Essential Hypertension J.J.M.L

Br. J. clin. Pharmac. (1983), 16, 39-44

EFFECTS OF INTRAVENOUS ENDRALAZINE IN ESSENTIAL HYPERTENSION J.J.M.L. HOFFMANNI"*, TH. THIEN2 & A. VAN 'T LAAR2 'Department of Experimental and Chemical Endocrinology and 2Division of General Internal Medicine, Department of Medicine, St Radboud Hospital, Nijmegen, The Netherlands

1 The effects of endralazine, administered intravenously, on blood pressure, heart rate, forearm blood flow, plasma renin activity, aldosterone, adrenaline and noradrenaline were studied in five patients with essential hypertension. 2 Endralazine reduced peripheral vascular resistance, resulting in decrease in mean arterial pressure from 141 to 116 mm Hg and increase in heart rate from 67 to 92 beats/min. 3 Plasma renin activity, adrenaline and noradrenaline increased significantly after endralazine infusion. 4 All effects observed are consistent with endralazine acting as a peripheral vasodilating drug.

Introduction

Endralazine (BQ 22-708) is a new antilhypertensive Another important difference between both drugs drug, which chemically and pharrniacologically is their major route of metabolism. After oral resembles hydralazine; endralazine is a substituted administration to fast acetylators, hydralazine is hydrazinopyridazine and hydralazine is;a hydrazino- mainly converted by acetylation of its hydrazino- derivative of phtalazine (Figure 1). Both drugs act as moiety, while in slow acetylators hydralazine-pyruvic peripheral vasodilators by direct relaxatioIn of vascular acid hydrazone is the major metabolite (Reece et al., smooth muscle, especially of the resistaince vessels. 1980). So, the patient's acetylator phenotype causes Besides the close relationship, the drugs (display some appreciable inter-individual variation in metabolic differences. On equal weight-basis enidralazine is half-life. Since the major pathway of endralazine about five times more potent than hydrzalazine, thus metabolism is accounted for by hydrazone formation allowing lower dosages. This possibly cc uld give rise with endogenous keto-compounds, its elimination to less immunological side-effects (the well-known rate seems to be virtually independent of acetylator lupus-like syndrome) than hydralazine does, since type (Reece et al., 1981). This important observation this side-effect seems to be dose-rellated (Koch may allow a less wide dosage range for endralazine as Weser, 1976). compared to hydralazine. The side-effects reported to occur during oral endralazine therapy are not essentially different from Endralazine those of hydralazine, even being partially inherent to the mechanism of action (Koch-Weser, 1974): head- c NH-NH ache, flushing, palpitations, tachycardia and oedema 11 2 (Lehmann et al., 1977; Kindler et al., 1981; Kirch & Axthelm, 1982). Immunological effects attributable to endralazine have not been reported, so far. At present, besides valuable animal studies (Salzmann et al., 1979; Oates & Stoker, 1981; HydraLazine Maxwell et al., 1981), only a limited number of N~~~~ clinical studies on endralazine have been published, all describing oral administration of endralazine to patients with resistant essential hypertension NH-NH2 (Lehmann et al., 1977, 1978; Kindler et al., 1981; Figure I Molecular structures of endrralazine and Kirch & Axthelm, 1982; Elliott et al., 1982), renal hydralazine. hypertension (Kindler et al., 1981; Lehmann et al., * Present address: Department of Clinic -al Chemistry 1978) and hypertensive crisis (Lehmann et al., 1977). Catharina Hospital. Eindhoven. The Netherllands. To our knowledge, the present study is the first one 39 40 J.J.M.L. HOFFMANN, TH. THIEN & A. VAN 'T LAAR

dealing with the effects of intravenously administered nected to a non-invasive blood pressure (BP) measur- endralazine in man. The aim of our study was to ing unit (Arteriosonde; Roche Instruments), equipped determine the effects of intravenous (i.v.) endralazine with an ECG module for recording heart rate (HR). administered to patients with severe, untreated BP and HR registrations were made every 2 min essential hypertension and to obtain data on its effect during the entire observation period, which began at on plasma renin activity (PRA) and plasma least 1 h before the start of the infusion. In three out catecholamines, which has not yet been described in of five patients also the forearm blood flow (FBF) was man. measured by venous occlusion plethysmography. About 30 min prior to the infusion, a short i.v. catheter for blood collection was inserted into the left Methods antecubital vein. Endralazine was infused by means of a Braun infusion pump with a mean rate of 0.27 Materials mg/min. The doses ranged from 4 to 10 mg (mean 6.6 mg). Endralazine (BQ 22-708; 6-benzoyl-3-hydrazino-5, Immediately before and 30 and 60 min after the 6, 7, 8,-tetrahydropyrido [4,3-c] pyridazine mesylate) start of the infusion a blood sample was taken and at was donated for this study by Sandoz B.V. (Uden, the same time FBF was measured in the three patients. the Netherlands). The desired amount of endralazine, Mean arterial pressure (MAP) was calculated as supplied as lyophilized powder in 1 mg ampoules, was the sum of diastolic BP and 1/3 of the pulse pressure. dissolved in the solvent provided (0.9% NaCI) just The BP, HR and MAP values given below are the before use and diluted further with sterile water. averages from four consecutive measurements each. Forearm vascular resistance (FVR) was calculated as Patients MAP divided by FBF and expressed in arbitrary units. In each plasma sample the following deter- The relevant clinical data on the patients are given in minations were performed: PRA by radioimmuno- Table 1. All patients had moderate or severe essential assay (Drayer & Benraad, 1975), aldosterone hypertension and were without medication for at least (ALDO) by direct radioimmunoassay (de Man & 4 weeks at the time of the study. Before participating, Benraad; 1977) and the catecholamines adrenaline they had been fully informed on the design of the and noradrenaline (A and NA) by radioenzymatic study and had given their consent. Pre-treatment assay (Hoffmann et al., 1982). values of haemoglobin and plasma electrolytes, creatinine, uric acid and liver function tests were Statistical calculations within normal limits for all patients. Correlation-analysis was performed by the method of Methodology least squares. Data of FBF and FVR were evaluated using the Wilcoxon non-parametric test for paired The experiments were carried out in the morning in a data. All other parameters were compared by quiet, constant temperature room. The patients were Student's t-test, but the PRA, ALDO, A and NA allowed to take a light breakfast, but had to abstain data only after logarithmic transformation. P values from smoking and coffee starting the evening before. lower than 0.05 were considered to be significant. All They were placed in a recumbent position and con- values are given as mean + s.d.

