The Antihypertensive Efficacy of Ketanserin in the Elderly Evaluated by Ambulatory Blood Pressure Measurement

The antihypertensive efficacy of ketanserin in the elderly evaluated by ambulatory blood pressure measurement

Patricia M. E. McCormack, John P. Cox, Joan Marron, Fainsia Mee, Neil Atkins, Eoin O'Brien and Kevin O'Malley The Blood Pressure Unit, Beaumont Hospital. Dublin 9 and Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St. Stephen's Green, Dublin 2, Ireland

Summary: To assess the role of the serotonin antagonist ketanserin in the management of hypertension in the elderly, 12 patients with a mean age of 68 years (range 60-79 years) were treated with ketanserin in a randomised double-blind placebo-controlled cross-over trial. Clinic BP, ambulatory BP, renal function, and phannacokinetics were assessed. The doses of ketanserin used were 40 mg (ten patients) and 20 mg (two patients) twice daily for 8 weeks. Mean clinic sitting BP was reduced from 169 f 5/98 f 2 on placebo to 155 f 5/88 f 3mmHg (P<0.05/ P < 0.05) and standing pressure from 168 f 6/100 f 3 to 157 f 5/91 f 3 mmHg (NS/P< 0.01). Mean ambulatory systolic BP was unaffected by active treatment (167 f 7 vs 164 f 5) while diastolic pressure was lowered from 99 f 2 to 94 f 2 mmHg (P< 0.05). This effect appeared to be mainly confined to the first two hours after drug administration. Renal blood flow was unaltered by treatment. The mean plasma half-life of ketanserin was 20.9 f 5.5 hours. Side effects were minimal. In conclusion, while ketanserin may be eKective as assessed in the clinic, its efficacy on ambulatory monitoring is substantially less impressive.

introduction

The results of both the European Working Party failure, peripheral vascular disease and chronic on High Blood Pressure in the Elderly study1and obstructive airways disease. Methyldopa causes the Hypertension Trial in Elderly Patients in Prim- central nervous system depression6.' and is not a ary Care2 provide a rational basis for an assertive suitable drug for many elderly patients. approach to the management of hypertension in Because hypertension in elderly patients is char- patients aged over 60 years. While data from three acterised in haemodynamic terms by a relatively major intervention studies support the view that high total peripheral resistance and a low cardiac thiazide diuretics are effective BP lowering agents output,R it would appear logical to use antihyper- in the elderly,' these drugs are associated with a tensive agents in this population to reduce vascu- dccrcasc in glucose tolerance, an increase in serum lar resistance without further lowering cardiac uric acid and creatinine levels1 and a lowering of output. Agents acting this way which have been plornerular filtration rate4 in older hypertensive shown to he effective in the elderly include the patients. Bcta-adrenoceptor blocking drugs, calcium channel blockers and the angiotensin con- though elTective in the elderl~,~may be contraindi- verting enzyme (ACE) The selective cated because of concommitant congestive heart S,-serotoninergic receptor antagonist, ketanserin,I2 which lowers BP mainly by reducing peri- Correspondence: Prof. K. O'Malley, MD, FRCP. De- pheral resistance, while causing a small and tran- partment or Clinical Pharmacology, Royal College of sient rise in heart rate and cardiac output".'4 with Surgcons in Ireland, Sl. Stephen's Green, Dublin 2, an increase in renal blood flowN4without metabolic Ireland di~turbance'~.'~seems an attractive choice in the Accepted: 12 February 1990 elderly.

Macmillan Press Limited, 1990 566 P. M. E. McCORMACK et al.

