Review: Antihypertensive Amlodipine for tackling circadian fluctuations of BP

Hypertension is the most powerful risk factor for cardiovascular diseases, including stroke, coronary artery disease, heart failure, chronic kidney disease, and aortic and peripheral arterial diseases (1). The blood pressure shows a classical pattern of diurnal variation with an upsurge in early morning hours that parallels the increased risk of cardiovascular events at around this time of the day (2). Thus it is imperative to understand the mechanics of this biological clock and refine our antihypertensive regimens in a way that the morning BP surge (MBPS) is dynamically controlled and the associated risk of cardiovascular events ameliorated.

The following review discusses the role and evidence base of the time-tested molecule amlodipine in managing the morning BP surge.

Decoding the mechanics of Cardiovascular circadian rhythms:

Vascular diseases of both the small and large arteries are considered to be not only consequences but also the leading cause of exaggeration of morning BP surge, a circumstance giving rise to a vicious cycle in the cardio-vascular continuum (3,4). Various mechanisms linked to this observation are summarized below:

1. The activation of various pressor neurohumoral factors, including the sympathetic nervous system and RAS, occurs early in the morning. Increased sympathetic activity, particularly of the alpha-adrenergic component, increases the vascular tone in the small resistance arteries and may contribute to the morning BP surge (1).

2. The plasma renin activity, angiotensin II, and aldosterone levels are all increased before awakening and then further increased after wakening and contribute to BP surge (1).

3. Dysfunction of the baroreflex in large arteries that is more prominent in early morning hours may contribute to circadian variation (1).

Pharmacological control of morning BP surge:

The effects of BP-lowering treatment in the morning hours have two distinct (although not unrelated) aspects: the need for adequate control of BP levels in the morning and the impact of treatment on the dynamic BP change (5).

The former issue is closely related to the duration of the antihypertensive effect of drugs; given that antihypertensive therapy is commonly given in the morning, the loss of BP-lowering action in the final hours of the dosing period in case of inadequate 24-hour coverage will inevitably lead to worsening of BP control in the morning hours, a frequent phenomenon among treated hypertensive patients (5).

Several factors might be involved in the determination of the effects of specific drugs on morning BP.

• Duration of BP-lowering action

Although for most currently used antihypertensive drugs, the reduction of BP-lowering effect during the hours preceding the next morning dose is gradual, it is possible that, in case of drugs providing an incomplete 24-hour coverage, a progressive decrease in drug concentration over the hours when MBPS is assessed (eg, between night-trough and post-awakening) might contribute to a major morning BP increase (5).

• Relationship between BP level and variability

Worse control of BP in the final hours of the dosing period with shorter-acting drugs could also favor major short-time changes in BP (such as MBPS), in line with the known direct relationship between BP levels and BP variability (5).

• Drug intake timing

Both the above mechanisms could be relevant when considering the "chronobiological" approach based on bedtime administration of antihypertensive drugs, especially the shorter-acting ones (5).

The rationale behind the effectiveness of amlodipine in ameliorating the morning BP surge.

The BP-lowering effect of long-acting calcium channel blockers like amlodipine depends on the baseline BP level, the higher ambulatory BPA levels decrease more extensively, the lowest nocturnal BP does not decrease as much, and, thus, the morning BP surge decreases significantly (1).

Amlodipine's effectiveness in controlling morning surge, a summary of evidence.

In a study comparing long-acting calcium antagonist, amlodipine, with intermediate-acting ACE receptor blocker (ARB), valsartan, in monotherapy, only the former significantly reduced morning SBP, while both agents reduced the lowest night SBP to a similar extent. Consequently, the reduction in morning SBP surge was significantly greater in patients treated with amlodipine (−6.1 vs. +4.5 mmHg, P<0.02) (6).

Interesting results were obtained in a study comparing high-dose (10 mg) amlodipine monotherapy with aliskiren/amlodipine (150/5 mg) association. In this study, the high dose of amlodipine controlled the morning BP and reduced morning BP surge better than the lower dose of aliskiren/amlodipine (7).

Kwon et al in their randomized study compared losartan with amlodipine and found that amlodipine had a greater tendency than losartan to produce a blunt morning surge (8).

