Newer Antihypertensive Agents: Angiotensin-Receptor Antagonists and Vasopeptidase Inhibitors

  • Domenic A. Sica
Part of the Atlas of Heart Diseases book series (AD)


The therapies available for the effective treatment of hypertension or end organ complications of hypertension continue to experience almost a geometric growth in their numbers. Such a proliferation of therapies creates a conundrum of sorts for the treating physician. The physician is called upon to position a new drug class in comparison to traditional therapies, oftentimes without adequate information to reach such therapeutic distinctions. In addition, as new members of a drug class inevitably become available, it is incumbent upon the physician to determine the relevance of supposed pharmacokinetic and pharmacodynamic differences. This is currently the case with the angiotensin-receptor antagonists (AT1-pRAs) where six such compounds are currently marketed in the United States and considerable controversy exists as to the significance of differences—both pharmacokinetic and pharmacodynamic— among individual class members. This is very much analogous to the situation with angiotensin converting enzyme (ACE) inhibitors for which ten such compounds are, at present, available in the United States.


Diastolic Blood Pressure Angiotensin Converting Enzyme Angiotensin Converting Enzyme Inhibitor Atrial Natriuretic Peptide Ambulatory Blood Pressure Monitoring 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mooser V, Nussberger J, Juillerat L, et al.: Reactive hyperreninemia is a major determinant of plasma angiotensin II during ACE inhibition. J Cardiovasc Pharmacol 1990, 15: 276–282.PubMedCrossRefGoogle Scholar
  2. 2.
    Ihara M, Urata H, Kinoshita A, et al.: Increased chymase-dependent production of angiotensin-II in human atherosclerotic aorta. Hypertension 1999, 33: 1399–1405.PubMedCrossRefGoogle Scholar
  3. 3.
    Murakami M, Matsuda H, Kubota E, et al.: Role of angiotensin-II generated by angiotensin converting enzyme-independent pathways in canine kidney. Kidney International 1997, 63: S132–S135.PubMedGoogle Scholar
  4. 4.
    Hollenberg NK, Fisher NDL, Price DA:Pathways for angiotensin II generation in intact human tissue. Evidence from comparative pharmacological interruption of the renin system. Hypertension 1998, 32: 387–392.PubMedCrossRefGoogle Scholar
  5. 5.
    McConnaughey MM, McConnaughey JS, Ingenito AJ:Practical considerations of the pharmacology of angiotensin receptor blockers. J Clin Pharmacol 1999, 39: 547–559.PubMedCrossRefGoogle Scholar
  6. 6.
    Mazzolai L, Maillard M, Rossat J, et al.: Angiotensin II receptor blockade in normotensive subjects. a direct comparison of three ATI-receptor antagonists. Hypertension 1999, 33: 850–855.PubMedCrossRefGoogle Scholar
  7. 7.
    McCrea JB, Cribb A, Rushmore T, et al.: Phenotypic and genotypic investigations of a healthy volunteer deficient in the conversion of losartan to its active metabolite E-3174. Clin Pharmacol Ther 1999, 65: 348–352.PubMedCrossRefGoogle Scholar
  8. 8.
    Kazierad DJ, Martin DE, Blum RA, et al.: Effect of fluconazole on the pharmacokinetics of eprosartan and losartan in healthy male volunteers. Clin Pharmacol Ther 1997, 62: 417–425.PubMedCrossRefGoogle Scholar
  9. 9.
    McCrea JB, Low MW, Furtek CI, et al.: Ketoconazole does not affect the systemic conversion of losartan to E-3174. Clin Pharmacol Ther 1996, 59–A169.Google Scholar
  10. 10.
    Goldberg MR, Lo MW, Deutsch PJ, et al.: henobarbital minimally alters plasma concentrations of losartan and its active metabolite E-3174. Clin Pharmacol Ther 1996, 59: 268–274.PubMedCrossRefGoogle Scholar
  11. 11.
