Intravenous Nicardipine

Summary Abstract Nicardipine is a water soluble calcium channel antagonist, with predominantly vasodilatory actions. Intravenous (IV) nicardipine (Cardene® IV), which demonstrates a relatively rapid onset/offset of action, is used in situations requiring the rapid control of blood pressure (BP). IV nicardipine was as effective as IV nitroprusside in the short-term reduction of BP in patients with severe or postoperative hypertension. A potential role for IV nicardipine in the intraoperative acute control of BP in patients undergoing various surgical procedures (including cardiovascular, neurovascular and abdominal surgery), and in the deliberate induction of reduced BP in surgical procedures in which haemostasis may be difficult (e.g. surgery involving the hip or spine) was demonstrated in preliminary studies. Preliminary studies also indicated the ability of a bolus dose of IV nicardipine to attenuate the hypertensive response, but not the increase in tachycardia, after laryngoscopy and tracheal intubation in anaesthetised patients. In large, well designed studies, IV nicardipine prevented cerebral vasospasm in patients with recent aneurysmal subarachnoid haemorrhage; however, overall clinical outcomes at 3 months were similar to those in patients who received standard management. Small preliminary studies have investigated the use of IV nicardipine in a variety of other settings, including acute intracerebral haemorrhage, acute ischaemic stroke, pre-eclampsia, acute aortic dissection, premature labour and electroconvulsive therapy. In conclusion, the efficacy of IV nicardipine in the short-term treatment of hypertension in settings for which oral therapy is not feasible or not desirable is well established. The ability to titrate IV nicardipine to the tolerance levels of individual patients makes this agent an attractive option, especially in critically ill patients or those undergoing surgery. Potential exists for further investigation of the use of this agent in clinical settings where a vasodilatory agent with minimal inotropic effects is appropriate. Pharmacological Properties Nicardipine is a dihydropyridine calcium channel antagonist, with greater selectivity for L-type calcium channels in vascular smooth muscle than cardiac myocytes. Nicardipine demonstrates strong coronary and cerebral vasodilatory activity. It induces relatively rapid changes in BP, with minimal inotropic cardiac effects and no significant venodilatory action. The vasodilatory effects of nicardipine appear to be greater in patients with hypertension than in healthy normotensive volunteers. Nicardipine is highly lipophilic. In patients with coronary artery disease, with and without impaired left ventricular function, IV nicardipine (with or without β-adrenoceptor antagonists) increased cardiac output, stroke volume and left ventricular ejection fraction, but had no significant effect on left ventricular end-diastolic pressure. The pharmacokinetics of a continuous infusion of IV nicardipine or a bolus dose of IV nicardipine were linear in patients with mild to moderate hypertension. Rapid dose-related increases in plasma concentrations of nicardipine occurred during the first 2 hours after initiation of a 48-hour continuous infusion of IV nicardipine. Thereafter, the nicardipine concentration rose more slowly and took 24–48 hours to reach steady state. Nicardipine plasma concentrations declined triexponentially after an IV infusion, with an initial rapid distribution half-life (t½α 2.7 minutes), followed by an intermediate elimination half-life (t½β 44.8 minutes) and a slow terminal elimination half-life (t½γ 14.4 hours). Nicardipine is highly bound to plasma proteins (>95%) over a wide range of concentrations. Nicardipine metabolism occurs mainly in the liver, primarily by cytochrome P450 (CYP)2C8, CYP2D6 and CYP3A4 enzyme isoforms. Excretion occurred in approximately equal proportions in the urine (49%) and faeces (43%), with no unchanged drug excreted. Therapeutic Efficacy A continuous infusion of IV nicardipine was as effective as a continuous infusion of IV nitroprusside in the reduction of BP in patients with severe hypertension (systolic BP >200mm Hg, diastolic BP >120mm Hg), with a similar proportion of patients (>93%) achieving the therapeutic BP target within a similar timeframe (approximately 60 minutes). IV nicardipine was as effective as IV nitroprusside in effectively controlling postoperative hypertension in patients who had undergone either cardiac or noncardiac surgery. However, with IV nicardipine, compared with IV nitroprusside, the time required to reach a therapeutic response was significantly less. Data from a number of preliminary studies support the intraoperative efficacy of IV nicardipine in the acute control of BP in patients undergoing various surgical procedures (including cardiac surgery, intracranial aneurysm clipping and abdominal surgery). IV nicardipine was effective in inducing deliberate hypotension (mean arterial pressure [MAP] 55–60mm Hg), and consequently limiting blood loss during specified surgical procedures in which surgical haemostasis may be difficult to achieve (e.g. surgery involving the hip or spine); once the infusion had ceased, the time to return to baseline MAP was longer with IV nicardipine than IV nitroprusside. Bolus IV nicardipine attenuated the hypertensive response, but not the occurrence of tachycardia, after laryngoscopy and tracheal intubation in normo- or hypertensive patients who had undergone induction anaesthesia. IV nicardipine was also effective in attenuating increases in BP during anaesthesia emergence and tracheal extubation. IV nicardipine prevented cerebral vasospasm in patients with recent aneurysmal subarachnoid haemorrhage, with a reduced need for prophylactic intentional hypervolaemia/induced hypertension. However, overall clinical outcomes at 3 months were similar to those in patients who received standard management. Data from small preliminary studies indicated that IV nicardipine had beneficial effects in patients with acute intracerebral haemorrhage and acute ischaemic stroke. Preliminary data also indicate that IV nicardipine effectively managed hypertension in pregnant women with pre-eclampsia, paediatric patients in the perioperative or intensive care settings, elderly hypertensive patients and patients with acute aortic dissection. In addition, IV nicardipine had beneficial effects on haemodynamic parameters in patients with acute heart failure. When administered in combination with labetalol, a bolus dose of IV nicardipine prevented the acute haemodynamic response to electroconvulsive therapy. Tolerability IV nicardipine was generally well tolerated in large well designed trials in patients requiring the short-term treatment of hypertension, with adverse events generally being non-serious and mostly the expected consequences of vasodilation. Headache, hypotension, nausea, vomiting and tachycardia were the most commonly reported adverse events, with the presence of adverse events occasionally requiring the adjustment of the dosage. A continuous infusion of IV nicardipine for up to 14 days was generally well tolerated in a well designed trial in patients with aneurysmal subarachnoid haemorrhage, with hypotension occurring in 35% of IV nicardipine recipients and 18% of placebo recipients. IV nicardipine was generally better tolerated than IV nitroprusside in patients requiring the acute control of hypertension in randomised, open-label, multicentre trials. The tolerability of IV nicardipine in children or pregnant women has not been established in well designed trials. However, IV nicardipine was generally well tolerated in small, open-label studies in these patients.