Natriuretic

tive study2 comparing nesiritide with inotrope therapy or maintenance dose is 30mg three times daily, but daily doses Uses and Administration glyceryl trinitrate in patients with acute decompensated of between 60 and 120 mg in divided doses may be given. Nesiritide is a recombinant brain natriuretic peptide (see heart failure found a similar risk of in-hospital mortality Modified-release preparations of nicardipine hydrochloride p. 1444. 1) used in the management of acutely decom­ with nesiritide and glyceryl trinitrate, which was signifi­ for dosage twice daily are also available. pensated heart failure (below). It is given intravenously as cantly lower than the risk with inotrope therapy. How­ Nicardipine hydrochloride may be given by slow the citrate, but dosage is expressed in terms of the base. The ever, a meta-analysis3 of controlled studies comparing intravenous infusion as a lOO micrograms/mL solution in initial dose of nesiritide is 2 micrograms/kg by intravenous nesiritide with non-inotrope control therapy found that the short-term treatment of hypertension. An initial injection over l minute, followed by a maintenance there was a trend to higher mortality at 30 days in patients infusion rate of 5 mg/hour is recommended, increased, as infusion of IOnanograms/kg per minute. given nesiritide; the results were not statistically signifi­ necessary, up to a maximum of 15 mg/hour and cant, but became so after correction of the number of subsequently reduced to 3 mg/hour. For more information Heart failure. The use of nesiritide in acute decompen­ deaths in one of the studies.4 A later meta-analysis5 also regarding suitable diluents and incompatibilities, see sated heart failure (p. 1262.3) has been reviewed l·4 It found a trend towards increased mortality with nesiritide Incompatibility, above. For intravenous use in children, may be used for short-term treatment as an alternative to at 30 days, but the results again were not statistically sig­ see below. standard intravenous therapy with vasodilators, inotropes, nificant, and there was no difference in mortality between Reduced oral doses of nicardipine hydrochloride and or diuretics, and appears to have no proarrhythmic effects; nesiritide and control patients at 180 days. longer dosing intervals may be necessary in patients with however, its effects on mortality are controversial (see I. Yancy CW. Benefit-risk assessment of nesiritide in the treatment of hepatic or renal impairment (see helow). under Adverse Effects and Precautions, below) and its role acute decompensated heart failure. Drug Safety 2007; 30: 765-81. 2. WT et al. in therapy remains unclear. There is some evidence that it Abraham , In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medica­ Reviews. to standard therapy'·' and may be safely used in addition tions: an analysis from the Acute Decompensated Heart Failure National I 1. Curran MP, et al. Intravenous nicardipine: its use in the short-term may have a role as a more prolonged treatment in patients Registry (ADHERE). JAm Coil Cardiol 2005; 46: 57-64. treatment of hypertension and various other indications. Drugs 2006; 66: I755-82. awaiting cardiac transplantation.8 Nesiritide has also been 3. Sackner-Bernstein JD, et al. Short-term risk of death after treatment given intermittently for outpatient management of chronic with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005; 293: I900-5. advised against such use.ll heart failure,9,10 but some have 4. Aaronson KD, Sackner-Bernstein J. Risk of death associated with Administration in children. Intravenous infusion of nicar­ l. Vichiendilokku! A, et al. Nesiritide: a novel approach for acute heart nesiritide in patients with acutely decompensated heart failure. lAMA dipine has been used in both infants and children for the failure. Ann Pharmacother 2003; 37: 247-58. 2006; 296: 1465-6. 2. Keating GM, Goa KL. Nesiritide: a review of its use in acute 5. Arora RR, et al. Short and long-term mortality with nesiritide. Am Heart J management of hypertension. In studies1·4 in patients decompensated hean failure. Drugs2003; 63: 47-70. 2006; 152: 1084-90. aged between 2 days and 17 years, initial doses ranged 3. Yancy CW. Benefit-risk assessment of nesiritide in the treatment of from 0.2 to 5 micrograms/kg per minute, with mainte­ Drug Safety 2007; 30: 765-81. acute decompensated heart failure. nance infusions of 0.15 to 6micrograms/kg per minute. 