Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Chronopharmacology of high blood pressure—a critical review of clinical evidence

Chronopharmacology of high blood pressure—a critical review of clinical evidence Physiological functions of cardiovascular system (CVS) are exhibiting circadian patterns regulated by complex system of endogenous factors. Preserving this rhythmicity is important for its normal function, whereas disturbing the synchronization with natural day–night cycle can increase the risk of cardiovascular damage. Cardiovascular pathophysiology also follows cyclic variation; time susceptibility and period with maximum risk associated with elevated blood pressure (BP) can be predicted. Given this rhythmic nature, significant changes in efficacy between morning and evening administration of the drug may occur; appropriate timing of pharmacological intervention in therapy of hypertension may affect the efficacy of the treatment. Keywords chronopharmacology – blood pressure – circadian rhythm – non-dipping INTRODUCTION The light–dark cycle is the most prominent rhythm on adrenaline, and catecholamines in the first hours after waking. the earth, and organisms have adapted to this rhythm by Renin-angiotensin-aldosterone hormone system (RAAS) the evolution of biological rhythms. Rhythmicity of life also plays an important role contributing to the composite processes is one of the key factors for survival by adapting to rhythm of BP with plasma concentrations of renin activity, environmental changes. This also applies to the cardiovascular angiotensin-converting enzyme (ACE), angiotensin I and II, system (CVS); its rhythmic features are important to and aldosterone all of them peaking in the morning before synchronize the organ response to external changes (Wu et awakening. Conversely, comparatively lower BP during sleep al., 2011). Conversely, loss of synchronization between the is a result of predominance of parasympathetic action over circadian oscillator and external stimuli can cause damage the sympathetic nervous system, lower RAAS concentration, to the cardiovascular organs, and in long term, it can lead to and maximum vasodilator levels—atrial natriuretic peptide increased morbidity and mortality risk. CVS exhibits distinct and nitric oxide (Hermida et al., 2011). In organisms with 24 hours rhythm within its physiological functions; main reversed day–night activities, that is, nocturnal animals, the features such as blood pressure (BP), cardiac output, and BP rhythm is opposite, so the highest values occur at night heart rate have a clear and characteristic circadian pattern. when animals are active and seek food, confirming that the Likewise, the pathophysiological mechanisms connected to day and night rhythm and differences in mental and physical morbidity and mortality display this rhythm. activities are a key factor affecting the circadian rhythm of BP. Values of BP are not constant throughout the day (Portaluppi CHRONOTHERAPY OF HYPERTENSION et al., 2012). A distinct 24-h rhythm given by cyclic alternation of day and night with subsequent changes in behavior (e.g., physical activity and mental stress) and circadian rhythm of The goal of chronotherapy is to achieve maximum drug endogenous factors can be observed. The rhythm character concentrations in synchrony with the intrinsic circadian rhythm is largely due to the dominance of the sympathetic nervous of the disease or symptoms process, thereby increasing the system with high levels of circulating noradrenaline, efficacy as well as reducing the adverse effects of treatment. * E-mail: petar.potucek@gmail.com © European Pharmaceutical Journal OR 32 Eur. Pharm. J. 2019, 66(2), 32-36 Chronopharmacology of high blood pressure—a critical review of clinical evidence Potucek P., Klimas J. Table 1: Administration-time-dependent effect of BP-lowering medications Study No. of Dosage Treatment Comparison of morning Author Medication length completed (mg per day) times vs. evening dosing (weeks) subjects Significant reduction Awakening Hermida et Valsartan 160 12 90 in asleep SBP/DBP with bedtime al., 2003 evening dosing Significant reduction Awakening Hermida et Olmesartan 20 12 133 in asleep SBP/DBP with bedtime al., 2009 evening dosing Significant reduction Awakening Hermida et Telmisartan 80 12 215 in asleep SBP/DBP with bedtime al., 2007 evening dosing 08:00; Significant reduction in Macchiarulo Lisinopril 20 16:00; 8 40 early morning SBP/DBP et al,. 1999 22:00 with evening dosing Significant reduction in Awakening Kuroda et al., Trandolapril 1 8 30 24-h BP mean with evening bedtime 2004 dosing Significant reduction in Awakening Hermida and Ramipril 5 6 115 48-h SBP/DBP mean with bedtime Ayala, 2009 evening dosing Significant reduction Awakening Hermida et Spirapril 6 12 165 in asleep SBP/DBP with bedtime al., 2010 evening dosing Significant reduction in Awakening Hermida et Nifedipine 30 8 180 48-h SBP/DBP mean with bedtime al., 2008 evening dosing Significant reduction in Awakening Hermida et Torasemide 5 6 113 48-h SBP/DBP mean with bedtime al., 2008 evening dosing This can be achieved by specific drug technologies but often this cascade—ACE inhibitors and AT1 blockers—and have by simply adjusting the time of administration of conventional indeed shown statistically significant changes in chronic non- therapy (Smolensky et al. 2010). Research has shown that dipping nocturnal adjustment when monotherapy was given the majority of patients with hypertension use BP-lowering in the evening and