Nisoldipine

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Abstract
Nisoldipine is an orally administered calcium entry blocking drug structurally related to nifedipine. In limited clinical trials it has been shown to be effective and relatively well tolerated in the treatment of patients with chronic stable angina pectoris and mild to moderate essential hypertension. As for all dihydropyridine-calcium antagonists, its major properties include potent peripheral and coronary vasodilation and improvement in myocardial oxygen supply relative to demand. These attions occur without depression of cardiac conduction or left ventricular function. Short term clinical trials have shown nisoldipine to produce both symptomatic and objective improvements in patients with chronic angina of effort and have suggested a benefit in vasospastic angina. A small number of comparative trials indicate that nisoldipine is equally as effective as nifedipine. In addition, in combination with β-adrenoceptor blockade nisoldipine appears to offer additional benefit compared with β-blockade alone and is well tolerated. In patients with mild to moderate essential hypertension nisoldipine monotherapy, in 1 or 2 daily doses, has maintained blood pressure control and has also been a useful addition to diuretics and β-adrenoceptor blocking drugs in patients with poorly controlled disease. Side effects appear to be dose related, generally mild and transient, and are primarily those resulting from potent peripheral vasodilation — headache, flushing and pretibial or ankle oedema. Although studies to date are promising, there are no published long term studies (>1 year) of nisoldipine in comparison with other calcium entry blockers and other drugs currently in clinical use for the treatment of angina pectoris or hypertension. Until such studies are completed the exact place of nisoldipine in the treatment of these diseases remains to be established. Nisoldipine, in common with other calcium entry blocking drugs, inhibits the inward movement of calcium ions through slow channels in the cardiac tissue and vasculature. Although myocardial contractility is inhibited in vitro, in humans this negative inotropic activity is offset by reflex haemodynamic changes in response to coronary and peripheral vasodilation. Oral doses of nisoldipine in hypertensive individuals produce dose-related decreases in systolic and diastolic blood pressure with peak effects occurring 1 to 3 hours after a single dose and persisting for at least 6 hours. Associated increases in heart rate have been variable and are generally less pronounced during exercise than at rest. Tachycardia has not been observed with long term treatment. The primary haemodynamic effect of nisoldipine is peripheral vasodilation which induces reflex sympathetic activation resulting in an increase (up to 40% and 42% for cardiac output and index, respectively) in cardiac pumping activity. While afterload reduction, ranging from decreases in systemic vascular resistance of 17 to 54%, is paramount, a probable indirect effect on preload is also evident, as demonstrated by reductions in left ventricular end diastolic pressure and pulmonary capillary wedge pressures in some patients. A net increase in stroke volume and/or left ventricular ejection fraction results in improved left ventricular function which is maintained on long term therapy. In comparison with intravenous nifedipine, intravenous doses of nisoldipine which produce equivalent reductions in systemic vascular resistance produce no cardiodepressant effects, probably due to a greater vascular specificity which allows significant haemodynamic effects at lower doses than those which inhibit myocardial contractility. In addition, nisoldipine has higher affinity binding to inactivated calcium channels, a slower dissociation and a large partition coefficient, resulting in a longer duration of therapeutic action than nifedipine. The combination of single intravenous doses of nisoldipine and metoprolol has produced a reduction in blood pressure and decreased systemic vascular resistance while increasing cardiac index and stroke volume index. The heart rate decrease seen with metoprolol is normalised by the addition of nisoldipine. Conversely, increases in resting heart rate observed after nisoldipine monotherapy are abolished when the drug is given in combination with metoprolol, while increases and decreases in cardiac and stroke volume indexes, and systemic vascular resistance, respectively, are maintained. In patients with proven cardiovascular disease nisoldipine produces significant coronary vasodilation and reduction in coronary vascular resistance without changing myocardial oxygen consumption. Although dilation in the peripheral vasculature appears to be greater and more prolonged than in the coronary vasculature, the latter effect is still significant with reported reductions in coronary vascular resistance and increases in coronary blood flow of up to about 50% with intravenous doses of nisoldipine. Blood distribution to ischaemic myocardial tissue is improved by nisoldipine with a concomitant increase in oxygen supply and a reduction in anaerobic glycolysis. Improvement in left ventricular function resulting from increased coronary collateral perfusion and tissue oxygenation has been maintained in patients with angina pectoris during short term studies. Although animal studies have shown that nisoldipine can limit infarct size and incidence of reperfusion arrhythmias if given before or immediately after coronary occlusion, the cardioprotective effects of nisoldipine after acute myocardial infarction in humans are unknown. Other pharmacological effects of single doses of nisoldipine include a direct diuretic action, but this renal effect appears to be compensated during long term administration. Plasma renin and aldosterone concentrations are variably affected by nisoldipine and appear to be minimally altered by long term therapy. The effect of the drug on plasma lipids has been minimal, but potentially beneficial effects on high density lipoprotein and apoprotein A concentrations were reported in 1 study. Nisoldipine has been shown to inhibit platelet aggregation in both in vitro and small in vivo studies. An increase in epinephrine (adrenalin)-induced platelet aggregation has also been demonstrated and persists after abrupt drug withdrawal, possibly accounting for the myocardial ischaemia observed in some patients when nisoldipine and other calcium entry blocking drugs are abruptly discontinued. The pharmacokinetic properties of nisoldipine have been studied in mostly single-dose trials employing healthy volunteers and patients with hypertension or renal or hepatic dysfunction; the effects of