Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Calcium Channel Antagonists in the Treatment of Hypertension


Calcium channel antagonists are widely used antihypertensive agents. Their popularity among primary care physicians is not only due to their blood pressure-lowering effects, but also because they appear to be effective regardless of the age or ethnic background of the patients. The first available calcium channel antagonists utilized immediate-release formulations which, although effective in patients with angina pectoris, were not approved by the US FDA for use in hypertension. When long-acting once-daily formulations were approved in this indication, the short-acting preparations — which had by then become generic and inexpensive — retained some residual unapproved use for hypertension. An observational case-controlled trial, based on such usage, noted that these agents were associated with a greater risk of myocardial infarctions than conventional agents such as diuretics and β-adrenoceptor antagonists. Further case-controlled trials showed, in fact, that the dangers of calcium channel antagonists were confined to the short-acting agents and that approved long-acting agents were at least as well tolerated and effective as other antihypertensive drugs.

Cardiovascular outcomes during treatment with calcium channel antagonists have been examined in randomized, controlled trials. Compared with placebo, the calcium channel antagonists clearly prevented strokes and other cardiovascular events and reduced mortality. The effects of these agents on survival and clinical outcomes were similar to those with other antihypertensive drugs. There is a slight tendency for the calcium channel antagonists to be more effective than other drug types in preventing stroke, but slightly less effective in preventing coronary events. These observations extend to high-risk patients with hypertension including those with diabetes mellitus. Even so, patients with evidence of nephropathy should not receive monotherapy with calcium channel antagonists. Such patients are optimally treated with angiotensin receptor antagonists or ACE inhibitors, although addition of other drugs, including calcium channel antagonists, is often required to achieve the tight blood pressure control necessary to provide adequate renal protection.

Calcium channel antagonists have a highly acceptable tolerability profile and careful reviews of available data have shown that their use is not associated with increased bleeding or promotion of tumor formation. It is now recognized that reduction of blood pressure in patients with hypertension to levels often <130/85mm Hg should be undertaken in presence of other cardiovascular risk factors or evidence of end organ damage. Because of this important concept, calcium channel antagonists, like the other antihypertensive drug classes, are progressively being prescribed less often as monotherapy, but more typically as part of combination regimens.

This is a preview of subscription content, log in to check access.

Table I
Table II
Fig. 1
Fig. 2
Table III
Fig. 3
Fig. 4
Fig. 5
Fig. 6


  1. 1.

    Siegel D, Lopez J. Trends in antihypertensive drug use in the United States. JAMA 1997; 278: 1747–8

  2. 2.

    MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke and coronary heart disease: part 1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335(8692): 765–74

  3. 3.

    The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med 1997; 157:2413-66

  4. 4.

    Guidelines Subcommittee. 1999 World Health Organization: International Society of Hypertension guidelines for the management of hypertension. J Hypertens 1999; 17: 151–83

  5. 5.

    Hansson L, Zanchetti A, Carruthers SC, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet 1998; 351(9118): 1755–62

  6. 6.

    UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13

  7. 7.

    Klahr S, Levy AS, Beck GJ, et al. The effects of dietary protein restriction and blood pressure control on the progression of chronic renal disease: modification of diet in renal disease study group. N Engl J Med 1994; 330: 877–84

  8. 8.

    Burt VL, Whelton P, Rocella EJ, et al. Prevalence of hypertension in the US adult population: results from the Third National Health and Nutrition Examination Survey 1988-1991. Hypertension 1995; 25: 305–13

  9. 9.

    Psaty B, Heckbert S, Koepsell T, et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 1995; 272: 620–5

  10. 10.

    Kolata G. Heart attacks may have tie to drug type. New York Times 1995 Mar 11, 1

  11. 11.

    Group Health Cooperative of Puget Sound. Drug formulary. Hudson (OH): Lexi-Comp Inc, 1995

  12. 12.

    Jick H, Derby I, Gurewich V, et al. The risk of myocardial infarction in persons with uncomplicated hypertension. Pharmacotherapy 1996; 16: 321–6

  13. 13.