Table I Clinical data of the patients before treatment Supine blood Age pressure* Weight Height Dose Patient (years) Sex (mm Hg) (kg) (cm) (mg) 55 M 173 127 80.8 166 9 2 41 F 183 120 76.0 165 5 3 55 F 197 115 78.0 169 5 4 31 M 169 128 83.3 178 4 5 49 M 214 152 100.4 188 10 Mean 46.2 187 128 83.5 173 6.6

* Mean of the last four Arteriosonde measurements before starting the infusion INTRAVENOUS ENDRALAZINE IN HYPERTENSION 41

Results 0.05) and FVR decreased from 79 to 50 U (not significant). An example of the course of an experiment with i.v. The results of the determinations in plasma are endralazine is shown in Figure 2. It can be seen that presented in Figure 4. PRA increased from 0.57 + within 5 min from starting the infusion, BP commences 0.24 to 1.30 + 0.79 (gg/l)/h, (P < 0.025) at 60 min; to decrease. Approximately 1/2 h later the plateau changes in aldosterone concentration were not value is reached, which is more than 20% lower than significant, the mean values being 361 ± 237 pmol/l pre-treatment BP in this patient. At the same time as before and 317 + 238 pmoll1 h after starting the the decrease in BP, a sharp rise in HR can be observed. infusion. Significant increases in plasma catecholamine The peak value, more than 30 beats/min higher than concentrations have been observed: NA rose from before the infusion, is obtained some 50 min after initially 2.18 + 0.39 nmol/l to finally 5.28 + 1.32 (P < starting the administration of endralazine. In this 0.005) and A from 0.19 + 0.08 nmol to 0.47 + 0.31 (P exemplary patient, who received 10 mg endralazine, < 0.005) respectively. Table 2 shows the correlation palpitations and chest pain began to develop during coefficients obtained by comparing changes in some the tachycardia period, accompanied by alterations of the parameters measured. Data of PRA, A and on the electrocardiogram (ECG) and therefore i.v. NA have been log-converted before evaluating their administration of metoprolol was regarded necessary correlation. One can see that the proportional (Figure 2). Immediately thereafter, HR normalised changes in MAP correlate significantly with changes and the patient no longer indicated cardiac complaints. in HR as well as with absolute changes in A and PRA. Some haemodynamic parameters are shown in Further, absolute changes in HR correlate with those Figure 3 (means of the five patients). Mean BP fell in A and NA. Finally, the decrease in MAP and the significantly from 186/119 (+ 28/14) before infusion increase in HR both correlate significantly with the to 1681/96 (+ 19/7) and 165/92 (+ 17/6) mm Hg 30 and dose of endralazine administered. 60 min later, respectively. As a consequence, mean In the present short-term study on endralazine, MAP decreased from 141 + 20 mm Hg to 121 + 7 (P several side-effects have been observed, almost < 0.01) and 116 + 8 (P < 0.005), respectively. exclusively in the patient of Figure 2 and in one other Concomitantly, HR increased from a basal value of patient (1), who both received the higher dose of 67 + 8 beats/min to 86 + 9 (P < 0.001) and 92 + 9 (P endralazine: flushing, palpitations, chest pain and < 0.001), respectively at the moments indicated. In alterations on the ECG, which were indicative for three patients FBF ultimately increased by 20% (P < ischaemia or left ventricular hypertrophy.

