Acta Med Scand 1983; 214: 125-30

Ketanserin in Hypertension Early Clinical Evaluation and Dose Finding Study of a New 5-HT2 Receptor Antagonist

LENNART ANDREN, ANDERS SVENSSON, BJORN DAHLOF, ROBERT EGGERTSEN and LENNART HANSSON From the Hypertension Section, Department of Medicine, Ostra Hospital, Uniwrsiw of Goteborg, Goteborg, Sweden

ABSTRACT. Andren L, Svensson A, Dahlof B, Eggertsen R, Hansson L. (Department of Internal Medicine, Ostra Hospital, Gothenburg, Sweden.] Ketanserin in hypertension. Acta Med Scand 1983; 214: 125-30. Ketanserin, a new 5-hydroxy-tryptamine antagonist, was given at three different dosage levels (double-blind, randomized) in a dose fmding study for 2 months to 31 patients with mild to moderately severe essential hypertension. Treatment with ketanserin was then continued until 9 months had been completed. A significant antihypertensive effect was demonstrated at daily dosages of 20 mg t.i.d. or 40 mg t.i.d. The antihypertensive effect was similar to that of previous multiple drug treatment with conventional drugs. However, 60 mg t.i.d. was not acceptable, at least not as initial dosage. At this dose level, 8 out of 10 patients had to be withdrawn from the study during the initial phase due to unwanted effects. It is conceivable that a,-adrenoceptor blockade may have played a role at this dose level, since postural reactions were observed which was otherwise not the case during this study. Ketanserin is a new and interesting alternative in the treatment of hypertension. At the same time it offers a tool by which the role of 5-hydroxy-tryptamine in the regulation of arterial pressure can be investigated. Key words: hypertension, serotonin, 5-HT2 recepror blockade, ketanserin.

The view has long been held in the Scandinavian countries that a patient with hypertension should be treated first with either a diuretic or a P-adrenoceptor blocking drug. However, this view is now more widely accepted (1). On the other hand, it is equally clear that treatment with such agents is not uniformly effective ( I ) , nor is it free from side-effects (1, 2). For such reasons there is a constantly ongoing search for more effective or better tolerated antihypertensive drugs. Numerous examples of such new agents could easily be given, e.g. calcium antagonists, angiotensin converting enzyme inhibitors, renin antago- nists and drugs with multiple actions such as B-adrenoceptor blockade combined with vasodilatation.

The present study concerns some early investigations with a new substance of a category which has previously not been used in the treatment of hypertension. The new substance, called ketanserin, is a 5-hydroxy-tryptamine2 (S-HT2) receptor antagonist. The purpose of the study was to try to establish whether this substance has an antihypertensive effect in hypertension and to find the effective dose.

PATIENTS AND METHODS Pharmacology Ketanserin (R 41 468, 3-[2[4~(4-fluorobenzoy1)-I-piperidinyll ethyll-2,4(1 H, 3 H) quinazolinedione) (Fig. 1) blocks the effect of serotonin on 5-HTz receptors in blood vessels, bronchial muscle and platelets (3). In brief, this agent is a selecriw serotonin2 receptor antagonist. In other words, it has no effect on 5-HT, receptors. Moreover, it is a pure blocker in the sense that, unlike previously available serotonin antagonists, it has no agonistic effects. Finally, ketanserin is a specific serotonin antagonist.

126 L . A n d r h et al. Acta Med Scand 1983: 214

0 Fig. 1. Structural formula and perspective illustration of the ketanserin molecule.

Thus, effects produced by other amines such as histamine, noradrenaline, adrenaline and others are not blocked by ketanserin at doses causing pharmacological 5-HT2 receptor blockade.

Patients Thirty-bne patients with mild to moderately severe essential hypertension were included in the trial. All hadlcompleted a routine investigation to rule out secondary forms of hypertension (4). There were 15 males and 16 females. Their average age w a s 52 years (range 29-49). Untreated diastolic blood pressures were within the range of 100-120 mmHg in all patients on at least three occasions. Patients with congestive heart failure, impaired renal function, myocardial infarction within the last 6 months, and psychiatric problems including alcoholism were excluded. Most patients had previously been treated with one or more antihypertensive drugs (Table I). All patients gave their written informed consent to participate in the study. This study w a s approved by the Ethical Committee of the University of G6teborg.