4. Tong AT, Rozner MA. The role of ne�iritide in heart failure. Expert Opin Interactions Drug Metab Toxicol 2009; 5: 823-34. Adverse effects were rare; one study4 reported adverse K.M pulmonary hypertension in The risk of may be increased in patients 5. O'Dell , et al. Nesiritide for secondary effects in 5 of 31 treatment courses, including tachycardia, patients with end-stage heart failure. Am J Health-Syst Pharm 2005; 62: receiving nesiritide with other drugs that lower blood flushing, palpitations. and hypotension. There has also 606-9. pressure. 6. Smull DL, Jorde UP. Concomitant use of nesiritide and milrinone in been a report5 of the successful use of intravenous infu­ decompensated congestive heart failure. Am J Health-Syst Pharm 2005; sion of nicardipine in 8 preterm infants (gestational age 28 62: 291-5. Pharmacokinetics to 36 weeks). Infusions were given at a dose of 0.5 to 7. Sakr A, et a!. Nesiritide in the initial management of acute 2 micrograms/kg per minute and continued for periods of decompensated congestive heart failure. Conn Med2008; 72: 517-2 3. Nesiritide is cleared from the circulation by 3 mechanisms: 3 to 36 days. Hypotension, oedema, or tachycardia were 8. Witteles R, et al. natriuretic peptide is effective therapy before uptake into cells; proteolytic cleavage by endopeptidases; care. Ann 141: 895. and excretion by the kidneys. It has a biphasic elimination. not seen. 9. Sheikh-Taha M. Intermittent nesiritide therapy in outpatients with The BNFC suggests that neonates and children up to age Pharm 2005; 62: 196-8. with a terminal elimination half-life of 18 minutes. chronic heart failure. Am J Health-Syst 18 years may be given nicardipine hydrochloride by I 0. Schwarz ER, et al. Intermittent outpatient nesiritide infusion reduces hospital admissions in patients with advanced heart failure. J Cardiovasc Preparations continuous intravenous infusion for the management of Pharmacal Ther 2007; 12: 232-6...... hypertensive crises. The initial dose is 500 nanograms/kg MA treatment of heart II. Bauer JB, Randazzo . Nesiritide for outpatient Proprietary Preparations (details are given in Volume B) per minute. adjusted according to response; the usual failure. Am J Health"Syst Pharm 2005; 62: 2639-42. Single-ingredient Preparations. Arg.: Natrecor; Canad.: Natrecor; maintenance dose is 1 to 4micrograms/kg per minute, with Indon.: Natrecort; Israel: Noratak; Singapore: Natrecort; a maximum dose of 250micrograms/minute. Adverse Effects and Precautions Switz.: Noratakt; USA: Natrecor; Venez. : Natrecor. 1. Treluyer JM, et al. Intravenous nicardipine in hypertensive children. Bur J Pediatr 1993; 152: 7l2-4. The most common adverse effects of nesiritide relate to 2. Sartori SC, et at. Intravenous nicardipine for treatment ol systemic vasodilatation and include hypotension, headache, and hyperten.:;ion in children. Pediatrics I999; 104 676-7. dizziness. Nausea and vomiting, abdominal pain, back pain, Nicardipine Hydrochloride 3. Tobias JD. Nicardipine to control mean angina pectoris, insomnia, and anxiety, have also been (BANM, USAN, r/NNM) cardiothoracic surgery in infants and children. Am reported. Cardiac arrhythmias have occurred but may be 4. Flynn JT, et al. Intravenous nicardipine for treatment of severe hypertension in children. .JPediatr 200I; 139: 38-43. HidfOdoruro de .· ni<:ardipln6; Nicardipina Cioridrato; Nicar" associated with the underlying condition. Adverse effects on 5. Gouyon JB, et al. Intravenous nicardipine in hypertensive preterm renal function have been reported. If hypotension occurs dipine; Chlorhydrate de; Nfcardipini Hydrochloridum; infants. Arch Dis Child 1997; 76: F126-F127. the infusion of nesiritide should be stopped or the dose Niqrdiptno, hidrodorum de: Nii

actively marketed The symbol denotes a substance whose use may be restricted in certain sports (see p. viii) The symbol t denotes a preparation no longer (8) 1446 Cardiovascular

