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Overview of clinical trials with urapidil
Overview of Clinical Trials with Urapidil C. Edward Schook, MD, Heinz Radtke, MD, Wilhelm Wurst, MD, and Gisela Thieme, MD
Urapidil has been approved as sustained-release capsules containing 30,50 and 50 mg, respectively, and as ampules containing 25 and 50 mg for treatment of all grades of hypertension, in several countries in Europe, South America, as well as in Japan and other Asian regions. In general, the treatment shoukl start with 50 mg twice daily, 1 capsule in the morning and 1 in the evening. This schedule may be adapted according to the therapeutk needs. During the last few years, urapidil has been investigated extensively in comparison with several types of established antihypertensive drugs. Urapidil given orally has been tested in comparative trials against placebo, acebutold, metoprold, captopril, nifedipine and nitrendipine with responder rates of 40 to 70%. These responder rates are to be expected for a variety of antihypertensive drugs in monotherapy. Further studiis with clonidine, praxosin and a-methyldopa showed similar responder rates as establlshed for the other antihypertensive drugs studied. Adverse reactions include dizziness, headache and nausea and occasiionally tiredness, orthostatic dysregulatkm and gastric disorders. These symptoms were transient, mostly occurring during the early phases of therapy and disappearing as treatment continued. Adverse effects are considered to be mainly due to blood pressure reduction. Intravenous comparative trials have been performed with urapldil against placebo, diaxoxide and sodium nitroprusslde. Adverse effects of parenterally applied urapidil are similar to those observed during oral treatment. 5pecDlc contraindkzitions for urapidil are unknown. However, as for other vasodilating drugs, intravenous urapidil should not be administered to patients with steno& of the aortic isthmus or with aortic valve insufftciency. (AmJCardid 1989;64:30D-37D)
he antihypertensiveactivity of urapidil is explained by peripheral at-adrenoceptor blockade and also by additional central hypotensive activity, both leading to a decreasein systemic vascular resistance.‘J The centrally mediatedcomponentof urapidil’s hypotensive action may be explained by the drug’s ~-HTIA agonistic activity.lT3g4Urapidil has been approved as sustained-release capsules containing 30, 60 and 90 mg, respectively,as well as ampulescontaining 25 and 50 mg in several European, South American and Asian countries. The most relevant indication for oral urapidil is long-term treatment of all gradesof hypertension,whereas the intravenous (i.v.) formulation is usedfor the management of hypertensive crisis and perioperative hypertension. For the urapidil-induced hemodynamic changes in humans, the reader is referred to the review by Bielen et al2 and de Leeuw5 in this supplement. This report reviews the most relevant clinical trials of urapidil that have beenperformed in hypertensivepatients and in hypertensiveemergenciesduring the last few yearsin different countries. The efficacy, safety and tolerability of urapidil will be described in comparison with those of other, establishedantihypertensive drugs.
T
URAPIDIL-ORAL APPLICATION Comparative studies: The therapeutic efficacy and
tolerability of urapidil wasinvestigatedin 11 randomized double-blind studies.6-16All studies were conducted on the basis of the following general protocols: Study design: The studiesweredesignedasambulatory, singleor multicenter, double-blind, randomizedparallel-group trials. One trial had a crossoverdesign.*t After a washout or a placebo period of 1 to 2 weeks,or both, patients were randomly assignedto individual treatment groups. Active treatment was performed over 3 to 12 weeks.A placebophaseprecededthe termination of some of the studies. Inclusion criteria: The ambulatory hypertensive patients studied were of either sex and had essential or secondaryhypertension,or both, and diastolic blood pressureranging from 95 to 120mm Hg (meanvalue of triple measurementin the supine position after 5 minutes of rest). In a few studies*0J2-14 diastolic blood pressurevaluesto 130 mm Hg were allowed. The age of the patients was between 20 and 80 years. Exclusion criteria: Exclusion criteria were:malignant hypertension, marked pathologic electrocardiographic changes,aortic valve stenosis,Conn’s syndrome, renal From the Clinical Research Department, Byk Nederland, Zwanen- damage, severe liver disease,neurologic or psychiatric burg, The Netherlands. Addressfor reprints: C.E. Schook,MD, Clinical ResearchDepart- diseases,pregnant and nursing women, antihypertensive ment, Byk Nederland, Weerenweg 29, 1161 AG Zwanenburg, The medication other than the test drug, and malignant disorNetherlands. ders. 30D
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
Blood pressure and heart rate measurement: Blood pressureand heart rate were determined with patients in both the supine and upright positions by triple measurement, after the patient had rested for at least 5 minutes. Blood pressure and heart rate were always measured before intake of the morning dose of urapidil (or reference drug) to obtain 1Zhour values. Various studies: Urapidil versusplacebo: Volpe et aI6 compared the antihypertensive effect and tolerability of urapidil, 60 mg twice daily, with placeboin 40 ambulant patients with essentialhypertension. After a baselineperiod of 2 weeksin which a placebowasadministeredtwice daily, the patients were randomized to one of the treatment groups.Baselinesupinediastolic blood pressurehad to be between 100 and 120 mm Hg before active treatment was begun. Blood pressure and heart rate were measured both during the placebo period and during the following 3 weeksof active treatment, at 4 and 12 hours after drug administration. Three patients treated with urapidil and 1 patient in the placebogroup withdrew from the study. The results with respectto the remaining 36 patients are listed in Table I. Mean supine systolic and diastolic blood pressures12 hours after drug intake decreasedfrom 157/106 to 142/ 89 mm Hg in the urapidil group and from 156/105 to 151/97 mm Hg in the placebo group after 3 weeks of treatment. The difference in diastolic blood pressuredecreasebetweenthe urapidil and placebo group were statistically significant (p
TABLE
Ill Comparative
TABLE I Effects of Urapidil(60
mg Twice Daily) Versus Placebo on Blood Pressure in 36 Hypertensive Patients*
u PL
SBP/DBP (mm 49
% RESP. Rate
Criteria
Before Treatment
After Treatment
(SUP. DBP 590 mm Hg)
lOch120 loo-120
157/106 156/105
142/89 151/97
60 25
* This was a double-blind. randomized. parallel group study. The period of treatment was 3 weeks. The differences I” diastolic blood pressure decrease between the urapidil and placebo groups were statistically significant (p
TABLE II Urapidil Versus Captopril in Antihypertensive Treatment*
U C
DBP
SBP/DBP
(mm &) Inclusion Criteria
(mm Hg) Before Treatment
SBP/DBP (mm f-k) After Treatment
% RESP. Rate (SUP. DBP 590 mm Hg)
95-120 95-l 20
175/103 175/103
154/89 154/90
62 58
*This was a double-blind. randomized. parallel group study in 295 patients. ment was for 12 weeks. C = captopril; other abbreviations as in Table I. Data adapted from Am J Cardiol.’
Studies Between Urapidil Versus Calcium Antagonists in Antihypertensive
n/T
Treatment
Dosage (w/day)
(mm W Inclusion Criteria
SBP/DBP (mm W Before Treatment
SBP/DBP (mm Hg) After Treatment
% RESP. Rate (SUP. DBP 590 mm Hg)
Slow release nifedipine*
168/12
u = 120 NIF = 40
95-120 95-120
168/102 170/103
158/91 151/90
43 57
Nitrendipinet
87/6
u = 120 NIT = 20
95-120 95-120
170/103 170/104
146/88 148/91
67 49
* Data adapted from Stumpe et al, 1989.0 t Data adapted from Winn, 1989.9 n = total number of patients; NIF = nifedlpine:
NIT = nltrendipine.
T = duration
Treat-
25 mg of captopril twice daily. After 2 weeks the dose could be adjustedaccording to the blood pressurevalues obtained. For further details of the study and results see the report by Rosenthal and Haerlin7 in this supplement and also Table II. Both antihypertensive drugs significantly reduced blood pressure(p
DBP Reference Drug
SBP/DBP (mm W
DBP (mm Hg) Inclusion
of treatment
period in weeks: U = urapldil: other abbreviations
as in Table I.
THE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 15, 1989
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A SYMPOSIUM: PHARMACOLOGIC AND THERAPEUTIC ASPECTS OF URAPIML
TABLE IV Comparative
Studies Between Urapidil and Beta-blocking
Drugs in Antihypertensive
Treatment
Dosage OWdaY)
DBP (mm H&9 Inclusion Criteria
SBP/DBP (mm f-k) Before Treatment
SBP/DBP (mm W After Treatment
% RESP. Rate (SUP. DBP 190 mm Hg) 80 60
Reference Drug
n/T
Acebutolol*
40/10
u=30-90 ACEB = 200-4W
lOc-130 100-130
167/107 164/107
l&I/87 147/92
Metoprololt
40/4
U = 60 MET0 = 200
100-120 LO&120
160/103 165/105
152/97 149/96
159/102 158/102
154/97 147/93
100-125 lCQ-125
164/109 167/111
150/96 M/94
23 4%
95-130 95-130
188/m 190/105
157/90 158/&?
