Urapidil

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Abstract
Urapidil is a peripheral postsynaptic α1-adrenoceptor antagonist with central agonistic action at serotonin 5-HT1a receptors. It reduces blood pressure by decreasing peripheral vascular resistance. Oral urapidil decreases blood pressure in patients with mild to moderate essential hypertension and associated risk factors such as hyperlipidaemia or type 2 (non-insulin-dependent) diabetes mellitus with no effect on heart rate. The antihypertensive efficacy of urapidil is similar to that of most comparators in patients with mild to moderate essential or secondary hypertension and no concomitant risk factors. However, the antihypertensive efficacy of urapidil was lower than that of hydrochlorothiazide in a well designed trial. Lipid levels and glucose metabolism are not adversely affected and may improve with urapidil in patients with lipid or glucose abnormalities. Urapidil can be safely combined with other antihypertensive agents such as hydrochlorothiazide and nifedipine and improves blood pressure control in previous nonresponders to monotherapy. Intravenous urapidil reduces blood pressure in patients with pre-eclampsia or hypertension in pregnancy and in patients with hypertensive crises or peri- or postoperative hypertension. The decrease in blood pressure is similar to that observed after nifedipine, enalaprilat, sodium nitroprusside and dihydralazine, greater than that of ketanserin according to 1 larger study, and greater than that of sublingual nitroglycerin in 1 trial in patients with nonsurgical hypertensive crises and pulmonary oedema. However, more patients responded to treatment with urapidil than with enalaprilat or nifedipine. Heart rate is less likely to be altered by urapidil than with some comparator drugs. Urapidil appears to be well tolerated, with most adverse events being mild and transient. The incidence of adverse events with urapidil is similar to that with prazosin, metoprolol, atenolol, sodium nitroprusside and hydrochlorothiazide and less than that with nifedipine and clonidine. Urapidil may not be as well tolerated as captopril and, in 1 study, more urapidil than nitrendipine recipients discontinued treatment because of adverse events. Conclusions. Urapidil reduces blood pressure without altering heart rate. The oral formulation is an effective choice in patients with hypertension and concomitant dyslipidaemia or type 2 diabetes mellitus, in whom the drug does not adversely affect and may improve lipid profiles and glucose metabolism. The intravenous formulation is effective in controlling various hypertensive crises and hypertension associated with pregnancy or surgery and is similar to or better than other first-line agents used in these conditions. Thus, urapidil may be a useful alternative to currently available antihypertensive agents. Urapidil decreases peripheral vascular resistance and thus lowers blood pressure, with no significant effect on heart rate. These effects were similar to those observed after clonidine, isosorbide dinitrate, sodium nitroprusside and ketanserin. Intravenous urapidil reduced preload (pulmonary capillary wedge pressure and pulmonary artery pressure) and afterload (systemic vascular resistance) in patients with peri- or postoperative hypertension, thus improving cardiac index and cardiac output. The haemodynamic effects were similar to those of sodium nitroprusside and isosorbide dinitrate but possibly greater than those of ketanserin. However, heart rate tended to increase more consistently after sodium nitroprusside and ketanserin than after urapidil. Urapidil does not have a detrimental effect on lipid profiles or glucose metabolism and may favourably influence these parameters in patients with dyslipidaemia or type 2 (non-insulin-dependent) diabetes mellitus. Urapidil decreases total renal vascular resistance, therefore increasing renal perfusion in patients with mild hypertension and normal renal function. This was not observed in patients with moderate to severe hypertension and normal renal function or in patients with impaired renal function. However, urapidil was not associated with any further deterioration in renal function in hypertensive patients with existing renal impairment. In 1 trial the preservation of renal perfusion was better after ketanserin than urapidil in patients with hypertension and normal renal function undergoing cardiopulmonary bypass surgery. The effects of urapidil on arterial oxygenation are unclear. Similarly, recent, albeit limited, evidence contradicts earlier data supporting a lack of effect on intracranial pressure. Urapidil improved the echocardiographic features of left ventricular structure in small noncomparative trials in patients with mild to moderate hypertension. However, in 1 additional trial, urapidil did not reduce left ventricular posterior wall thickness, whereas this effect was observed after methyldopa. Urapidil may have greater effects on fibrinolysis than atenolol, as shown in 1 trial. The pharmacokinetic parameters of urapidil are similar after oral and intravenous administration. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) are linearly proportional to dosage. After a single dose of oral urapidil (15 to 60mg), Cmax (0.14 to 0.65 mg/L) is achieved in 0.5 to 6 hours (tmax), as shown in young, healthy volunteers. The absolute bioavailability of oral controlled-release urapidil relative to the intravenous formulation is 72%. The apparent volume of distribution (Vd) of intravenous urapidil is 0.59 to 0.77 L/kg and 75 to 80% of the drug is bound to plasma protein. Urapidil crosses the blood-brain barrier: in 6 patients with intact blood-brain barriers, the maximum concentration in the cerebrospinal fluid (0.023 to 0.175 mg/L) was achieved in 0.5 to 3 hours. A large proportion of the urapidil dose is eliminated via the renal route (50 to 70%); 10 to 15% of the dose is excreted as unchanged drug and the remainder as 1 major inactive (aryl-p-hydroxylated urapidil) and 2 minor active (O-demethyl-ated urapidil and uracil-N-demethylated urapidil) metabolites. The total body clearance of intravenous urapidil is 0.11 to 0.23 L/kg/h and the elimination half-life (t½) of oral and intravenous urapidil ranges from 2 to 4.8 hours. The pharmacokinetic parameters of urapidil were generally unchanged in patients with varying degrees of renal failure in most single-dose studies. However, the t½ of single-dose oral urapidil was longer in patients undergoing dialysis. Furthermore, the clearance of single-dose intravenous urapidil was slightly reduced in 1 study of patients with moderate or severe renal impairment compared with healthy volunteers and hypertensive patients with normal renal function. The t½ of urapidil increases in patients with severe liver impairment by several-fold (to about 15 hours) after a single dose and in elderly patients by about 2-fold after single intravenous or oral doses. Urapidil does not appear to influence the rate or extent of absorption of digoxin. Coadministration of cimetidine with urapidil increases the AUC of urapidil, increases the amount of unchanged urapidil recovered in the urine and decreases the urinary excretion of the major metabolite. However, the total amount of drug-related compounds in the urine is not altered. Oral Therapy. As shown in short term studies (6 to 26 weeks) urapidil (30 to 180 mg/day) reduces diastolic and systolic blood pressure in patients with mild to moderate essential or secondary hypertension and with or without concomitant cardiovascular risk factors such as hyperlipidaemia or type 2 diabetes mellitus. The antihypertensive efficacy of urapidil was similar to that of nitrendipine (20 mg/day) in patients with no concomitant risk factors. However, comparisonswith hydrochlorothiazide (≤50 mg/day) in these types of patients were not consistent: urapidil had a similar or, in a larger trial, a lower efficacy than hydrochlorothiazide. Heart rate was not significantly altered by any agent. Combining urapidil (30 to 120 mg/day) with nifedipine (40 mg/day) or hydrochlorothiazide (25 mg/day) for 4 to 12 weeks effectively decreased diastolic and systolic blood pressure in patients with mild to moderate essential hypertension and no concomitant risk factors who were unresponsive to monotherapy with the above agents. In the largest study, urapidil plus nifedipine was similar in efficacy to metoprolol plus nifedipine. However, in the subgroup of elderly patients (>60 years) the reduction in diastolic and systolic blood pressure was greater after urapidil than metoprolol. Intravenous Therapy. Urapidil decreases systolic and diastolic blood pressure in patients with hypertensive crises. Mean blood pressure reductions with urapidil (12.5 to 75mg) were at least as great as those with intravenous enalaprilat (5mg), sublingual nifedipine capsules or spray (10mg), sublingual nitro-glycerin (glyceryl trinitrate) [0.8 to 3.2mg] and intravenous sodium nitroprusside (≤3 μg/kg/min). The percentage of patients responding to urapidil was greater than that in the enalaprilat or nifedipine groups and similar to that in the sodium nitroprusside group. However, blood pressure increased within 4 hours in more sodium nitroprusside than urapidil recipients. Furthermore, blood pressure control was achieved faster after urapidil than