    Williamson KM, Patterson JH, McQueen RH, et al.: Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers. Clin Pharmacol Ther 1998, 63: 316–323.PubMedCrossRefGoogle Scholar
  12. 12.
    Goldberg MR, Lo MW, Bradstreet TE, et al.: Effects of Cimetidine on pharmacokinetics and pharmacodynamics of losartan, an AT1-selective non-peptide angiotensin II receptor antagonist. Eur J Clin Pharmacol 1995, 49: 115–119.PubMedCrossRefGoogle Scholar
  13. 13.
    Kaukonen KM, Olkkola KT, Neuvonen PJ:Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. Eur J Clin Pharmacol 1998, 53: 445–449PubMedCrossRefGoogle Scholar
  14. 14.
    Riddell JG:Bioavailability of candesartan is unaffected by food in healthy volunteers administered candesartan cilexitil. J Hum Hypertens 1997, 11 (suppl 2): S29–S30.Google Scholar
  15. 15.
    Tenero D, Martin D, Ilson B, et al.: Pharmacokinetics of intravenously and orally administered eprosartan in healthy males: absolute bioavailability and effect of food. Biopharm Drug Disp 1998, 19: 351–356.CrossRefGoogle Scholar
  16. 16.
    Cox PJ, Bush BD, Gorycki PD, et al.: The metabolic fate of eprosartan in healthy volunteers. Exp Toxicol Pathol 1996, 48 (suppl II): 75–82.Google Scholar
  17. 17.
    Bottorff MB, Tenero DM:Pharmacokinetics of eprosartan in healthy subjects, patients with hypertension, and special populations. Pharmacotherapy 1999, 19: 73S–78S.PubMedCrossRefGoogle Scholar
  18. 18.
    Chapelsky MC, Martin DE, Tenero DM, et al.: A dose proportionality study of eprosartan in healthy male volunteers. J Clin Pharmacol 1998, 38: 34–39.PubMedGoogle Scholar
  19. 19.
    Vachharajani NN, Shyu WC, Chando TJ, et al.: Oral bioavailability and disposition characteristics of irbesartan, an angiotensin antagonist, in healthy volunteers. J Clin Pharmacol 1998, 38: 702–707.PubMedGoogle Scholar
  20. 20.
    Vachharajani NN, Shyu WC, Mantha S, et al.: Lack of effect of food on the oral bioavailability of irbesartan in healthy male volunteers. J Clin Pharmacol 1998, 38: 433–436.PubMedGoogle Scholar
  21. 21.
    Lo MW, Goldberg MR, McCrea JB, et al.: Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans. Clin Pharmacol Ther 1995, 58: 641–649.PubMedCrossRefGoogle Scholar
  22. 22.
    Stangier J, Heinzel G, Capf S, et al.: Clinical pharmacokinetics of telmisartan. 2nd International Symposium on Angiotensin-II Antagonism; 1999; London, United Kingdom.Google Scholar
  23. 23.
    Flesch G, Muller P, Lloyd P:Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man. Eur J Clin Pharmacol 1997, 52: 115–120.PubMedCrossRefGoogle Scholar
  24. 24.
    Sica DA, Halstenson C, Gehr TWB, Keane W:The pharmacokinetics and pharmacodynamics of losartan in end stage renal disease. Submitted to, Clinical Pharmacokinetics.Google Scholar
  25. 25.
    Sica DA, Marino MR, Hammett JL, et al.: The pharmacokinetics of irbesartan in renal failure and maintenance hemodialysis. Clin Pharmacol Ther 1997, 62: 610–618.PubMedCrossRefGoogle Scholar
  26. 26.
    Prasad P, Mangat S, Choi L, et al.: Effect of renal function on the pharmacokinetics of valsartan. Clin Drug Invest 1997, 13: 207–214.CrossRefGoogle Scholar
  27. 27.
