Current Applications for Nicardipine in Invasive and
Interventional Cardiology

Invasive coronary procedures, such as rotational atherectomy and coronary artery bypass graft (CABG) stenting, are associated with vasoconstriction that sometimes results in increased morbidity or death. The “no-reflow” phenomenon, an adverse effect of cardiac catheterization, and transient perioperative hypertension are examples of vasoconstriction-related complications. Vasodilators such as injectable calcium channel blockers, sodium nitroprusside and adenosine are effective agents for the treatment of these complications. Nicardipine, a dihydropyridine calcium channel blocker, has several unique properties that make it an appealing treatment option for reversing vasoconstriction. Intracellular calcium release triggered by the calcium influx into the myocyte binds the regulatory protein troponin, resulting in a calcium-troponin complex. This allows actin and myosin to interact and contract. Calcium channel blockers prevent this cascade of events by blocking the calcium influx into myocytes and vascular smooth muscle cells.1 The calcium channel blocking agents block receptors on the L-type calcium channel, giving rise to a slowly inactivating high-threshold current in cardiac cells. The currently available calcium channel blockers include the dihydropyridines (nifedipine, amlodipine, nicardipine, nitrendipine and others); verapamil, which is structurally similar to papaverine; diltiazem, a benzothiazepine derivative; and bepridil, a nonspecific calcium blocker that is infrequently used in the United States. These various calcium channel blocking agents have varying mechanisms of action, leading to different effects on cardiovascular function and to different types of potentially adverse side-effects (Table 1). The dihydropyridine calcium channel blockers demonstrate the following characteristics: 1) dose-dependent blockade of the slow calcium channels;2,3 2) greater selectivity for vascular smooth muscle than for the myocardium, making these drugs more potent vasodilators than either verapamil or diltiazem; 3) vasodilatation of epicardial and arteriolar coronary arteries, which increases coronary blood flow and reduces coronary resistance, possibly enhancing the development of coronary collaterals;4–6 and 4) dose-dependent, reflex tachycardia.7 Nicardipine is an antagonist of the L-type calcium channels. It demonstrates greater selectivity for binding of calcium channels in vascular smooth muscle cells than in the cardiac myocytes.8 This relative tissue selectivity is important in the drug’s utility for the treatment of hypertension and angina. The efficacy in treating these conditions has been demonstrated in animal models as well as in man.9 In animal studies of cerebral ischemia and myocardial infarction, nicardipine has also demonstrated a possible membrane stabilizing action, linked to its lipophilic character. This is a property that is not shared by other dihydropyridine calcium channel blockers.10–12 In addition, unlike other dihydropyridines, nicardipine is photoresistant, water-soluble, and can be administered intravenously. Intravenous nicardipine has a rapid onset of action (1–2 minutes) with an elimination half-life of 40 ± 10 minutes. It is also rapidly distributed, extensively metabolized in the liver and rapidly eliminated.13 Unlike the oral form of nicardipine, there is a linear pharmacokinetic response observed with the intravenous form. After an intravenous infusion, the plasma concentration of the drug declines triexponentially, with a rapid early redistribution phase (half life, 2.7 minutes), an intermediate phase (half life, 44.8 minutes) and a slow terminal phase (half life, 14.4 hours) detected after the long-term infusions.14 Intracoronary nicardipine has been demonstrated to be highly effective in increasing coronary blood flow, while producing minimal systemic side effects.15,16 Nicardipine is predominantly vasoselective, and unlike intracardiac diltiazem and verapamil, it is associated with very modest negative chronotropic and inotropic action.17,18 In this review, we describe the potential evidence-based uses of nicardipine in percutaneous coronary interventions (PCI) and slow and no-reflow phenomena, in CABG, and in the management of acute hypertension in the cardiac catheterization laboratory. Nicardipine and the prevention or reversal of slow or “no-reflow.” “No-reflow” or “slow-reflow” is a common complication of percutaneous coronary interventions in the setting of saphenous vein graft (SVG) angioplasty or stenting. This complication also may lessen the efficacy of PCI-based myocardial reperfusion in the setting of acute myocardial infarction interventions. The no-reflow phenomenon is defined as a severe reduction in antegrade coronary blood flow (Thrombolysis in Myocardial Infarction grade of 2 or lower) without angiographic evidence of persistent mechanical vessel obstruction.19,20 There is a large body of evidence to suggest that this condition is primarily caused by microvascular dysfunction/vasoconstriction, and to a lesser extent, mechanical obstruction of the microvascular bed from atheroembolic and/or thrombotic debris.26,29,31 Overall, the etiology