not in the morning (Hermida et al., 2013; medication in the morning; some data refer up to 80% of Schillaci et al., 2015). The thiazide diuretics have also been patients with hypertension taking all antihypertensive drugs shown to have a greater efficacy with evening treatment, in the morning (De La Sierra et al., 2009). In contrary to this being significantly more effective in reducing the incidence practice, a number of randomized clinical trials (RCTs) have of severe cardiovascular events, adjustment of circadian demonstrated that appropriate timing of administration of an pattern, and reduction of nocturnal BP values (Kasiakogias antihypertensive drug can affect the efficacy and safety of the et al., 2015; Liu et al. 2014). A meta-analysis comparing the treatment, so that changes in efficacy between morning and results of more than 20 RCTs involving almost 2,000 patients evening drug delivery may be significant for individual drugs. with primary hypertension confirmed that more effective BP control was achieved with evening monotherapy (Zhao et al., Monotherapy 2011). However, this does not apply to all antihypertensive drugs. Clinical trials focusing on monotherapy have been performed Given their long elimination half-life, trials with calcium with all available classes of drugs used in the treatment of channel blockers have shown no significant difference hypertension, that is, ACE inhibitors, diuretics, α-blockers, between morning and evening administration of majority β-blockers, direct renin inhibitor, angiotensin receptor of the dihydropyridines (amlodipine, isradipine, lacidipine) blockers, and calcium channel blockers (see Table 1). (Qui et al., 2003; Lemmer, 2006); however, studies with Significant treatment-time differences were confirmed for nifedipine have shown reduction of the mean BP values to several classes of antihypertensive drugs. With the RAAS be significantly better with bedtime dosing (Hermida et al., being highly circadian rhythmic, most of the recent and 2008). Conversely, β-blockers appear to be more effective in well-designed studies have focused on drugs acting on morning administration and alter the circadian BP toward a 33 34 Eur. Pharm. J. 2019, 66(2), 32-36 Chronopharmacology of high blood pressure—a critical review of clinical evidence Potucek P., Klimas J. Table 2: Administration-time-dependent effect of selected BP-lowering medications in combination treatment Study No. of Combination Dosage Treatment Comparison of morning Author length completed treatment (mg per day) times vs. evening dosing (weeks) subjects No difference in mean, Valsartan/ 06:00–10:00 8 463 asleep, and awake SBP/ Asmar et al., amlodipine 160/5-10 18:00–22:00 DBP with evening or 2011 (free combination) morning dosing Valsartan/ Significant reduction in amlodipine Awakening Hermida et 160/5 12 203 asleep SBP/DBP and mean (fixed/free bedtime al., 2010 SBP with evening dosing combination) Valsartan/HCT Significant reduction in Awakening Hermida et (fixed 160/12.5 12 204 asleep SBP with evening bedtime al., 2011 combination) dosing Amlodipine/HCT Significant reduction in 8:00 Zeng et al., (fixed 5/25 12 80 mean and asleep SBP/DBP 22:00 2011 combination) with evening dosing Amlodipine/ 7:00–8:00 Significant reduction in Meng et al., fosinopril 5/10 7:00–8:00/ 4 40 asleep SBP/DBP with split (free combination) 20:00–21:00 evening dosing Amlodipine/ 7:00–8:00 Significant reduction in Meng et al., fosinopril 5/10 7:00–8:00/ 4 40 asleep SBP/DBP with split (free combination) 20:00–21:00 evening dosing nondipper profile. This can be reasonably expected with the other one (Hermida et al., 2010; Asmar et al., 2011). With the concentration of catecholamines as well as the expression study length being the only difference between these two of beta-receptors being lowest during the night, thus owing studies, this fact might indicate that the duration of treatment the administration of β-blockers in the evening lower effect can also influence the chrono-effect. Similar results were also compared with that in the morning (Langner, Lemmer, 1988) confirmed in preclinical settings (Potucek et al., 2017). DISCUSSION Fixed combination therapy Although the treatment of hypertension is usually initiated Circadian rhythms at targeted site of action are a as monotherapy, in most cases, combination therapy, that primary prerequisite for chronopharmacology. This is is, use of multiple antihypertensive agents simultaneously, confirmed by several experiments showing that the peak is also indicated (Dahlöf, 2009). Therapy with lower doses of pharmacodynamic (PD) effect of drugs does not correlate with two or more drugs is preferable to monotherapy at higher the plasma concentration peak, thus suggesting a circadian doses with one drug, because better control of BP is achieved stage dependency of the drug plasma concentration– along with better tolerability and related patient compliance. antihypertensive effect relationship (Smolensky et al. 2010). Compared with large number of studies investigating However, PD and/or pharmacokinetic (PK) profile of the drug difference between morning and evening dosing, studies must also be taken into consideration before selecting suitable with combination therapy investigating the chrono-effect candidates, because molecules with a longer elimination half- are still limited (see Table 2). In these cases, it is assumed life or slow dissociation from the receptor-binding site are that chronopharmacological profiles of each drug might prone to have