be a favourable effect on cognitive function with been used as a lipid regulating drug in hyperlipidaemias and lschaemic heart disease. A large multicentre double-blind nicardipine.u as a vasodilator in the treatment of -peripheral vascular randomised placebo-controlled study1 suggested that disease. L Amenta F, et a!. Nicardipine: a hypotensive dihydropyridine-type , in addition to its anti-anginal effects, may have calcium antagonist with a peculiar cerebrovascular profile. Clin Bxp cardioprotective properties. The incidence of major coron­ 30: References. Hypertens 2008; 808-26. ary events, particularly unplanned admission for chest 2. Dorhout Mees S, et al. Calcium antagonists for aneurysmal subarachnoid 1. Owada A. et a!. Antiproteinuric effect of niceritrol, a nicotinic add derivative, in chronic renal disease with hyperlipidemia: a randomized haemorrhage. Available in The Cochrane Database of Systematic pain, was significantly reduced in patients with stable Am 1 Med 114: Reviews; Tssuc 3. Chichester: John Wiley; 2007 {accessed 25/07/08). trial. 2003; 347-53. angina at high risk of future adverse events. Mortality 3. Amenta F, et a!. Nicardipine use in cerebrovascular disease: a review of may also be reduced.2 Nicorandil may mimic the mechan­ 283: controlled clinical studies. J Neurol Sci 2009; 219-2 3. epa t ons ism of ischaemic pre�conditioning, whereby a brief period 4. Barth M, et al. Effect of nicardipine prolonged-release implants on P.r. m i of ischaemia makes the myocardium resistant to damage cerebral vasospasm and clinical outcome after severe aneurysmal ProprietaryPreparations (details are given in Volume B) subarachnoid hemorrhage: a prospective, randomized, double-blind from a further episode, 3 but it is not clear how much this phase Ira study. Stroke 2007; 38: 33()-..6. Single-ingredient Preparations. Jpn: Perycit. mechanism contributes to its effects. There is some evi­ 5. Krischek B, et a!. Nicardipine prolonged-release implants for preventing dence4-9 that nicorandil improves outcomes when given at cerebral vasospasm after subarachnoid hemorrhage: effect and outcome in the first 100 patients. Neural Med Chir (Tokyo) 2007; 47: 389-94. the time of percutaneous coronary intervention, although o 6. Goodson K. et al. Intraventricular nicardipine for refractory cerebral a large studyr in patients with myocardial infarction failed vasospasm after subarachnoid hemorrhage. Neurocrit Care 2008; 8: 247- to confirm a benefit. It has been suggested6 that an antoxi­ 52. dant effect may be part of the mechanism involved. 7. Tejada JG, et al. Safety and feasibility of intra-arterial nicardipine for the treatment of subarachnoid hemorrhage-associated vasospasm: initial I. The IONA Study Group. Effect of nicorandil on coronary events in clinical experience with high-dose infusions. A1NR Am 1 Neuroradiol patients with stable angina: the Impact Of Nicorandil in Angina (IONA) 2007; 28: 844-8. randomised trial. Lancet 2002; 359: 1269-75. Correction. ibid.; 360: 806. B. Reddy P, Yeh YC. Use of injectable nicardipine for neurovascular 2. Horinaka S, et al. JCAD Study Investigators. Effects of nicorandil on indications. Pharmacotherapy 2009; 29: 398-409. cardiovascular events in patients with coronary artery disease in the Japanese Coronary Anery Disease (JCAD) study. Circ l 2010; 74: 503-9. 3. Lesnefsky EJ. The IONA study: preparing the myocardium for Adverse Effects, Treatment, and Precautions ischaemia? Lancet 2002; 359: 1262-3. 4. Matsuo H, et al. Evidence of pharmacologic preconditioning during As for dihydropyridine calcium-channel blockers (see PTCA by intravenous pretreatment with ATP-sensitive K+ channel Nifedipine, p. 1450.2). opener nicorandil. Bur Heart 1 2003; 24: 1296-1303. 5. Ikeda N, et al. Nicorandil versus as adjunctive Nicomol is a derivative of, and has general properties similar treatment to direct balloon angioplasty in acute myocardial infarction. Interactions to, nicotinic acid (p. 2083.1) to which it is hydrolysed. It is Heart 2004; 90: 181-5. used as a lipid regulating drug in hyperlipidaemias, and as a 6. Ono H, et a!. Nicorandil improves cardiac function and clinical outcome As for dihydropyridine calcium-channel blockers (see vasodilator in the treatment of peripheral circulatory in patients with acute myocardial infarction undergoing primary Nifedipine, p. 1453.2). percutaneous coronary intervention: role of inhibitory effect on reactive disorders such as chilblains, Raynaud's syndrome, and limb