Methods The study was carried out in two parts. The objective of the first part (phase I), which had a duration of 10 weeks, w a s to try to establish the effective and tolerable daily dosage. Following a 2-week

Table I. Maximal change in blood pressure (BP, mmHg) and heart rate (HR, beatslmin) during the initial 8 weeks of treatment with ketanserin (mean k SEM) Initial treatment (no. of pats.): /?-blocker 1, /?-blocker + diuretic 10, ,!%blocker + hydralazine 6, other 4. BPs = systolic BP, BPd = diastolic BP

Initial Placebo Ketanserin

Ketanserin 20 mg t.i.d. (n=11) BPs supine 151.4f6.7 166.8k7.5 153.0+7.5** BPd supine 97.3f2.4 102.7f2.3 97.0f2.7* HR supine 73.8f4.1 61.4f3.4 70.0f3.8 BPs standing 150.5f7.0 161.8k7.0 155.0f9.1 BPd standing 102.3k1.8 111.8f2.9 104.5+3.5***

Kaanserin 40 mg t.i.d. (n=lO) BPs supine 154.5f4.2 173.0f6.5 158.5 k5.1 BPd supine 95.0f1.8 101.5f2.9 91.0f3.6* HR supine 72.4f3.4 64.4f3.9 68.2 ? 3.6 BPs staqding 149.0f4.9 I71 .Of6.0 157.2f9.3 BPd standing 100.0f1.3 108.0f3.1 98.0f3.5*

Statistical comparison between placebo and ketanserin * p<0.05, **p<0.02, ***p<O.Ol.

Acta Med Scand 1983: 214 Ketanserin in hypertension 127

placebo period, patients were randomized (double-blindly) to treatment with tablets in doses of either 20 rng t.i.d., 40 mg t.i.d. or 60 mg t.i.d. The first dose of active medication was always given in the clinic and the patients were supervised for at least one hour thereafter. Exactly one hour after the first dose, a blood sample was taken for determination of the plasma ketanserin concentration.

Patients were then seen in the clinic after 1, 2, 4 and 8 weeks of active treatment. Blood pressure was measured in a standardized fashion by the same nurses throughout the study using a mercury sphygmomanometer (cuff balloon 13x35 cm). The disappearance (phase V) of Korotkoff sounds was taken as the diastolic blood pressure. On each occasion the average of three measurements was recorded. Recumbent blood pressure was measured after 5 min of supine rest and standing blood pressure after 1-2 min in erect posture. Heart rate was recorded in the recumbent position. In addition, all patients measured home blood pressures in the sittiqg position twice daily throughout the study.

A wide range of clinical chemistry laboratory parameters were assessed at the end of the placebo period and again following 4 and 8 weeks of active treatment.

Blood samples for analysis of plasma ketanserin concentration were drawn 1 hour after tablet intake on day 1, as described above, and again following 4 and 8 weeks of active treatment.

Following the dose finding study (phase I), patients were invited to continue treatment with ketanserin for up to 9 months. During this period (phase 11) blood pressure and clinical chemistry data were checked at intervals of 1-2 months.

Sialisiical methods Student’s i-test for paired observations was used for the statistical calculations, p<0.05 was consid- ered significant.