    Kovacs SJ, Tenero DM, Martin DE, et al.: Pharmacokinetics and protein binding of eprosartan in hemodialysis-dependent patients with end-stage renal disease. Pharmacotherapy 1999, 19: 612–619.PubMedCrossRefGoogle Scholar
  28. 28.
    de Zeeuw D, Remuzzi G, Kirch W:The pharmacokinetics of candesartan cilexitil in patients with renal or hepatic impairment. J Human Hypertension 1997, 11 (suppl 2): S37–S42.Google Scholar
  29. 29.
    Martin DE, Chapelsky MC, Ilson B, et al.: Pharmacokinetics and protein binding of eprosartan in healthy volunteers and in patients with varying degrees of renal impairment. J Clin Pharmacol 1998, 38: 129–137.PubMedGoogle Scholar
  30. 30.
    Sica DA, Shaw WC, Lo MW, et al.: The pharmacokinetics of losartan in renal insufficiency. J Hypertension 1995, 13 (suppl 1): S49–S52.Google Scholar
  31. 31.
    Sica DA, Cutler RE, O’Connor DT, Ford NF:Comparison of the steady-state pharmacokinetics of fosinopril, lisinopril and enalapril in patients with chronic renal insufficiency. Clin Pharmacokinetics 1991, 20: 420–427.CrossRefGoogle Scholar
  32. 32.
    Sica DA, Deedwania P:Cardiorenal implications of angiotensin-receptor therapy. Cong Heart Failure 1998, 4: 35–40.Google Scholar
  33. 33.
    Sica DA, Kelleher N, Gehr TWB, Fakhry I:Losartan and uric acid in chronic renal failure and end-stage renal disease. Amer J Hypertens 1998, 11: 103A.CrossRefGoogle Scholar
  34. 34.
    Vleeming W, van Amsterdam JGC, Stricker BH, et al.: ACE inhibitor-induced angioedema. incidence, prevention, and management. Drug Safety 1998, 18: 171–188.PubMedCrossRefGoogle Scholar
  35. 35.
    van Rijnsoever EW, Kwee-Zuiderwijk WJM, Feenstra J:Angioneurotic edema attributed to the use of losartan. Arch Int Med 1998, 158: 2063–2065.CrossRefGoogle Scholar
  36. 36.
    Verresen L, Fink E, Lemke HD, Vanrenterghem Y:Bradykinin is a mediator of anaphylactoid reactions during hemodialysis with AN69 membranes. Kidney Int. 1994, 45: 1497–1503.PubMedCrossRefGoogle Scholar
  37. 37.
    Saracho R, Martin-Malo A, Martinez I, et al.: Evaluation of the losartan in hemodialysis (ELHE) study. Kidney Int. 1998, 54 (Supp 68): S125–S129.CrossRefGoogle Scholar
  38. 38.
    Sica DA, Gehr TWB:The pharmacokinetics of angiotensin converting enzyme inhibitors in end-stage renal disease. Seminars Dialysis 1994, 7: 205–213.CrossRefGoogle Scholar
  39. 39.
    Sica DA, Gehr TWB:Risk-benefit ration of angiotensin-receptor blockers vs. angiotensin-converting enzyme inhibitors in end-stage renal disease. Drug Safety 2000, in press.Google Scholar
  40. 40.
    Pitt B, Segal R, Martinez FA, et al.: Randomized trial of losartan versus Captopril in patients over 65 with heart failure. Lancet 1997, 349: 747–752.PubMedCrossRefGoogle Scholar
  41. 41.
    Oster JR, Materson BJ:Renal and electrolyte complications of congestive heart failure with angiotensin converting enzyme inhibitors. Arch Intern Med 1992, 152: 704–710.PubMedCrossRefGoogle Scholar
  42. 42.
    Kon V, Fogo A, Ichikawa I:Bradykinin causes selective efferent arteriolar dilation during angiotensin I converting enzyme inhibition. Kidney Int. 1993, 44: 545–550.PubMedCrossRefGoogle Scholar
  43. 43.
