 24‐hour daytime and nighttime PR values were significantly suppressed in the azelnidipine group, but were increased in the amlodipine group. In our real‐world observational At HOME study, office and morning home BP values were reduced to a similar extent during azelnidipine therapy, but approximately 20 mmHg for SBP and about 10 mmHg for DBP (Figure 5.13) [327] . Figure 5.11 Changes in 24‐hour systolic blood pressure (SBP) during treatment with cilnidipine in patient subgroups based on nighttime dipping status. Source: Kario et al. J Clin Hypertens. 2013; 15: 465–472 [323] . The RAS is activated in the morning and could contribute to the MBPS and the morning increase in cardiovascular risk. Long‐acting angiotensin‐converting enzyme (ACE) inhibitors have been reported to lower ambulatory BP without disruption of diurnal BP variation. It has been demonstrated that, in addition to circulating factors in the cardiovascular system, tissue RAS also exhibits diurnal variation, possibly in relation to a clock gene [118, 328]. In addition to reducing morning BP, ACE inhibitors may also suppress morning activation of the tissue RAS, improving protection against organ damage, and cardiovascular events in patients with hypertension. Trandolapril is an ACE inhibitor with one of the longest‐acting activity profiles, and therefore BP‐lowering effects, due to its lipophilic nature [329] . The effects of bedtime vs. morning dosing of trandolapril on morning BP were studied. In the bedtime‐administered group, prewakening and morning SBP levels were significantly decreased (Figure 5.14) [329] . Conversely, reductions in prewakening SBP and morning SBP did not reach statistical significance in the morning‐administered group. There was no additional reduction in lowest nighttime BP in either group. Thus, bedtime administration of trandolapril appears to control morning BP without causing excessive nighttime falls in BP [329] . As well as ACE inhibitors, previous large clinical trials have shown that treatment with an ARB is associated with significant suppression of organ damage and cardiovascular events [330–332]. However, different ARBs have markedly different effects on morning BP levels and the MBPS. This is due to differences in plasma half‐life and the characteristics of binding to and dissociation from vascular angiotensin II receptors. Valsartan is a short‐acting ARB, and ideally, treatment should be given twice a day. The morning BP‐lowering effect of once‐daily valsartan is weaker than that of long‐acting amlodipine [317] . Figure 5.12 Diurnal variation of systolic and diastolic blood pressure and pulse rate before (solid circles) and after (open circles) after six weeks of treatment with azelnidipine in a six‐week randomized double‐blind study of 46 patients with essential hypertension. Source: Kuramoto et al. Hypertens Res. 2003; 26: 201–208 [326] . Figure 5.13 Effects of azelnidipine on office and morning home blood pressure (BP), and pulse rate. At HOME (Azelnidipine Treatment for Hypertension Open‐label Monitoring in the Early morning) study. CCB, calcium channel blocker; DBP, diastolic BP; SBP, systolic BP. Source: Created based on data from Kario et al. Drugs R D. 2013; 13: 63–73 [327] . Figure 5.14 Effect of bedtime dosing of the long‐acting angiotensin‐converting enzyme inhibitor, trandolapril, on morning systolic blood pressure (SBP) in patients with hypertension. Source: Kuroda et al. Hypertens Res. 2004; 27: 15–20 [329] . Telmisartan is a lipophilic ARB with the longest half‐life (24 hours) of all agents in this class. A meta‐analysis of the clinical efficacy of telmisartan with respect to reductions in BP in the morning hours was superior to that of short‐acting nonlipophilic ARBs [333] . Candesartan is a specific and competitive antagonist of angiotensin‐1 receptors [334] . A prospective crossover study in 73 patients with essential hypertension compared the effects of candesartan and lisinopril on ambulatory BP and early‐morning BP, assessed using ABPM, and low doses of a thiazide diuretic could be added if needed [335] . The two agents had satisfactory and almost identical effects on 24‐hour BP. When patients were classified into a morning surge group (the highest quartile of morning SBP surge; >36 mmHg) and a nonmorning surge group (the remaining three quartiles of morning SBP surge), candesartan was superior to lisinopril for decreasing morning BP and the MBPS [335] . The open‐label, multicenter Japan Target Organ Protection (J‐TOP) study was conducted in 450 patients with hypertension with self‐measured home SBP >135 mmHg [223] . The results showed that bedtime dosing of candesartan titrated based on self‐measured home BP was more effective for reducing albuminuria than morning dosing of an ARB in subjects with sufficiently