antagonist, amlodipine

Transcription

1 Br. J. clin. Pharmac. (1989), 27, h blood pressure control with the once daily calcium antagonist, amlodipine M.. HBR, G. BRGDN,. AL-KHAWAJA &. B. RAFTRY The Cardiology Department and the Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex 1 Amlodipine is a novel calcium antagonist which, although pharmacologically similar to other dihydropyridine calcium antagonists, has a long plasma half-life, permitting steady state blood levels to be achieved with a once-daily dose regimen. 2 We have performed a study to examine the effects of this drug on the blood pressure of hypertensive patients over a 24 h period. After a placebo run-in, the drug was administered to 11 patients at a starting dose of 5 mg, and increased to 1 mg after 2 weeks of treatment if the cuff diastolic blood pressure response was unsatisfactory. Cuff measurements were made at entry, after 2 weeks treatment with placebo, after 2 weeks on amlodipine 5 mg once daily, and after a further 4 weeks on amlodipine 5 mg or 1 mg once daily. ntraarterial blood pressure recordings were made at the end of the placebo phase and at completion of the study. 3 Mean supine blood pressure measured sphygmomanometrically was 168/13 (n = 11) mm Hg at entry, 169/14 (n = 11) mm Hg at the end of the placebo phase, 153/95 (n = 11) mm Hg after 2 weeks of treatment and 146/92 (n = 11) mm Hg at the end of the study. Blood pressure curves plotted for each phase of the study revealed an effective 24 h duration of action. Mean daytime blood pressure was reduced from 165/13 to 147/89 mm Hg (P <.5, n = 1), and mean night-time blood pressure was reduced from 137/79 to 121/69 mm Hg (P <.5, n = 1). There was no change in heart rate. 4 One patient developed ankle swelling which would have required discontinuation of medication had she not already been at the end of the study. The drug was otherwise well tolerated. 5 These results indicate that amlodipine is effective as a once daily antihypertensive agent, and is well tolerated. Keywords amlodipine hypertension ambulatory recording ntroduction Amlodipine is a novel member of the family of achieved with a once-daily dosing regimen calcium blocking agents which have emerged as (Faulkner etal., 1986). Studies in dogs with renal important drugs in the treatment of hyper- hypertension have demonstrated smooth lowertension (Olivari et al., 1979; Jones et al., 1983). ing of the blood pressure following daily doses of Although pharmacologically similar to other.5 mg kg-1 (Dodd & Machin 1985). Studies in dihydropyridine calcium antagonists, amlodi- patients with hypertension have shown useful pine has a long (about 45 h) plasma half-life in antihypertensive effect in the dose range 2.5 to man permitting steady state blood levels to be 1 mg (Webster et al., 1987), and side effects Correspondence: Dr. B. Raftery, Cardiology Department, Northwick Park Hospital, Watford Road, Harrow, Middlesex HAl 3UJ 359