60 87
U = 60 MET0 = 200 Atenolol*
W8
u = -120 ATEN = 50-100
Metipranolol§ + butizide
30/6
u=30-60 METI = 20-40 B = 2.5-5
* Dataadaptedfrom Tzincoca et al, 198~T~~ t Data adapted frQm Leoneti, et& 1986” * Data adaptedfrom Tdrdk eta/., 1988.12 5 Data adapted from ScfSfer. 1 98LL3 ACE6 = acebutolol; ATEN = atenolol; B = butazide;
METI = metipranolol;
MET0 = metoprolol;
release20-mg capsuletwice daily. Beforerandomization, there was a period of l-week washout and 1 week of placebotreatment. Two hundredninety-two patients pre senting with essential or secondary hypertension were admitted to the study. Patients were subjectedto active treatment for 12 weeks. Blood pressure,and heart rate were measured during the entire study before morning drug intake, i.e., approximately 12 hours after the last capsulehad been administered. Of 292 patients, 168 remained evaluablewith respectto blood pressureafter the subtraction of 86 protocol violators, 22 withdrawals for nonmedical reasonsor reasonsunrelated to the test drugs and 16 withdrawals. Of the 94 urapidil-treated patients, 3 withdrew becauseof insufficient efficacy and 10 because of adverseeffects.Accordingly, 81 subjectsconcludedthe study in accordance with the study protocol after 12 weeks of the drug phase. Of the 90 nifedipine-treated patients, 1 withdrew becauseof lack of efficacy and adverse effects, and 2 becauseof adverseeffects only. Accordingly, 87 patients remained in the study throughout the drug phase. Both drugs reduced blood pressuremarkedly and significantly (p 10.05). The reduction in systolicblood pressure from nifedipine was more pronounced than the reduction in diastolic,pressure.The difference betweenresponderrates (Table III) wasnot statistically significant. Heart rate during the entire study was lower in supine and standing patients in the urapidil- than in nifedipinetreated patients. In the secondstudy,9patients receivedeither urapidil (60 mg) in the morning and evening or nitrendipine (20 mg) in the morning and placebocapsulesin the evening. The design of the study was vir+ally the sameas that of the previous one with the exceptions of the number of patients, an active treatment phase of 6 instead of 12 weeks and a post-treatment phase of 2 weeks without therapy. In all, 89 patients were admitted to the study. Of those, 2 withdrew during the placebo run-in phase. 320
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
all other abbreviations
35 42
as in Tables I and Ill.
Table III lists the results of this study. In the 43 urapidil-treated patients, a mean supine diastolic blood pressureof 88 mm Hg was reached,which is below the “therapeutic goal” of 90 mm Hg, whereasin the nitrendipine group a mean value of 91 mm Hg was achieved. There was no difference between the 2 groups in blood pressure reduction. The responder rate in the urapidil group was 67% and that in the nitrendipine group 49%. More patients with an increasein pulse rate were found during the first 2 we& in the nitrendipine group than in those treated with urapidil. After 6 weeksof treatment there was no difference in pulse rate between the 2 groups. Urapidil versus beta blockers: Table IV lists the results of 4 randomized,double-blind trials of urapidil vs @ blockers.The metoprolol study by Leonetti et al” was a crossover investigation. The other studies1°J2J3had a parallel-group design. They all had a washout period with an active treatment period ranging from 4 to 10 weeks.This was followeil by a placeboperiod with the exceptionof the ateno101study. The metoprolol regimen had a 2-weekwashout period betweenthe 2 active phasesof 4 weeks.All studies included only patients with essential hypertension. The supine diastolic blood pressure at the beginning of the active treatment phaseranged from 95 to 130 mm Hg. The dosagesof the drugs (urapidil and the B blockers) varied. Only the urapidil dosein the metoprolol study was fixed. In the study by Schlfer,13 metipranolol was combined with butizide. In all 4 studies,a signficant decreaseof mean supine systolic as well as diastolic blood pressureswas obtained at the end of the active treatment period. The responder rates differ from each other, b;t a significant difference between urapidil and the /3 blocker has not been proved. In all studies with /3blockade, heart rate was 10 to 15 beats/min lower than in the urapidil group, as expected.
TABLE V Comparative
Studies Between Urapidil and Centrally Acting Drugs in Antihypertensive
Treatment
Dosage (w/day)
inclusion
Before
Criteria
Treatment
SBP/DBP (mm W After Treatment
20/5
u=3&60 CLON = 0.15-0.3
llcb130 110-130
191/116 196/120
144/92 153/93
50 50
35/12
u = 120-180 METH =100&1500
95-115 95-115
152/101 151/99
142/94 129/93
54 62
DBP (mm W
Reference Drug
n/T
Clonidine* a-Methyldopat
* Data adapted from Eisel and Ha&in. 1981 .I4 t Data adapted from Feldstein, et al., 1988.‘5 CLON = clonidine; METH = methyldopa; other abbreviabons
TABLE VI Comparative
SBP/DBP (mm W
% RESP. Rate (SUP. DBP 590 mm Hg)
as I” Tables I and III.
Study: Urapidil Versus Prazosin in Antihypertensive
Treatment
Dosage WWday)
DBP (mm W Inclusion Criteria
SBP/DBP (mm W Before Treatment
SBP/DBP (mm W After Treatment
% RESP. Rate Mean BP RED 213 mm Hg
Reference Drug
n/T
Prazosin*
222/12
U = 30-120 PRA=1.5-6
295 295
175/103 171/103
162/91 150/91
64 64
Prazosin* + thiazide diuretics
190/12
U = 3&120 PRA = 1.56
295 295
172/102 173/103
150/89 152/92
67 65
* Data adapted from Kaneko, 1988’6 Mean BP RED = mean blood pressure
reduction;
PRA = prazosin;
all other abbreviations
Urapidil versus centrally acting drugs: Eisel and Haerlini4 performed a study of 20 patients with WHO classification grade III to IV hypertension with urapidil vs clonidine, whereasFeldstein et al,ls in a similar study, comparedurapidil with cu-methyldopa.In the a-methyldopa study, 35 patients from an outpatient clinic (17 men and 18 women, aged 33 to 77 years) with WHO classification stage I or II essentialhypertension were included. All patients discontinued previous antihypertensive drug therapy and receivedplacebocapsulesfor 4 weeks.After this equilibration period, patients were randomly allocated to treatment with either urapidil or methyldopa. Urapidil therapy was begun at an initial doseof 60 mg twice daily. After 4 weeks, patients whose supine diastolic blood pressure was >95 mm Hg had urapidil dosages increased to 90 mg twice daily. This dosagewas maintained for an additional 8 weeks. Treatment with methyldopa was begun at an initial doseof 500 mg twice daily. If the supine diastolic blood pressureafter 4 weeksof treatment was >95 mm Hg, cxmethyldopa was increased to 750 mg twice daily; this dosagewas also maintained for a further 8 weeks.Each active drug was continued at the initial dosageif supine diastolic blood pressureafter 4 weekswas <95 mm Hg. Both in the Eisel and in the Feldstein study, mean blood pressuresignificantly declined after the active treatment phase(Table V). No significant differenceswere found in reduction of diastolic blood pressurein the clonidine and a-methyldopa studies.The responderrate, defined as supine diastolic blood pressure195 mm Hg, did not differ in both studies. Urapidil versus prazosix Table VI lists the results of a randomized multicenter, double-blind, comparative
as in Tables I and Ill.
study of urapidil vs prazosinperformedin Japan by Kaneko16in more than 400 outpatients with mild to moderate essentialhypertension.Two hundred and twenty-two patients were treated with monotherapy and 190 patients were treated with either urapidil or prazosin combined with thiazide diuretics. For this reasonthe results of this multicenter trial are divided into 2 sections.The study consistedof a 4-week, single-blind, control period with placebo, followed by a 12-week,randomized,double-blind, parallel period, during which the patients first receivedurapidil, 15 mg twice daily, or prazosin,0.5 mg 3 times daily, as monotherapy or in combination with thiazide diuretics. If the antihypertensive effect was insufficient (a decrease in pressure by -2O/-10 mm Hg or remaining pressurevalues over 150/90 mm Hg), urapidil was increasedstepwiseto 60 mg twice daily and prazosin to 2 mg 3 times daily. The final dose ratio of urapidil to prazosinin this study wasnearly 30/ 1.5and thus comparable with the ratio at the beginning of the study. Urapidil and prazosin causedsimilar declinesin systolic and diastolic blood pressuresduring the treatment period in the monotherapy as well as in the combination therapy group. Responderrates in the 2 groups (notice the differencein definition) were not significantly different. Heart rate did not change in a clinically relevant manner. Openstudies: Urapidil hasbeenassessedin a number of open noncontrolled studies by Haerlin et al,” Kaneko et a1,18Meurer,19 Thuma20 and Liebau et a1.21Over 9,000 patients have beentreated with urapidil in order to study safety and efficacy of the drug. The doserange of urapidil in thesestudieswas 30 to 180mg/day for periods ranging from 4 weeksto 3 years.