decreased chronopharmacological effect (Liu contribute to the dosing-time-dependent influences on the et al., 2011). efficacy and safety of combined hypertension medication, The appropriate choice of the drug and the timing of its with results suggesting evening dosing to be more effective administration must, therefore, respect PK profile of the in terms of BP reduction and/or normalization of the circadian molecule, but, at the same time, circadian rhythms of body rhythm of BP (Potúček, Klimas, 2013). However, interesting may as well affect the fate of the drug in the body. Gastric observation came from the comparison of two independent emptying, motility, and perfusion are significantly longer studies investigating the chrono-effect of the same in the morning, whereas gastric acid secretion reaches its combination (amlodipine and valsartan). While significant maximum in the evening. Lipophilic molecules seem to be reduction in asleep BP and mean BP values with evening more prone to circadian rhythms of the body affecting their PK dosing was proven in one of the studies, no difference and then hydrophilic one with respect to differences between between time of administration has been observed in the the maximum plasma concentrations (Cmax) measured after 33 34 Eur. Pharm. J. 2019, 66(2), 32-36 Chronopharmacology of high blood pressure—a critical review of clinical evidence Potucek P., Klimas J. morning and evening administration (Lemmer et al., 1991; normal diurnal pattern, it was confirmed that there is a clear Shiga et al., 1993). However, no significant changes in AUC association with the risk of cardiovascular disease (Takeda, were observed so far suggesting that circadian changes in Maemura, 2011). Normotensive non-dippers are exposed the PD of medicines used in chronotherapy of CVS are the to almost the same risk of cardiovascular mortality as result of direct interaction with the target system rather than hypertensive dippers. It has been also shown that when the changes in efficacy because of changes in PK. diurnal rhythm of BP was normalized, free survival of patients Last but not the least; consideration must be also given with heart failure has increased, whereas non-dipping is to the duration of treatment. Short elimination half-life associated with increased incidence of cardiovascular events suggests greater drug fluctuations in plasma. In short-term (Salles et al., 2016). Therefore, normalization of the circadian administration, this may also translate to more pronounced rhythm of BP is one of the primary targets in the treatment differences between morning and evening treatments of hypertension. Vast majority of reviewed RCT have shown (Portaluppi et al., 2007), especially when comparing the normalization of the dipping profile and/or changes in asleep difference in decreasing the mean BP values. Conversely, once BP values when applying chronotherapy, and this fact may the steady state of drug is reached in the body and the plasma have even more clinical impact than the differences in the levels of the drug are constant, the chronopharmacological mean 24-h BP reduction alone. effect may be waning, so the difference between morning CONCLUSION and evening doses is less profound. Thus, with respect to the treatment duration, chrono-effect is expected to be more prominent in the beginning rather than after long- The results from the RCTs clearly indicate that appropriate term administration. Therefore, chronotherapy might be of timing for dosing of antihypertensive drugs may increase clear benefit in settings, where rapid onset of treatment or the control of the hypertension; however, consideration normalization of BP pattern is needed. must always be given to the circadian rhythm of the targeted However, it is of important note that significant difference site of action, kinetic profile of the drug, and also to the between dosing regimens in terms of dipping prevalence duration of treatment. Although the comparison between has been observed in long-term treatment even if there was morning and evening dosing has not been always translated no more effect on the mean 24-h BP values. It is known that into significant difference in the decrease in the mean 24-h loss of the physiological circadian pattern of BP may lead to BP values, normalization of the circadian rhythm of BP has pathological mechanism associated with increased morbidity been achieved with appropriate timing of pharmacological and mortality (Ohkubo et al., 2002). Chronically increased intervention. With the later having the clear clinical relevance BP may even lead to general dysfunctional circadian body in terms of decreased CVS morbidity, these data substantiate rhythms. For all blood pressure profiles with impaired, the need for chronopharmacological approach in clinical disturbed, or otherwise deviating rhythmicity compared with settings. References [1] Asmar R, Gosse P, Quere S, Achouba A. Efficacy of morning regulation. Chronobiology international. 2013 Mar 1;30(1-2):280- and evening dosing of amlodipine/valsartan combination in 314. hypertensive patients uncontrolled by 5 mg of amlodipine. [6] Hermida RC, Ayala DE, Fontao MJ, Mojón A, Fernández JR. Blood pressure monitoring. 2011 Apr 1;16(2):80-6. Chronotherapy with valsartan/amlodipine fixed combination: [2] Dahlöf B. Management of cardiovascular risk with RAS inhibitor/ improved blood pressure control of essential hypertension CCB combination therapy. Journal of human hypertension. 2009 with bedtime dosing. Chronobiology international. 