Clinical experience with ketanserin in young and middle-aged patients is sizable."Js Also, the acute antihypertensive effect of ketanserin admin- Clinic BP was measured with the Hawksley ran- istered intravenoi~slyhas been shown to increase dom zero sphygmomanometer, Korotkov phase V with age.'? Moreover, an age-related increase in being taken for diastolic pressure. BP and heart diastolic blood pressure (DBP) response rate with rate recordings were made with the patient sitting ketanserin has been observed.20However, there is after ten minutes' rest and after one minute stand- only one published randomised placebo-con- ing, with the arm supported at heart The trolled study of the antihypertensive efficacy of mean of three readings taken at 1-2 minute inter- this drug in the elderly.21 The present study vals was used. addresses this issue as well as assessing the Ambulatory BP and heart rate were measured duration of antihypertensive effect using ambul- non invasively at half-hourly intervals using a atory BP measurement. In addition, the effects of semi-automated portable recorder, the Remler ketanserin on renal haemodynamics and some M2000 (Remler Corp., San Francisco, C.A.).23 aspects of the pharmacokinetics of the drug in this The Remler was operated by the patient from 0900 population were studied. to 2200 hours. On the day of the ambulatory BP study the patients' medication was administered by a nurse. All Remler tapes were decoded by one Patients and methods operator. Renal blood flow was estimated using plasma Twelve patients (seven females, mean age 68 years, clearance of intravenously injected '251hippuran as range 6&79 years) with clinic BP greater than 1601 described elsewhere.? Serum creatinine levels were 90 mmHg entered the study. Patients with BP measured using a standard laboratory technique. greater than 2401120 mmHg, secondary hyperten- The pharmacokinetics of ketanserin and its sion, cardiac conduction defects including sinus metabolite ketanserin-ol were studied at the end of bradycardia (< 50 beats per minute), liver impair- the titration phase from blood samples taken ment (any liver enzyme greater than twice normal) before and at intervals after the last dose (30 or serum creatinine greater than 220 pmol/l were minutes, 1, 2, 4, 6, 12, 24, 32, and 48 hours). excluded. The study protocol was approved by the Plasma samples were stored at - 20°C prior to Hospital Ethics Committee and informed consent assay by high-performance liquid chromato- was obtained. graph~.~~The elimination half-lives of ketanserin and ketanserin-ol were calculated from the slope Srudy design of the line derived by linear least squares regres- sion analysis of the terminal part of the log con- Five patients on diuretic therapy for hypertension centration time curve; the area under the plasma (four were on a second agent - three on a beta- concentration time-curve was calculated by the blocking drug and one on rauwolfia, one patient trapezoidal rule. The values for ketanserin-ol half- was on a third agent - hydralazine) had these life are apparent values as they probably over- medications discontinued over the first two weeks estimate the elimination half-life due to continuing of a three-week run-in placebo phase. Those formation of ketanserin-ol from ketanserin. whose sitting BP remained within the limits 160- Side effects were assessed by asking the patient 220190-120 mmHg at the end of the run-in phase to report any symptoms experienced during treat- entered an open titration phase during-which the ment. dose of ketanserin was 20 mg twice daily, taken at Ambulatory BP data were analysed using a 0900 and 1800 hours for four weeks, increasing to computer programme designed to half-hourly 40 mg twice daily for the fifth week if sitting clinic readings on ketanserin with readings for the same BP was greater than 160190 mmHg. time if day on placebo. unpaired data were A randomised double-blind placebo-controlled omitted. Mean ambulatory BP was calculated cross over phase followed using the dose of ketan- using the mean of each patient's day-time readings serin as indicated on titration. During this phase on ketanserin and placebo. Student's paired I-test patients were seen after one, two, five and eight was used for all comparisons and the influence of weeks in each eight week placebo and treatment treatment, order and interaction effects were deter- period for measurement of clinic BP, heart rate mined by the method appropriate for cross-over and weight, and documentation of side effects. trials suggested by Hills and Armitage.25 It was Ambulatory BP measurement and renal studies calculated using the power calculation of Hills and were carried out at the end of each treatment ArmitageZJthat nine patients would be required to period in the double-blind phase. detect the expected fall in ambulatory BP of KETANSERIN IN ELDERLY HYPERTENSIVES 567

1015 mniHg. A probability value of less than 5% was taken to be significant. 190 Systolic '0° F