THE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 15, 1989
33D
A SYMPOSIUM: PHARMACOLOBIC AND THERAPEUTIC ASPECTS OF URAPIDIL
Normalization rates, defined as the percentageof patients whosediastolic blood pressuredecreasedbelow 90 mm Hg, were 50 to 80%, whereas 34, 39 and 13% of patients required 60, 90 and 120 mg/day of urapidil, respectively.The remaining 14%of patients required additional antihypertensive therapy. Liebau et aP studied 182 of 916 patients during a follow-up period of 3 years. One hundred eighty-two patients (77 men, 105 women, aged 22 to 80 years [mean 581) completed the 3-year examination. One hundred five patients (57.7%) had 1 or more concomitant diseasescontributing to an increased cardiovascular risk (diabetes, 36 patients; coronary artery disease,43 patients; hyperlipidemia, 55 patients). Systolic and diastolic blood pressurevalues (mean f standard deviation) were: 174 f 13/103 f 6 mm Hg at the beginning; 149 f lo/86 f 6 mm Hg after 1, 150 f 12/86 f 7 mm Hg after 2, and 146 f lo/85 f 7 mm Hg after 3 years of treatment. Heart rate decreasedfrom 77 & 10 to 73 f 8 beats/mm during the first year and was virtually constant during the following 2 years. Body TABLE VII Collective Incidence of Adverse Effects in 11 Comparative
Studies* Incidence of Adverse Effects
Reference Drug
%
Uradipil W)
Placebo Captopril Nifedipine Nitrendipine Acebutolol Metoprolol Atenolol Metipranololt Clonidine a-Methyldopa Prazosin Prazosin*
0 11.5 28.0 38.6 0 7.5 29.0 0 30.0 44.0 11.3 14.3
10 28.8 17.0 20.9 0 17.0 32.0 6.6 20.0 38.0 15.9 16.2
l The results of the prazosin study have bean divided in 2 sections (see text). t + butizide. * + thiazide diuretics. Data adapted from References 6 to 16
TABLE VIII Adverse Effects of the 11 Comparative
Symptoms
No. of Adverse Effects
%
Dizziness Nausea Headache Palpitations Tiredness Stomach disorders Orthostatic dysregulation Edema Sleep disturbances Other Total
52 27 27 15 6 6 6 6 3 46 195
8.0 4.2 4.2 2.3 0.9 0.9 0.9 0.9 0.5 7.3 -
Studies*
TABLE IX Type and Frequency of Adverse Effects of Urapidil*
’ Studiis performed with orally administered urapidil have bean taken together (see text). Only the symptoq the number and frequency of adverse effects of urapidil have been tabulated. In 121 of more than 650 patients treated with urapidil, 195 adverse effects have been reported. Data adapted from References 6 to 16.
34D
weight remained constant; no signsof sodium and water retention could be observed.Relevant alterations of laboratory parameters did not occur. Safety and tolerability: Registration of the adverse effectsand determination of laboratory parametershave been performed in all the clinical studies with urapidil. The incidence of adverseeffects observedin the aforementioned 11 randomizeddouble-blind trial&l6 wasalso established (Table VII). The results of Kanekot6 are divided into those receiving monotherapy (prazosin) and those receiving combination therapy (prazosin with thiazide diuretics). When all adverseeffectsof the 11 comparativestudiesare taken together, it appearsthat in 121 of more than 650 treated patients with urapidil, 195 adverseeffects have been reported. The most important symptoms were dizziness, nauseaand headache(Table VIII). The various adverse effectswere minor and transient in all trials, rarely causing withdrawal from therapy. After a few days of treatment with urapidil, most of the adverseeffects,like dizziness,nauseaand headache, disappearedspontaneously.Theseadverseeffectsmay be attributed to the decreasein blood pressure,frequently observedat the beginning of active treatment with an antihypertensive drug. Being fully aware of the existing bias, we have compared the type and frequency of adverseeffectsof urapidil of the 11comparativestudieswith the data of 1 year of treatment in more than 900 patients participating in the open noncontrolled multicenter trial with urapidil. This comparisonby Liebau et a122(Table IX) draws attention to the fact that the type and the frequency of adverse effects are rather similar in all studies. In the courseof the various clinical trials, laboratory parametersreflecting liver and kidney function, electrolytes, red and white cell counts together with differential blood counts, thrombocyte counts, as well as cholesterol, triglycerides, uric acid and blood glucoselevels were determined routinely. In the comparative studies this was performed as a pre-/postcomparison,and in the open long-term studies,
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
Symptoms
Comparative Studies (%)
Multicenter Study (“4
Dizziness Nausea Headache Palpitations Tiredness Stomach disorders Orthostatic dysregulation Edema Sleep disturbances Other
8.0 4.2 4.2 2.3 0.9 0.9 0.9 0.9 0.5 7.3
5.5 3.4 2.5 0.7 1.4 1.1 1.1 0.7 5.2
* Tr;r” and frequency of adverse effects of urapidil of the 11 comparative stud&-’ have been compared with data on 1 year of treatment in over 900 patients participating in the open noncontrolled multicenter trial with urapidil performed by Liebau et a1.a
additional laboratory values were measured at regular intervals. No clinically relevant changeswere found in daily dosesbetween 30 and 180 mg/day of urapidil. In this respect,urapidil differs from p blockersand diuretics, which are known to alter various laboratory parameters like glucose, uric acid and potassium levels. With regard to the influence of antihypertensivedrugs on lipid metabolism, fi blockers and diuretics are known to induce somenegativeeffects,whereasurapidil appears to be neutral.23Urapidil also doesnot influence airways resistance.Accordingly, urapidil may be safely given to patients with obstructive airways diseaseor diabetesmellitus. Specific contraindications for urapidil are unknown. Thus far, no rebound hypertension has beenobservedfor urapidil, neither in the performed clinical trials nor in daily practice. Similarly, no clinically relevant interactions with other drugs (e.g.,digoxin and cimetidine) have been observedfor urapidil.24 URAPIDIL-INTRAVENOUS
APPLICATION
Intravenous single-dose studies performed for investigational purposes in patients with essential hypertension (phase I): In 6 studies, a total of 90 patients with
essentialhypertension received single dosesup to 50 mg intravenously, someas repetitive injections and someas a continuous infusion.25-30The duration of the blood pressure-reducing effect was generally between 15 minutes and 6 hours. The maximal effect occurred within the first 60 minutes and it usually faded away after the fourth hour. Heart rate changedonly shortly after administration in some investigations. The effect proved transient. Peripheral vascular resistance was greatly reduced while cardiac output and myocardial functions were altered Renal plasma flow was only slightly or not at all. 26,28,29 somewhatincreased.Plasma renin activity and the concentrations of norepinephrine and epinephrine, angiotensin II, and sometimesaldosterone25,30 increasedslightly. Adverse effects, mainly orthostatic hypotension, rarely occurred.29In hypertensivepatients with obstructive lung disease(n = 10) and in normotensivepatients with hyperreactive bronchi (n = lo), no deterioration of lung functions after urapidil administration was observed.31Obstructive airways diseasedoesnot appearto be a contraindication to urapidil. Urapidil applied intravenously gencies: In 6 studies involving
in hypertensive
emer-
134 patients with hypertensiveemergencies,the patients received1 or more injections of urapidi1.32-37 In somecasescontinuous infusions were applied. Two studies32,33 were conducted in singleblind manner so that initial placebo doseswere followed by urapidil. Adverse effects in 36 patients were recorded and all appeared to be related to rapid blood pressure reduction. Theseadversereactionswereusually transient. Severehypotensive reactions occurred after a 25-mg i.v. dose was administered to 1 patient who had been pretreated with captopri134and after a 50-mg i.v. dosewas administered to another patient.35In a third patient who initially received 20 mg of urapidil followed by a 40 mg injection, these reactions also occurred.36
Comparative studies in hypartansion with urapidil administered intravenously: A comparative study was
performed by Rosenthal,38who treated 6 patients with hypertensiveemergencieswith urapidil followed by sodium nitroprusside, and 4 patients with sodium nitroprusside followed by urapidil. In all casesan adequateblood pressurereduction was achieved.Obvious adversedrug reactions did not occur. A further comparative study against diazoxide in 42 patients was performed by Vrhovac et a1.39Urapidil was given as 25-mg injections and, if necessary,in dosesup to 200 mg in several hours. Mean arterial blood pressure decreasedfrom 182.7 f 20 to 139.5 f 16.9 mm Hg (p <0.05). Diazoxide wasgiven as a lOO-mgi.v. injection; if necessary,it was increased to 200 mg. Mean arterial pressurein this casedecreasedfrom 174 f 19.1 to 132.2 f 25.2 mm Hg (p <0.05). Urapidil in pregnancy-induced hypertension: Twenty-one patients with severe preeclampsia were treated with repetitive single i.v. injections of 25 to 50 mg of urapidil, followed by continuous infusions of urapidil in order to maintain the antihypertensive effect.40For prevention of eclamptic seizures,magnesiumascorbatewas applied asa concomitant treatment. Comparedwith other antihypertensive drugs, urapidil was consideredto be preferable in this case, particularly becausethis compound does not increase intracranial pressure. Urapidil in congestive heart failure: With regard to the effectsof i.v. dosesof urapidil in patients with congestive heart failure due to various underlying diseases,3 studies should be mentioned41-43:Metcalf et a1,41Reiterer42and Wang et a143studied a total of 35 patients in New York Heart AssociationclassII to IV using invasive methods.Urapidil wasadministered in 1 or 2 subsequent dosesand, in some cases,as continuous infusions. Left ventricular performance, myocardial oxygen consumption, coronary blood flow, cardiac output, vascular resistance, and pulmonary artery and systemicarterial pressures were quantified. Negative inotropic activity or increasedmyocardial oxygenconsumptionwere not measured and undue adverse reactions were not observed. The combination of urapidil and dobutamine in the lowoutput syndrome after coronary artery bypass surgery was examined in 12 patients.44Urapidil alone raised the cardiac index from 1.8 liters/m2 X minutes to 2.7 liters/ m2X minutes.The addition of dobutamine, 5 pg/kg body weight X minutes increasedthe cardiac index further to a value of 3.4 liters/m2 X minutes. Heart rate remained unchanged and no significant effects on the myocardial oxygen balance were determined. Urapidil wasfound to be effectivein combination with dobutamine in the treatment of low-output syndrome after bypasssurgery. In all, the effectsof urapidil in these small and uncontrolled studies were judged favorable. Use of urapidil in anesthesia: In 10 intraoperative studiesduring various typesof anesthesia(altogether 245 patients), urapidil wasfound to be effective and safe.The amount of urapidil applied greatly varied. In comparative treatments with sodium nitroprusside45,46or phentolamine,47the absenceof reflex tachycardia wasobvious.45