well‐controlled home BP levels both in the morning and in the evening [223] . This beneficial effect was greater in subjects with morning‐dominant hypertension (morning and evening difference in home SBP of >15 mmHg) than in those with a morning and evening difference of <15 mmHg (Figure 5.15) [223] . In the J‐TOP study, even though the morning BP‐lowering effect was similar between the bedtime‐dosing and morning‐dosing groups, bedtime dosing of an ARB may be more effective for reducing albuminuria because it might suppress tissue RAS during the sleep‐early morning period more potently than morning dosing [223] . Figure 5.15 Effect of bedtime vs. morning dosing of candesartan on the urinary albumin‐creatinine ratio (UACR) in patients with hypertension (HT). Source: Kario et al. J Hypertens. 2010; 28: 1574–1583 [223] . Olmesartan is a potent ARB with persistent BP‐lowering effects for 24 hours, including the nighttime and morning periods. Olmesartan can restore nighttime BP fall, as seen with diuretics and sodium restriction, possibly by enhancing daytime sodium excretion [336] . Once‐daily use of olmesartan reduces morning home BP to a similar extent as office BP. The home BP‐lowering effects of olmesartan were examined using data from the Home BP measurement with Olmesartan Naive patients to Establish Standard Target blood pressure (HONEST) study, a prospective observational study in patients with hypertension (n = 21 341). Olmesartan reduced both office and morning home BP levels to a similar extent, indicating that the BP‐lowering effect of olmesartan persists for 24 hours (Figure 5.16) [56, 337]. The BP‐lowering effect of olmesartan for both morning home and office BP depends on the baseline BP level, as shown by similar slopes for the relationship between BP reduction and baseline BP (Figure 5.17) [338] . The effects of 16 weeks’ treatment with olmesartan on office and morning home BP were comparable in previously treated and previously untreated patients with hypertension (Figure 5.18) [338] . When study subjects were stratified into masked hypertension, white‐coat hypertension, poorly controlled hypertension, and well‐controlled hypertension groups based on baseline office and morning home BP readings at 16 weeks, changes in office SBP were −1.0, −15.2, −23.1, and 1.8 mmHg, respectively, and changes in morning home SBP were −12.5, 1.0, −20.3, and 2.0 mmHg, respectively (Figure 5.19) [337] . Thus, in real‐world clinical practice, olmesartan‐based treatment decreased high morning home BP or office BP without excessive decreases in normal morning home BP or office BP in patient subgroups defined by the type of hypertension [339] . Figure 5.16 Change in office and morning home blood pressure (BP). At baseline, morning home BP was 151.2/86.9 mmHg, and office BP was 153.6/87.1 mmHg. Favorable BP control was maintained for two years. After two years, morning home BP was 131.5/76.3 mmHg, and office BP was 132.6/75.6 mmHg. DBP, diastolic BP; SBP, systolic BP. Source: Kario et al. Hypertension. 2014;64: 989–996 [56] . HONEST study data for patients who were not on antihypertensive medication at baseline were classified based on quartiles of baseline morning home SBP (MHSBP). In each group, patients were further classified based on baseline morning home pulse rate (MHPR). Patients with hypertension and chronic kidney disease (CKD) who had baseline MHSBP values in the fourth quartile (≥165 mmHg) and a MHPR ≥70 beats/minute showed a greater reduction in BP (−36.9 mmHg) than those with MHPR <70 bpm (−30.4 mmHg) after 16 weeks of olmesartan treatment. BP reductions were even greater in patients with vs. without CKD in this group (−6.6 vs. −2.2 mmHg) (Figure 5.20) [340] . These data show that olmesartan was more effective in patients with hypertension who had high MHSBP and MHPR ≥70 beats/minute, especially in those with CKD, suggesting that olmesartan may have enhanced BP‐lowering effects by improving renal ischemia in patients with hypertension and CKD, and potential increased sympathetic nerve activity. Azilsartan, a novel ARB, has been reported to be more effective for lowering BP than other ARBs, and to have a potent antihypertensive effect over 24 hours. A randomized, double‐blind study of 14 weeks’ treatment with azilsartan (20–40 mg once daily; n = 273) or candesartan (8–12 mg once daily; n = 275) in Japanese patients with hypertension showed that azilsartan lowered nighttime BP in those with a dipper pattern of nighttime BP (≥10% decrease from daytime SBP) more extensively than daytime BP in non‐dippers. In addition, azilsartan reduced the MBPS to a greater extent in those with exaggerated MBPS, reduced daytime SBP to a greater extent than nighttime SBP, and decreased daytime SBP to a significantly greater extent than candesartan (Figure 5.21) [341] . Thus, once‐daily azilsartan improved non‐dipping nighttime SBP to a greater extent than candesartan in this patient group. Figure 5.17 Changes from baseline in systolic blood pressure (BP) after 16 weeks of olmesartan‐based treatment. SD, standard deviation. Source: Kario et al. Hypertens Res. 2016;39: 334–341 [338] . Figure 5.18 Change in clinic and morning home blood pressure (BP) after 16 weeks of olmesartan (OLM) monotherapy or combination therapy (excluding patients who switched antihypertensive treatment). ßB, beta‐blocker; CCB, calcium channel blocker; D, diuretic. Source: Kario et al. Hypertens Res. 2016;39: 334–341 [338] . We also compared the efficacy of azilsartan and candesartan for controlling morning SBP surges in patients with and without BP surges at baseline. In the morning surge group (n = 147; sleep‐trough BP surge ≥35 mmHg), azilsartan significantly reduced both the sleep‐trough surge and the prewakening surge at week 14 compared with candesartan (least squares mean between‐group differences of −5.8 [p = 0.0395] and −5.7 mmHg [p = 0.0228], respectively) (Figure 5.22) [342] . This shows that once‐daily azilsartan improved the sleep‐trough surge and pre‐wakening surge to a greater extent than candesartan in Japanese patients with hypertension. There are several characteristics of azilsartan that could account for its better 24‐hour BP‐lowering profiles compared with valsartan, including (1) higher affinity for, and slower dissociation from, angiotensin II type‐1 receptors; (2) a longer half‐life of around 13 hours; and (3) increased lipophilicity. In the multicenter, randomized, open‐label, parallel Azilsartan Circadian and Sleep Pressure – the 1st (ACS1) study, the nighttime BP‐lowering effect of azilsartan 20 mg was weaker than that of amlodipine 5 mg, especially in older patients with hypertension [343] . In a post hoc analysis, azilsartan significantly reduced DBP compared with amlodipine in male patients aged <60 years, but amlodipine was significantly more effective than azilsartan at lowering SBP in female patients aged ≥60 years. In both younger and older patients with hypertension, shorter duration of hypertension history was significantly associated with greater 24‐hour SBP reduction during therapy (Table 5.4) [344] . Figure 5.19 Change in office and morning home blood pressure (BP) after 16 weeks of olmesartan treatment in patient groups based on the type of hypertension. SBP, systolic BP. Source: Kario et al. J Hum Hypertens. 2013;27: 721–728 [337] . Figure 5.20 Change in morning home systolic blood pressure (SBP) after 16 weeks of olmesartan treatment in patient subgroups based on quartiles of baseline morning SBP and pulse rate (PR), in patients with or without coexisting chronic kidney disease. Source: Kario et al. J Clin Hypertens. 2014;16:442–450 [339] . Figure 5.21 Differential effect of azilsartan on 24‐hour ambulatory systolic blood pressure (SBP) in patients with a dipper or non‐dipper profile of nighttime blood pressure. Source: Rakugi et al. Blood Press. 2013;22 Supl 1:22–28 [341] . Copyright Sk‐andinaviska Stiftelsen för Hjärt‐och Kärlforskning, reprinted by permission of Taylor & Francis Ltd. www.tandfonline on behalf of Skandinaviska Stiftelsen för Hjärt‐och Kärlforskning.
CHAPTER 5
Antihypertensive medication
Concept of 24‐hour BP lowering including nighttime and morning BPs
Chronotherapy
Antihypertensive drug choice
Calcium channel blockers
Non‐specific
Specific
Morning hypertension
(exaggerated morning BP surge)
Long‐acting drug
Bedtime dosing of calcium channel blocker,
RAS inhibitors, alpha‐blocker
Nocturnal hypertension
(Riser/non‐dipper)
Long‐acting drug
Diuretics (thiazides, mineral corticoid blocker)
Bedtime dosing of RAS inhibitors, calcium channel blocker, alpha‐blocker, Sacubitril/valsartan (LCZ696) SGLT2 inhibitor
CCBs
ARB/ACEi
Thiazide diuretics
β‐blockers
Left ventricular hypertrophy
●
●
Heart failure with reduced ejection fraction
●a
●
●a
Tachycardia
●(non‐dihydropyridines)
●
Angina
●
●b
Post‐myocardial infarction
●
●
CKD patients with microalbuminuria and proteinuria
●
Type
Location
Location/Function
L‐type
Vascular smooth muscle
Contraction of smooth muscle of blood vessels
Contraction of myocardium
Causes vasoconstriction
N‐type
NeuronsBrain
Regulates the release of norepinephrine from neuronal endings
T‐type
HeartKidneyAdrenalglands
In heart, regulates pacemaker activityDilates the afferent & efferent arterioles in the kidneysStimulates the release of aldosterone
P‐/Q‐/R‐type
Neurons
Neurotransmitter release
Amlodipine
Nifedipine
Cilnidipine
Azelnidipine
Angiotensin‐converting enzyme inhibitors
Angiotensin receptor blockers (ARBs)
Valsartan
Telmisartan
Candesartan
Olmesartan
Azilsartan
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