Prognostic implications of morning BP control

Several studies support an independent relationship of morning BP surge with organ damage, cerebrovascular complications, and mortality. (5) For example, exaggerated morning surge in BP constitutes a risk for stroke independent of 24-hour BP (9). this morning surge has also been incriminated in the causation of hypertensive heart disease, albuminuria in diabetics, increased plaque vulnerability, etc. (1,10,11).

Thus, stringent BP control in the morning hours with drugs like amlodipine can serve to drastically reduce the complications of end-organ damage in hypertensive's.

Amlodipine: ensuring compliance.

Amlodipine which has a long half-life endows an attractive therapeutic potential with a once-daily dosing regimen; which makes it a prime choice compared to other available calcium channel blockers (such as Nifedipine) which require twice or thrice dosing due to its short half-life (12, 13).

Amlodipine: ensuring adherence.

The keystone in managing chronic conditions like hypertension is ensuring compliance. Amlodipine by its safe side-effect profile ensures good compliance. Further, this drug is available in special blister packaging that has "day" reminders printed on it. All the days of the week are printed sequentially with an arrow-guided sequence to ensure optimal dose adherence. Such simple measures help to achieve drug compliance goals in patients who are on polypharmacy or those in the elderly age group who are unlikely to keep a strict record of their daily medicine intake (14).

Conclusion

MBPS is a complex phenomenon driven by several mechanisms, among which sympathetic activation plays a central role. It is closely related to target organ damage in chronic hypertensive's. Therefore, choosing a drug that is backed by sound scientific evidence and is time-tested in clinical practice can ensure better long-term outcomes for this population.

Amlodipine, by its long-acting profile and backed by robust clinical evidence tackles the morning BP surge effectively and the availability of blister packs that ensure adherence make it one of the best options available to a physician today.

References

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2. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79:733–743.

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4. Kario K. Preceding linkage between a morning surge in blood pressure and small artery remodeling: an indicator of prehypertension? J Hypertens. 2007;25:1573–1575.

5. Bilo, G., Grillo, A., Guida, V., &Parati, G. Morning blood pressure surge: pathophysiology, clinical relevance and therapeutic aspects. 2018. Integrated blood pressure control, 11, 47–56. https://doi.org/10.2147/IBPC.S130277

6. Eguchi K, Kario K, Hoshide Y, et al. Comparison of valsartan and amlodipine on ambulatory and morning blood pressure in hypertensive patients. 2004. Am J Hypertens.;17:112–117.

7. Mizuno H, Hoshide S, Fukutomi M, Kario K. Differing effects of aliskiren/amlodipine combination and high-dose amlodipine monotherapy on ambulatory blood pressure and target organ protection. 2016.J ClinHypertens. ;18:70–78.

8. Kwon HM, Shin JW, Lim JS, Hong YH, Lee YS, Nam H. Comparison of the effects of amlodipine and losartan on blood pressure and diurnal variation in hypertensive stroke patients: a prospective, randomized, double-blind, comparative parallel study. 2013. Dec;35(12):1975-82.

9. Kario K, Pickering TG, Umeda Y, et al. Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study. Circulation. 2003;107:1401–1406.

10. Gosse P, Lasserre R, Minifie C, Lemetayer P, Clementy J. Blood pressure surge on rising. 2004.J Hypertens.;22:1113–1118.

11. Caramori ML, Pecis M, Azevedo MJ. Increase in nocturnal blood pressure and progression to microalbuminuria in diabetes. 2003. N Engl J Med.;348:261–262.

12. Burges RA, Dodd MG, Gardiner DG. Pharmacologic profile of amlodipine. 1989. Am J Cardiol. Nov 7;64(17):10I-18I; discussion 18I-20I.

13. Khan KM, Patel J, Schaefer TJ. Nifedipine. [Updated 2021 Aug 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK537052/

14. Bosworth, H. B., Granger, B. B., Mendys, P., Brindis, R., Burkholder, R., Czajkowski, S. M., et.al. Medication adherence: a call for action.2011 American heart journal, 162(3), 412–424. https://doi.org/10.1016/j.ahj.2011.06.00.