THE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 15, 1989
35D
A SYMPOSIUM:
PHARMACOLOGIC
AND THERAPEUTIC
ASPECTS OF URAPIDIL
During controlled hypotension,a three- to fourfold reduction of the required amount of sodium nitroprussidecould be achieved,if urapidil had been preinjected.46Because urapidil doesnot directly affect myocardial performance and doesnot causetachycardia, it may be useful in coronary bypasssurgery.47-52Furthermore, urapidil appears suitable for the treatment of hypertensive episodesin patients who have undergone neurosurgery. In 8 hypertensive patients, van Aken et aP3 found no increase in intracranial blood flow and intracranial pressure(seealso reference 54). Use of urapidil in postoperative hypertension: In 2 studiesof postoperativehypertensionafter aortocoronary bypasssurgery,55v56 20 patients treated with urapidil were comparedwith 19 patients treated with sodium nitroprusside. Junger et aP found smoother blood pressuretime curves with urapidil than with sodium nitroprusside. With the exception of 1 patient,55no increase in heart rate was observed.After aortocoronary bypasssurgery, no increase in pulmonary right to left shunting (venous admixture) was seenduring treatment of hypertension with urapidil therapy in artificially ventilated patients. In contrast, patients under the sameconditions, but treated with sodium nitroprusside, had increasedvenousadmixture and, therefore, decreasedarterial oxygen pressure values.57 Treatment of severepostoperativehypertension after cardiovascularsurgery wasstudied in 19children aged 12 days to 14 years (mean 7.2 years).58 A prompt decreasein blood pressure was achieved within the first 15 minutes after i.v. single injections. This effect could be maintained throughout the entire period of urapidil application infused continuously (range 1 to 95 hours). In 1 case,a severehypotensiveeffect occurred within 5 minutes after the start of the infusion. CONCLUSIONS Chronic application of urapidil in dosesranging from 30 to 90 mg twice daily appearsto reduce blood pressure adequately in patients with various grades of hypertension as shown in different studies in several countries. The degreeof blood pressurereduction by urapidil is not significantly different from that causedby captopril, slow-releasenifedipine, nitrendipine, acebutolol, metoprolol, atenolol, metipranolol combined with butizide, clonidine, cY-methyldopaand prazosin.‘-l6 Responder rates in thesetrials varied from 40 to 70%and globally no differenceswere found betweenurapidil and the various comparative drugs. In all studiesperformed thus far, and also in daily practice, urapidil appearsto be effective and well-tolerated, with an acceptablepattern of adverseeffects.Urapidil can also be applied intravenously in hypertensive emergencies. The blood pressure-lowering effectsafter single injections appear within the first 15 minutes and persist for 4 to 6 hours. Urapidil given intravenously appearsto be a suitable treatment in various acute situations of hypertension. The efficacy of i.v. urapidil is similar to that of diazoxide and sodium nitroprusside. Like other vasodilating drugs, urapidil should not be given intravenously to 36D
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
patients with stenosisof the aortic isthmus or with aortic valve disease.The adversereactions appear to be mainly transient orthostatic reactionsoccurring soonafter application of urapidil. No reflex tachycardia was found, except in the first minutes after rapid injections. No adverse reactions occurred in combination with various agents usedduring general anesthesia.A specialadvantagemay be that urapidil, although a vasodilator, doesnot causean increase in intracranial pressure. REFERENCES
1. van Zwieten PA. Pharmacologicprofile of urapidil. Am J Cwdioi 1989,64: 10-60.
2. Bielen E, Fagard R, StaessenJ, Lijnen P, van Hoof R, Amery A. Urapidilinduced hemodynamicchangesin humans.Am J Cwdiol 1989,64:16D-210. 3. KolassaN, Beller KD, SandersKH. Involvementof brain ~-HT~Areceptorsin the hypotensiveresponseto urapidil. Am J Cwdiol 1989,64;7D-100. 4. Saxena PR. 5Hydroxytryptamine receptors:functional responsesand potential clinical usesof agonist and antagonistdrugs.J Drug Ther Res f989;14:6-8. 5. de Leeuw PW, Birkenhlger WH. Acute responsesto urapidil in hypertensive persons. Am J Cwdiol
1989,64:22D-240,
6. Volpe M, Trimarco B, Rosiello G, Mele AF, Cuocolo A, Ricciardelli B, Chiariello M. Antihypertensive effect of urapidil: a randomized, double-blind study in mild or moderatehypertensivepatients In: Amery A, ed. Treatment of Hypertension with urapidil: Preclinical and Clinical Update. London Roy Sot Med Services, 1986:135-142.
7. RosenthalMD, Haerlin R. Therapeutic assessmentof urapidil or angiotensinconverting enzymeinhibition in systemichypertension.Am J Cwdiol 1989~54: ZSD-29D.
8. Stump E, FeldhausP, Haerlin R. Antihypertensive Wirksamkeit und Vertraglichkeit von Urapidil. Fortschr Med 1989;107:54-57. 9. Winn K. Klinische Erfahrungen mit Urapidil und Nitrendipin. In: Ganten D, Hayduk K, Hitxenberger G, ads.Beitrage xur Hypertonie: Klinische Aspekte der modernenHochdruckbehandlung.Frankfurt rzm Maim Uniuersimed- Verl., 1988; 50-53. 10. Txincoca C, LevensonJ, Petitet A, EngelstzItterR, Safar ME. Therapeutic assessment of acebutololand urapidil in essentialhypertensionunder doubleblind conditions. Curr Ther Res 1985;38:579-585. il. Leonetti G, Mazola C, Boni S. Guffanti E, Meani A, Zanchetti A. Comparisonof the antihypertensiveeffect of urapidil and metoprolol in hypertension.EurJ Clin Pharmacol 1989;30.637-640.
12. Tijrak E, Wagner M, Podmanicxlq M. Comparisonof urapidil and atenolol in hypertension.Drugs 1988:35:suppl 6:164-l 72. 13. Schafer N. Doppelblindstudieeinen vergleichendenantihypertensiven Behandlungmit Urapidil gegeneine Kombination von Metipranolol und Butizid. In: Kaufman W. BruckschenEG, eds.Urapidil. Darstellung einer neuenantihypertensievenSubstanz. Amsterdam Excerpto Medica, 1982:243-250. 14. Eisel K, Haerlin R. Double-blind, parallel-group study with urapidil and clonidine in 20 patients with essentialhypertension(grade III-IV). Byk Gulden Phwmanrticals; Research Report 48911979: Konstotaz, West Germany. 15. Feldstein CA, Olivieri AO, Sabaris RP. Comparisonbetweenthe effects of urapidil and methyldopa on left ventricular hypertrophy and haemodynamicsin humans.Drugs 1988;3S:suppl6.9&97. 16. Kaneko Y. Doubleblind comparisonof urapidil and praxcsinin the treatment of patients with essentialhypertension.Drugs 1988:35:suppl 6:156-163. 17. Haerlin R, Engelstiitter R, Henze F, Radtke HW. Treatment of primary and secondaryhypertension:long-termuseof urapidil. Clin Trials J 1985;22:215-223. 13. Kaneko Y, Yasuda H, Yoshinaga K, Inagaki Y, Ishii M, Taniguchi K, Mixuno Y, OmaeT, Takeda T, Kokubu T, Arakawa K. Experiencewith urapidil in Japan: open study in hypertensivepatients. In Ref 6:155-164. 19. Meurer KA. Treatment of hypertension.Efftcacy, tolerability and therapeutic spectrum of the antihypertensive agent urapidil in general practice. Theropiewoche 1986:36:4&V-401
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20. Thuma G. Experiencewith urapidil in an outpatient facility. Therapiewoche 1983;33:6933-6936. 21. Liebau H, Solleder P, Harden I, Wurst W. Drei JahreTherapie mit Urapidil. Offene multizentrische prospektivePrtifung xur Vertraglichkeit, Sicherkeit und Wirksamkeit von Urapidil. Byk Gulden Pharmaceuticals; Research Report 3231 1988: Kon.stam, West Germany. 22. Liebau H, Haehn KD, Behr H, Wurst W. Antihypertensiveaction of urapidil: results of a multicentre trial. In Ref 6:165-l 71. 23. Weidman P. Ferrier C, Saxenhofer H, Uehlinger DE, Trost BN. Serum lipoproteins during treatment with antihypertensivedrugs. Drugs 1988;35:suppf 6:118-134. 24. Kirsten R, Nelson K, SteinijansVW, Zech K, Haerlin R. Clinical pharmacokinetics of urapidil. Clin Phwmacokinet 1988:14:129-140. 25. de Leeuw PW, van Es PN, de Bryn HAM, Birkenhlger WH. Renal haemo dynamic and neurohumoral responsesto urapidil in hypertensive man. Drugs
1988;35:suppl 6:74-77. 26. Messerli FH, Kobrin C, Amodea C, Ventura HO, Frohlich ED. Immediate cardiovascular effects of urapidil in essential hypertension.In Ref 6:87-92.
27. MagometscbniggD, Bather S. Acute haemodynamicresponsesto single intravenous dosesof urapidil in essentialhypertensivepatients. In Ref 6347-51. 28. LevensonJ, Simon AC, Bouthier JD, BenetosA, Safar ME. Post-synaptic alpha-blockadeand brachial artery compliancein essentialhypertension.J Hypertem 1984;2:37-41.