2 36 M.. Heber et al. have been mild and infrequent. The purpose of the present study was to evaluate the effect of the drug over 24 h to confirm its potential for once daily dosing. A further aim was to assess its effect on postural blood pressure control, and on blood pressure during isometric and dynamic exercise. Methods Patients Patients were recruited from the Harrow Hypertension Clinic. They were considered for inclusion in the study if their supine and standing diastolic blood pressures were in the range mm Hg after a minimum of 2 weeks on no therapy. Precise previous therapeutic details are as follows: 6 patients - 2 patients - No previous therapy Diuretics only, withdrawn 6 weeks and 4 weeks prior to entry. 3 patients-,b-adrenoceptor blockers, withdrawn 3 months, 3 months and 2 weeks prior to entry. Before entry into the amlodipine phase of the study, the average of three measurements of diastolic blood pressure, both supine and standing, had to be within the same range ( mm Hg). Both men and women between the ages of 18 and 65 years were selected for the study, but women of child-bearing potential were excluded. Other exclusion criteria were malignant or accelerated hypertension, clinically important conduction abnormalities or bradycardia of less than 5 beats min-1, and any other severe concomitant pathological condition. All patients gave written informed consent and the study was approved by the Harrow Health Authority thics Committee. Study design This was a single-blind study. Patients were told they were to receive placebo at some stage, but were not told when. At entry into the study, blood pressure was measured using an arm cuff and a mercury-inglass sphygmomanometer, after 15 min supine rest and 2 min after standing. Three measurements were made each time, and the mean calculated. Patients then received 2 weeks of placebo therapy, one capsule daily at 8. h. They were instructed to omit their medication on the morning of their hospital visits throughout the study. After 2 weeks of placebo treatment, patients returned to the hospital, blood pressure was measured sphygmomanometrically as described above and they were then given a placebo capsule. ntra-arterial ambulatory blood pressure recording was commenced, and patients underwent a standard regime of physiological testing before leaving to resume their normal daily activities. The following morning they returned to the hospital for removal of the intra-arterial cannula and recording equipment. ach patient was then given amlodipine capsules at a starting dose of 5 mg, to be taken daily at 8. h. At the end of 2 weeks they returned to hospital for assessment of their blood pressure control, judged as described above by sphygmomanometer. f the diastolic blood pressure had not decreased to less than 9 mm Hg, or to at least 1 mm Hg below the mean baseline diastolic blood pressures, both supine and standing, the dose of amlodipine was increased to 1 mg, administered as a single capsule daily. After a further 4 weeks of drug treatment, patients returned to the hospital for a second period of intra-arterial blood pressure monitoring. Amlodipine 5 or 1 mg was given after sphygmomanometric blood pressure assessment, between 9. h-1. h. ntra-arterial monitoring was then established, and a similar regime of physiological testing was carried out. As before, the patients then went about their normal daily activities, returning the following morning for removal of the equipment. Patients were weighed at entry and at each visit. Blood and urine samples were taken for routine haematological and biochemical screening at entry, after 2 weeks medication and at completion of the study. lectrocardiograms were obtained at entry and at completion of the study. The occurrence of any side effects was noted, as was concomitant drug administration. ntra-arterial ambulatory blood pressure recording The technique of ambulatory blood pressure monitoring used in this laboratory has been fully documented previously (Millar-Craig et al., 1978b). Briefly, a French 3 gauge cannula (Seldicath) was introduced into the brachial artery of the non-dominant arm, under local anaesthesia. The blood pressure signal from this cannula and the electrocardiogram from bipolar chest leads were recorded using a specially designed transducer/perfusion unit connected to

3 a tape recorder (Medilog Mark 1), which also incorporated a time channel with an event marker. The equipment was specially designed so that patients could be fully ambulant and able to carry out their normal daily activities. After insertion of the cannula and fitting and calibration of the equipment, patients underwent a standard regimen of physiological testing, comprising 2 min of supine rest, followed by head up tilt to 6, maintained for 9 s. sometric exercise was then performed using a hand-grip dynanometer for 2 min at 5% of maximal voluntary contraction. After a minimum of 5 min recovery, patients performed dynamic exercise on a bicycle ergometer, commencing at a workload of 25 watts. The workload was increased in 25 watt increments at 3 min intervals until patients indicated they were exhausted. After a further 5 min rest the equipment was checked and recalibrated and patients left the hospital to resume their normal activities. They returned in the evening for a further equipment check and calibration, and the following morning for removal of the equipment. Analysis of data The ambulatory tape recordings were replayed and written out on a linear direct-writing recorder to allow assessment of the analog signal quality and elimination of any artefact (Cashman et al., 1978). Hourly sections were then analysed on a hybrid computer to give mean levels of systolic and diastolic blood pressure and heart rate. Hourly mean values for all the patients were pooled, and curves to show the 24 h profiles of blood pressure and heart rate on placebo and amlodipine therapy were constructed. Mean daytime and mean night-time blood pressures were calculated (Mann et al., 1978) and the differences between baseline and 6 week values were assessed using Student's paired t-test (two-tailed). The results of supine rest, tilt, isometric and dynamic exercise were computed using a standard digitized programme previously described (Hornung et al., 1983). Results on placebo and active therapy were again assessed using Student's paired t-test (two-tailed). Mean values of sphygmomanometric measurements of supine and standing blood pressure at entry, after 2 weeks of placebo, after 2 weeks of treatment with amlodipine and at completion of the study were pooled, and the latter three measurements compared with the measurements at entry using Student's paired t-test (twotailed). Results Clinical course Amlodipine in hypertension 361 Fourteen patients (1 men, four women), mean age 5 years (range 3 to 66) were entered into the study. Two patients failed to fulfil the blood pressure criteria at the end of the placebo phase and were withdrawn, one patient was found to have elevated creatinine during the placebo phase and was also withdrawn. These patients were excluded from the efficacy analysis. Another patient, although he completed the full treatment period of the study, refused a second intra-arterial recording. This patient was excluded from the analysis of the intra-arterial blood pressure recordings. ight patients required dose titration to 1 mg amlodipine after 2 weeks, three remained on 5 mg daily. One patient developed ankle swelling on the higher dose (1 mg) of amlodipine, of a severity to warrant withdrawal of the drug if she had not already completed the study. Two other patients complained of minor headaches at various stages of the study, none of sufficient severity to warrant withdrawal of the treatment. One other patient complained of 'hot legs', but this was not a rash and he did not find it particularly unpleasant. No patients developed any significant haematological or biochemical derangement, nor did any develop electrocardiographic abnormalities during the course of the study. No significant change in body weight occurred except in the patient who developed swollen ankles (+3. kg). Sphygmomanometric blood pressure Pooled systolic and diastolic blood pressure measurements for 11 patients for each visit are shown graphically in Figure 1. No significant difference in blood pressure occurred between entry (168/13 mm Hg supine, 162/14 mm Hg standing) and the completion of the placebo phase of the study (169/13 mm Hg supine, 164/17 mm Hg standing), but significant falls were noted after 2 weeks (153/98 mm Hg supine, 149/98 mm Hg standing) and 6 weeks (145/92 mm Hg supine, 141/95 mm Hg standing) treatment with amlodipine. ntra-arterial blood pressure The 24 h profiles, plotted from consecutive mean hourly blood pressure and heart rates on placebo and amlodipine therapy in 1 patients are shown in Figure 2. The shape of the circadian