of no reflow is multifactorial, complex and variable among different patient subsets. Contributing factors include myocardial necrosis and stunning, reperfusion injury from oxygen free radical production, endothelial cell edema, distal embolization of plaque and/or thrombus, local release of active tissue factor, alpha-adrenergic mediated vasoconstriction and activated platelet-mediated (serotonin and thromboxane) macrovascular and microvascular vasoconstriction.19,21–25 No reflow occurs in 11–25% of patients after percutaneous intervention for acute myocardial infarction but in only 2% of patients undergoing elective PCI. The risk of “no-reflow” is much higher during the treatment of saphenous vein grafts, after atherectomy and during PCI of thrombus containing lesions.26,27 No reflow is associated with adverse clinical outcomes in both elective and emergent percutaneous interventions. Both mechanical and/or pharmacological methods have been shown to be effective in the prevention and/or treatment of no reflow. Pharmacologic options include intravenous glycoprotein IIb/IIIa inhibitors, nicorandil, papaverine, calcium channel blockers, sodium nitroprusside and adenosine. The mechanical options include the intra-aortic balloon pump, distal (or proximal) protection devices and coronary thrombectomy devices.28 The important role of microvascular vasoconstriction as a predominant mechanism of no-reflow has been demonstrated by the successful reversal of the complication using a variety of microvascular vasodilators (verapamil, diltiazem, adenosine, nitroprusside, etc.).33,34,40,41 The nearly complete reversal of this complication by vasodilators in the majority of cases suggests that mechanical obstruction from distal embolic debris, in most cases, plays a less important role in the causation of no reflow, particularly in SVG interventions.33,34,40,41 Intracoronary calcium channel blockers to treat and/or prevent no-reflow. Intracoronary calcium channel blockers are often administered during PCI when there is evidence of reduced flow.26,29–31 They have also been prophylactically used before an interventional procedure.32,33 Both intracoronary verapamil and diltiazem have been demonstrated to successfully reverse no-reflow after SVG interventions. However, both of these agents may have dose-limiting chronotropic, dromotropic and negative inotropic effects on the heart.15,16,31,34 Nicardipine has been demonstrated to have superior coronary vascular selectivity in animal and in vitro studies. In a recent study involving a beating canine heart model, Jang and Kim observed that nicardipine was associated with a significant increase in local myocardial perfusion after a coronary occlusion was released (Figure 1).35 In a study by Lambert and colleagues, intravenous nicardipine triggered a potent and somewhat more selective vasodilator response in the coronary bed than in the systemic bed.36 In a subsequent study by the same authors, intracoronary nicardipine produced a marked and sustained increase in coronary blood flow that persisted for 7 minutes after administration and only a mild and transient depression of left ventricular contractile function and impairment of left ventricular relaxation.37 In another study, Terris and colleagues employed the same protocol using nifedipine.38 A comparison of the data from the two studies reveals that nicardipine was associated with greater increases in coronary blood flow and less myocardial depression.37 In an important study by Fugit and colleagues, intracoronary nicardipine (200 µg), diltiazem (10,000 µg) and verapamil (200 µg) were serially administered in a randomized double blind fashion to 9 patients who had minimally diseased ( 2 times the upper limit of normal) was observed in only 2/34 patients (5.8%). The successful use of this strategy during PCI of a very high-risk, occluded and thrombus-laden SVG is shown in Figure 2. These favorable results (recently submitted for publication) appear to be at least comparable to, if not superior to, published data using distal protection devices. However, these results should be reconfirmed in a larger randomized trial comparing premedication with nicardipine (combined with direct stenting) to the more standardized and better-studied approaches using distal protection. It is too early to recommend intracoronary nicardipine prophylaxis as a routine alternative to distal protection in high-risk SVG interventions. Use of nicardipine in coronary bypass grafting surgery. Arterial grafts have a been shown to have long-term advantages over venous grafts as conduits for CABG surgery. Arterial grafts, like the radial artery or the musculoelastic part of the internal mammary artery (distal third), have a well-known propensity to spasm.42,43 The frequent failure of the radial artery grafts during the early 1970s was largely attributable to the problems with spasm and intimal hyperplasia.44 The use of spasmolytic calcium channel blockers (e.g., diltiazem) has led to a revival of the radial artery graft procedure for bypass surgery.45 Nicardipine may have several advantages in this clinical setting. First, its duration of action enables titration of the effects during the perioperative and postoperative