29. Leonetti G, Terzolli L, Rupolli L, Gradnik D, Zancbetti A. Effects of intravenous urapidil on blood pressure,renal plasma flow and responsivenessto vasoconstrictor agents in hypertensive patients. In Ref 6:l J-18. 30. Wambach G, Godebardt E, Lang R, Heitz W, Meurer KA, Kaufmann W. Pharmacodynamicsof urapidil in essential hypertension and in chronic renal failure. In Ref 6:63-70. 31. Wiebmann KJ, Miinninghoff J, Kriiger CH. Antihypertensive therapy with urapidil in patients with obstructive lung disease.Forts&r Med 1983;101:291294. 32. Serra P. Eflicacy of urapidil iv. in patients with severehypertension.Byk Gulden Pharmaceuticals; External Research Report 34&E/1987: Konrtonz, West Gt?iWll7ny.
43. Wang RYC, Chow JSF, Chan KH, Pan HYM, Wong RPY. Acute haemodynamic and myocardial metabolic effects of intravenousurapidil in severeheart failure. Eur Heart J 1984:5:745-751. 44. SchuckerP, Franke N, van Ackern K, Peter K, Kreuzer E. Therapy of the low-output syndromewith urapidil and dobutamine.Anaesthesist 1981;30:22-27. 45. SchnebeleN, Heuser D, GuggenbergerH, Ebcling J, Kottler B. Controlled hypotensionin neurosurgery:Pharmacologicalaspectsand comparative clinical experimentsin preventionand therapy of posthypertensiveBP deterioration with special regard to propranolol and urapidil. MD Thesis, Faculty of Medicine, Eberhard-Karls-University
Tubingen, 1986.
46. Worm 1,Liiben V, Klug W. HempelmannG. Comparisonof urapidil iv. and sodium nitroprussideduring controlled hypotension.Byk GuJden Pharmaceuticals; External Research Report 144Ef1988: Konstanz, West Germany.
47. Hess W, Schulte-SasseU, Tarnow J, Veit S. Comparisonof phentolamine and urapidil in controlling acute intraoperative hypertensionin patientssubjected to coronary artery bypasssurgery. Eur J Anaesthesiol 1985:2:21-27. 48. Zghringer J, HBtling B, Schmtikel M, Giinther B. Treatment of intraoperative hypertensionwith urapidil. Anaesth Intensiumed 1986;152-155. 49. Alvarez CB, Urapidil i.v. in reactive hypertension during aortocoronary bypasssurgery. Byk Gulden Pharmaceuticals; External Research Report 465E/
33. Perri D. Efficacy of urapidil i.v. in patients with severe hypertension.Byk
1984: Komtanz, West Germany.
Gulden Pharmaceuticals; West Germany.
50. Franke N, SchmuckerP, van Ackern K, Reichert B. Antihypertensive therapy with urapidil during anaesthesia.Therapiewoche 1980;30:880-886, 51. Franke N, SchmuckerP, Vogel H, Liihr H. Changesin haemodynamicsand myocardial oxygenconsumptionduring intraoperative BP reductionwith urapidil. In: Kaufmann W, BruckschenEG, eds.Urapidil. Darstelhmgeiner neuenantibypcrtensivenSubstanz.Amsterdam: Excerpta Medica, 1982:I 13-I 18. 52. Barankay A, Goeb E, Richter JA. Treatment of hypertensionin coronary bypasssurgery. Clinical experiencewith urapidil. Arzneimittelforschung 1981;
External Research Report RR 34711987: Konrtanz,
34. zhringer J, Klepzig J. Greif J, Ludwig B, Strauer B. Haemcdynamic changesduring treatment of hypertensiveemergencieswith urapidil. J Hypertens 1984;2:103.
35. Thuma G. Urapidil as basic therapeutic agent in the treatment of severe hypertension.Fortxhr Med 1986;104:457-460. 36. Cless KH, Cram M, Helmstaedter V. The effect of intravenously administered urapidil on the blood pressure of patients with hypertensivecrises. Therapiewoche 1978;28:6266-6270.
37. SchusterP, Sturm A. Use of antihypertensiveEbrantil in hypertensivecrises. Klinikarzt
1986;12:106.
198I;IO:202-212.
38. RosenthalJ. Urapidil versussodiumnitroprussidein IO patientswith primary and secondary hypertension. Byk Gulden Pharmaceuticals; Internal Research Report RR 370/1979: Konstanz, West Germany.
39. Vrhovac B, Rumboldt Z, Gasparovic V. Single-blind comparative study of urapidil and diazoxide in the treatment of malignant hypertensionof hypertensive crisis. In: Proceedingsof the 10th Scientific Meeting of the International Society of Hypertension. Interlaken 1984:899-900. 40. Dame WR, van Aken H. Treatment of pregnancy-inducedhypertensionby a new antihypertensive agent: urapidil. In Ref 6:I 21-J 26. 41. Metcalfe JM, Smytb P, Monaghan MM, Atkinson LM, Jewitt DE. Urapidil in the treatment of congestivecardiac failure. In Ref 6~11J-J 14. 42. Reiterer W. Long-term effects of urapidil on exercise hemodynamicsin patients with hypertension and left heart failure (abstr). In: Proceedingsof the I Ith Scientific Meeting of the International Society of Hypertension (abstr). Heidelberg 1986;484.
31:849-852.
53. van Aken H, PuchsteinCH, Sicking K, Kriibling H, K8nig W. Antihypertensivetreatmentwith urapidil doesnot increaseICP in patients.Intenrioe Care Med 54. Lehmann KA, Heimig TH. Circulatory responseto urapidil during general and regional anaesthesia.Anaesthesist 1985;34:435-445. 55. Downer J, Williams DJM, Major E. Urapidil in the treatment of hypertension. A comparisonwith sodium nitroprusside following coronary artery bypass surgery. In Ref 6:115-l 20. 56. Junger H, van Deyk K, Kopp M. Haemodynamicsduring antihypertensive therapy with urapidil and sodium nitroprusside.In: Kaufmann W, Bruckschen EG, eds.Urapidil. Darstellung einer neuenantihypertenivenSubstanz.Amsterdam: Excerpta Medica, 1982:139-146.
57. MBllhoff TH, Mulier JP, Miiller E, van Acken H, Lauwers P. Influence of sodiumnitroprussideand urapidil on venousadmixture in the treatment of hypertension following coronary artery bypassgrafting. Am J Hypertension 1989; in press.
58. Sch&er JG, Pilossoff W, Biihlmeyer K. Urapidil therapy for acute hypertensive crisis in infants and children. Eur J Pediatr 1984;143;87-91.
THE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 15. 1989
37D
Urapidil has been approved as sustained-release capsules containing 30,50 and 50 mg, respectively, and as ampules containing 25 and 50 mg for treatment of all grades of hypertension, in several countries in Europe, South America, as well as in Japan and other Asian regions. In general, the treatment shoukl start with 50 mg twice daily, 1 capsule in the morning and 1 in the evening. This schedule may be adapted according to the therapeutk needs. During the last few years, urapidil has been investigated extensively in comparison with several types of established antihypertensive drugs. Urapidil given orally has been tested in comparative trials against placebo, acebutold, metoprold, captopril, nifedipine and nitrendipine with responder rates of 40 to 70%. These responder rates are to be expected for a variety of antihypertensive drugs in monotherapy. Further studiis with clonidine, praxosin and a-methyldopa showed similar responder rates as establlshed for the other antihypertensive drugs studied. Adverse reactions include dizziness, headache and nausea and occasiionally tiredness, orthostatic dysregulatkm and gastric disorders. These symptoms were transient, mostly occurring during the early phases of therapy and disappearing as treatment continued. Adverse effects are considered to be mainly due to blood pressure reduction. Intravenous comparative trials have been performed with urapldil against placebo, diaxoxide and sodium nitroprusslde. Adverse effects of parenterally applied urapidil are similar to those observed during oral treatment. 5pecDlc contraindkzitions for urapidil are unknown. However, as for other vasodilating drugs, intravenous urapidil should not be administered to patients with steno& of the aortic isthmus or with aortic valve insufftciency. (AmJCardid 1989;64:30D-37D)
he antihypertensiveactivity of urapidil is explained by peripheral at-adrenoceptor blockade and also by additional central hypotensive activity, both leading to a decreasein systemic vascular resistance.‘J The centrally mediatedcomponentof urapidil’s hypotensive action may be explained by the drug’s ~-HTIA agonistic activity.lT3g4Urapidil has been approved as sustained-release capsules containing 30, 60 and 90 mg, respectively,as well as ampulescontaining 25 and 50 mg in several European, South American and Asian countries. The most relevant indication for oral urapidil is long-term treatment of all gradesof hypertension,whereas the intravenous (i.v.) formulation is usedfor the management of hypertensive crisis and perioperative hypertension. For the urapidil-induced hemodynamic changes in humans, the reader is referred to the review by Bielen et al2 and de Leeuw5 in this supplement. This report reviews the most relevant clinical trials of urapidil that have beenperformed in hypertensivepatients and in hypertensiveemergenciesduring the last few yearsin different countries. The efficacy, safety and tolerability of urapidil will be described in comparison with those of other, establishedantihypertensive drugs.
