The Current Role of Clevidipine in the Management of Hypertension.

Bo Xu, Zhen Chen, Gaorui Tang
Author Information
  1. Bo Xu: College of Pharmacy, University of South China, No. 28, Changsheng West Road, Zhengxiang District, Hengyang, 421001, Hunan, China. xuboj20@foxmail.com. ORCID
  2. Zhen Chen: College of Pharmacy, University of South China, No. 28, Changsheng West Road, Zhengxiang District, Hengyang, 421001, Hunan, China.
  3. Gaorui Tang: College of Pharmacy, University of South China, No. 28, Changsheng West Road, Zhengxiang District, Hengyang, 421001, Hunan, China.

Abstract

Acute hypertension, which may damage blood vessels, causes irreversible organ damage to the vasculature, central nervous system, kidney, and heart. Clevidipine, the first third-generation calcium channel antagonist approved by the Food and Drug Administration (FDA) in the past 20 years, is an ultra-short-acting calcium channel blocker that inhibits L-type calcium channels with high clearance and low distribution, can be rapidly metabolized into the corresponding inactive acid, and is rapidly hydrolyzed into inactive metabolites by esterase in arterial blood. Clevidipine is the same as nicardipine in that the main physiological effect is vasodilation and the main target is the arterial system, which has a limited effect on capacitor vessels. Unlike nitroglycerin, Clevidipine has a limited effect on preload. In contrast to other direct-acting vasodilators, Clevidipine has an ultra-short half-life due to metabolism by nonspecific blood and tissue esterases. Clevidipine trials conducted in adult populations have proven that it can rapidly control blood pressure in cardiac surgery situations and that adverse reactions to Clevidipine are similar to those with other antihypertensive agents. In recent years, clinical trials have shown that Clevidipine has excellent blood pressure-lowering capability in patients with acute neurological injury (hemorrhage, stroke, and subarachnoid and acute intracerebral hemorrhage), those  undergoing coronary artery bypass graft or spinal surgery, and in those with cerebral aneurysm/pheochromocytoma, acute heart failure, acute aortic syndromes, or renal insufficiency with severe hypertension, and it is equivalent to commonly used blood pressure-lowering medicines such as nicardipine or nitroglycerin. However, there is a lack of large-scale clinical trial data on the efficacy and safety of Clevidipine in children during the perioperative period.