2010 Jul Feb;23(2):77. 1;27(6):1287-303. [3] De La Sierra A, Redon J, Banegas JR, Segura J, Parati G, Gorostidi M, [7] Hermida RC, Ayala DE, Mojón A, Fernández JR. Chronotherapy de la Cruz JJ, Sobrino J, Llisterri JL, Alonso J, Vinyoles E. Prevalence with nifedipine GITS in hypertensive patients: improved and factors associated with circadian blood pressure patterns in efficacy and safety with bedtime dosing. American journal of hypertensive patients. Hypertension. 2009 Mar 1;53(3):466-72. hypertension. 2008 Aug 1;21(8):948-54. [4] Hermida RC, Ayala DE, Fernández JR, Portaluppi F, Fabbian F, [8] Kasiakogias A, Tsioufis C, Thomopoulos C, Andrikou I, Aragiannis Smolensky MH. Circadian rhythms in blood pressure regulation D, Dimitriadis K, Tsiachris D, Bilo G, Sideris S, Filis K, Parati G. and optimization of hypertension treatment with ACE inhibitor Evening versus morning dosing of antihypertensive drugs in and ARB medications. American journal of hypertension. 2011 hypertensive patients with sleep apnoea: a cross-over study. Apr 1;24(4):383-91 Journal of hypertension. 2015 Feb 1;33(2):393-400. [5] Hermida RC, Ayala DE, Fernández JR, Mojón A, Smolensky MH, [9] Langner B, Lemmer B. Circadian changes in the pharmacokinetics Fabbian F, Portaluppi F. Administration-time differences in effects and cardiovascular effects of oral propranolol in healthy subjects. of hypertension medications on ambulatory blood pressure European journal of clinical pharmacology. 1988 Nov 1;33(6):619-24. 35 36 Eur. Pharm. J. 2019, 66(2), 32-36 Chronopharmacology of high blood pressure—a critical review of clinical evidence Potucek P., Klimas J. [10] Lemmer B. The importance of circadian rhythms on drug response [22] Shiga T, Fujimura A, Tateishi T, Ohashi K, Ebihara A. Differences in hypertension and coronary heart disease—from mice and of chronopharmacokinetic profiles between propranolol man. Pharmacology & therapeutics. 2006 Sep 1;111(3):629-51. and atenolol in hypertensive subjects. The Journal of Clinical [11] Lemmer B, Nold G, Behne S, Kaiser R. Chronopharmacokinetics Pharmacology. 1993 Aug;33(8):756-61. and cardiovascular effects of nifedipine. Chronobiology [23] Smolensky MH, Hermida RC, Ayala DE, Tiseo R, Portaluppi F. international. 1991 Jan 1;8(6):485-94. Administration–time-dependent effects of blood pressure- [12] Liu X, Liu X, Huang W, Leo S, Li Y, Liu M, Yuan H. Evening-versus lowering medications: basis for the chronotherapy of morning-dosing drug therapy for chronic kidney disease hypertension. Blood pressure monitoring. 2010 Aug 1;15(4):173- patients with hypertension: a systematic review. Kidney and 80. Blood Pressure Research. 2014;39(5):427-40. [24] Takeda N, Maemura K. Circadian clock and cardiovascular disease. [13] Liu Y, Ushijima K, Ohmori M, Takada M, Tateishi M, Ando H, Journal of cardiology. 2011 May 1;57(3):249-56. Fujimura A. Chronopharmacology of angiotensin II–receptor [25] Wu X, Liu Z, Shi G, Xing L, Wang X, Gu X, Qu Z, Dong Z, Xiong J, Gao blockers in stroke-prone spontaneously hypertensive rats. X, Zhang C. The circadian clock influences heart performance. Journal of pharmacological sciences. 2011:1101240507-. Journal of biological rhythms. 2011 Oct;26(5):402-11. [14] Ohkubo T, Hozawa A, Yamaguchi J, Kikuya M, Ohmori K, [26] Zhao P, Xu P, Wan C, Wang Z. Evening versus morning dosing Michimata M, Matsubara M, Hashimoto J, Hoshi H, Araki T, Tsuji regimen drug therapy for hypertension. Cochrane Database of I. Prognostic significance of the nocturnal decline in blood Systematic Reviews. 2011(10). pressure in individuals with and without high 24-h blood pressure: the Ohasama study. Journal of hypertension. 2002 Nov 1;20(11):2183-9. [15] Portaluppi F, Lemmer B. Chronobiology and chronotherapy of ischemic heart disease. Advanced drug delivery reviews. 2007 Aug 31;59(9-10):952-65. [16] Portaluppi F, Tiseo R, Smolensky MH, Hermida RC, Ayala DE, Fabbian F. Circadian rhythms and cardiovascular health. Sleep medicine reviews. 2012 Apr 1;16(2):151-66. [17] Potucek P, Klimas J. Chronotherapy of hypertension with combination treatment. Die Pharmazie-An International Journal of Pharmaceutical Sciences. 2013 Dec 2;68(12):921-5. [18] Potucek P, Radik M, Doka G, Kralova E, Krenek P, Klimas J. mRNA levels of circadian clock components Bmal1 and Per2 alter independently from dosing time-dependent efficacy of combination treatment with valsartan and amlodipine in spontaneously hypertensive rats. Clinical and Experimental Hypertension. 2017 Nov 17;39(8):754-63. [19] Qiu YG, Chen JZ, Zhu JH, Yao XY. Differential effects of morning or evening dosing of amlodipine on circadian blood pressure and heart rate. Cardiovascular drugs and therapy. 2003 Jul 1;17(4):335-41. [20] Salles GF, Reboldi G, Fagard RH, Cardoso CR, Pierdomenico SD, Verdecchia P, Eguchi K, Kario K, Hoshide S, Polonia J, de la Sierra A. Prognostic effect of the nocturnal blood pressure fall in hypertensive patients: the ambulatory blood pressure collaboration in patients with hypertension (ABC-H) meta- analysis. Hypertension. 2016 Apr;67(4):693-700. [21] Schillaci G, Battista F, Settimi L, Schillaci L, Pucci G. Antihypertensive drug treatment and circadian blood pressure rhythm: a review of the role of chronotherapy in hypertension. Current pharmaceutical design. 2015 Feb 1;21(6):756-72. 35 36 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Facultatis Pharmaceuticae Universitatis Comenianae de Gruyter

Chronopharmacology of high blood pressure—a critical review of clinical evidence

Loading next page...