    Ruddy MC. The INSIGHT and NORDIL Trials. Are calcium antagonists equivalent to established drug therapies for cardiovascular protein? Curr Hypertens Rep 2001; 3: 289–96

  14. 14.

    Landmark K, Reikvam A, Abdelnoor M, et al. Acute myocardial infarction mortality related to use of calcium antagonists before admission to hospital. Cardiovasc Drugs Ther 1998; 12: 183–7

  15. 15.

    Alderman MH, Cohen H, Roque R, et al. Effect of long-acting calcium antagonists on cardiovascular outcomes in hypertensive patients. Lancet 1997; 349: 594–8

  16. 16.

    Klungel OH, Heckbert SP, Longstreth WT, et al. Antihypertensive drug therapies and the risk of ischemic stroke. Arch Intern Med 2001; 161: 37–43

  17. 17.

    Pahor M, Guralnik J, Corti M, et al. Long-term survival and use of antihypertensive medications in older persons. J Am Geriatr Soc 1995; 43: 1–7

  18. 18.

    Koenig W, Lowel H, Lewis M, et al. Long-term survival after myocardial infarction: relationship with thrombolysis and discharge medication: results of the Augsburg Myocardial Infarction follow-up Study 1985 to 1993. Eur Heart J 1996; 17: 199–206

  19. 19.

    Braun S, Boyko V, Behar S, et al. Calcium antagonists and mortality in patients with coronary artery disease: a cohort study of 11 575 patients. J Am Coll Cardiol 1996; 28: 7–11

  20. 20.

    Abascal VM, Larson MG, Evans JC, et al. Calcium antagonists and mortality risk in men and women with hypertension in the Framingham Heart study. Arch Intern Med 1998; 158: 1882–6

  21. 21.

    Michels KB, Rosner BA, Manson JE, et al. Prospective study of calcium channel blocker use cardiovascular disease and total mortality among hypertensive women: the Nurse’ Health Study. Circulation 1998; 97: 1540–8

  22. 22.

    Grossman E, Messerli FH. Effect of calcium antagonists on plasma norepinephrine levels, heart rate, and blood pressure. Am J Cardiol 1997; 80: 1453–8

  23. 23.

    Ruzicka M, Leenen FH. Relevance of 24 h blood pressure profile and sympathetic activity for outcome on short versus long-acting 1, 4 dihydropyridines. Am J Hypertens 1996; 9: 86–94

  24. 24.

    Grossman E, Messerli EH, Grodzicki T, et al. Should a moratorium be placed on nifedipine capsules in hypertensive emergencies and pseudoemergencies? JAMA 1996; 276: 1328–31

  25. 25.

    Ruzicka M, Leenen FHH. Relevance of intermittent increases in sympathetic activity for adverse outcome on short-acting calcium channel antagonists. In: Laragh JH, Brenner BM, editors. Hypertension: pathophysiology, diagnosis and management. 2nd ed. New York: Raven Press, 1995: 2815–25

  26. 26.

    Leenen FHH. Dihydropyridine calcium antagonists and sympathetic activity: relevance to cardiovascular morbidity and mortality. In: Epstein M, editor. Calcium antagonists in clinical medicine. Philadelphia, (PA): Hanley and Belfus, 1998: 527–52

  27. 27.

    Huang BS, Leenen FHH. Sympathoinhibitory effects of central nifedipine in spontaneously hypertensive rats on high versus regular sodium intake. Hypertension 1999; 33: 32–5

  28. 28.

    Murzenok PP, Huang BS, Leenen FHH. Sympatho-inhibition by central and peripheral infusion of nifedipine in spontaneously hypertensive rats. Hypertension 2000; 35: 631–6

  29. 29.

    Leenen FHH, Ruzicka M, Huang BS. Central sympathoinhibitory effects of calcium channel blockers. Curr Hypertens Rep 2001; 3: 314–21

  30. 30.

    Lichtenberg G, Blankestijn PJ, Oey L, et al. Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med 1999; 340: 1321–8

  31. 31.

    Amery A, Birkenhager W, Bulpitt CJ, et al. SYST-EUR. A multicenter trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol, and organization. Aging Clin Exp Res 1991; 3: 287–302

  32. 32.