References

  1. Rivera A, Montoya E, Varon J. Intravenous clevidipine for management of hypertension. Integr Blood Press Control. 2010;3:105–11. [PMID: 21949626]
  2. Borrell-Vega J, Uribe AA, Palettas M, Bergese SD. Clevidipine use after first-line treatment failure for perioperative hypertension in neurosurgical patients: a single-center experience. Medicine (Baltimore). 2020;99(1):e8541.
  3. Keating GM. Clevidipine: a review of its use for managing blood pressure in perioperative and intensive care settings. Drugs. 2014;74(16):1947–60. [PMID: 25312594]
  4. Alviar CL, Gutierrez A, Cho L, et al. Clevidipine as a therapeutic and cost-effective alternative to sodium nitroprusside in patients with acute aortic syndromes. Eur Heart J Acute Cardiovasc Care. 2020;9(3_suppl):S5–12. [PMID: 29877737]
  5. Kenyon KW. Clevidipine: an ultra short-acting calcium channel antagonist for acute hypertension. Ann Pharmacother. 2009;43(7):1258–65. [PMID: 19584385]
  6. Prlesi L, Cheng-Lai A. Clevidipine: a novel ultra-short-acting calcium antagonist. Cardiol Rev. 2009;17(3):147–52. [PMID: 19384089]
  7. Ericsson H, Tholander B, Björkman JA, Nordlander M, Regårdh CG. Pharmacokinetics of new calcium channel antagonist clevidipine in the rat, rabbit, and dog and pharmacokinetic/pharmacodynamic relationship in anesthetized dogs. Drug Metab Dispos. 1999;27(5):558–64. [PMID: 10220482]
  8. Ndefo UA, Erowele GI, Ebiasah R, Green W. Clevidipine: a new intravenous option for the management of acute hypertension. Am J Health Syst Pharm. 2010;67(5):351–60. [PMID: 20172984]
  9. Ericsson H, Fakt C, Höglund L, Jolin-Mellgård A, Nordlander M, Sunzel M, Regårdh CG. Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion. Eur J Clin Pharmacol. 1999;55(1):61–7. [PMID: 10206087]
  10. Ericsson H, Tholander B, Regårdh CG. In vitro hydrolysis rate and protein binding of clevidipine, a new ultrashort-acting calcium antagonist metabolised by esterases, in different animal species and man. Eur J Pharm Sci. 1999;8(1):29–37. [PMID: 10072476]
  11. Ericsson H, Bredberg U, Eriksson U, Jolin-Mellgård A, Nordlander M, Regårdh CG. Pharmacokinetics and arteriovenous differences in clevidipine concentration following a short- and a long-term intravenous infusion in healthy volunteers. Anesthesiology. 2000;92(4):993–1001. [PMID: 10754618]
  12. Smith WB, Marbury TC, Komjathy SF, Sumeray MS, Williams GC, Hu MY, Mould DR. Pharmacokinetics, pharmacodynamics, and safety of clevidipine after prolonged continuous infusion in subjects with mild to moderate essential hypertension. Eur J Clin Pharmacol. 2012;68(10):1385–94. [PMID: 22457015]
  13. Ericsson H, Fakt C, Jolin-Mellgård A, Nordlander M, Sohtell L, Sunzel M, Regårdh CG. Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers. Br J Clin Pharmacol. 1999;47(5):531–8. [PMID: 10336577]
  14. Zhang Y, Zhao S, Zhou H, Ding L. Development and validation of samples stabilization strategy and LC-MS/MS method for simultaneous determination of clevidipine and its primary metabolite in human plasma: Application to clinical pharmacokinetic study in Chinese healthy volunteers. J Chromatogr B Analyt Technol Biomed Life Sci. 2020;1161:122448. [PMID: 33246284]
  15. Wang Y, et al. Pharmacokinetics and tissue distribution study of clevidipine and its primary metabolite H152/81 in rats. Biomed Chromatogr. 2018;32(2):e4048.
  16. Erickson AL, DeGrado JR, Fanikos JR. Clevidipine: a short-acting intravenous dihydropyridine calcium channel blocker for the management of hypertension. Pharmacotherapy. 2010;30(5):515–28. [PMID: 20412001]