 
/lp/de-gruyter/chronopharmacology-of-high-blood-pressure-a-critical-review-of-qrU9RddhGz
Publisher
de Gruyter
Copyright
© 2019 P. Potucek et al., published by Sciendo
ISSN
1338-6786
eISSN
2453-6725
DOI
10.2478/afpuc-2019-0017
Publisher site
See Article on Publisher Site

Abstract

Physiological functions of cardiovascular system (CVS) are exhibiting circadian patterns regulated by complex system of endogenous factors. Preserving this rhythmicity is important for its normal function, whereas disturbing the synchronization with natural day–night cycle can increase the risk of cardiovascular damage. Cardiovascular pathophysiology also follows cyclic variation; time susceptibility and period with maximum risk associated with elevated blood pressure (BP) can be predicted. Given this rhythmic nature, significant changes in efficacy between morning and evening administration of the drug may occur; appropriate timing of pharmacological intervention in therapy of hypertension may affect the efficacy of the treatment. Keywords chronopharmacology – blood pressure – circadian rhythm – non-dipping INTRODUCTION The light–dark cycle is the most prominent rhythm on adrenaline, and catecholamines in the first hours after waking. the earth, and organisms have adapted to this rhythm by Renin-angiotensin-aldosterone hormone system (RAAS) the evolution of biological rhythms. Rhythmicity of life also plays an important role contributing to the composite processes is one of the key factors for survival by adapting to rhythm of BP with plasma concentrations of renin activity, environmental changes. This also applies to the cardiovascular angiotensin-converting enzyme (ACE), angiotensin I and II, system (CVS); its rhythmic features are important to and aldosterone all of them peaking in the morning before synchronize the organ response to external changes (Wu et awakening. Conversely, comparatively lower BP during sleep al., 2011). Conversely, loss of synchronization between the is a result of predominance of parasympathetic action over circadian oscillator and external stimuli can cause damage the sympathetic nervous system, lower RAAS concentration, to the cardiovascular organs, and in long term, it can lead to and maximum vasodilator levels—atrial natriuretic peptide increased morbidity and mortality risk. CVS exhibits distinct and nitric oxide (Hermida et al., 2011). In organisms with 24 hours rhythm within its physiological functions; main reversed day–night activities, that is, nocturnal animals, the features such as blood pressure (BP), cardiac output, and BP rhythm is opposite, so the highest values occur at night heart rate have a clear and characteristic circadian pattern. when animals are active and seek food, confirming that the Likewise, the pathophysiological mechanisms connected to day and night rhythm and differences in mental and physical morbidity and mortality display this rhythm. activities are a key factor affecting the circadian rhythm of BP. Values of BP are not constant throughout the day (Portaluppi CHRONOTHERAPY OF HYPERTENSION et al., 2012). A distinct 24-h rhythm given by cyclic alternation of day and night with subsequent changes in behavior (e.g., physical activity and mental stress) and circadian rhythm of The goal of chronotherapy is to achieve maximum drug endogenous factors can be observed. The rhythm character concentrations in synchrony with the intrinsic circadian rhythm is largely due to the dominance of the sympathetic nervous of the disease or symptoms process, thereby increasing the system with high levels of circulating noradrenaline, efficacy as well as reducing the adverse effects of treatment. * E-mail: petar.potucek@gmail.com © European Pharmaceutical Journal OR 32 Eur. Pharm. J. 2019, 66(2), 32-36 Chronopharmacology of high blood pressure—a critical review of clinical evidence Potucek P., Klimas J. Table 1: Administration-time-dependent effect of BP-lowering medications Study No. of Dosage Treatment Comparison of morning Author Medication length completed (mg per day) times vs. evening dosing (weeks) subjects Significant reduction Awakening Hermida et Valsartan 160 12 90 in asleep SBP/DBP with bedtime al., 2003 evening dosing Significant reduction Awakening Hermida et Olmesartan 20 12 133 in asleep SBP/DBP with bedtime al., 2009 evening dosing Significant reduction Awakening Hermida et Telmisartan 80 12 215 in asleep SBP/DBP with bedtime al., 2007 evening dosing 08:00; Significant reduction in Macchiarulo Lisinopril 20 16:00; 8 40 early morning SBP/DBP et al,. 1999 22:00 with evening dosing Significant reduction in Awakening Kuroda et al., Trandolapril 1 8 30 24-h BP mean with evening bedtime 2004 dosing Significant reduction in Awakening Hermida and Ramipril 5 6 115 48-h SBP/DBP mean with bedtime Ayala, 2009 evening dosing Significant reduction Awakening Hermida et Spirapril 6 12 165 in asleep SBP/DBP with bedtime al., 2010 evening dosing Significant reduction in Awakening Hermida et Nifedipine 30 8 180 48-h SBP/DBP mean with bedtime al., 2008 evening dosing Significant reduction in Awakening Hermida et Torasemide 5 6 113 48-h SBP/DBP mean with bedtime al., 2008 evening dosing This can be achieved by specific drug technologies but often this cascade—ACE inhibitors and AT1 blockers—and have by simply adjusting the time of administration of conventional indeed shown statistically significant changes in chronic non- therapy (Smolensky et al. 2010). Research has shown that dipping nocturnal adjustment when monotherapy was given the majority of