oxygen species formation. Am Heart 1 2004; 148: EIS. arterial occlusive disease. The usual oral dosage is 600 to 7. Ishii H, et al. Impact of a single intravenous administration of nicorandil Pharmacokinetics 1200 mg daily in 3 divided doses after food. before reperfusion in patients with ST-segment-elevation myocardial infarction. Circulation 2005; 112: 1284-8. Nicardipine is rapidly and completely absorbed from the 8. Ishii H, et al. Effects of intravenous nicorandil before reperfusion for gastrointestinal tract but is subject to saturable first-pass Preparations acute myocardial infarction in patients with stress hyperglycemia. hepatic metabolism. Bioavailability of about 35% has been Diabetes Care 2006; 29: 202-6. Proprietary Preparations (details are given in Volume B) reported after a 30-mg dose at steady state. The 9. Iwakura K, et at. Nicorandil treatment in patients with acute myocardial infarction: a meta-analysis. Circ J 2009; 73: 925�31. pharmacokinetics of nicardipine are non -linear due to the Single-ingredient Preparations. Jpn: Cholexamin. 10. Kitakaze M, et al. J-WIND investigators. Human atrial natriuretic peptide saturable first-pass hepatic metabolism and an increase in and nicorandil as adjuncts to reperfusion treatment for acute myocardial dose may produce a disproportionate increase in plasma infarction (J-WIND): two randomised trials. Lancet 2007; 370: 1483-93. concentration. There is also considerable interindividual variation in plasma-nicardipine concentrations. Nicardipine Adverse Effects and Precautions is more than 95% bound to plasma proteins. Nicardipine is extensively metabolised in the liver and is excreted in the Adverse effects reported with nicorandil are headache urine and faeces, mainly as inactive metabolites. The (which is usually transitory and seen at the start of therapy), terminal plasma half-life is about 8.6 hours, thus steady­ cutaneous vasodilatation and flushing, nausea, vomiting, state plasma concentrations occur after 2 to 3 days of dosing dizziness, and weakness. Rarely reported effects include three times daily. myalgia, rashes, and oral ulceration, and there have been References. very rare reports of angioedema and hepatic function 1. Graham DJM, et a!. Pharmacokinetics of nicardipine following oral and abnormalities. A reduction in blood pressure and/or an intravenous administration in man. Postgrad Med 1 1984; 60 (suppl 4): 7- increase in heart rate may occur with high doses. 10. Nicorandil is contra-indicated in patients with cardia­ BP 2014: (Nicorandil). A white crystalline powder. 2. Graham DJM, et al. The metabolism and pharmacokinetics of genic shock, left ventricular failure with low filling nicardipine hydrochloride in man. Br J Clin Pharmacal 1985; 20: 23S- Sparingly soluble in water; freely soluble in alcohol and in pressures, and hypotension. In patients with hypovolaemia, 28S. methyl alcohol. Store in airtight containers at a temperature low systolic blood pressure, acute pulmonary oedema, or 3. Razak TA, et al. The effect of hepatic cirrhosis on the pharmacokinetics of 2 degrees to 8 degrees. and blood pressure response to nicardipine. Clin Pharmacal Ther 1990; 47: acute myocardial infarction with acute left ventricular 463-9. failure and low filling pressures, nicorandil should 4. Porchet HC, Dayer P. Serum concentrations and effects of (±)­ nicardipine compared with nifedipine in a population of healthy Uses and Administration preferably be avoided but may be used with caution. subjects. Clin Pharmacal Ther 1990; 48: 155-60. Nicorandil is a nitrate derivative of nicotinamide (p. 2083.1) and acts as a vasodilator. It is a potassium-channel opener Incidence of adverse effects. Postmarketing surveillance P epa a ons for nicorandil was carried out by prescription-event moni­ ..r...... r....t.i. . . . . (p. 1245.2) providing vasodilatation of arterioles and large ...... toring1 of 13 620 patients, and showed that adverse reac­ Proprietary Preparations (details are given in Volume B) coronary arteries and its nitrate component produces venous vasodilatation through stimulation of guanylate tions occurred in 175. The most frequent was headache, Single-ingredient Preparations. Belg.: Rydene; China: A Fa Duo cyclase. It thus reduces both preload and afterload, and occurring in 58 patients, mainly in the first month of (1Jl!J;5f'); (!Jlil'T); Xin (''li'!