other cardiovascular diseases and long term therapy on the pharmacokinetic profile of nisoldipine are as yet unknown. Studies to date have shown that nisoldipine is well absorbed after oral dosing with peak plasma concentrations reached in about 1.5 hours. Both plasma concentration and area under the plasma concentration-time curve (AUC) are dose dependent. Nisoldipine has a low systemic bio-availability (3.7 to 8.4%) due to extensive presystemic metabolism. The effect of food on these parameters appears to be minimal, and no accumulation of nisoldipine has occurred in hypertensive patients receiving oral doses of the drug twice daily for 4 weeks. The volume of distribution after an intravenous bolus dose of nisoldipine has been reported to be 1.6 to 5.9 L/kg and at steady-state during intravenous infusion 2.3 to 7.1 L/kg. Unbound fraction of the drug in humans has been calculated to be 0.27%, indicating high protein binding. In addition, the drug has a large volume of distribution, indicating that nisoldipine penetrates well to the tissues; however, its specific tissue distribution profile has yet to be elucidated. Nisoldipine is rapidly and extensively removed by hepatic first-pass metabolism and at least 5 and up to 18 metabolites have been demonstrated; however, the total number of metabolites identified in plasma and their contribution to the pharmacological activity of nisoldipine are unknown. Intravenous nisoldipine clearance values have ranged from 0.5 to 0.95 L/h/kg. Recovery of nisoldipine plus metabolites after a single oral dose of nisoldipine administered to healthy volunteers has been reported as 70 to 74% in urine and 6 to 12% in faeces. The corresponding values after an intravenous dose were 80 to 82% and 14%, respectively. The half-life of elimination of nisoldipine has ranged from 2 to 15 hours with the larger values reported in studies employing more sensitive detection procedures. Liver dysfunction appears to increase systemic availability, reduce clearance, and prolong the elimination half-life of the drug, making dosage reduction desirable in such patients. The effect of renal dysfunction on the pharmacokinetics of nisoldipine appears to be minimal but caution should be exercised in such patients until further studies have been completed. In patients with chronic stable angina pectoris single doses of nisoldipine have increased exercise tolerance by 11 to 59% and reduced the degree of ST segment depression by 23 to 70%. Time to onset of angina and ST segment depression have been increased by 20 to 25% and 20 to 60%, respectively. Changes have been dose related with optimal results reported after oral doses of 10 to 20mg. These effects have been reported to last 7 to 8 hours and are not accompanied by significant changes in blood pressure or heart rate. In placebo-controlled trials of 2 to 6 weeks’ duration and in one 12-month uncontrolled study, the acute antianginal effects of nisoldipine have generally been maintained and the incidence of both anginal attacks and nitrate consumption have been reduced. The antianginal activity of nisoldipine has been comparable to that of nifedipine and oral or sublingual nitrates in short term trials. Verapamil (360 mg/day) was more effective than nisoldipine (20 mg/day) in reducing ST segment depression at a fixed workload 3 hours after administration, but the difference had diminished by 7 hours. In combination with β-adrenoceptor antagonists, nisoldipine generally produces significant increases in exercise tolerance and reduces the number of anginal episodes from those observed with β-blocker monotherapy. In several open and placebo-controlled trials in patients with mild to moderate hypertension the antihypertensive efficacy of nisoldipine has been maintained for periods up to 1 year. Patients have generally responded to 10 to 20mg of nisoldipine daily, with a drop in systolic and diastolic blood pressures of 23 to 30mm Hg and 15 to 17mm Hg, respectively; furthermore, these effects have been achieved without significant effects on heart rate. In a crossover comparison with nifedipine, each administered for 8 weeks, nisoldipine was equally effective in antihypertensive activity. In a parallel study nifedipine (40 mg/day) and nisoldipine (2.5 to 20 mg/day) both had a significant effect on blood pressure but nifedipine normalised pressure in more patients at the doses used in that study. A few non-controlled trials have demonstrated a beneficial antihypertensive effect of nisoldipine in patients with hypertension and renal impairment without a worsening of renal function. Further comparative studies with diuretics, and studies involving other calcium antagonists and other drugs commonly used in the treatment of hypertension are necessary before an adequate assessment of the relative place of nisoldipine in this disease state can be gained. In patients with congestive heart failure nisoldipine has provided improvement in left ventricular function and clinical symptoms in several small short term trials. However, some patients with severe disease and associated angina developed pulmonary oedema and deteriorated clinically. It appears that, like other calcium entry blockers, nisoldipine will benefit some, but not all, patients with congestive heart failure. Finally, a preliminary study has demonstrated subjective improvement in patients with idiopathic Raynaud’s phenomenon. Side effects of treatment with nisoldipine appear to be relatively minor, transient in nature and dose related, disappearing after the first few weeks of therapy. The most common side effects in patients with cardiovascular disease are due to marked peripheral vasodilation — headache (9 to 14% of patients), flushing (13%) and peripheral oedema (4 to 7%), although in patients with hypertension the frequencies of these adverse effects may be higher. Occasionally, headache and oedema have been severe and have necessitated drug withdrawal in a few patients. Other cardiovascular effects such as palpitations and hypotension have not been severe and gastrointestinal and neurological effects have occurred infrequently. The abrupt withdrawal of nisoldipine after 6 weeks of therapy induced severe unstable angina in 3 of 15 patients in 1 study. In adults with stable angina pectoris, hypertension or congestive heart failure the usual oral daily dose is 10 to 20mg given in 2 equally divided doses. Some patients will require an increase in dosage to a maximum of 40 mg/day. Administration with food may minimise side effects. Patients with liver dysfunction may require reduced dosages of the drug, and abrupt withdrawal of nisoldipine treatment is not recommended in patients with angina pectoris as myocardial ischaemia has been precipitated in a few patients.