Hypertension complicating angina: Tackling the dual menace with amlodipine-atenolol combination

The present review aims to answer these uncertainties and present a framework for physicians tackling this situation in their routine practice. Following a brief discussion of mechanisms of co-existent hypertension and angina, we explore the role of beta-blocker and calcium channel blocker (CCB) combination as an effective treatment strategy for this scenario.

Problem statement: The Framingham Heart Study has estimated the remaining lifetime risk of developing hypertension at ≈ 90% for men and women not yet hypertensive by middle age. (2) According to meta-analysis, each increase in SBP of 20 mm Hg (or each 10-mm Hg increase in DBP) doubles the risk of a fatal coronary event. (3)

Mechanisms of hypertension and Coronary artery disease.

A variety of pathophysiological mechanisms contribute to the genesis of BP elevation and related target-organ damage, including CAD. These mechanisms include increased sympathetic nervous system and RAAS activity; deficiencies in the release or activity of vasodilators, and changes in the natriuretic peptide concentration; increased expression of growth factors and inflammatory cytokines in the arterial tree; hemodynamic effects; and structural and functional abnormalities in conductance and resistance arteries, particularly increased vascular stiffness and endothelial dysfunction. (4) (1)

These neurohumoral pathways interact with genetic, demographic, and environmental factors to determine whether a person will develop hypertension and related CAD. (1)

How treatment of either may relieve both?

The management of hypertension in patients with chronic CAD and chronic stable angina is directed toward the prevention of death, MI, and stroke; a reduction in the frequency and duration of myocardial ischemia; and the amelioration of symptoms. (1)

By analyzing the mechanisms discussed above it can be inferred that amelioration of common underlying causes like increased sympathetic activity and vasoconstriction, one can achieve adequate control of BP and CAD symptoms together.

Lifestyle changes and the adoption of a heart-healthy approach are critical, with the usual attention to diet, sodium intake, moderation of alcohol intake, regular exercise, weight loss, smoking cessation, glycemic control, lipid management, and antiplatelet therapy. (1)

Role of beta-blockers and CCBs in managing the dual foe.

a) Combatting hypertension:

The most significant hemodynamic derailment in hypertension is the increase in peripheral resistance and hence quite understandably the most commonly used drugs for hypertension like calcium channel blockers, ACE inhibitors, etc. are vasodilators. But their antihypertensive effects are often countered by reflex mechanisms in the body, like reflex activation of the sympathetic arc that acts to blunt their BP-lowering effect. Thus, a satisfactory blood pressure response is rarely reached with monotherapy alone. (5)

The best answer is a combination of two drugs which (5):

a) act through different mechanisms to lower BP,

b) show an additive or synergistic effect, and

c) improve the side-effect profile and tolerability of each other.

β-Blockers are the drugs of the first choice for the treatment of hypertension in patients with CAD that causes angina. (16,7) As a class, CCBs reduce myocardial oxygen demand by decreasing peripheral vascular resistance and lowering BP, and increase myocardial oxygen supply by coronary vasodilation. Long-acting dihydropyridine agents like amlodipine are preferred over non-dihydropyridines (diltiazem or verapamil) for use in combination with β-blockers to avoid excessive bradycardia or heart block. (1)

The combination therapy with amlodipine- a CCB and atenolol- a beta-blocker for hypertension is suitable for two reasons: first, these two drugs act on different physiological systems.(8) Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Atenolol is a beta₁-selective (cardio-selective) beta-adrenergic receptor blocking agent that has cardioinhibitory, central sympatholytic, and renin-angiotensin axis inhibitory properties to ameliorate high BP.(8)

Second, amlodipine blocks the counterregulatory responses that are activated by the perturbation of the blood pressure regulatory mechanisms, for example, reflex tachycardia induced by amlodipine mediated vasodilation is mitigated by negative chronotropic effects of atenolol. Similarly, studies have shown that the relative risk of developing constipation is 4 times more in patients who are taking amlodipine alone as compared to those patients who are on a combination of amlodipine and atenolol. (8)

Many of the side effects of these drugs are dose-dependent, for eg. the chances of developing pedal edema with amlodipine increase if the dose is increased from 5 mg to 10 mg. Thus when target BP is not achieved on a 5mg daily dose, the addition of a second drug like atenolol may be more rational than increasing the dose of monotherapy. (8)

b) Combatting Angina:

As for angina relief, being a third-generation CCB, amlodipine has a gradual onset of action and a prolonged half-life (9) that causes little or no reflex tachycardia. (10) These properties improve its efficacy in suppressing ischemia.

Amlodipine reduces coronary tone, decreases coronary vasoreactivity, and lowers cardiac oxygen demand by reducing afterload. (11) Atenolol belonging to the class of cardio-selective beta-blockers (17) and also the most effective drug class for angina relief. It does so by reducing both the double product at onset of ischemia during treadmill testing and heart rate at onset of ischemia during ambulatory monitoring. (15)

When combined together, these two drugs improve time to ST-segment depression on exercise testing by 34% (improved only 3%) by atenolol alone. (15) The frequency of ischemic episodes decreases by 72% (57% with atenolol alone). (15)

Back in 1998, Dunselman et al (14) showed that the addition of amlodipine to atenolol in the treatment of myocardial ischemia despite optimal beta-blockade was well tolerated and led to improvement in symptomatic angina. The number of patients with chest pain during exercise decreased significantly in the amlodipine group Most notable was the finding of the improved safety aspects. Only 1 patient had treatment-related withdrawal.