periods. In addition, nicardipine may protect the cardiac myocytes against the calcium load produced by ischemia, provides membrane stabilizing action and protects myocardial metabolism in the presence of ischemia.46 In an in vitro study by He and Yang, the antispastic effects of nicardipine, nifedipine, verapamil and diltiazem were studied in the human radial artery.47 The results show that the dihydropyridines (nifedipine and nicardipine) were better spasmolytics than verapamil or diltiazem. Specifically, they were more potent in reversing the existing contraction and in preventing the potassium-induced contraction in the radial artery. Verapamil and diltiazem had no effect on preventing contraction in the radial artery. Cable and colleagues also reported that diltiazem has little effect on human radial artery contraction.48 In a study by Radermecker and colleagues,50 consecutive patients underwent myocardial revascularization using the radial artery. Hydrostatic dilatation of the graft was performed with a diluted solution of papaverine (1%), and perioperative intravenous nicardipine was infused, initially at 0.25 µg/kg/min after a 1 mg bolus and adjusted according to the systemic arterial pressure.49 On day 2, nicardipine was administered orally, 20–30 mg three times daily. Angiography performed between days 8 and 10 in the last 20 patients showed a 95% patency in the radial artery grafts. This study demonstrated that nicardipine is at least as effective as the diltiazem protocol. Since nicardipine is not associated with negative inotropic adverse effects, it is easily combined with beta-blockers in postoperative therapy. Acute management of hypertension in the cardiac cath lab. Intravenous nicardipine has been well studied and is approved for the short-term treatment of hypertension.13,50–54 Intravenous nicardipine has been shown to effectively and safely control the acute increase in blood pressure in patients with severe hypertension with and without end-organ damage.55 Because postoperative hypertension occurs in 4–30% of patients after cardiac and noncardiac surgery, rapid control of the condition is desirable. In a randomized study involving patients who had undergone cardiac or noncardiac surgery, intravenous nicardipine was effective in controlling blood pressure in 92% of patients.51 A therapeutic response was achieved in a mean time of 10–12 minutes. Hemodynamic findings in this study included a significant decrease in systemic vascular resistance and a significant increase in cardiac index with no change in heart rate, suggesting that nicardipine does not depress cardiac function. Halpern and colleagues compared intravenous nicardipine and sodium nitroprusside in postoperative hypertension.52 The two agents were equally efficacious and were not associated with any complications, although patients given nicardipine achieved blood pressure control more rapidly and with fewer dosage adjustments while having a significantly lower heart rate. Van Wezel and colleagues studied the efficacy of nicardipine and nitroprusside in preventing poststernotomy hypertension in 45 patients undergoing CABG.56 Both drugs reduced blood pressure effectively, but the incidence of myocardial ischemia was significantly lower among patients given nicardipine (9% versus 24%). Similar results were reported in the other studies that compared these two drugs in the management of hypertension in patients who had undergone CABG.57–60 Vecht and colleagues found that intravenous nicardipine was superior to intravenous nitroglycerin for controlling hypertension after CABG.59 After both drugs were administered as needed to maintain blood pressure below 110 mmHg, the blood pressure dropped sooner among patients given nicardipine than among those given nitroglycerin (mean infusion time, 7.7 hours and 11.9 hours, respectively). In addition, the mean systolic blood pressure dropped to 94 mmHg in the nicardipine group but only to 108 mmHg in the nitroglycerin group. Furthermore, unlike some patients in the nitroglycerin group, none of those in the nicardipine group required a second drug to control their blood pressure. Although no comparative studies have addressed the different agents available for the management of transient hypertension in the cardiac catheterization laboratory, nicardipine remains an excellent choice, and is frequently used in that setting. Conclusion. Intravenous and intracoronary nicardipine administration is safe, easy to use, and produces a predictable response. This drug has several potential advantages over other agents in a variety of settings in the cardiac catheterization laboratory. Nicardipine may be effective in the prevention and reversal of the no-reflow phenomenon during PCI, and in treating coronary vasospasm in arterial grafts (particularly the radial artery) during harvesting and after CABG. Nicardipine may have certain advantages over other calcium channel blockers for these applications, because of its sustained and potent arteriolar vasodilatory effect, with minimal inotropic or chronotropic effects. Finally, the intravenous administration of nicardipine appears to be a safe and effective approach to control hypertension during cardiac procedures.