4 362 M.. Heber et al. 'a 18 16,T 1 -r U- U) co _- * 11- * * * 8 L Systolic Diastolic Systolic Diastolic Supine Standing Figure 1 Mean sphygmomanometric blood pressure at each visit (O entry, after 2 weeks placebo, B after 2 weeks amlodipine 5 mg and l after 6 weeks amlodipine 5-1 mg) for 11 patients. *P <.5, **P <.2, ***P <.5 significance of difference with week. CDU f 'a CU. Co m ~ ' Time of day (h) Figure 2 24 h diurnal curves of blood pressure and heart rate on placebo () and amlodipine () therapy. Table 1 Comparison of daytime and night-time intra-arterial blood pressure and heart rate in 1 patients, on placebo and amlodipine therapy. Values are shown as mean (s.d.) Placebo Amlodipine P value Day systolic BP (mm Hg) (23) (1) Day diastolic BP (mm Hg) (13) (13) Day heart rate (beats mint) (1) (8) Night systolic BP (mm Hg) (22) (15) Night diastolic BP (mm Hg) (15) (13) Night heart rate (beats min-') (6) (6) c. a) r- L- cn Co a Co L 22 cm OsU on Systolic,4 o~o Diastolic - UL Pre x x 1 12 Time (min) &W%-,* Recovery Figure 3 ntra-arterial blood pressure and heart rate response to bicycle exercise on placebo () and amlodipine () therapy. curve was not altered by therapy, and a reduction in blood pressure was observed throughout the 24 h period of monitoring. No significant changes in heart rate were observed. Comparison of mean daytime and mean night time blood pressures on amlodipine and on placebo are shown in Table 1. There was a significant reduction in both daytime and night time blood pressure, but no change in heart rate. Blood pressure and heart rate during rest, 6

5 Table 2 ntra-arterial blood pressure and heart rate during physiological tests Supine rest (last 5 of 2 min) Head up tilt (6 ) 15s Heart rate (beats min') 3s 6s 9s Heart rate BP (mm Hg) Pre isometric exercise Peak isometric exercise Amlodipine in hypertension 363 Blood pressure (mm Hg) Placebo Amlodipine P value <.5 <.1 <.5 <.5 <.5 <.2 <.5 <.5 head up tilt, and at peak of isometric hand-grip approximately 1 h after dosing are shown in Table 2. Blood pressure was significantly reduced by therapy, but no postural drop occurred on tilting, nor was there any change in the proportional increase in blood pressure at peak isometric exercise. A trend towards a higher heart rate during all the physiological tests was noted, but this only reached statistical significance (P ) 6 s after tilting. Blood pressure was reduced throughout dynamic exercise by amlodipine compared with placebo (Figure 3), although this only reached conventional levels of statistical significance (P <.5) at the first and eighth minutes. Heart rate was higher relative to placebo throughout exercise but again this did not reach conventonal levels of significance. The reduction in blood pressure during the recovery phase following exercise was significant (P ). Discussion The mode of action of calcium antagonist drugs in reducing vascular smooth muscle tone (Massingham, 1973) and thus the raised peripheral resistance which is the consistent haemodynamic abnormality in essential hypertension (Frohlich et al., 1969; Lund-Johansen, 1967), makes these drugs potentially useful in the treatment of this condition. However, they share many of the side effects of other peripheral vasodilators, including reflex tachycardia, orthostatic hypotension and fluid retention. There is some evidence that the incidence of side-effects is reduced with long-acting or slowrelease preparations (Caruana et al., 1987), presumably because of a steadier plasma level without sudden peaks. Moreover, it has been suggested (Blackwell, 1973) that compliance is improved by once-daily therapies, especially in non-painful conditions such as hypertension (Kubacka & Juhl, 1985). Thus the development of a calcium antagonist with an effective 24 h duration of action has several theoretical therapeutic advantages. Our results indicate that amlodipine effectively reduced blood pressure over 24 h, with a mean daytime reduction of the same order of magnitude as other calcium channel antagonists such as verapamil (Caruana et al., 1987) and