Results

All 12 patients completed the study. Mean sitting BP at the end of the three-week run-in phase on placebo was 174 f 41101 f 2 mmHg. The doses of ketanserin used were 20 mg twice daily (in two patients) for eight weeks and 40 nig twice daily (in ten patients) for seven weeks. The mean (f SD) number of paired ambulatory BP readings per patient was 14.5 f 3.7. Ketanserin reduced clinic sitting and standing BP to a similar extent (Table I) although the difference between placebo and active treatment was not statistically significant for standing systolic pressure (SBP). Mean sitting DBP after treat- t* ment was reduced to 90 mmHg or less in only five 80 L patients (42%) and SBP to 160 mmHg or less in Ill I Ill I l l 1 10 12 14 16 18 20 eight patients (67%). The correlation between Hours entry BP and response to treatment was not significant. For standing BP the corresponding values Figure 1 Curves derived from the means of hourly were four and nine patients for DBP and SBP values of ambulatory systolic and diastolic blood pres- respectively. Heart rate and weight were not signi- sures on placebo (A) and ketanserin (A) afier eight ficantly affected with treatment. weeks' treatment (n= 12). Mean ambulatory DBP (Figure 1) was reduced with active treatment from 98.7 to 94.1 mmHg interval. - 6.2: 11.2). There were no order or inter- (treatment difference, 4.6 mmHg; 95% confidence action effects. interval, 0.8:8.4; P<0.05) with the effect being Renal blood flow on placebo was greatest at 1100 hours. However, there was no 608.8 f 47.0ml/minute and on active treatment significant reduction in mean ambulatory SBP on 607 f 58.4 mllminute. Similarly plasma creatinine active treatment (from 166.7 to 164.3 mmHg; levels were unchanged (87.2 f 6.4 vs. 88.2 f 5.9 treatment difference, 2.5 mtnHg; 95% confidence pmoI/l).

Table I Clinic blood pressure, heart rate and weight on placebo or ketanserin

Placebo Ketanserin Treatment 95% Confidence Significance drference interval

Sitting BP. mmHg Systolic 169.2f 4.8 155.4f 5.4 13.8 f 5.7 1.1:26.4 P< 0.05 Diastolic 98.0 f 1.9 87.8 f 3.3 10.2f 3.7 1.9:18.4 P< 0.05 Standing BP, mmHg Systolic 168.2f 5.5 157.4 f 4.6 10.8f 6.1 - 2.8:27.3 NS Diastolic 100.4f 2.7 91.2*2.5 9.2f 2.2 4.4: 14.1 P

Heart rate, beats/min Sitting 78.6 * 3.0 75.2f 2.5 3.4f 2.4 - 1.9: 8.7 NS Standing 79.2 f 3.7 76.3 f 3.6 2.8 f 3.2 -4.3: 9.9 NS

Weight, Kg 73.2 f 3.6 75.6f 3.6 - 2.4 f 2.0 -6.9: 2.2 NS Dosc of ketanserin was 20 mg twice daily in two patients and 40 mg twice daily in ten patients Values are mean f SEM; n = 12. 568 P. M. E. McCORMACK el al.