1. Hardman JG, Limbird LE (eds). Goodman’s & Gilman’s The Pharmacological Basis of Therapeutics. 9th Ed. New York, New York: McGraw-Hill Publishers, 1996. 2. Kohlhardt M, Fleckenstein A. Inhibition of the slow inward current by nifedipine in mammalian ventricular myocardium. Naunyn Schmiedebergs Arch Pharmacol 1977;298:267. 3. Bayer R, Rodenkirchen R, Kaufmann R, et al. The effects of nifedipine on contraction and monophasic action potential of isolated cat myocardium. Naunyn Schmiedebergs Arch Pharmacol 1977;301:29. 4. Kaltenbach M, Shulz W, Kober G. Effects of nifedipine after intravenous and intracoronary administration. Am J Cardiol 1979;44:832. 5. Henry PD, Schuchleib R, Clark RE, Perez JE. Effect of nifedipine on myocardial ischemia: Analysis of collateral flow, pulsatile heat and regional muscle shortening. Am J Cardiol 1979;44:817. 6. Kitakaze M, Asanuma H, Takashima S, et al. Nifedipine-induced coronary vasodilation in ischemic hearts is attributable to bradykinin- and NO-dependent mechanisms in dogs. Circulation 2000;101:311. 7. Casolo GC, Balli E, Poggesi L, Gensini GF. Increase in number of myocardial ischemic episodes following nifedipine administration in two patients: Detection of silent episodes by Holter monitoring and role of heart rate. Chest 1989;95:541. 8. Clarke B, Grant D, Patmore L. Comparative calcium entry blocking properties of nicardipine, nifedipine and PY-108-68 on cardiac and vascular smooth muscle. Br J Pharmacol 1983;79:333P. 9. Alps BJ, Calder C, Wilson A. Nicardipine in models of myocardial infarction. Br J Clin Pharmacol 1985;20(Suppl 1):29S–49S. 10. Alps BJ, Hass WK. The potential beneficial effect of nicardipine in a rat model of transient forebrain ischemia. Neurology 1987;37:809–814. 11. Nakaya H, Kanno M. Effects of nicardipine, a new dihydropyridine vasodilator, on coronary circulation and ischemia-induced conduction delay in dogs. Arzneimittel-Forschung 1982;32:626–629. 12. Michel AD, Whiting RL. Cellular action of nicardipine. Am J Cardiol 1989;64:3H–7H. 13. Cardene IV [package insert]. Edison, NJ: ESP Pharma, Inc.: 2003. 14. Whiting RL, Dow RJ, Graham DJ, Mroszczak EJ. An overview of the pharmacology and pharmacokinetics of nicardipine. Angiology 1990;41(11 Pt 2):987–991. 15. Lambert CR, Pepine CJ. Effects of intravenous and intracoronary nicardipine. Am J Cardiol 1989;64:8H–15H. 16. Kaufmann P, Vassalli G, Utzinger U, Hess OM. Coronary vasomotion during dynamic exercise: Influence of intravenous and intracoronary nicardipine. J Am Col Cardiol 1995;26:624–631. 17. Henry PD. Comparative pharmacology of calcium antagonists: Nifedipine, verapamil and diltiazem. Am J Cardiol 1980;46:1047–1058. 18. Singh BN, Josephson MA. Clinical pharmacology, pharmacokinetics and hemodynamic effects of nicardipine. Am Heart J 1990;119(2 Pt 2):427–434. 19. Rezkalla SH, Kloner RA. No-reflow phenomenon. Circulation 2002;105:656. 20. Eeckhout E, Kern MJ. The coronary no-reflow phenomenon: A review of mechanisms and therapies. Eur Heart J 2001;22:729. 21. Hearse DJ, Bolli R. Reperfusion induced injury: Manifestations, mechanisms and clinical relevance. Cardiovasc Res 1992;26:101. 22. Kloner RA, Rude RE, Carlson N, et al. Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: Which comes first? Circulation 1980;62:945. 