$r!X); Bei Er Ping Bei Li Ning Ka improves coronary blood flow. treatment. Unspecified adverse effects occurred in 36 Ni Ya Ka Shu Tai Perdipine (11\!J;); Xian Li (i'!tliJ!i); (-HiHl'); Nicorandil is given orally for prevention and long-term patients. Other effects included dizziness ( 19 patients), ({Wil); Xin Shu Li Da (IV:!il'}J±5); Yu Luo Tong Fr.: (liif�il!i); treatment of angina pectoris, including reduction of the nausea ( 17 patients), malaise (13 patients), palpitations (8 Loxen; Ger.: Antagonilt; Indon.: Blistra; Perdipine; !tal. : Bioni­ patients), flushing and vomiting (6 patients each), and las­ card; Cardiotent; Cardipt; Lisanirc; Nicapresst; Nicardal; Nicar­ risk of acute coronary events in high-risk patients I situde (4 patients). Rare adverse effects included 3 cases Jp n: Malaysia: (p. 12 54.3). The usual initial oral dose is 0 mg twice daily pint; Nicaven; Perdipina; Vasodin; Perdipine; each of angioedema and photosensitivity. Cardepine; Neth.: Cardene; Philipp. : Cardepine; Perdipine; (or 5 mg twice daily in patients susceptible to headache), 1. Dunn N, et al. Safety profile of nicorandil-prescription-event Port.: Nerdipina; Singapore: Cardibloc; Spain: Dagan; Fluse­ increased as necessary to a maximum of 30 mg twice daily; monitoring (PEM) study. Pharmacoepidemiol Drng Safety 1999; 8: 197- mide; Lecibral; Lincil; Lucenfalt; Nerdipina; Vasonase; Thai.: the usual therapeutic dose is in the range of 10 to 20 mg 205. Cardepine; Turk.: Loxen; UK: Cardene; USA: Cardene. twice daily. Nkorandil is also given intravenously in the manage­ Ulceration. Nicorandil has been associated with ulceration unstable angina acute heart failure ment of and of mucosal surfaces. Painfut large aphthous ulcers on the Niceritrol (BAN, r!NN) (p. 1262.3). For unstable angina, a solution containing 100 tongue and oral mucosa have been reported1·3 in patients to 300 micrograms/mL is given by intravenous infusion in a receiving nicorandil for angina. The ulcers were usually dose of 2 mg/hour, adjusted according to response, to a resistant to treatment but all healed when nicorandil was maximum dose of 6 mg/hour. For acute heart failure, a withdrawn. Colchicine or thalidomide treatment has solution containing 400 to 2 500 micrograms/mL is used; the improved ulcers associated with nicorandil in a few usual dose is 200 micrograms/kg given by intravenous patients, but relapse occurred when the colchicine or tha­ injection over 5 minutes, followed by continuous intra­ lidomide was stopped. 3 However, a large study4 casts some venous infusion at a dose of 200 micrograms/kg per hour. doubt on the evidence for a causal link between nicorandil The dosage should be adjusted according to response, within and oral ulceration, although it was suggested that this the range of 50 to 200 micrograms/kg per hour. could be further investigated. NOTE. The synonym PETN has been applied to both niceritrol General references. Anal ulceration has been reported5-7 in patients taking and pentaerithrityl tetranitrate. l. Markham A, et al. Nicorandil: an updated review of its use in ischaemic nicorandil. Healing of the ulcers occurred in those patients Drugs heart disease with emphasis on its cardioprotective effects. 2000; in whom nicorandil was withdrawn. Pharmacopoeias. In Jp n. 60: 955-74. 2. Gomma AH, et at. Potassium channel openers in myocardial ischaemia: Multiple ulcers of the upper and lower gastrointestinal therapeutic potential of nicorandil. Drugs 2001; 12: 1705-IO. tract, in addition to oral and anal ulceration, have been Profile 3. Anonymous. Nicorandil for angina - an update. Drng Ther Bull 2003; 41: reported8 in a patient taking nicorandil; all of the ulcers Niceritrol, an ester of pentaerythritol and nicotinic add, has 86-8. healed when nicorandil was stopped. There have also been 4. Simpson D, Wellington K. Nicorandil: a review of its use in the general properties similar to those of nicotinic acid several cases of peristomal ulceration, which resolved after f ngina pectoris, including high-risk patients. 1 (p. 2083.1 ), to which it is slowly hydrolysed. Niceritrol has �r:�;;�����4� 1 ��i�� 5� stopping nicorandil. 9

All cross-references refer to entries in Volume A