T
URAPIDIL-ORAL APPLICATION Comparative studies: The therapeutic efficacy and
tolerability of urapidil wasinvestigatedin 11 randomized double-blind studies.6-16All studies were conducted on the basis of the following general protocols: Study design: The studiesweredesignedasambulatory, singleor multicenter, double-blind, randomizedparallel-group trials. One trial had a crossoverdesign.*t After a washout or a placebo period of 1 to 2 weeks,or both, patients were randomly assignedto individual treatment groups. Active treatment was performed over 3 to 12 weeks.A placebophaseprecededthe termination of some of the studies. Inclusion criteria: The ambulatory hypertensive patients studied were of either sex and had essential or secondaryhypertension,or both, and diastolic blood pressureranging from 95 to 120mm Hg (meanvalue of triple measurementin the supine position after 5 minutes of rest). In a few studies*0J2-14 diastolic blood pressurevaluesto 130 mm Hg were allowed. The age of the patients was between 20 and 80 years. Exclusion criteria: Exclusion criteria were:malignant hypertension, marked pathologic electrocardiographic changes,aortic valve stenosis,Conn’s syndrome, renal From the Clinical Research Department, Byk Nederland, Zwanen- damage, severe liver disease,neurologic or psychiatric burg, The Netherlands. Addressfor reprints: C.E. Schook,MD, Clinical ResearchDepart- diseases,pregnant and nursing women, antihypertensive ment, Byk Nederland, Weerenweg 29, 1161 AG Zwanenburg, The medication other than the test drug, and malignant disorNetherlands. ders. 30D
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
Blood pressure and heart rate measurement: Blood pressureand heart rate were determined with patients in both the supine and upright positions by triple measurement, after the patient had rested for at least 5 minutes. Blood pressure and heart rate were always measured before intake of the morning dose of urapidil (or reference drug) to obtain 1Zhour values. Various studies: Urapidil versusplacebo: Volpe et aI6 compared the antihypertensive effect and tolerability of urapidil, 60 mg twice daily, with placeboin 40 ambulant patients with essentialhypertension. After a baselineperiod of 2 weeksin which a placebowasadministeredtwice daily, the patients were randomized to one of the treatment groups.Baselinesupinediastolic blood pressurehad to be between 100 and 120 mm Hg before active treatment was begun. Blood pressure and heart rate were measured both during the placebo period and during the following 3 weeksof active treatment, at 4 and 12 hours after drug administration. Three patients treated with urapidil and 1 patient in the placebogroup withdrew from the study. The results with respectto the remaining 36 patients are listed in Table I. Mean supine systolic and diastolic blood pressures12 hours after drug intake decreasedfrom 157/106 to 142/ 89 mm Hg in the urapidil group and from 156/105 to 151/97 mm Hg in the placebo group after 3 weeks of treatment. The difference in diastolic blood pressuredecreasebetweenthe urapidil and placebo group were statistically significant (p
TABLE
Ill Comparative
TABLE I Effects of Urapidil(60
mg Twice Daily) Versus Placebo on Blood Pressure in 36 Hypertensive Patients*
u PL
SBP/DBP (mm 49
% RESP. Rate
Criteria
Before Treatment
After Treatment
(SUP. DBP 590 mm Hg)
lOch120 loo-120
157/106 156/105
142/89 151/97
60 25
* This was a double-blind. randomized. parallel group study. The period of treatment was 3 weeks. The differences I” diastolic blood pressure decrease between the urapidil and placebo groups were statistically significant (p
TABLE II Urapidil Versus Captopril in Antihypertensive Treatment*
U C
DBP
SBP/DBP
(mm &) Inclusion Criteria
(mm Hg) Before Treatment
SBP/DBP (mm f-k) After Treatment
% RESP. Rate (SUP. DBP 590 mm Hg)
95-120 95-l 20
175/103 175/103
154/89 154/90
62 58
*This was a double-blind. randomized. parallel group study in 295 patients. ment was for 12 weeks. C = captopril; other abbreviations as in Table I. Data adapted from Am J Cardiol.’
Studies Between Urapidil Versus Calcium Antagonists in Antihypertensive
n/T
Treatment
Dosage (w/day)
(mm W Inclusion Criteria
SBP/DBP (mm W Before Treatment
SBP/DBP (mm Hg) After Treatment
% RESP. Rate (SUP. DBP 590 mm Hg)
Slow release nifedipine*
168/12
u = 120 NIF = 40
95-120 95-120
168/102 170/103
158/91 151/90
43 57
Nitrendipinet
87/6
u = 120 NIT = 20
95-120 95-120
170/103 170/104
146/88 148/91
67 49
* Data adapted from Stumpe et al, 1989.0 t Data adapted from Winn, 1989.9 n = total number of patients; NIF = nifedlpine:
NIT = nltrendipine.
T = duration
Treat-
25 mg of captopril twice daily. After 2 weeks the dose could be adjustedaccording to the blood pressurevalues obtained. For further details of the study and results see the report by Rosenthal and Haerlin7 in this supplement and also Table II. Both antihypertensive drugs significantly reduced blood pressure(p
DBP Reference Drug
SBP/DBP (mm W
DBP (mm Hg) Inclusion
of treatment
period in weeks: U = urapldil: other abbreviations
as in Table I.
THE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 15, 1989
31D
A SYMPOSIUM: PHARMACOLOGIC AND THERAPEUTIC ASPECTS OF URAPIML
TABLE IV Comparative
Studies Between Urapidil and Beta-blocking
Drugs in Antihypertensive
Treatment
Dosage OWdaY)
DBP (mm H&9 Inclusion Criteria
SBP/DBP (mm f-k) Before Treatment
SBP/DBP (mm W After Treatment
% RESP. Rate (SUP. DBP 190 mm Hg) 80 60
Reference Drug
n/T
Acebutolol*
40/10
u=30-90 ACEB = 200-4W
lOc-130 100-130
167/107 164/107
l&I/87 147/92
Metoprololt
40/4
U = 60 MET0 = 200
100-120 LO&120
160/103 165/105
152/97 149/96
159/102 158/102
154/97 147/93
100-125 lCQ-125
164/109 167/111
150/96 M/94
23 4%
95-130 95-130
188/m 190/105
157/90 158/&?
60 87
U = 60 MET0 = 200 Atenolol*
W8
u = -120 ATEN = 50-100
Metipranolol§ + butizide
30/6
u=30-60 METI = 20-40 B = 2.5-5
* Dataadaptedfrom Tzincoca et al, 198~T~~ t Data adapted frQm Leoneti, et& 1986” * Data adaptedfrom Tdrdk eta/., 1988.12 5 Data adapted from ScfSfer. 1 98LL3 ACE6 = acebutolol; ATEN = atenolol; B = butazide;
METI = metipranolol;
MET0 = metoprolol;
release20-mg capsuletwice daily. Beforerandomization, there was a period of l-week washout and 1 week of placebotreatment. Two hundredninety-two patients pre senting with essential or secondary hypertension were admitted to the study. Patients were subjectedto active treatment for 12 weeks. Blood pressure,and heart rate were measured during the entire study before morning drug intake, i.e., approximately 12 hours after the last capsulehad been administered. Of 292 patients, 168 remained evaluablewith respectto blood pressureafter the subtraction of 86 protocol violators, 22 withdrawals for nonmedical reasonsor reasonsunrelated to the test drugs and 16 withdrawals. Of the 94 urapidil-treated patients, 3 withdrew becauseof insufficient efficacy and 10 because of adverseeffects.Accordingly, 81 subjectsconcludedthe study in accordance with the study protocol after 12 weeks of the drug phase. Of the 90 nifedipine-treated patients, 1 withdrew becauseof lack of efficacy and adverse effects, and 2 becauseof adverseeffects only. Accordingly, 87 patients remained in the study throughout the drug phase. Both drugs reduced blood pressuremarkedly and significantly (p 10.05). The reduction in systolicblood pressure from nifedipine was more pronounced than the reduction in diastolic,pressure.The difference betweenresponderrates (Table III) wasnot statistically significant. Heart rate during the entire study was lower in supine and standing patients in the urapidil- than in nifedipinetreated patients. In the secondstudy,9patients receivedeither urapidil (60 mg) in the morning and evening or nitrendipine (20 mg) in the morning and placebocapsulesin the evening. The design of the study was vir+ally the sameas that of the previous one with the exceptions of the number of patients, an active treatment phase of 6 instead of 12 weeks and a post-treatment phase of 2 weeks without therapy. In all, 89 patients were admitted to the study. Of those, 2 withdrew during the placebo run-in phase. 320
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
all other abbreviations
35 42
as in Tables I and Ill.
Table III lists the results of this study. In the 43 urapidil-treated patients, a mean supine diastolic blood pressureof 88 mm Hg was reached,which is below the “therapeutic goal” of 90 mm Hg, whereasin the nitrendipine group a mean value of 91 mm Hg was achieved. There was no difference between the 2 groups in blood pressure reduction. The responder rate in the urapidil group was 67% and that in the nitrendipine group 49%. More patients with an increasein pulse rate were found during the first 2 we& in the nitrendipine group than in those treated with urapidil. After 6 weeksof treatment there was no difference in pulse rate between the 2 groups. Urapidil versus beta blockers: Table IV lists the results of 4 randomized,double-blind trials of urapidil vs @ blockers.The metoprolol study by Leonetti et al” was a crossover investigation. The other studies1°J2J3had a parallel-group design. They all had a washout period with an active treatment period ranging from 4 to 10 weeks.This was followeil by a placeboperiod with the exceptionof the ateno101study. The metoprolol regimen had a 2-weekwashout period betweenthe 2 active phasesof 4 weeks.All studies included only patients with essential hypertension. The supine diastolic blood pressure at the beginning of the active treatment phaseranged from 95 to 130 mm Hg. The dosagesof the drugs (urapidil and the B blockers) varied. Only the urapidil dosein the metoprolol study was fixed. In the study by Schlfer,13 metipranolol was combined with butizide. In all 4 studies,a signficant decreaseof mean supine systolic as well as diastolic blood pressureswas obtained at the end of the active treatment period. The responder rates differ from each other, b;t a significant difference between urapidil and the /3 blocker has not been proved. In all studies with /3blockade, heart rate was 10 to 15 beats/min lower than in the urapidil group, as expected.