0 11 III

240 - a b

0) I E 200- E .' 100* 0)L- E 4,4 0 160- en Cna, -8080- ~0 a) mn° 120- a 60 I 80- * X**P -T 40 60 80 100 120 140 160 Time (min) Figure 2 Complete course of an experiment (patient 5). At t = 0, monitoring of blood pressure (BP) and heart rate (HR) started. Moments indicated by Roman numerals are: 0 insertion of catheter and I-tII blood collection. The bars indicate intravenous administration of (a) endralazine 10 mg and (b) metoprolol It) mg. Open symbols represent HR and filled circles mean arterial pressure. 42 J.J. M.L. HOFFMANN, TH. THIEN & A. VAN 'T LAAR

200

I E 140- m * 80-

I I II 1I III

b 160 - Z 100- ._ I Cu E .0 E 120 - 80- *~~~** 0 0L Cu t 80 - 60-

I I I I I I 11 III 11 III

Fuigre 3 a) Means of systolic and diastolic blood pressure just before and 30 and 60 min after starting the infusion. *P < 0.05 and **P < 0.005. b) Values of mean arterial pressure (MAP) and heart rate at t = 0, 30 and 60 min, respectively. *P < 0.01, **P < 0.005, ***P < 0.001.

Discussion In nearly all patients with hypertension an increased PRA measurements in our investigations of the vascular resistance is the only haemodynamic effects of intravenous endralazine. abnormality observed (Koch-Weser, 1974) and The results presented (Figures 3 and 4) demonstrate therefore, vasodilators should theoretically be con- that endralazine is a potent vasodilator, producing a sidered as the drugs of first choice for treatment. decrease in peripheral vascular resistance, and con- However, in practice their use is limited because of sequently in blood pressure, accompanied by the occurrence of unfavourable side-effects, which sympathetic activation which results in increases in partially are inherent to the mode of action (Koch- HR and PRA. In turn, PRA should cause a rise in Weser, 1974, 1976). Ongoing research recently plasma aldosterone, which we could not detect in our resulted in the synthesis of a new compound with study, however. Due to the duration of our experi- vasodilating properties, endralazine (Schenker & ments it was not possible to observe the effects of Salzmann, 1979). Preliminary pharmacological data, endralazine on electrolytes and fluid balance which obtained in animal experiments with i.v. administration, can be expected to occur as a consequence of both showed among others that the increase in PRA, increase in aldosterone and decreased renal plasma which can be expected to occur as a reflex to flow (Thien, 1980). From the literature one can con- vasodilation, remained absent (Salzmann et al., clude that in some patients considerable sodium 1979). This phenomenon prompted us to include retention can occur during long-term oral use of INTRAVENOUS ENDRALAZINE IN HYPERTENSION 43

500- might explain these conflicting data. The correlation E study (Table 2) indicates that several major effects of 2.0 endralazine are closely related, demonstrating that E 300-3 endralazine behaves according to the general model 1.0 01. for direct vasodilation which has been presented by ~100 Koch-Weser (1974). The side-effects observed are not essentially different from those occurring during long-term oral endralazine administration (Kindler et al., 1981; Lehmann et al., 1977 and 1978; Elliott et al., 1982; Kirch & 5.0 0.5 U Axthelm, 1982), partially being consequences of the mechanism of action (Koch-Weser, 1976). As shown o E II II II II in Figure 2, a very rapid onset of effect on BP is 3.0 0.3 achieved with i.v. endralazine. Within 5 min after starting the infusion a substantial decrease in especially z 1.0 1 0.1 1 diastolic BP was observed, which is even faster than has been reported for i.v. hydralazine (Koch-Weser, 1976). Thus, combined with data from the literature, we may conclude that endralazine is a potential alter- Figure 4 Effects of endralazine on plasma renin activity (PRA), plasma aldosterone, plasma noradrenaline native when acute treatment of hypertension is (NA) and adrenaline (A) in the five patients. Mean + needed, with the restriction that the administration s.d. is given. k'P < 0.025 and **P < 0.005. should be monitored carefully because of the occurrence of possibly harmful side-effects, especially in patients with coronary insufficiency. The general endralazine (Kindler et al., 1981; Reubi, 1978; Kirch limitations for treatment of hypertension with direct- & Axthelm, 1982). ly vasodilating drugs do hold for endralazine, too. Concerning the rise in PRA, identical results have The absence, up to now, of immunological side-effects been reported after oral administration of endralazine forms a clear advantage over hydralazine. For short- (Reubi, 1978; Elliott et al., 1982), so the discrepancy and long-term therapy, endralazine administration with the animal studies (Salzmann et al., 1979) is should be combined with J8-adrenoceptor blocking confirmed here. Different experimental conditions drugs and for long-term treatment with diuretics as between the human and the animal experiments well.

Table 2 Correlation coefficients of changes in heart rate (HR), mean arterial pressure (MAP), plasma renin activity (PRA), adrenaline (A) and noradrenaline (NA). For all correlations two observations per patient were used (n = I1). HR A NA PRA Dose M6o (nmol!l) (nmol l) ([AgJl]/h) (mg) MAP r = 0.673 r = 0.684 r = 0.350 r = 0.658 r = 0.948 (%) P<0.025 P<0.025 NS* P<0.025 P<0.01 HR r= 0.552 r= 0.793 r= 0.201 r= 0.842 (beats min) P < 0.05 P < 0.005 NS* P < 0.05 * NS = not significant

References

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