    Kassler-Taub K, Littlejohn T, Elliott W, et al.: Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan, in mild-to-moderate hypertension. Am J Hypertens 1998, 11: 445–453.PubMedCrossRefGoogle Scholar
  44. 44.
    Oparil S, Guthrie R, Lewin AJ, et al.: An elective-titration study of the comparative effectiveness of two angiotensin II-receptor blockers, irbesartan and losartan. Clin Ther 1998, 20: 398–409.PubMedCrossRefGoogle Scholar
  45. 45.
    Andersson OK, Neldam S:The antihypertensive effect and tolerability of candesartan cilexitil, a new generation angiotensin II antagonist in comparison with losartan. Blood Pressure 1998, 7: 53–59.PubMedCrossRefGoogle Scholar
  46. 46.
    Hedner T, Oparil S, Rasmussen K, et al.: A comparison of the angiotensin II antagonists valsartan and losartan in the treatment of essential hypertension. Am J Hypertens 1999, 12: 414–417.PubMedCrossRefGoogle Scholar
  47. 47.
    Maillon J, Siche J, Lacourciere Y:ABPM comparison of the antihypertensive profiles of the selective angiotensin II receptor antagonists telmisartan and losartan in patients with mild-to-moderate hypertension. J Hum Hypertens 1999, 13: 657–664.CrossRefGoogle Scholar
  48. 48.
    Gradman AH, Lewin A, Bowling BT, et al.: Comparative effects of candesartan cilexitil and losartan in patients with systemic hypertension. Heart Disease 1999, 1: 52–57.PubMedGoogle Scholar
  49. 49.
    Lacourciere Y, Asmar R:A comparison of the efficacy and duration of action of candesartan cilexitil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients. A placebo-controlled, forced dose-titration study. Amer J Hypertens 1999, 12: 1181–1187.CrossRefGoogle Scholar
  50. 50.
    Plum J, Bunten B, Nemeth R, Grabensee B:Effects of angiotensin II antagonist valsartan on blood pressure, proteinuria, and renal hemodynamics in patients with chronic renal failure and hypertension. J Am Soc Nephrol 1998, 9: 2223–2234.PubMedGoogle Scholar
  51. 51.
    Ichikawa I:Will angiotensin II receptor antagonists be reno-protective in humans? Kidney Int. 1996, 50: 684–692.Google Scholar
  52. 52.
    Wilmink HW, Banga ID, Hijmering M, et al.: Effect of angiotensin-converting enzyme inhibition and angiotensin-II type 1 receptor antagonism on postprandial endothelial dysfunction. J Am Coll Cardiol 1999, 34: 140–145.PubMedCrossRefGoogle Scholar
  53. 53.
    Hedner T:Management of hypertension: the advent of a new angiotensin II receptor antagonist. J Hypertension 1999, 17 (Suppl 2): S21–S25.Google Scholar
  54. 54.
    Schwarzbeck A, Wittenmeier KW, Hallfritzsch U:Anemia in dialysis patients as a side-effect of sartanes. Lancet 1998, 352: 286.PubMedCrossRefGoogle Scholar
  55. 55.
    Russo D, Pisani A, Balletta MM, et al.: Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kid Dis 1999, 33: 851–856.PubMedCrossRefGoogle Scholar
  56. 56.
    Hamroff G, Blaufarb I, Mancini D, et al.: Angiotensin-II receptor blockade reduces afterload safely in patients maximally treated with angiotensin-converting enzyme inhibitors in heart failure. J Cardiovasc Pharmacol 1997, 30: 533–536.PubMedCrossRefGoogle Scholar
  57. 57.
    Dahlof B, Devereux R, de Faire U, et al.: The Losartan Intervention for Endpoint Reduction (LIFE) in Hypertension Study. Rationale, design, and methods. J Hypertens 1997, 10: 705–713.CrossRefGoogle Scholar
  58. 58.
    Hansson L, Lithell H, Skoog I, et al.: Study on cognition and prognosis in the elderly (SCOPE). Blood Press 1999, 8(3): 177–183.PubMedCrossRefGoogle Scholar
  59. 59.