6 364 M.. Heber et al. tiapamil (Caruana et al., 1985), although slightly less than that of nifedipine (Gould et al., 1983). t has been suggested that mean night-time blood pressure (Smirk et al., 1959), the rate of early morning rise in blood pressure (Millar- Craig et al., 1978a), and the extent of blood pressure increase in response to normal daily stress (Sokolow et al., 1966), are more closely associated with cardiovascular events than is the casual daytime blood pressure. For this reason mean night-time and mean daytime blood pressure, rate of early morning rise and the blood pressure response to isometric and dynamic exercise, components of everyday activity, are routinely assessed in our laboratory when investigating new antihypertensive agents. Amlodipine modified the absolute level of blood pressure during the night and early morning, but did not modify the rate of the early morning rise. Similarly, the absolute level of blood pressure was reduced during isometric and dynamic exercise, but the proportional increase in blood pressure was not altered. Furthermore, the pressor response to isometric exercise depends on peripheral vasoconstriction, whereas the increase in systolic blood pressure and heart rate during dynamic exercise is mainly due to sympathetic stimulation of 13-adrenoceptors. The failure of amlodipine to modify these responses, combined with the absence of any postural hypotension, suggests that these cardiovascular reflexes are not greatly affected by the drug. Our results did show a consistent trend towards a slightly higher heart rate during exercise when patients were taking amlodipine compared with placebo, but this did not reach statistical significance. Although the prognostic importance of ensuring adequate 24 h control of blood pressure and control of blood pressure response to exercise cannot be doubted, it is by casual clinic blood pressures, measured sphygmomanometrically, that blood pressure control must of necessity be assessed. t was thus considered pertinent to include cuff blood pressure measurements obtained during the study in this report. The degree of blood pressure reduction measured sphygmomanometrically in this study was similar to the reduction in mean daytime blood pressure measured by the intra-arterial technique. t has been previously established that no placebo effects are seen on intra-arterial blood pressure recording (Gould et al., 1981), and because of the invasive nature of the technique a third intra-arterial line before commencement of placebo therapy was avoided. n fact, no placebo effect was observed on cuff measurement of blood pressure in this study. One patient developed severe ankle swelling, a well recognized side effect of other calcium channel antagonists. Because of the relatively small numbers of patients in this study it is not possible to comment on the relative incidence of side-effects compared with other calcium antagonists, but the drug is clearly not entirely free of them. n conclusion, this study has shown that amlodipine is an effective once daily antihypertensive agent and is generally well tolerated; it may thus have a useful therapeutic role in the treatment of hypertension. We wish to thank Dr H. Prince and Mrs P. Smart for their technical assistance with this study, which was sponsored by Pfizer Central Research. References Blackwell, B. (1973). Drug therapy: Patient compliance. New ngl. J. Med., 289, Caruana, M., Al-Khawaja,., Prince, H. & Raftery,. B. (1985). ffects of tiapamil, a new calcium channel blocker on ambulatory intraarterial blood pressure and exercise induced changes in blood pressure. J. cardiovasc. Pharmac., 8, Caruana, M., Heber, M., Brigden, G. & Raftery,. B. (1987). Assessment of 'once daily' verapamil for the treatment of hypertension using ambulatory, intra-arterial blood pressure recording. ur. J. clin. Pharmac., 32, Cashman, P. M., Stott,. D. & Millar-Craig, M. W. (1987). Hybrid system for fast data reduction of long term blood pressure recordings. Med. Biol. ng. Comput., 17, Dodd, M. G. & Machin,. (1985). Antihypertensive effects of amlodipine, a novel dihydropyridine calcium channel blocker. Br. J. clin. Pharmac., 85, 335P. Faulkner, J. K., McGibney, D., Chasseaud, L. F., Perry, J. L. & Taylor,. W. (1986). The pharmacokinetics of amlodipine in healthy volunteers after single intravenous and oral doses and after 14 repeated oral doses given once daily. Br. J. clin. Pharmac., 22, Frohlich,. D., Tarazi, R. C. & Dustan, H. P. (1969). Re-examination of the haemodynamics of hypertension. Am. J. med. Sci., 257, 9-23.

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