  17. The Medicines Company. Cleviprex (clevidipine butyrate) package insert. Parsippany, NJ; 2008.
  18. Frank Peacock W, Varon J, Ebrahimi R, DunbarPollack LCVJRJ. Clevidipine for severe hypertension in patients with renal dysfunction: a VELOCITY trial analysis. Blood Press Suppl. 2011;1(Suppl 1):20–5. [PMID: 21091269]
  19. Brower KI, Murphy C, Arias-Morales CE, Rankin D, Palettas M, Bergese SD. Safety and efficacy of intravenous clevidipine for the perioperative control of acute hypertension in neurosurgical patients: a dose update. Clin Med Insights Ther. 2017. https://doi.org/10.1177/1179559X17712517 . [DOI: 10.1177/1179559X17712517]
  20. Segawa D, Sjöquist PO, Nordlander M, Wang QD, Gonon A, Rydén L. Cardiac inotropic vs. chronotropic selectivity of isradipine, nifedipine and clevidipine, a new ultrashort-acting dihydropyridine. Eur J Pharmacol. 1999;380(2–3):123–8. [PMID: 10513571]
  21. Lemkuil BP, Gierl BT, Patel PM, Pearn ML, Nguyen LC, Minokadeh A, Drummond JC. The Effect of clevidipine on cerebral blood flow velocity and carbon dioxide reactivity in human volunteers. J Neurosurg Anesthesiol. 2016;28(4):337–40. [PMID: 26447497]
  22. Stephens CT, Jandhyala BS. Effects of fenoldopam, a dopamine D-1 agonist, and clevidipine, a calcium channel antagonist, in acute renal failure in anesthetized rats. Clin Exp Hypertens. 2002;24(4):301–13. [PMID: 12069360]
  23. Abdelgalel EF. Controlled hypotensive anesthesia for endoscopic endonasal repair of cerebrospinal fluid rhinorrhea: a comparison between clevidipine and esmolol: Randomized controlled study. Egypt J Anaesth. 2018;34(1):1–7.
  24. Gradman AH, Vivas Y. New therapeutic perspectives with clevidipine: an ultra-short-acting intravenous Ca2+ channel blocker. Expert Opin Investig Drugs. 2007;16(9):1449–57. [PMID: 17714030]
  25. Nguyen HM, Ma K, Pham DQ. Clevidipine for the treatment of severe hypertension in adults. Clin Ther. 2010;32(1):11–23. [PMID: 20171407]
  26. Aronson S, Dyke CM, Stierer KA, Levy JH, Cheung AT, Lumb PD, Kereiakes DJ, Newman MF. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg. 2008;107(4):1110–21. [PMID: 18806012]
  27. Aronson S. Clevidipine in the treatment of perioperative hypertension: assessing safety events in the ECLIPSE trials. Expert Rev Cardiovasc Ther. 2009;7(5):465–72. [PMID: 19419254]
  28. Powroznyk AV, Vuylsteke A, Naughton C, Misso SL, Holloway J, Jolin-Mellgård A, Latimer RD, Nordlander M, Feneck RO. Comparison of clevidipine with sodium nitroprusside in the control of blood pressure after coronary artery surgery. Eur J Anaesthesiol. 2003;20(9):697–703. [PMID: 12974590]
  29. Espinosa A, Ripollés-Melchor J, Casans-Francés R, et al. Perioperative Use of Clevidipine: A Systematic Review and Meta-Analysis. PLoS ONE. 2016;11(3):e0150625. [PMID: 27018586]
  30. Ulici A, Jancik J, Lam TS, Reidt S, Calcaterra D, Cole JB. Clevidipine versus sodium nitroprusside in acute aortic dissection: a retrospective chart review. Am J Emerg Med. 2017;35(10):1514–8. [PMID: 28669696]
  31. Noviawaty I, Uzun G, Qureshi AI. Drug evaluation of clevidipine for acute hypertension. Expert Opin Pharmacother. 2008;9(14):2519–29. [PMID: 18778189]
  32. Huraux C, Makita T, Szlam F, Nordlander M, Levy JH. The vasodilator effects of clevidipine on human internal mammary artery. Anesth Analg. 1997;85(5):1000–4. [PMID: 9356090]
  33. Pascual MJ, Sastre JA, Calvo JM. Intraoperative clevidipine use to manage an acute hypertensive episode in a patient with a simultaneous kidney-pancreatic transplant. J Clin Anesth. 2018;45:53–4. [PMID: 29275266]