RESULTS Phase 1 The effects on blood pressure and heart rate during the dose finding part of the study (phase I) are shown in Table I. It soon became apparent that several patients did not tolerate ketanserin in a starting dosage of 60 mg t.i.d. In fact, one patient, a 27-year-old man, had a severe orthostatic reaction following the first dose of 60 rng. He apparently fainted and fell on the floor about 45 rnin after intake of the first tablet. He soon recovered and could leave the clinic after a few hours of observation. Later his plasma concentration was found to be remarkably high (see below). One more patient had acute symptoms of dizziness associated with a rapid fall in standing blood pressure following the first dose of 60 mg. He soon recovered after lying down for some 30 min. Altogether 8 of the 10 patients receiving ketanserin 60 mg t.i.d. were unable to complete the 8 weeks of active therapy

Table 11. Changes in blood pressure (BP, mmHg) and heart rate (HR, beatslmin) in 15 patients following treatment with ketanserin for 9 months (mean k SEM) Initial treatment (no. of pats.): /?-blocker 2,D-blocker + diuretic 9, /?-blocker + hydralazine 2, other 2. BPs = systolic BP, BPd = diastolic BP

Initial Placebo Ketanserin

BPs supine 152.0t3.4 167.0k6.0 154.6+3.9‘*’ BPd supine 95,7k I .7 102.0k2.0 95.0f 1.7** HR supine 73.7f2.8 63.5k3.5 72.6f3.4* BPs standing 148.7k4.3 163.3 k5.3 158.9f5.4 BPd standing 101.3+1.4 110.0k2.3 103.9+2.2**

Statistical comparison between placebo and ketanserin (*)p=0.058, * p<O.OS, ** p<0.02.

128 L. Andrin et al. Acta Med Scand 1983: 214

intended during phase I. Two of the I 1 patients receiving 20 mg t.i.d. and one of those 10 treated with 40 mg t.i.d. dropped out due to side-effects.

The most common side-effects causing withdrawal of ketanserin were fatigue (7 pa- tients, 4 of whom had multiple complaints). Fatigue was also reported by 8 patients (5 with multiple complaints) who nevertheless were able to continue on ketanserin for 8 weeks.

The average plasma ketanserin concentration following the first dose was 61 ng/ml in the 20 mg t.i.d. group, 80 ng/ml in the 40 mg t.i.d. group and 120 ndml in the 60 mg t.i.d. group. The patient with the severe initial hypotensive reaction had a plasma level of 207 ng/ml one hour after the first 60 mg tablet.

During prolonged treatment, plasma levels of individual patients usually showed some increase. The highest plasma level, 258 ng/ml, was observed following 8 weeks of treat- ment with 60 mg t.i.d. in a 60-year-old man. This was not associated with any symptoms or side-effects.

There was no correlation between plasma concentrations and the antihypertensive effect of ketanserin. No changes were observed in the clinical chemistry laboratory variables. Average weight increased by 1.5 kg (n.s.).

Phase II Out of the 20 patients who completed phase I, 16 agreed to continue treatment with ketanserin for another 7 months. Most of them were treated with 40 mg t.i.d. or 20 mg t.i.d., with minor adjustments. The average total daily dosage at the end of 9 months was 91 mg. Statistically significant effects on blood pressure and heart rate were noted during this long-term phase (Table 11).

Apart from some mild complaints of fatigue during the early part of this phase, most patients had no complaints or side-effects. No clinical chemistry laboratory abnormalities were observed. Body weight did not change.

DISCUSSION

Blockade of 5-HT2 receptors with the specific antagonist ketanserin is a new approach to the treatment of hypertension. It was only in 1954 that Page described the physiological effects of serotonin, after first having unravelled the chemistry of this substance to give it the name 5-hydroxy-tryptamine (5 ) . Today the role of 5-HT in relation to the circulatory system is well known. Thus, the release of 5-HT from aggregating platelets may trigger acute vasospastic episodes in larger arteries, which can lead to tissue ischemia, particular- ly in the coronary and cerebral circulations (6). It has also been possible to define, in pharmacological terms, the existence of 5-HT receptors in isolated intracranial and extra- cranial vessels of cat and man (7). In addition, 5-HT can modulate the adrenergic neuroeffector interaction locally in the blood vessel wall (8). Against this background it has been naturally asked what role, if any, 5-HT plays in hypertension and whether it would be possible to use a selective and specific 5-HT receptor blocking agent in the treatment of hypertension.