patients with hypertension use BP-lowering in the evening and not in the morning (Hermida et al., 2013; medication in the morning; some data refer up to 80% of Schillaci et al., 2015). The thiazide diuretics have also been patients with hypertension taking all antihypertensive drugs shown to have a greater efficacy with evening treatment, in the morning (De La Sierra et al., 2009). In contrary to this being significantly more effective in reducing the incidence practice, a number of randomized clinical trials (RCTs) have of severe cardiovascular events, adjustment of circadian demonstrated that appropriate timing of administration of an pattern, and reduction of nocturnal BP values (Kasiakogias antihypertensive drug can affect the efficacy and safety of the et al., 2015; Liu et al. 2014). A meta-analysis comparing the treatment, so that changes in efficacy between morning and results of more than 20 RCTs involving almost 2,000 patients evening drug delivery may be significant for individual drugs. with primary hypertension confirmed that more effective BP control was achieved with evening monotherapy (Zhao et al., Monotherapy 2011). However, this does not apply to all antihypertensive drugs. Clinical trials focusing on monotherapy have been performed Given their long elimination half-life, trials with calcium with all available classes of drugs used in the treatment of channel blockers have shown no significant difference hypertension, that is, ACE inhibitors, diuretics, α-blockers, between morning and evening administration of majority β-blockers, direct renin inhibitor, angiotensin receptor of the dihydropyridines (amlodipine, isradipine, lacidipine) blockers, and calcium channel blockers (see Table 1). (Qui et al., 2003; Lemmer, 2006); however, studies with Significant treatment-time differences were confirmed for nifedipine have shown reduction of the mean BP values to several classes of antihypertensive drugs. With the RAAS be significantly better with bedtime dosing (Hermida et al., being highly circadian rhythmic, most of the recent and 2008). Conversely, β-blockers appear to be more effective in well-designed studies have focused on drugs acting on morning administration and alter the circadian BP toward a 33 34 Eur. Pharm. J. 2019, 66(2), 32-36 Chronopharmacology of high blood pressure—a critical review of clinical evidence Potucek P., Klimas J. Table 2: Administration-time-dependent effect of selected BP-lowering medications in combination treatment Study No. of Combination Dosage Treatment Comparison of morning Author length completed treatment (mg per day) times vs. evening dosing (weeks) subjects No difference in mean, Valsartan/ 06:00–10:00 8 463 asleep, and awake SBP/ Asmar et al., amlodipine 160/5-10 18:00–22:00 DBP with evening or 2011 (free combination) morning dosing Valsartan/ Significant reduction in amlodipine Awakening Hermida et 160/5 12 203 asleep SBP/DBP and mean (fixed/free bedtime al., 2010 SBP with evening dosing combination) Valsartan/HCT Significant reduction in Awakening Hermida et (fixed 160/12.5 12 204 asleep SBP with evening bedtime al., 2011 combination) dosing Amlodipine/HCT Significant reduction in 8:00 Zeng et al., (fixed 5/25 12 80 mean and asleep SBP/DBP 22:00 2011 combination) with evening dosing Amlodipine/ 7:00–8:00 Significant reduction in Meng et al., fosinopril 5/10 7:00–8:00/ 4 40 asleep SBP/DBP with split (free combination) 20:00–21:00 evening dosing Amlodipine/ 7:00–8:00 Significant reduction in Meng et al., fosinopril 5/10 7:00–8:00/ 4 40 asleep SBP/DBP with split (free combination) 20:00–21:00 evening dosing nondipper profile. This can be reasonably expected with the other one (Hermida et al., 2010; Asmar et al., 2011). With the concentration of catecholamines as well as the expression study length being the only difference between these two of beta-receptors being lowest during the night, thus owing studies, this fact might indicate that the duration of treatment the administration of β-blockers in the evening lower effect can also influence the chrono-effect. Similar results were also compared with that in the morning (Langner, Lemmer, 1988) confirmed in preclinical settings (Potucek et al., 2017). DISCUSSION Fixed combination therapy Although the treatment of hypertension is usually initiated Circadian rhythms at targeted site of action are a as monotherapy, in most cases, combination therapy, that primary prerequisite for chronopharmacology. This is is, use of multiple antihypertensive agents simultaneously, confirmed by several experiments showing that the peak is also indicated (Dahlöf, 2009). Therapy with lower doses of pharmacodynamic (PD) effect of drugs does not correlate with two or more drugs is preferable to monotherapy at higher the plasma concentration peak, thus suggesting a circadian doses with one drug, because better control of BP is achieved stage dependency of the drug plasma concentration– along with better tolerability and related patient compliance. antihypertensive effect relationship (Smolensky et al. 2010). Compared with large number of studies investigating However, PD and/or pharmacokinetic (PK) profile of the drug difference between morning and evening dosing, studies must also be taken into consideration before selecting suitable with combination therapy investigating the chrono-effect candidates, because molecules with a longer elimination half- are still limited (see Table 2). In these cases, it is assumed life or slow dissociation from the receptor-binding site are that chronopharmacological