  34. Levy JH, Mancao MY, Gitter R, Kereiakes DJ, Grigore AM, Aronson S, Newman MF. Clevidipine effectively and rapidly controls blood pressure preoperatively in cardiac surgery patients: the results of the randomized, placebo-controlled efficacy study of clevidipine assessing its preoperative antihypertensive effect in cardiac surgery-1. Anesth Analg. 2007;105(4):918–25 (table of contents). [PMID: 17898366]
  35. Singla N, Warltier DC, Gandhi SD, Lumb PD, Sladen RN, Aronson S, Newman MF, Corwin HL, ESCAPE-2 Study Group. Treatment of acute postoperative hypertension in cardiac surgery patients: an efficacy study of clevidipine assessing its postoperative antihypertensive effect in cardiac surgery-2 (ESCAPE-2), a randomized, double-blind, placebo-controlled trial. Anesth Analg. 2008;107(1):59–67. [PMID: 18635468]
  36. Bekker A, Didehvar S, Kim S, et al. Efficacy of clevidipine in controlling perioperative hypertension in neurosurgical patients: initial single-center experience. J Neurosurg Anesthesiol. 2010;22(4):330–5. [PMID: 20622687]
  37. Freiberger NA, Tellor KB, Stevens AM. Comparison of clevidipine versus sodium nitroprusside for the treatment of postoperative hypertension in cardiac surgery patients. Hosp Pharm. 2016;51(6):461–7. [PMID: 27354747]
  38. Wu M, Ryan KR, Rosenthal DN, Jahadi O, Moss J, Kwiatkowski DM. The use of clevidipine for hypertension in pediatric patients receiving mechanical circulatory support. Pediatr Crit Care Med. 2020;21(12):e1134–9. [PMID: 32796396]
  39. Pollack CV, Varon J, Garrison NA, Ebrahimi R, Dunbar L, Peacock WF 4th. Clevidipine, an intravenous dihydropyridine calcium channel blocker, is safe and effective for the treatment of patients with acute severe hypertension. Ann Emerg Med. 2009;53(3):329–38. [PMID: 18534716]
  40. Barrett TW, Schriger DL, Pollack CV, Varon J, Garrison NA, Annals of Emergency Medicine Journal Club, et al. Clevidipine, an intravenous dihydropyridine calcium channel blocker, is safe and effective for treatment of patients with acute severe hypertension. Ann Emerg Med. 2009;53(3):339–40. [PMID: 19231664]
  41. Rosenfeldt Z, Conklen K, Jones B, Ferrill D, Deshpande M, Siddiqui FM. Comparison of nicardipine with clevidipine in the management of hypertension in acute cerebrovascular diseases. J Stroke Cerebrovasc Dis. 2018;27(8):2067–73. [PMID: 29627171]
  42. Allison TA, Bowman S, Gulbis B, Hartman H, Schepcoff S, Lee K. Comparison of clevidipine and nicardipine for acute blood pressure reduction in patients with stroke. J Intensive Care Med. 2019;34(11–12):990–5. [PMID: 28820038]
  43. Finger JR, Kurczewski LM, Brophy GM. Clevidipine versus nicardipine for acute blood pressure reduction in a neuroscience intensive care population. Neurocrit Care. 2017;26(2):167–73. [PMID: 27995512]
  44. Graffagnino C, Bergese S, Love J, Schneider D, Lazaridis C, LaPointe M, Lee K, Lynch G, Hu MY, Williams GC. Clevidipine rapidly and safely reduces blood pressure in acute intracerebral hemorrhage: the ACCELERATE trial. Cerebrovasc Dis. 2013;36(3):173–80. [PMID: 24135526]
  45. Varelas PN, Abdelhak T, Corry JJ, James E, Rehman MF, Schultz L, Mays-Wilson K, Mitsias P. Clevidipine for acute hypertension in patients with subarachnoid hemorrhage: a pilot study. Int J Neurosci. 2014;124(3):192–8. [PMID: 24007334]
  46. Bettesworth JG, Martin DP, Tobias JD. Intraoperative use of clevidipine in a patient with von Hippel-Lindau disease with associated pheochromocytoma. J Cardiothorac Vasc Anesth. 2013;27(4):749–51. [PMID: 22305918]