When ketanserin has been given to hypertensive animals and humans, it has not inhibited the vasodilator effects of S-HT, which may be a 5-HT1 receptor effect (9). Nor do the antihypertensive properties of ketanserin appear to involve al-adrenergic inhibition in the doses commonly used (9). Others have questioned such statements, since studies in rats have indicated that the al adrenoceptor blockade rather than 5-HT2 blockade would appear to be the major factor contributing to the hypotensive/antihypertensive action of ketanserin (10). This view has been supported by two independent groups who have investigated the cardiovascular effects of ketanserin in the rat (1 I , 12).

Acta Med Scand 1983; 214 Ketanserin in hypertension 129

The present study clearly demonstrates that ketanserin has a beneficial antihypertensive effect when given as single therapy to hypertensive patients. In this respect, our study confirms the early experience by De Crke et al. (13). It is also obvious from our dose finding phase that at least initiation of treatment with ketanserin should not be attempted in dosages involving 60 mg tablets. In fact, 8 out of 10 patients who began treatment with 60 mg t.i.d. had to be withdrawn from the trial because of side-effects.

Our study further show$ that 40 mg t.i.d. appears to be more effective than 20 mg t.i.d. in the treatment of mild to moderately severe hypertension. Therefore 40 mg tablets seem to be most logical when initiating treatment. It is still an open question whether ketanserin has to be given three times daily. We did not investigate other alternatives, but it is conceivable that twice or even once daily administration could have been effective.

It is also possible that the full antihypertensive potential of ketanserin was not demon- strated in the present study. For technical reasons an unusually short placebo period (2 weeks) had to be used, and it is conceivable that this period was too short to allow full return of arterial pressure to a truly untreated level in these patients, most of whom had been on treatment with multiple antihypertensive drugs prior to the present trial.

During our long-term evaluation of ketanserin it was obvious that this compound maintained an antihypertensive effect. By and large, the blood pressure levels obtained were similar to those previausly seen in the same patients when diuretics andor B- adrenoceptor blocking agents had been administered. Ketanserin also appeared to be well tolerated both subjectively and as judged from the clinical chemistry latoratory param- eters.

Our attempt was not to investigate the mechanism by which ketanserin lowers blood pressure. In acute studies of hypertensive patients, intravenous administration of ketan- serin has reduced arterial pressure mainly through a reduction of total peripheral resist- ance (14). Hemodynamic studies in spontaneously hypertensive rats have confirmed that arteriolar vasodilatation, with little effects on the veins, appears to be the major factor underlying the antihypertensive response and that the reduction in blood pressure is not accompanied by reflex cardiac acceleration (15). This agrees with our findings, which did not demonstrate an increase in heart rate when blood pressure was reduced during the first 8 weeks, although a slight increase was seen after 9 months.

The possible contribution of al-adrenoceptor blockade to the antihypertensive response to ketanserin was not investigated in our study. In several animal studies, al-adrenoceptor blockade, rather than blockade of 5-HTz receptors, has been claimed to be the important effect underlying the hypotensive response (10-12). However, Vanhoutte et al. (9) have shown that the al-adrenergic blocking effect is of importance only when higher doses of this compound are administered. The initial orthostatic reactions in two of our patients given the highest dose of ketanserin (60 mg) appears to support the view that a1- adrenoceptor blockade could play a role, at least at this dosage level. However, during prolonged treatment with ketanserin in lower doses (on the average 91 mg daily) there were no indications of postural hypotension or orthostatic reactions.

An interesting observation was made in two male patients, 68 and 69 years of age, with severe intermittent claudication. Their ability to walk was limited to 50-100 m and, in addition, one of them had vasospastic problems of the Raynaud kind which made him very sensitive to cold. After having been placed on ketanserin (single-blind) the first patient came back after one week of treatment reporting that he had walked to the hospital (approximately 3 km) without interruption. The other patient claimed similar dramatic improvements in his walking ability. He reported also that he was now able to walk in deep snow at - 15°C wearing rubber boots without experiencing any vasospastic problems. Both these patients were treated with 40 mg t.i.d. This experience prompted us to conduct

9-838712

130 L. AndrCn et al. Acta Med Scand 1983; 214

a double-blind trial in 10 patients with intermittent claudication who received placebo or ketanserin, 20 mg b.i.d., in randomized order. In this unpublished trial we were unable to demonstrate a beneficial effect, possibly due t o the low dosage chosen. Thus, it is conceivable that ketanserin, in adequate dosage, may have a positive effect in patients with intermittent claudication. Such an effect would not be unexpected in view of the vasoconstricting effects of serotonin released from platelets and merits further study.