profiles of each drug might prone to have decreased chronopharmacological effect (Liu contribute to the dosing-time-dependent influences on the et al., 2011). efficacy and safety of combined hypertension medication, The appropriate choice of the drug and the timing of its with results suggesting evening dosing to be more effective administration must, therefore, respect PK profile of the in terms of BP reduction and/or normalization of the circadian molecule, but, at the same time, circadian rhythms of body rhythm of BP (Potúček, Klimas, 2013). However, interesting may as well affect the fate of the drug in the body. Gastric observation came from the comparison of two independent emptying, motility, and perfusion are significantly longer studies investigating the chrono-effect of the same in the morning, whereas gastric acid secretion reaches its combination (amlodipine and valsartan). While significant maximum in the evening. Lipophilic molecules seem to be reduction in asleep BP and mean BP values with evening more prone to circadian rhythms of the body affecting their PK dosing was proven in one of the studies, no difference and then hydrophilic one with respect to differences between between time of administration has been observed in the the maximum plasma concentrations (Cmax) measured after 33 34 Eur. Pharm. J. 2019, 66(2), 32-36 Chronopharmacology of high blood pressure—a critical review of clinical evidence Potucek P., Klimas J. morning and evening administration (Lemmer et al., 1991; normal diurnal pattern, it was confirmed that there is a clear Shiga et al., 1993). However, no significant changes in AUC association with the risk of cardiovascular disease (Takeda, were observed so far suggesting that circadian changes in Maemura, 2011). Normotensive non-dippers are exposed the PD of medicines used in chronotherapy of CVS are the to almost the same risk of cardiovascular mortality as result of direct interaction with the target system rather than hypertensive dippers. It has been also shown that when the changes in efficacy because of changes in PK. diurnal rhythm of BP was normalized, free survival of patients Last but not the least; consideration must be also given with heart failure has increased, whereas non-dipping is to the duration of treatment. Short elimination half-life associated with increased incidence of cardiovascular events suggests greater drug fluctuations in plasma. In short-term (Salles et al., 2016). Therefore, normalization of the circadian administration, this may also translate to more pronounced rhythm of BP is one of the primary targets in the treatment differences between morning and evening treatments of hypertension. Vast majority of reviewed RCT have shown (Portaluppi et al., 2007), especially when comparing the normalization of the dipping profile and/or changes in asleep difference in decreasing the mean BP values. Conversely, once BP values when applying chronotherapy, and this fact may the steady state of drug is reached in the body and the plasma have even more clinical impact than the differences in the levels of the drug are constant, the chronopharmacological mean 24-h BP reduction alone. effect may be waning, so the difference between morning CONCLUSION and evening doses is less profound. Thus, with respect to the treatment duration, chrono-effect is expected to be more prominent in the beginning rather than after long- The results from the RCTs clearly indicate that appropriate term administration. Therefore, chronotherapy might be of timing for dosing of antihypertensive drugs may increase clear benefit in settings, where rapid onset of treatment or the control of the hypertension; however, consideration normalization of BP pattern is needed. must always be given to the circadian rhythm of the targeted However, it is of important note that significant difference site of action, kinetic profile of the drug, and also to the between dosing regimens in terms of dipping prevalence duration of treatment. Although the comparison between has been observed in long-term treatment even if there was morning and evening dosing has not been always translated no more effect on the mean 24-h BP values. It is known that into significant difference in the decrease in the mean 24-h loss of the physiological circadian pattern of BP may lead to BP values, normalization of the circadian rhythm of BP has pathological mechanism associated with increased morbidity been achieved with appropriate timing of pharmacological and mortality (Ohkubo et al., 2002). Chronically increased intervention. With the later having the clear clinical relevance BP may even lead to general dysfunctional circadian body in terms of decreased CVS morbidity, these data substantiate rhythms. For all blood pressure profiles with impaired, the need for chronopharmacological approach in clinical disturbed, or otherwise deviating rhythmicity compared with settings. References [1] Asmar R, Gosse P, Quere S, Achouba A. Efficacy of morning regulation. Chronobiology international. 2013 Mar 1;30(1-2):280- and evening dosing of amlodipine/valsartan combination in 314. hypertensive patients uncontrolled by 5 mg of amlodipine. [6] Hermida RC, Ayala DE, Fontao MJ, Mojón A, Fernández JR. Blood pressure monitoring. 2011 Apr 1;16(2):80-6. Chronotherapy with valsartan/amlodipine fixed combination: [2] Dahlöf B. Management of cardiovascular risk with RAS inhibitor/ improved blood pressure control of essential hypertension CCB combination therapy. Journal of human hypertension. 