  47. Luis-García C, Arbonés-Aran E, Teixell-Aleu C, Lorente-Poch L, Trillo-Urrutia L. Clevidipine for hypertension treatment in pheochromocytoma surgery. Rev Esp Anestesiol Reanim. 2018;65(4):225–8.
  48. Meyer T, Tobias JD. Perioperative blood pressure management with clevidipine during coiling of cerebral artery aneurysms. Saudi J Anaesth. 2009;3(2):83–6. [PMID: 20532109]
  49. Kako H, Gable A, Martin D, Beebe A, Thung A, Samora W, Klamar J, Bhalla T, Tobias JD. A prospective, open-label trial of clevidipine for controlled hypotension during posterior spinal fusion. J Pediatr Pharmacol Ther. 2015;20(1):54–60. [PMID: 25859171]
  50. Tobias JD, Hoernschemeyer DG. Clevidipine for controlled hypotension during spinal surgery in adolescents. J Neurosurg Anesthesiol. 2011;23(4):347–51. [PMID: 21623231]
  51. Peacock F, Varon J, Ebrahimi R, Dunbar L, Pollack CV Jr. Clevidipine for severe hypertension in acute heart failure: a VELOCITY trial analysis. Congest Heart Fail. 2010;16(2):55–9. [PMID: 20412469]
  52. Stoicea N, Joseph N, Bergese SD. Clevidipine-induced dyspnea relief in acute heart failure patients. EBioMedicine. 2016;10:23–4. [PMID: 27495792]
  53. Dahl GP, Conner GE, Qiu F, Wang J, Spindler E, Campagna JA, Larsson HP. High affinity complexes of pannexin channels and L-type calcium channel splice-variants in human lung: possible role in clevidipine-induced dyspnea relief in acute heart failure. EBioMedicine. 2016;10:291–7. [PMID: 27349457]
  54. Peacock WF, Chandra A, Char D, et al. Clevidipine in acute heart failure: results of the a study of blood pressure control in acute heart failure—a Pilot Study (PRONTO). Am Heart J. 2014;167(4):529–36. [PMID: 24655702]
  55. Patel M, Meyer T, Tharakan A, Tobias JD. Intraoperative administration of clevidipine to prevent vasospasm after radial and internal mammary artery grafts during coronary artery bypass grafting. Am J Ther. 2012;19(3):e114–7. [PMID: 20634670]
  56. Kieler-Jensen N, Jolin-Mellgård A, Nordlander M, Ricksten SE. Coronary and systemic hemodynamic effects of clevidipine, an ultra-short-acting calcium antagonist, for treatment of hypertension after coronary artery surgery. Acta Anaesthesiol Scand. 2000;44(2):186–93. [PMID: 10695913]
  57. Bailey JM, Lu W, Levy JH, Ramsay JG, Shore-Lesserson L, Prielipp RC, Brister NW, Roach GW, Jolin-Mellgard A, Nordlander M. Clevidipine in adult cardiac surgical patients: a dose-finding study. Anesthesiology. 2002;96(5):1086–94. [PMID: 11981147]
  58. Merry AF, Avery EG, Nussmeier NA, Playford HR, Warman GR, Wang Y, Sladen RN. Clevidipine compared with nitroglycerin for blood pressure control in coronary artery bypass grafting: a randomized double-blind study. Can J Anaesth. 2014;61(5):398–406. [PMID: 24700403]
  59. Peacock WF, Angeles JE, Soto KM, Lumb PD, Varon J. Parenteral clevidipine for the acute control of blood pressure in the critically ill patient: a review. Ther Clin Risk Manag. 2009;5(3):627–34. [PMID: 19707278]
  60. Tobias JD, Allee J, Ramachandran V, Groshong T. Clevidipine controls intraoperative blood pressure in an adolescent with renal failure. J Pediatr Pharmacol Ther. 2009;14(3):144–7. [PMID: 23055902]
  61. Wang QD, Segawa D, Ericsson H, Sjöquist PO, Johansson L, Rydén L. Time-dependent cardioprotection with calcium antagonism and experimental studies with clevidipine in ischemic-reperfused pig hearts: part I. J Cardiovasc Pharmacol. 2002;40(2):228–34. [PMID: 12131552]