after nifedipine or nitroglycerin. In a limited number of studies, urapidil decreased diastolic and mean arterial pressure in women with pre-eclampsia or severe hypertension in pregnancy, and was similar in efficacy to intravenous dihydralazine. Similarly, systolic and diastolic blood pressure was reduced by urapidil in patients with peri— or postoperative hypertension during coronary artery bypass graft surgery. The antihypertensive efficacy of urapidil was better than that ofintravenous ketanserin according to a large well-designed trial and similar to that of intravenous sodium nitroprusside. In addition, treatment failure occurred less often in urapidil recipients than in patients receiving sodium nitroprusside and to a similar or lesser extent than in ketanserin recipients. In a single, small study urapidil decreased systolic and diastolic blood pressurebefore clamping of the abdominal aorta and prevented an increase during clamping to a similar extent to isosorbide dinitrate in patients undergoing surgery of the abdominal aorta. The majority of adverse events occurring during urapidil therapy are mild and transient, usually subsiding after long term treatment. The most common events reported during oral or intravenous therapy are dizziness, nausea and headache. Adverse events associated with intravenous urapidil are usually due to a too rapid decrease in blood pressure. In short term (up to 12 weeks) studies, the incidence of adverse events after oral urapidil (30 to 180 mg/day) was similar to that with oral prazosin, metoprolol, atenolol and hydrochlorothiazide and less than that with nifedipine and clonidine. However, urapidil did not seem to be as well tolerated as captopril. Treatment discontinuation because of adverse events occurred in a larger number of urapidil than nitrendipine recipients. The incidence of adverse events with intravenous urapidil was similar to that with intravenous sodium nitroprusside. However, hypotension occurred more frequently in sodium nitroprusside than in urapidil recipients. In contrast, hypotension was more common after urapidil than after intravenous ketanserin. Early combination studies of urapidil with β-blockers and thiazide diuretics and a more recent study combining urapidil with nifedipine did not highlight any new adverse events compared with monotherapy with urapidil. The incidence of adverse events with combination therapy with urapidil plus nifedipine was similar to that with metoprolol plus nifedipine. Intravenous urapidil in women with pre-eclampsia or severe hypertension in pregnancy was not associated with any apparent adverse effects on the fetus. In general, urapidil did not adversely influence laboratory parameters. However, in a small number of early studies changes in serum electrolyte, uric acid, cholesterol, hepatic enzyme and creatine kinase levels and in the eosinophil count have been observed with no significant clinical effect. The combination of urapidil with thiazide diuretics may alter some laboratory values. Intravenous urapidil is indicated for the management of hypertensive crises, severe or treatment-resistant hypertension and peri- or postoperative hypertension. The initial dose for hypertensive crises or severe or treatment-resistant hypertension is 10 to 50mg as a bolus. A second 50mg dose can be administered if no effect is observed within 5 minutes. Alternatively, a continuous infusion of urapidil can be administered at an initial rate of 2 mg/min and a maintenance infusion of 9 mg/h. To control peri- or postoperative hypertension, an initial bolus dose of 25mg can be repeated after 2 minutes and increased to 50mg after another 2 minutes if there is no response. The maintenance infusion is initiated with 6mg over 1 to 2 minutes but can then be reduced according to response. Intravenous administration should not exceed 7 days. Oral urapidil is indicated for the management of mild to moderate essential hypertension. The initial dose is 30 to 60mg twice daily taken with meals and the maintenance dose ranges from 30 to 90mg twice daily. Doses should be reduced in elderly patients and in patients with liver or severe renal impairment. However, recommended dosage guidelines in these groups of patients were not provided. Contraindications to urapidil include sensitivity to any of the ingredients, aortic isthmus stenosis or arteriovenous shunt (excluding haemodynamic noneffective dialysis shunt) and lactation. Urapidil should be prescribed in pregnancy only after assessing the benefits versus the risks of treatment. Urapidil may affect the ability to drive or handle machinery and caution is recommended, particularly in the early stages of treatment.