2009 with bedtime dosing. Chronobiology international. 2010 Jul Feb;23(2):77. 1;27(6):1287-303. [3] De La Sierra A, Redon J, Banegas JR, Segura J, Parati G, Gorostidi M, [7] Hermida RC, Ayala DE, Mojón A, Fernández JR. Chronotherapy de la Cruz JJ, Sobrino J, Llisterri JL, Alonso J, Vinyoles E. Prevalence with nifedipine GITS in hypertensive patients: improved and factors associated with circadian blood pressure patterns in efficacy and safety with bedtime dosing. American journal of hypertensive patients. Hypertension. 2009 Mar 1;53(3):466-72. hypertension. 2008 Aug 1;21(8):948-54. [4] Hermida RC, Ayala DE, Fernández JR, Portaluppi F, Fabbian F, [8] Kasiakogias A, Tsioufis C, Thomopoulos C, Andrikou I, Aragiannis Smolensky MH. Circadian rhythms in blood pressure regulation D, Dimitriadis K, Tsiachris D, Bilo G, Sideris S, Filis K, Parati G. and optimization of hypertension treatment with ACE inhibitor Evening versus morning dosing of antihypertensive drugs in and ARB medications. American journal of hypertension. 2011 hypertensive patients with sleep apnoea: a cross-over study. Apr 1;24(4):383-91 Journal of hypertension. 2015 Feb 1;33(2):393-400. [5] Hermida RC, Ayala DE, Fernández JR, Mojón A, Smolensky MH, [9] Langner B, Lemmer B. Circadian changes in the pharmacokinetics Fabbian F, Portaluppi F. Administration-time differences in effects and cardiovascular effects of oral propranolol in healthy subjects. of hypertension medications on ambulatory blood pressure European journal of clinical pharmacology. 1988 Nov 1;33(6):619-24. 35 36 Eur. Pharm. J. 2019, 66(2), 32-36 Chronopharmacology of high blood pressure—a critical review of clinical evidence Potucek P., Klimas J. [10] Lemmer B. The importance of circadian rhythms on drug response [22] Shiga T, Fujimura A, Tateishi T, Ohashi K, Ebihara A. Differences in hypertension and coronary heart disease—from mice and of chronopharmacokinetic profiles between propranolol man. Pharmacology & therapeutics. 2006 Sep 1;111(3):629-51. and atenolol in hypertensive subjects. The Journal of Clinical [11] Lemmer B, Nold G, Behne S, Kaiser R. Chronopharmacokinetics Pharmacology. 1993 Aug;33(8):756-61. and cardiovascular effects of nifedipine. Chronobiology [23] Smolensky MH, Hermida RC, Ayala DE, Tiseo R, Portaluppi F. international. 1991 Jan 1;8(6):485-94. Administration–time-dependent effects of blood pressure- [12] Liu X, Liu X, Huang W, Leo S, Li Y, Liu M, Yuan H. Evening-versus lowering medications: basis for the chronotherapy of morning-dosing drug therapy for chronic kidney disease hypertension. Blood pressure monitoring. 2010 Aug 1;15(4):173- patients with hypertension: a systematic review. Kidney and 80. Blood Pressure Research. 2014;39(5):427-40. [24] Takeda N, Maemura K. Circadian clock and cardiovascular disease. [13] Liu Y, Ushijima K, Ohmori M, Takada M, Tateishi M, Ando H, Journal of cardiology. 2011 May 1;57(3):249-56. Fujimura A. Chronopharmacology of angiotensin II–receptor [25] Wu X, Liu Z, Shi G, Xing L, Wang X, Gu X, Qu Z, Dong Z, Xiong J, Gao blockers in stroke-prone spontaneously hypertensive rats. X, Zhang C. The circadian clock influences heart performance. Journal of pharmacological sciences. 2011:1101240507-. Journal of biological rhythms. 2011 Oct;26(5):402-11. [14] Ohkubo T, Hozawa A, Yamaguchi J, Kikuya M, Ohmori K, [26] Zhao P, Xu P, Wan C, Wang Z. Evening versus morning dosing Michimata M, Matsubara M, Hashimoto J, Hoshi H, Araki T, Tsuji regimen drug therapy for hypertension. Cochrane Database of I. Prognostic significance of the nocturnal decline in blood Systematic Reviews. 2011(10). pressure in individuals with and without high 24-h blood pressure: the Ohasama study. Journal of hypertension. 2002 Nov 1;20(11):2183-9. [15] Portaluppi F, Lemmer B. Chronobiology and chronotherapy of ischemic heart disease. Advanced drug delivery reviews. 2007 Aug 31;59(9-10):952-65. [16] Portaluppi F, Tiseo R, Smolensky MH, Hermida RC, Ayala DE, Fabbian F. Circadian rhythms and cardiovascular health. Sleep medicine reviews. 2012 Apr 1;16(2):151-66. [17] Potucek P, Klimas J. Chronotherapy of hypertension with combination treatment. Die Pharmazie-An International Journal of Pharmaceutical Sciences. 2013 Dec 2;68(12):921-5. [18] Potucek P, Radik M, Doka G, Kralova E, Krenek P, Klimas J. mRNA levels of circadian clock components Bmal1 and Per2 alter independently from dosing time-dependent efficacy of combination treatment with valsartan and amlodipine in spontaneously hypertensive rats. Clinical and Experimental Hypertension. 2017 Nov 17;39(8):754-63. [19] Qiu YG, Chen JZ, Zhu JH, Yao XY. Differential effects of morning or evening dosing of amlodipine on circadian blood pressure and heart rate. Cardiovascular drugs and therapy. 2003 Jul 1;17(4):335-41. [20] Salles GF, Reboldi G, Fagard RH, Cardoso CR, Pierdomenico SD, Verdecchia P, Eguchi K, Kario K, Hoshide S, Polonia J, de la Sierra A. Prognostic effect of the nocturnal blood pressure fall in hypertensive patients: the ambulatory blood pressure collaboration in patients with hypertension (ABC-H) meta- analysis. Hypertension. 2016 Apr;67(4):693-700. [21] Schillaci G, Battista F, Settimi L, Schillaci L, Pucci G. Antihypertensive drug treatment and circadian blood pressure rhythm: a review of the role of chronotherapy in hypertension. Current pharmaceutical design. 2015 Feb 1;21(6):756-72. 35 36

Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianaede Gruyter

Published: Nov 1, 2019

Keywords: chronopharmacology; blood pressure; circadian rhythm; non-dipping

References