It can be concluded that ketanserin, which is a new, pure, specific and selective 5-HTz receptor blocker, has a beneficial antihypertensive effect. It is well tolerated during prolonged treatment provided the daily dosage is kept within the range of 60-120 mg at least during initial treatment. This interesting compound deserves further evaluation in the treatment of hypertension (and in intermittent claudication). Its use may provide new and useful information on the role of 5-HTz in the regulation of arterial pressure.

REFERENCES 1 . Editorial. Diuretic or beta-blocker as first-line treatment for mild hypertension? Lancet 1982;

2: 1316-7. 2. Medical Reserarch Council Working Party on Mild to Moderate Hypertension. Adverse reactions

to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981; 2: 53943. 3. Leysen JE, Awouters F, Kenis L, Laduron PM, Vanderberk J, Janssen PAJ. Receptor binding

profile of R41468, a novel antagonist at 5-HT2 receptors. Life Sci 1981; 28: 1015-22. 4. Anderson 0, Berglund G, Hansson L et al. Organization and efficacy of an out-patient hyperten-

sion clinic. Acta Med Scand 1978; 203: 391-8. 5. Page IH. Serotonin (5-hydroxytryptamine). Physiol Rev 1954; 34: 563-88. 6. Vanhoutte PM. 5-Hydroxytryptamine and vascular disease. Fed Proc 1983; 42: 83-7. 7. Edvinsson L, Hardebo JE, Owman C. Pharmacological analysis of 5-hydroxytryptamine recep-

tors in isolated intracranial and extracranial vessels of cat and man. Circ Res 1978; 42: 143-51. 8. Vanhoutte PM, Verbeuren TJ, Webb RC. Local modulation of the adrenergic neuroeffector

interaction in the blood vessel wall. Physiol Rev 1981; 61: 151-247. 9. Vanhoutte PM, Van Nueten JM. Symoens J, Janssen PAJ. Antihypertensive properties of

ketanserin (R41468). Fed Proc 1983; 42: 32-5. 10. Fozard JR. Mechanism of the hypotensive effect of ketanserin. J Cardiovasc Pharmacol 1982;

4: 829-38. 11 . Kalkman HO, Timmermans PBMWM, Van Zwieten PA. Characterization of the antihypertensive

properties of ketanserin (R41468) in rats. J Pharmacol Exp Ther 1982; 222: 227-31. 12. Persson B, Hedner T, Henning M. Cardiovascular effects in the rat of ketanserin, a novel 5-

hydroxytryptamine receptor blocking agent. J Pharm Pharmacol 1982; 34: 442-5. 13. De Cree J, Leempoels J, Geukens H, De Cock W, Verhaegen H. The antihypertensive effects of

ketanserin (R414681, a novel 5-hydroxytryptamine-blocking agent, in patients with essential hypertension. Clin Sci 1981; 61: 4 7 3 ~ 4 s .

14. Wenting GJ, Man in ‘t Veld AJ, Woittiez AJ, Boomsma F, Schalekamp MADH. Treatment of hypertension with ketanserin, a new selective 5-HTz receptor antagonist. Br Med J 1982;

15. Pegram BL, Kardon MB, Frohlich ED. Antihypertensive effects of ketanserin in chronically instrumented conscious spontaneously hypertensive rats (Abstract). The American Physiological Society, 1982 Fall Meeting.

284: 537-9.

Received Feb. 15, 1983.

Correspondence to: L. Hansson, Dept. of Internal Medicine, Ostra sjukhuset, S-416 85 Goteborg, Sweden.