23. Ito H, Okamura A, Iwakura K, et al. Myocardial perfusion patterns related to thrombolysis in myocardial infarction perfusion grades after coronary angioplasty in patients with acute anterior wall myocardial infarction. Circulation 1996;93:1993. 24. Bonderman D, Teml A, Jakowitsch J, et al. Coronary no-reflow is caused by shedding of active tissue factor from dissected atherosclerotic plaque. Blood 2002;99:2794. 25. Gregorini L, Marco J, Kozakova M, et al. Alpha-adrenergic blockade improves recovery of myocardial perfusion and function after coronary artery stenting in patients with acute myocardial infarction. Circulation 1999;99:482. 26. Piana RN, Paik GY, Moscucci M, et al. Incidence and treatment of no reflow after percutaneous coronary intervention. Circulation 1994;89:2514. 27. Morishima I, Sone T, Okumura K, et al. Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J Am Coll Cardiol 2000;36:1202. 28. Eeckhout E, Kern MJ. The coronary no-reflow phenomenon: A review of mechanisms and therapies. Eur Heart J 2001;22:729–739. 29. Weyrens FJ, Mooney J, Lesser J, Mooney MR. Intracoronary diltiazem for microvascular spasm after interventional therapy. Am J Cardiol 1995;75:849–850. 30. Abbo KM, Dooris M, Glazier S, et al. Features and outcome of no-reflow after percutaneous coronary intervention. Am J Cardiol 1995;75:778–782. 31. Kaplan BM, Benzuly KH, Kinn JW, et al. Treatment of no-reflow in degenerated saphenous vein graft interventions: Comparison of intracoronary verapamil and nitroglycerin. Cathet Cardiovasc Diagn 1996;39:113–118. 32. Jalinous F, Mooney JA, Mooney MR. Pretreatment with intracoronary diltiazem reduces non-Q wave myocardial infarction following directional atherectomy. J Invas Cardiol 1997;9:270–273. 33. Taniyama Y, Ito H, Iwakura K, et al. Beneficial effect of intracoronary verapamil on microvascular and myocardial salvage in patients with acute myocardial infarction. J Am Coll Cardiol 1997;30:1193–1199. 34. McIvor ME, Undemir C, Lawson J, Reddinger J. Clinical effects and utility of intracoronary diltiazem. Cathet Cardiovasc Diagn 1995;35:287–291; discussion, 92–93. 35. Jang YH, Kim JM. Nicardipine augments local myocardial perfusion after coronary artery reperfusion in dogs. J Korean Med Sci 2003;18:23–26. 36. Lambert CR, Hill JA, Nichols WW, et al. Coronary and systemic hemodynamic effects of nicardipine. Am J Cardiol 1985;55:652–656. 37. Lambert CR, Pepine CJ. Effects of intravenous and intracoronary nicardipine. Am J Cardiol 1989;64:8H–15H. 38. Terris S, Bourdillon PD, Cheng DT, Pitt B. Direct cardiac and peripheral vascular effects of intracoronary and intravenous nifedipine. Am J Cardiol 1986;58:25–30. 39. Fugit MD, Rubal BJ, Donovan DJ. Effects of intracoronary nicardipine, diltiazem and verapamil on coronary blood flow. J Invas Cardiol 2000;12:80–85. 40. Michaels AD, Appleby M, Otten MH, et al. Pretreatment with intragraft verapamil prior to percutaneous coronary intervention of saphenous vein graft lesions: Results of the randomized, controlled vasodilator prevention on no-reflow (VAPOR) trial. J Invas Cardiol 2002;14:299–302. 41. Fischell TA, Lauer MA. Prevention and management of “no-reflow” during coronary interventions. In: Nissen S, Popma J, Kern M (eds). Cardiac Catheterization and Interventional Self-Assessment Program (CathSap II). Bethesda, Maryland: American College of Cardiology Foundation: 2001. 