Table I1 summarises the pharmacokinetic find- measurement is possibly due to the fact that these ings. The mean (f SD) elimination half-life for measurements were made during normal daily ketanserin was 20.9 f 5.5 hours. Pre-dose and activity when the patients were in the upright maximum post-dose concentrations (C,,,) of position Tor much of the time. The fact that SBP ketanserin increased with increasing doses of the was unalrected by active treatment from 1000 until drug. Times to C,,, did not differ substantially 1800 hours (Figure I), a time when patients were between doses. Data for ketanserin-ol were simllar likely to be in the upright position and ambulant, in trend. tends to confirm this observation. In an intra- arterial ambulatory BP assessment carried out in 18 patients by Woittiez and colleagues,2* mean 24 Table I1 Ketanserin and ketanserin-ol pharmacokin- hour SBPs and DBPs were reduced compared to etics placebo. However. hourly means for SBP were not significantly reduced on active treatment when Paratl~erer Kerarlserin Kerat~serin-01 patients were more likely to be in the upright position and ambulant, namely from 0600 to 2000 1, , 8. hr 20.84~ 6.0 22.9f 5.7 hours. AUC 0-12 753.0f 260.0 2723.0f 840.9 From the ambulatory data in the present study ng/ml/hr it is evident that ketanserin had its maximal effects Cmi,nglml 33.4f 17.9 180.5+ 52.0 on DBP at l I00 hours (Figure I), two hours after C,,, nglml 123.0~38.1 324.4f 121.9 the morning dose was administered by the nurse La. Ilr 2.2f 1.4 2.8f 1.3 who fitted the BP recorder. It is of interest to note Data are mean * SD; Dose or ketanserin, 40 mg twice that in the study in which clinic standing SBP was daily; n= 10; t, , B = elimination half-life; AUC 0-12 = significantly reduced, the measurements were area under plasma concentration-time curve during a taken two hours after the morning dose.J2 Clinic dosing interval; C,,, = pre-dose drug plasma concentra- measurement was carried out between 1000 and tion; C,,,, = peak drug plasma concentration; t,,, = 1200 hours in the present study, and if only these, time to C,,,. measurements had been relied upon to assess drug efficacy, ketanserin would have been adjudged an effective BP lowering agent. These findings further Side effects in the open titration phase included emphasise the importance of performing ambula- headache (3 patients), insomnia (2 patients), light- tory BP measurement in efficacy studies of anti- headedness (I), facial flushing (I) and gastric full- hypertensive drugs." ness (I). Patients on ketanserin in the double-blind Renal blood flow was unchanged on treatment phase complained of dizziness (2), lightheadedness with ketanserin in keeping with the findings of a (I), headache (I), insomnia (I), irritability (I) and similar study of slightly younger patients (mean constipation (I). There were complaints of fatigue age 57 years)" but in contrast to an intravenous (I), paraesthesiae (I), unsteady gait (I) and head- study in younger patients where renal blood flow ache (I) on placebo in the double-blind phase. Side was increased.I4 It is possible that nephrosclerosis, effects were transient and did not necessitate stop- which is commoner in older hypertensive patient^,^ ping therapy. attenuates possible effects of ketanserin on renal vascular tone. Although the number of patients observed in the present study was small, the main- tenance of renal function in the face of a fall in DBP with ketanserin in elderly hypertensive The present study shows that while ketanserin as patients who might be expected to have decreased non no therapy was effective in reducing clinic DBP, renal p~rfusion~~.'~is reassuring. the effect on SBP, especially in the standing posi- The elimination half-life for ketanserin of 20.9 tion. was less impressive. These findings are in hours is longer than that of 14.3 hours reported in agreement with most other placebo-controlled similar studies of younger patient^.^ During chro- ~tudies'~"in younger patients where BP was nic oral treatment, steady-state levels for the 40 mg measured in the standing position. though Amery twice daily dosing regimen fluctuate between and colleagues found a significant fa11 in both 40 nglml (pre-dose drug plasma concentration) standing SBP and DBP? Similarly, in a ran- and I00 to 140 ng/ml (peak drug plasma concen- domised placebo-controlled study of ketanserin in tration) within two hours of dosing3%hich are elderly hypertensive patients only the reduction in similar to our findings. DBP was significant." In conclusion these findings suggest that while The lack of effect on SBP with ambulatory ketanserin may be effective as monotherapy as KETANSERIN IN ELDERLY HYPERTENSIVES 569

assessed in the clinic, its elficacy. by ambulatory Acknowledgements BP monitoring in the elderly group of patients studied, is substantially less impressive. On the hi^ study was supported by (he charitable infirmary basis of the evidence from the present study, this Trust. the Royal College of Surgeons in Ireland and drug cannot be recommended as monotherapy in grants from the Health Research Board (Ireland) and elderly hypertension. Janssen Pharmaceuticals.

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