    Staessen JA, Fagard R, Thijs L, et al., for the Systolic Hypertension in Europe (SYST-EUR) Trial Investigators. Randomized double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension [published erratum appears in Lancet 1997; 350:1639). Lancet 1997; 350: 757–4

  33. 33.

    Staessen JA, Thijs L, Birkenhager WH, et al., on behalf of the SYST-EUR Investigators. Update on the Systolic Hypertension in Europe (SYST-EUR) trial. Hypertension 1999; 33: 1476–7

  34. 34.

    Staessen JA, Thijs L, Fagard RH, et al., for the Systolic Hypertension in Europe (SYST-EUR) Trial Investigators. Calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertension. Hypertension 1998; 32: 404–9

  35. 35.

    Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiat Res 1975; 12: 189–98

  36. 36.

    Forette F, Seux ML, Staessen JA, et al., on behalf of the SYST-EUR Investigators. Prevention of dementia in randomized double-blind placebo-controlled Systolic Hypertension in Europe (SYST-EUR) trial. Lancet 1998; 352: 1347–51

  37. 37.

    SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: 3255–64

  38. 38.

    Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366–72

  39. 39.

    NORDIL Study Group. The Nordic Diltiazem Study (NORDIL). A prospective intervention trial of calcium antagonist therapy in hypertension. Blood Press 1993; 4: 312–21

  40. 40.

    Hansson L, Hedner T, Lund-Johansen P, et al. Randomized trial of effects of calcium antagonists compared with diuretics and beta blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 2000; 356: 359–65

  41. 41.

    Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull 1994; 50: 272–98

  42. 42.

    Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285(21): 2719–26

  43. 43.

    Lewis EJ, Hunsicker G, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345(12): 851–9

  44. 44.

    Brenner BM, Cooper ME, DeZeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345(12): 861–9

  45. 45.

    Estacio RO, Jeffers BW, Hiatt WR, et al. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998; 338: 645–52

  46. 46.

    Schrier RW, Estacio RO. Additional follow-up from the ABCD trial in patients with type 2 diabetes and hypertension. N Engl J Med 2000; 343: 1969

  47. 47.

    Sica D. Lessons learned from prematurely terminated clinical trials. Curr Hypertens Rep 2001; 3: 360–6

  48. 48.

    Tatti P, Guarisco R, De Mauro P, et al. Reduced risk of major cardiac events with the association of two antihypertensive therapies in non-insulin-dependent diabetic population [abstract]. Diabetes 1996; 45: A198

  49. 49.

    Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998; 21: 597–602

  50. 50.

    Curb JD, Pressel SL, Cutler JA, et al., for the Systolic Hypertension in the Elderly Cooperative Research Group. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. JAMA 1996; 276: 1886–92

  51. 51.

    Tuomilehto J, Rastenyte D, Birkenhager WH, et al., for the Systolic Hypertension in Europe (SYST-EUR) Trial Investigators. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999; 340: 677–84

  52. 52.

    Staessen JA, Thijs L, Fagard RH, et al., for the Systolic Hypertension in Europe (SYST-EUR) Trial Investigators. Calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertension. Hypertension 1998; 32: 404–9

  53. 53.

    Staessen JA. Clinical trials in older patients with systolic hypertension. In: Kaplan NM, editor. Hypertension therapy annual 2000. London: Martin Dunitz, 2000: 93–120

  54. 54.

    Wang JG, Staessen JA, Gong L, et al. Chinese trial on isolated systolic hypertension in the elderly. Systolic Hypertension in China (Syst-China) Collaborative Group. Arch Intern Med 2000 Jan 24; 160(2): 211–20

  55. 55.

    Cutler JA. Calcium-channel blockers for hypertension: uncertainty continues. N Engl J Med 1998; 338: 679–81

  56. 56.

    Hansson L, Zanchetti A, Carruthers SG, et al., for the HOT Study Group. Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet 1998; 351: 1755–62

  57. 57.

    BP Trialists, Blood Pressure Lowering Treatment Trialist’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressuring-lowering drugs: results of prospectively designed overviews of randomized trials. Lancet 2000; 355: 1955–64

  58. 58.