The CASIS study showed that ischemia during treadmill testing was more effectively suppressed by amlodipine, whereas ischemia during ambulatory monitoring was more effectively suppressed by atenolol. Their combination on the other hand was more effective than monotherapy with either drug. (15)

Woodmansey et al showed that this drug combination improved exercise time and time to onset of angina without significant change in heart rate or cardiac output. (16)

Role of drug adherence and methods to achieve it.

Most currently available CCBs require twice or thrice daily dosing due to their short half-lives. (18) Amlodipine and atenolol combination has a long half-life which endows it an attractive therapeutic potential with a once-daily dosing regimen. (8)

How do special drug packs promote adherence?

The keystone in managing chronic conditions is ensuring compliance. Amlodipine –atenolol fixed-dose combination by virtue of its safe side-effect profile ensures good compliance. Further, this combination is available in special blister packaging that has "day" reminders printed on it. All the days of the week are printed in a sequential manner 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.

Conclusion:

Hypertension complicating CAD is a common clinical scenario that needs to be addressed by physicians. Due to their intricately linked underlying mechanisms, both these conditions respond well to beta-blockers and CCB combinations. One such combination of amlodipine and atenolol is highly effective, safe, and ensures adequate drug compliance in special pill packs.

References:

1. Rosendorff C, Lackland DT, Allison M, et al; Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. Circulation. 2015 May 12;131(19):e435-70.

2. Vasan RS, Beiser A, Seshadri S, Larson MG, Kannel WB, D'Agostino RB, Levy D. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study.JAMA. 2002; 287:1003–1010.

3. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies [published correction appears in Lancet. 2002;361:1060].Lancet. 2002; 360:1903–1913.

4. Acelajado MC, Calhoun DA, Oparil S. Pathogenesis of hypertension., Black H, Elliott W, eds. In: Hypertension: A Companion to Braunwald's Heart Disease. 2nd ed.Philadelphia, PA: Elsevier Sanders; 2012:12–26

5. Sever PS, Messerli FH. Hypertension management 2011: optimal combination therapy. Eur Heart J. 2011 Oct;32(20):2499-506. doi: 10.1093/eurheartj/ehr177. Epub 2011 Jun 22. PMID: 21697169.

6. Smith SC, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and the American College of Cardiology Foundation.Circulation.2011; 124:2458–2473.

7. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.Circulation.2012; 126:3097–3137.

8.Diksha Sharma, Dinesh Kumar Mehta, Karun Bhatti, Rina Das, Ram Mohan Chidurala. Amlodipine And Atenolol: Combination Therapy Versus Monotherapy In Reducing Blood Pressure - A Focus On Safety And Efficacy. Research J. Pharm. and Tech 2020; 13(6): 3007-3013. doi: 10.5958/0974-360X.2020.00532.6

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

10. Follath F. The role of calcium antagonists in the treatment of myocardial ischemia. Am Heart J. 1989 Nov;118(5 Pt 2):1093-6

11. RICHARD F. DAVIES, FACC, HABIBULLAH HABIBI, W. PETER KLINKE, M Effect of Amlodipine, Atenolol and Their Combination on Myocardial Ischemia During Treadmill Exercise and Ambulatory Monitoring. J Am Coil Cardiol 1995

12. Bache RJ. Effects of calcium entry blockade on myocardial blood flow. Circulation. 1989 Dec;80(6 Suppl):IV40-6

13.Åke Hjalmarson, International beta-blocker review in acute and postmyocardial infarction, The American Journal of Cardiology, Volume 61, Issue 3, 1988, Pages 26-29.

14.Dunselman PH, van Kempen LH, Bouwens LH, Holwerda KJ, Herweijer AH, Bernink PJ. Value of the addition of amlodipine to atenolol in patients with angina pectoris despite adequate beta blockade. Am J Cardiol. 1998 Jan 15;81(2):128-32.

15. Davies RF, Habibi H, Klinke WP, et al. Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmill exercise and ambulatory monitoring. Canadian Amlodipine/Atenolol in Silent Ischemia Study (CASIS) Investigators. J Am Coll Cardiol. 1995 Mar 1;25(3):619-25

16. Woodmansey PA, Stewart AG, Morice AH, Channer KS. Amlodipine in patients with angina uncontrolled by atenolol. A double blind placebo-controlled cross-over trial. Eur J Clin Pharmacol. 1993;45(2):107-11

17. Carl A Gruette ( 2007) xPharm: The Comprehensive Pharmacology Reference. doi.org/10.1016/B978-008055232-3.61259-0

18. Abdul Ahad, Fahad I Al-Jenoobi, Abdullah M Al-Mohizea, Mohd Aqil & Kanchan Kohli. Transdermal delivery of calcium channel blockers for hypertension. 2013. doi.org/10.1517/17425247.2013.783562