  62. Gourine AV, Pernow J, Poputnikov DM, Sjöquist PO. Calcium antagonist clevidipine reduces myocardial reperfusion injury by a mechanism related to bradykinin and nitric oxide. J Cardiovasc Pharmacol. 2002;40(4):564–70. [PMID: 12352318]
  63. Segawa D, Sjöquist PO, Wang QD, Gonon A, Rydén L. Time-dependent cardioprotection with calcium antagonism and experimental studies with clevidipine in ischemic-reperfused pig hearts: part II. J Cardiovasc Pharmacol. 2002;40(3):339–45. [PMID: 12198319]
  64. Odenstedt J, Månsson C, Grip L. Failure to demonstrate myocardial protective effects of the ultra short-acting calcium antagonist clevidipine in a closed-chest reperfusion porcine model. J Cardiovasc Pharmacol. 2004;44(4):407–15. [PMID: 15454848]
  65. Kaur H, Nattanamai P, Qualls KE. Propofol and clevidipine-induced hypertriglyceridemia. Cureus. 2018;10(8):e3165. [PMID: 30357028]
  66. Short JH, Fatemi P, Ruoss S, Angelotti T. Clevidipine-induced extreme hypoxemia in a neurosurgical patient: a case report. A A Pract. 2020;14(2):60–2. [PMID: 31770132]
  67. Zhang JG, Dehal SS, Ho T, Johnson J, Chandler C, Blanchard AP, Clark RJ Jr, Crespi CL, Stresser DM, Wong J. Human cytochrome p450 induction and inhibition potential of clevidipine and its primary metabolite h152/81. Drug Metab Dispos. 2006;34(5):734–7. [PMID: 16501008]
  68. Wang X, Guo XY, Xu L, Liu B, Zhou LL, Wang XF, Wang D, Sun T. Studies on the competitive binding of cleviprex and flavonoids to plasma protein by multi-spectroscopic methods: a prediction of food-drug interaction. J Photochem Photobiol B. 2017;175:192–9. [PMID: 28892755]
  69. Towe E, Tobias JD. Preliminary experience with clevidipine in the pediatric population. J Intensive Care Med. 2010;25(6):349–52. [PMID: 20837631]
  70. Tobias JD, Tulman DB, Bergese SD. Clevidipine for perioperative blood pressure control in infants and children. Pharmaceuticals (Basel). 2013;6(1):70–84.
  71. Tobias JD, Schechter WS, Phillips A, Weinstein S, Michler R, Berkenbosch JW, Montoya C. Clevidipine for perioperative blood pressure control in infants and children undergoing cardiac surgery for congenital heart disease. J Pediatr Pharmacol Ther. 2011;16(1):55–60. [PMID: 22477825]
  72. Clevidipine. Drugs R D. 2002;3(3):190–2.
  73. Nordlander M, Sjöquist PO, Ericsson H, Rydén L. Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control. Cardiovasc Drug Rev. 2004;22(3):227–50. [PMID: 15492770]
  74. Aronson S, Levy JH, Lumb PD, Fontes M, Wang Y, Crothers TA, Sulham KA, Navetta MS. Impact of perioperative blood pressure variability on health resource utilization after cardiac surgery: an analysis of the ECLIPSE trials. J Cardiothorac Vasc Anesth. 2014;28(3):579–85. [PMID: 24726635]
  75. The Medicines Company. Cleviprex (clevidipine) injectable emulsion for intravenous use: US prescribing information. 2011. http://www.cleviprex.com/ . Accessed Mar 22, 2021
  76. Staff PDR, editor. Red book: pharmacy’s fundamental reference, 2008. Montvale: Thomson Healthcare; 2008.
  77. Aronson S, Dasta JF, Levy JH, Lumb PD, Fontes M, Wang Y, Crothers TA, Sulham KA, Navetta MS. A cost analysis of the impact of a new intravenous antihypertensive in managing perioperative blood pressure during cardiac surgery. Hosp Pract (1995). 2014;42(3):26–32.

MeSH Term

Adult
Antihypertensive Agents
Blood Pressure
Calcium Channel Blockers
Child
Humans
Hypertension
Pyridines

Chemicals

Antihypertensive Agents
Calcium Channel Blockers
Pyridines
clevidipine

Word Cloud

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