TABLE V Comparative
Studies Between Urapidil and Centrally Acting Drugs in Antihypertensive
Treatment
Dosage (w/day)
inclusion
Before
Criteria
Treatment
SBP/DBP (mm W After Treatment
20/5
u=3&60 CLON = 0.15-0.3
llcb130 110-130
191/116 196/120
144/92 153/93
50 50
35/12
u = 120-180 METH =100&1500
95-115 95-115
152/101 151/99
142/94 129/93
54 62
DBP (mm W
Reference Drug
n/T
Clonidine* a-Methyldopat
* Data adapted from Eisel and Ha&in. 1981 .I4 t Data adapted from Feldstein, et al., 1988.‘5 CLON = clonidine; METH = methyldopa; other abbreviabons
TABLE VI Comparative
SBP/DBP (mm W
% RESP. Rate (SUP. DBP 590 mm Hg)
as I” Tables I and III.
Study: Urapidil Versus Prazosin in Antihypertensive
Treatment
Dosage WWday)
DBP (mm W Inclusion Criteria
SBP/DBP (mm W Before Treatment
SBP/DBP (mm W After Treatment
% RESP. Rate Mean BP RED 213 mm Hg
Reference Drug
n/T
Prazosin*
222/12
U = 30-120 PRA=1.5-6
295 295
175/103 171/103
162/91 150/91
64 64
Prazosin* + thiazide diuretics
190/12
U = 3&120 PRA = 1.56
295 295
172/102 173/103
150/89 152/92
67 65
* Data adapted from Kaneko, 1988’6 Mean BP RED = mean blood pressure
reduction;
PRA = prazosin;
all other abbreviations
Urapidil versus centrally acting drugs: Eisel and Haerlini4 performed a study of 20 patients with WHO classification grade III to IV hypertension with urapidil vs clonidine, whereasFeldstein et al,ls in a similar study, comparedurapidil with cu-methyldopa.In the a-methyldopa study, 35 patients from an outpatient clinic (17 men and 18 women, aged 33 to 77 years) with WHO classification stage I or II essentialhypertension were included. All patients discontinued previous antihypertensive drug therapy and receivedplacebocapsulesfor 4 weeks.After this equilibration period, patients were randomly allocated to treatment with either urapidil or methyldopa. Urapidil therapy was begun at an initial doseof 60 mg twice daily. After 4 weeks, patients whose supine diastolic blood pressure was >95 mm Hg had urapidil dosages increased to 90 mg twice daily. This dosagewas maintained for an additional 8 weeks. Treatment with methyldopa was begun at an initial doseof 500 mg twice daily. If the supine diastolic blood pressureafter 4 weeksof treatment was >95 mm Hg, cxmethyldopa was increased to 750 mg twice daily; this dosagewas also maintained for a further 8 weeks.Each active drug was continued at the initial dosageif supine diastolic blood pressureafter 4 weekswas <95 mm Hg. Both in the Eisel and in the Feldstein study, mean blood pressuresignificantly declined after the active treatment phase(Table V). No significant differenceswere found in reduction of diastolic blood pressurein the clonidine and a-methyldopa studies.The responderrate, defined as supine diastolic blood pressure195 mm Hg, did not differ in both studies. Urapidil versus prazosix Table VI lists the results of a randomized multicenter, double-blind, comparative
as in Tables I and Ill.
study of urapidil vs prazosinperformedin Japan by Kaneko16in more than 400 outpatients with mild to moderate essentialhypertension.Two hundred and twenty-two patients were treated with monotherapy and 190 patients were treated with either urapidil or prazosin combined with thiazide diuretics. For this reasonthe results of this multicenter trial are divided into 2 sections.The study consistedof a 4-week, single-blind, control period with placebo, followed by a 12-week,randomized,double-blind, parallel period, during which the patients first receivedurapidil, 15 mg twice daily, or prazosin,0.5 mg 3 times daily, as monotherapy or in combination with thiazide diuretics. If the antihypertensive effect was insufficient (a decrease in pressure by -2O/-10 mm Hg or remaining pressurevalues over 150/90 mm Hg), urapidil was increasedstepwiseto 60 mg twice daily and prazosin to 2 mg 3 times daily. The final dose ratio of urapidil to prazosinin this study wasnearly 30/ 1.5and thus comparable with the ratio at the beginning of the study. Urapidil and prazosin causedsimilar declinesin systolic and diastolic blood pressuresduring the treatment period in the monotherapy as well as in the combination therapy group. Responderrates in the 2 groups (notice the differencein definition) were not significantly different. Heart rate did not change in a clinically relevant manner. Openstudies: Urapidil hasbeenassessedin a number of open noncontrolled studies by Haerlin et al,” Kaneko et a1,18Meurer,19 Thuma20 and Liebau et a1.21Over 9,000 patients have beentreated with urapidil in order to study safety and efficacy of the drug. The doserange of urapidil in thesestudieswas 30 to 180mg/day for periods ranging from 4 weeksto 3 years.
THE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 15, 1989
33D
A SYMPOSIUM: PHARMACOLOBIC AND THERAPEUTIC ASPECTS OF URAPIDIL
Normalization rates, defined as the percentageof patients whosediastolic blood pressuredecreasedbelow 90 mm Hg, were 50 to 80%, whereas 34, 39 and 13% of patients required 60, 90 and 120 mg/day of urapidil, respectively.The remaining 14%of patients required additional antihypertensive therapy. Liebau et aP studied 182 of 916 patients during a follow-up period of 3 years. One hundred eighty-two patients (77 men, 105 women, aged 22 to 80 years [mean 581) completed the 3-year examination. One hundred five patients (57.7%) had 1 or more concomitant diseasescontributing to an increased cardiovascular risk (diabetes, 36 patients; coronary artery disease,43 patients; hyperlipidemia, 55 patients). Systolic and diastolic blood pressurevalues (mean f standard deviation) were: 174 f 13/103 f 6 mm Hg at the beginning; 149 f lo/86 f 6 mm Hg after 1, 150 f 12/86 f 7 mm Hg after 2, and 146 f lo/85 f 7 mm Hg after 3 years of treatment. Heart rate decreasedfrom 77 & 10 to 73 f 8 beats/mm during the first year and was virtually constant during the following 2 years. Body TABLE VII Collective Incidence of Adverse Effects in 11 Comparative
Studies* Incidence of Adverse Effects
Reference Drug
%
Uradipil W)
Placebo Captopril Nifedipine Nitrendipine Acebutolol Metoprolol Atenolol Metipranololt Clonidine a-Methyldopa Prazosin Prazosin*
0 11.5 28.0 38.6 0 7.5 29.0 0 30.0 44.0 11.3 14.3
10 28.8 17.0 20.9 0 17.0 32.0 6.6 20.0 38.0 15.9 16.2
l The results of the prazosin study have bean divided in 2 sections (see text). t + butizide. * + thiazide diuretics. Data adapted from References 6 to 16
TABLE VIII Adverse Effects of the 11 Comparative
Symptoms
No. of Adverse Effects
%
Dizziness Nausea Headache Palpitations Tiredness Stomach disorders Orthostatic dysregulation Edema Sleep disturbances Other Total
52 27 27 15 6 6 6 6 3 46 195
8.0 4.2 4.2 2.3 0.9 0.9 0.9 0.9 0.5 7.3 -
Studies*
TABLE IX Type and Frequency of Adverse Effects of Urapidil*
’ Studiis performed with orally administered urapidil have bean taken together (see text). Only the symptoq the number and frequency of adverse effects of urapidil have been tabulated. In 121 of more than 650 patients treated with urapidil, 195 adverse effects have been reported. Data adapted from References 6 to 16.