    Weber M:Emerging treatments for hypertension: potential role for vasopeptidase inhibition. Amer J Hypertens 1999, 12: 139S–147S.Google Scholar
  60. 60.
    Burnett JC Jr:Vasopeptidase inhibition: a new concept in blood pressure management. J Hypertens 1999, 17 (suppl 1): S37–S43.Google Scholar
  61. 61.
    Vesterqvust O, Liao W, Manning JA, et al.: Pharmacodynamic effects of multiple doses of omapatrilat in healthy subjects. Clin Pharmacol Ther 1999, 65: 132.CrossRefGoogle Scholar
  62. 62.
    Hammett JL, Sica DA, Scicli G, et al.: Omapatrilat increases key vascular/renal markers regardless of renal function. Clin Pharmacol Ther 1999, 65: 131.CrossRefGoogle Scholar
  63. 63.
    Liao W, Delaney CL, Catanzariti A, et al.: Omapatrilat is not a diuretic: single and multiple-dose analysis of the urinary excretion of sodium. Am J Hypertens 2000, in press.Google Scholar
  64. 64.
    Uderman HD, Delaney CL, Catanzariti A, et al.: Coadministration of omapatrilat does not alter furosemide-induced diuresis: single and multiple-dose analysis of the urinary excretion of sodium. Am J Hypertens 2000, in press.Google Scholar
  65. 65.
    Zusman R, Atlas S, Kochar M, et al.: Efficacy and safety of omapatrilat, a vasopeptidase inhibitor. Am J Hypertens 1999, 12: 125A.CrossRefGoogle Scholar
  66. 66.
    Larochelle P, Smith DHG, Ouellet JP, et al.: Efficacy and safety of omapatrilat in subjects with isolated systolic hypertension. Am J Hypertens 2000, in press.Google Scholar
  67. 67.
    Neutel J, Weber M, Shepherd A, et al.: Antihypertensive efficacy of omapatrilat, a vasopeptidase inhibitor, compared with lisinopril. J Hypertens 1999, 17 (suppl 3):S67.CrossRefGoogle Scholar
  68. 68.
    Asmar R, Fredebohm W, Senftleber I, et al.: Omapatrilat compared with lisinopril in treatment of hypertension as assessed by ambulatory blood pressure monitoring. Am J Hypertens 2000, in press.Google Scholar
  69. 69.
    Ruilope LM, Palatini P, Grossman E, et al.: Randomized double-blind comparison of omapatrilat with amlodipine in mild-to-moderate hypertension. Am J Hypertens 2000, in press.Google Scholar
  70. 70.
    Ferdinand KC, Saini RK, Lewin AJ, et al.: Efficacy and safety of omapatrilat with hydrochlorothiazide for the treatment of hypertension in subjects nonresponsive to hydrochlorothiazide alone. Am J Hypertens 2000, in press.Google Scholar
  71. 71.
    Ikram H, McClean DR, Mehta S, et al.: Long-term beneficial hemodynamic and neurohumoral effects of vasopeptidase inhibition with omapatrilat in heart. J Am Coll Cardiol 1999, 33: 185A.Google Scholar
  72. 72.
    McClean DR, Ikram H, Melton I, et al.: Cardiac, renal, and endocrine effects of 3-month treatment of chronic heart failure with the vasopeptidase inhibitor, omapatrilat. J Am Coll Cardiol 1999, 33 (suppl A): 185A.Google Scholar
  73. 73.
    Sica DA:Vasopeptidase inhibition and its role in congestive heart failure. Congestive Heart Failure 2000, 6: 158–163.Google Scholar
  74. 74.
    Kostis JB, Weber MA, Alderman MH, et al.: OPERA: Design and rationale for a novel placebo control trial testing the benefits of blood pressure reduction in patients with stage I isolated systolic hypertension. Am J Hypertens 2000, in press.Google Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Domenic A. Sica

There are no affiliations available

Personalised recommendations