    Pahor M, Psaty BM, Alderman MH, et al. Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomized controlled trials. Lancet 2000; 356: 1949–54

  59. 59.

    Opie LH. Calcium channel blockers (CCBs) in hypertension: reappraisal after new trials and major meta-analyses. Am J Hypertens. 2001 Oct; 14(10): 1074–81

  60. 60.

    Borhani N, Mercuri M, Borhani P, et al. Final outcome results of the multicenter isradipine diuretic atherosclerosis study (MIDAS): a randomized controlled trial. JAMA 1996; 276: 785–91

  61. 61.

    Casiglia E, Spolaore P, Mazza A, et al. Effect of two different therapeutic approaches on total and cardiovascular mortality in a Cardiovascular Study of the Elderly (CASTEL). Jpn Heart J 1994; 35: 589–600

  62. 62.

    Pahor M, Guralnik JM, Furberg CD, et al. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet 1996; 347: 1061–5

  63. 63.

    Pahor M, Guralnik JM, Salive ME, et al. Do calcium channel blockers increase the risk of cancer? Am J Hypertens 1996; 9: 695–9

  64. 64.

    Pahor M, Guralnik JM, Ferrucci L, et al. Calcium channel blockade and incidence of cancer in aged populations. Lancet 1996; 348: 493–7

  65. 65.

    Connor J, Sawczuk IS, Benson MC, et al. Calcium channel antagonists delay regression of androgen dependent tissues and suppress gene activity associated with cell death. Prostate 1988; 13: 119–30

  66. 66.

    Ray SD, Kamendulis LM, Gurule MW, et al. Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. FASEB J 1993; 7: 453–63

  67. 67.

    Carson DA, Ribeiro JM. Apoptosis and disease. Lancet 1993; 341: 1251–4

  68. 68.

    Martin SJ, Green DR. Apoptosis and cancer: the failure of controls on cell death and cell survival. Crit Rev Oncol Hematol 1995; 18: 137–53

  69. 69.

    Dargie HJ. Calcium channel blockers and the clinician. Lancet 1996; 348: 488–9

  70. 70.

    Epstein M. Safety of calcium antagonists as antihypertensive agents: an update. Am J Hypertens 1996; 9: 110–21

  71. 71.

    Packer M, O’Connor CM, Ghali JK, et al., for the Prospective Randomized Amlodipine Survival Evaluation Study Group (PRAISE). Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996; 335: 1107–14

  72. 72.

    Gong L, Zhan W, Zhu Y, et al. Shanghai Trial of Nifedipine in the Elderly (STONE). J Hypertens 1996; 14: 1237–45

  73. 73.

    Dahlof B. Anglo-Scandinavian cardiac outcomes trial. Am J Hypertens 1998; 11: 9A–10A

  74. 74.

    Black HR, Elliott WJ, Neaton JD, et al. Rationale and design for the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) Trial. Control Clin Trials 1998; 19: 370–90

  75. 75.

    Herbette LG, Vecchiarelli M, Sartani A, et al. Lercanidipine: short plasma half-life, long duration of action and high cholesterol tolerance: updated molecular model to rationalize its pharmacokinetic properties. Blood Press 1998; 7 Suppl. 2:10–7

  76. 76.

    Fogari R, Malamani GD, Zoppi A, et al. Comparative effect of lercanidipine and nifedipine gastrointestinal therapeutic system on ankle volume and subcutaneous interstitial pressure in hypertensive patients: a double-blind, randomized, parallel-group study. Curr Ther Res Clin Exp 2000; 61: 850–62

Download references


The support of Lorraine Wilson and the Dean’s Office at SUNY Downstate College of Medicine in preparing this article is gratefully acknowleged.

Author information

Correspondence to Dr Michael A. Weber.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Weber, M.A. Calcium Channel Antagonists in the Treatment of Hypertension. Am J Cordiovosc Drugs 2, 415–431 (2002).

Download citation


  • Amlodipine
  • Calcium Channel Antagonist
  • Fosinopril
  • Lercanidipine
  • Antihypertensive Drug Class