34D
weight remained constant; no signsof sodium and water retention could be observed.Relevant alterations of laboratory parameters did not occur. Safety and tolerability: Registration of the adverse effectsand determination of laboratory parametershave been performed in all the clinical studies with urapidil. The incidence of adverseeffects observedin the aforementioned 11 randomizeddouble-blind trial&l6 wasalso established (Table VII). The results of Kanekot6 are divided into those receiving monotherapy (prazosin) and those receiving combination therapy (prazosin with thiazide diuretics). When all adverseeffectsof the 11 comparativestudiesare taken together, it appearsthat in 121 of more than 650 treated patients with urapidil, 195 adverseeffects have been reported. The most important symptoms were dizziness, nauseaand headache(Table VIII). The various adverse effectswere minor and transient in all trials, rarely causing withdrawal from therapy. After a few days of treatment with urapidil, most of the adverseeffects,like dizziness,nauseaand headache, disappearedspontaneously.Theseadverseeffectsmay be attributed to the decreasein blood pressure,frequently observedat the beginning of active treatment with an antihypertensive drug. Being fully aware of the existing bias, we have compared the type and frequency of adverseeffectsof urapidil of the 11comparativestudieswith the data of 1 year of treatment in more than 900 patients participating in the open noncontrolled multicenter trial with urapidil. This comparisonby Liebau et a122(Table IX) draws attention to the fact that the type and the frequency of adverse effects are rather similar in all studies. In the courseof the various clinical trials, laboratory parametersreflecting liver and kidney function, electrolytes, red and white cell counts together with differential blood counts, thrombocyte counts, as well as cholesterol, triglycerides, uric acid and blood glucoselevels were determined routinely. In the comparative studies this was performed as a pre-/postcomparison,and in the open long-term studies,
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
Symptoms
Comparative Studies (%)
Multicenter Study (“4
Dizziness Nausea Headache Palpitations Tiredness Stomach disorders Orthostatic dysregulation Edema Sleep disturbances Other
8.0 4.2 4.2 2.3 0.9 0.9 0.9 0.9 0.5 7.3
5.5 3.4 2.5 0.7 1.4 1.1 1.1 0.7 5.2
* Tr;r” and frequency of adverse effects of urapidil of the 11 comparative stud&-’ have been compared with data on 1 year of treatment in over 900 patients participating in the open noncontrolled multicenter trial with urapidil performed by Liebau et a1.a
additional laboratory values were measured at regular intervals. No clinically relevant changeswere found in daily dosesbetween 30 and 180 mg/day of urapidil. In this respect,urapidil differs from p blockersand diuretics, which are known to alter various laboratory parameters like glucose, uric acid and potassium levels. With regard to the influence of antihypertensivedrugs on lipid metabolism, fi blockers and diuretics are known to induce somenegativeeffects,whereasurapidil appears to be neutral.23Urapidil also doesnot influence airways resistance.Accordingly, urapidil may be safely given to patients with obstructive airways diseaseor diabetesmellitus. Specific contraindications for urapidil are unknown. Thus far, no rebound hypertension has beenobservedfor urapidil, neither in the performed clinical trials nor in daily practice. Similarly, no clinically relevant interactions with other drugs (e.g.,digoxin and cimetidine) have been observedfor urapidil.24 URAPIDIL-INTRAVENOUS
APPLICATION
Intravenous single-dose studies performed for investigational purposes in patients with essential hypertension (phase I): In 6 studies, a total of 90 patients with
essentialhypertension received single dosesup to 50 mg intravenously, someas repetitive injections and someas a continuous infusion.25-30The duration of the blood pressure-reducing effect was generally between 15 minutes and 6 hours. The maximal effect occurred within the first 60 minutes and it usually faded away after the fourth hour. Heart rate changedonly shortly after administration in some investigations. The effect proved transient. Peripheral vascular resistance was greatly reduced while cardiac output and myocardial functions were altered Renal plasma flow was only slightly or not at all. 26,28,29 somewhatincreased.Plasma renin activity and the concentrations of norepinephrine and epinephrine, angiotensin II, and sometimesaldosterone25,30 increasedslightly. Adverse effects, mainly orthostatic hypotension, rarely occurred.29In hypertensivepatients with obstructive lung disease(n = 10) and in normotensivepatients with hyperreactive bronchi (n = lo), no deterioration of lung functions after urapidil administration was observed.31Obstructive airways diseasedoesnot appearto be a contraindication to urapidil. Urapidil applied intravenously gencies: In 6 studies involving
in hypertensive
emer-
134 patients with hypertensiveemergencies,the patients received1 or more injections of urapidi1.32-37 In somecasescontinuous infusions were applied. Two studies32,33 were conducted in singleblind manner so that initial placebo doseswere followed by urapidil. Adverse effects in 36 patients were recorded and all appeared to be related to rapid blood pressure reduction. Theseadversereactionswereusually transient. Severehypotensive reactions occurred after a 25-mg i.v. dose was administered to 1 patient who had been pretreated with captopri134and after a 50-mg i.v. dosewas administered to another patient.35In a third patient who initially received 20 mg of urapidil followed by a 40 mg injection, these reactions also occurred.36
Comparative studies in hypartansion with urapidil administered intravenously: A comparative study was
performed by Rosenthal,38who treated 6 patients with hypertensiveemergencieswith urapidil followed by sodium nitroprusside, and 4 patients with sodium nitroprusside followed by urapidil. In all casesan adequateblood pressurereduction was achieved.Obvious adversedrug reactions did not occur. A further comparative study against diazoxide in 42 patients was performed by Vrhovac et a1.39Urapidil was given as 25-mg injections and, if necessary,in dosesup to 200 mg in several hours. Mean arterial blood pressure decreasedfrom 182.7 f 20 to 139.5 f 16.9 mm Hg (p <0.05). Diazoxide wasgiven as a lOO-mgi.v. injection; if necessary,it was increased to 200 mg. Mean arterial pressurein this casedecreasedfrom 174 f 19.1 to 132.2 f 25.2 mm Hg (p <0.05). Urapidil in pregnancy-induced hypertension: Twenty-one patients with severe preeclampsia were treated with repetitive single i.v. injections of 25 to 50 mg of urapidil, followed by continuous infusions of urapidil in order to maintain the antihypertensive effect.40For prevention of eclamptic seizures,magnesiumascorbatewas applied asa concomitant treatment. Comparedwith other antihypertensive drugs, urapidil was consideredto be preferable in this case, particularly becausethis compound does not increase intracranial pressure. Urapidil in congestive heart failure: With regard to the effectsof i.v. dosesof urapidil in patients with congestive heart failure due to various underlying diseases,3 studies should be mentioned41-43:Metcalf et a1,41Reiterer42and Wang et a143studied a total of 35 patients in New York Heart AssociationclassII to IV using invasive methods.Urapidil wasadministered in 1 or 2 subsequent dosesand, in some cases,as continuous infusions. Left ventricular performance, myocardial oxygen consumption, coronary blood flow, cardiac output, vascular resistance, and pulmonary artery and systemicarterial pressures were quantified. Negative inotropic activity or increasedmyocardial oxygenconsumptionwere not measured and undue adverse reactions were not observed. The combination of urapidil and dobutamine in the lowoutput syndrome after coronary artery bypass surgery was examined in 12 patients.44Urapidil alone raised the cardiac index from 1.8 liters/m2 X minutes to 2.7 liters/ m2X minutes.The addition of dobutamine, 5 pg/kg body weight X minutes increasedthe cardiac index further to a value of 3.4 liters/m2 X minutes. Heart rate remained unchanged and no significant effects on the myocardial oxygen balance were determined. Urapidil wasfound to be effectivein combination with dobutamine in the treatment of low-output syndrome after bypasssurgery. In all, the effectsof urapidil in these small and uncontrolled studies were judged favorable. Use of urapidil in anesthesia: In 10 intraoperative studiesduring various typesof anesthesia(altogether 245 patients), urapidil wasfound to be effective and safe.The amount of urapidil applied greatly varied. In comparative treatments with sodium nitroprusside45,46or phentolamine,47the absenceof reflex tachycardia wasobvious.45
THE AMERICAN JOURNAL OF CARDIOLOGY AUGUST 15, 1989
35D
A SYMPOSIUM:
PHARMACOLOGIC
AND THERAPEUTIC
ASPECTS OF URAPIDIL
During controlled hypotension,a three- to fourfold reduction of the required amount of sodium nitroprussidecould be achieved,if urapidil had been preinjected.46Because urapidil doesnot directly affect myocardial performance and doesnot causetachycardia, it may be useful in coronary bypasssurgery.47-52Furthermore, urapidil appears suitable for the treatment of hypertensive episodesin patients who have undergone neurosurgery. In 8 hypertensive patients, van Aken et aP3 found no increase in intracranial blood flow and intracranial pressure(seealso reference 54). Use of urapidil in postoperative hypertension: In 2 studiesof postoperativehypertensionafter aortocoronary bypasssurgery,55v56 20 patients treated with urapidil were comparedwith 19 patients treated with sodium nitroprusside. Junger et aP found smoother blood pressuretime curves with urapidil than with sodium nitroprusside. With the exception of 1 patient,55no increase in heart rate was observed.After aortocoronary bypasssurgery, no increase in pulmonary right to left shunting (venous admixture) was seenduring treatment of hypertension with urapidil therapy in artificially ventilated patients. In contrast, patients under the sameconditions, but treated with sodium nitroprusside, had increasedvenousadmixture and, therefore, decreasedarterial oxygen pressure values.57 Treatment of severepostoperativehypertension after cardiovascularsurgery wasstudied in 19children aged 12 days to 14 years (mean 7.2 years).58 A prompt decreasein blood pressure was achieved within the first 15 minutes after i.v. single injections. This effect could be maintained throughout the entire period of urapidil application infused continuously (range 1 to 95 hours). In 1 case,a severehypotensiveeffect occurred within 5 minutes after the start of the infusion. CONCLUSIONS Chronic application of urapidil in dosesranging from 30 to 90 mg twice daily appearsto reduce blood pressure adequately in patients with various grades of hypertension as shown in different studies in several countries. The degreeof blood pressurereduction by urapidil is not significantly different from that causedby captopril, slow-releasenifedipine, nitrendipine, acebutolol, metoprolol, atenolol, metipranolol combined with butizide, clonidine, cY-methyldopaand prazosin.‘-l6 Responder rates in thesetrials varied from 40 to 70%and globally no differenceswere found betweenurapidil and the various comparative drugs. In all studiesperformed thus far, and also in daily practice, urapidil appearsto be effective and well-tolerated, with an acceptablepattern of adverseeffects.Urapidil can also be applied intravenously in hypertensive emergencies. The blood pressure-lowering effectsafter single injections appear within the first 15 minutes and persist for 4 to 6 hours. Urapidil given intravenously appearsto be a suitable treatment in various acute situations of hypertension. The efficacy of i.v. urapidil is similar to that of diazoxide and sodium nitroprusside. Like other vasodilating drugs, urapidil should not be given intravenously to 36D
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64
patients with stenosisof the aortic isthmus or with aortic valve disease.The adversereactions appear to be mainly transient orthostatic reactionsoccurring soonafter application of urapidil. No reflex tachycardia was found, except in the first minutes after rapid injections. No adverse reactions occurred in combination with various agents usedduring general anesthesia.A specialadvantagemay be that urapidil, although a vasodilator, doesnot causean increase in intracranial pressure. REFERENCES
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