42. Carpentier A, Guermonprez JL, Deloche A, et al. The aorta-to-coronary radial artery bypass graft. A technique avoiding pathological changes in grafts. Ann Thorac Surg 1973;16:1111–1121. 43. Chamiot-Clerc P, Copie X, Renaud JF, et al. Comparative reactivity and mechanical properties of human isolated internal mammary and radial arteries. Cardiovasc Res 1998;37:811–819. 44. Curtis JJ, Stoney WS, Alford WC Jr., et al. Intimal hyperplasia: A cause of radial artery aortocoronary bypass graft failure. Ann Thorac Surg 1975;20:628–635. 45. Acar C, Jebara VA, Portoghese M, et al. Revival of the radial artery for coronary artery bypass grafting. Ann Thorac Surg 1992;54:652–659. 46. Turlapaty P, Vary R, Kaplan JA. Nicardipine, a new intravenous calcium antagonist: A review of its pharmacology, pharmacokinetics and perioperative applications. J Cardiothorac Anesth 1989;3:344–355. 47. He GW, Yang CQ. Comparative study on calcium channel antagonists in the human radial artery: Clinical implications. J Thorac Cardiovasc Surg 2000;119:94–100. 48. Cable DG, Caccitolo JA, Pearson PJ. New approaches to prevention and treatment of radial artery graft vasospasm. Circulation 1998;98(Suppl):II-15–II-22. 49. Radermecker MA, Grenade T, Cao-Thian SK, et al. Nicardipine protocol for CABG using the radial artery clinical and angiographic data. Acta Chir Belg 2001;101:185–189. 50. Goldberg ME, Clark S, Joseph J, et al. Nicardipine versus placebo for the treatment of postoperative hypertension. Am Heart J 1990;119(2 Pt 2):446–450. 51. Goldberg ME and the IV Nicardipine Study Group. Efficacy and safety of intravenous nicardipine in the control of postoperative hypertension. Chest 1991;99:393–398. 52. Halpern NA, Alicea M, Krakoff LR, Greenstein R. Postoperative hypertension: A prospective, placebo-controlled, randomized, double-blind trial, with intravenous nicardipine hydrochloride. Angiology 1990;41(11 Pt 2):992–1004. 53. Halpern NA, Goldberg M, Neely C, et al. Postoperative hypertension: A multicenter, prospective, randomized comparison between intravenous nicardipine and sodium nitroprusside. Crit Care Med 1992;20:1637–1643. 54. Halpern NA, Sladen RN, Goldberg JS, et al. Nicardipine infusion for postoperative hypertension after surgery of the head and neck. Crit Care Med 1990;18:950–955. 55. Wallin JD, Fletcher E, Ram CV, et al. Intravenous nicardipine for the treatment of severe hypertension. A double-blind, placebo-controlled multicenter trial. Arch Internl Med 1989;149:2662–2669. 56. van Wezel HB, Koolen JJ, Visser CA, et al. The efficacy of nicardipine and nitroprusside in preventing poststernotomy hypertension. J Cardiothorac Anesth 1989;3:700–706. 57. Combes P, Durand M. Comparison of nicardipine and sodium nitroprusside in the treatment of hypertension after coronary bypass surgery (a pilot study). Acta Anaesthesiol Belg 1992;43:113–119. 58. David D, Dubois C, Loria Y. Comparison of nicardipine and sodium nitroprusside in the treatment of paroxysmal hypertension following aortocoronary bypass surgery. J Cardiothorac Vasc Anesth 1991;5:357–361. 59. Vecht RJ, Swanson KT, Nicolaides EP, et al. Comparison of intravenous nicardipine and nitroglycerin to control systemic hypertension after coronary artery bypass grafting. Am J Cardiol 1989;64:19H–21H. 60. Oh Y, Hong Y, Band S, Kwak Y. The comparison of sodium nitroprusside and nicardipine on postoperative hypertension in coronary artery graft surgery. Anesth Analg 2002;93:SCA75.