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

Journal of Human Hypertension (1988) 2,41-47

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

John P. Cox2, Ciaran A. O'~oyle~,Fairisia Meel, John ~elly~,Neil ~tkins',Davis Coakley2,Eoin T. 0'~rien'and Kevin 0'Malley3 'The Blood Pressure Clinic, Charitable Injrmary, Jervis Street, Dublin I, 'Department of Geriatric Medicine, St. James's Hospital, James's Street, Dublin 8 and Departments of 'Clinical Pharmacology and 'Psychology, Royal College of Surgeons in Ireland, Dublin 2, Ireland

Summary: To assess the efficacy, tolerability and pharmacokinetics of verapamil in the elderly, ten patients with blood pressure > 160190 mmHg were studied in a randomized double- blind placebo-controlled cross-over trial. Nine patients aged 75 ( f 4.9) years completed the study. After titration, doses of verapamil varying from 40 to 120 mg (40 mg in four, 80 mg in one and 120 mg in four patients) twice daily for six weeks were taken. Mean (f SEM) clinic lying blood pressure was reduced on verapamil from ,187 f 6.81100 f 4.1 to 167 f 4.6186 f 3.1 mmHg, ((P < 0.001). Mean ambulatory blood pressure was reduced. from 174 f 1.4195 f 1.0 to 169 f 1.3190 f 0.8 mmHg, (P < 0.01). Lying heart rate was significantly reduced but glomerular filtration rate, renal blood flow and mental function, were not altered by treatment. The mean plasma half-life of verapamil was 6.9 f 1.1 hours. Side effects were minimal. We conclude that verapamil is an effective blood pressure lowering agent in the elderly.

Introduction Verapamil is an effective BP lowering agent in young and middle-aged hypertensive^^^-'^ and Epidemiological studies show that hypertension is while there is some evidence that verapamil is an important risk factor for cardiovascular dis- effective in the elderly,16 its efficacy has not been eases in the elderly.' Furthermore the European fully evaluated. In this study we examined the Working Party on High Blood Pressure in the antihypertensive efficacy, tolerability and pharma- Elderly (EWPHE) has demonstrated a beneficial cokinetics of verapamil in a group of elderly effect of lowering BP in patients with hypertension patients. Because of the possibility that antihyper- aged over 60 years2 However, the efficacy and tensive therapy may compromise regional blood acceptability of different BP lowering drugs in this flow particularly in the elderly we also assessed age group await clarification.' In the EWPHE mental and renal function by psychometric testing trial BP was controlled with diuretic therapy alone and renal haemodynamic studies. in 65% of patients,' but there was a decrease in glucose tolerance4 and an increase in serum uric acid5 and creatinine le~els.~Beta-adrenoceptor Patients and methods blocking drugs may be less than ideal as treatment in the elderly because of the reduction in stroke Ten patients (seven females), mean age 75 years, volume,7 a decrease in beta-adrenoccptor- range 65-83 years) who had been receiving no mediated respon~iveness~.~and some evidence for therapy for at least one month and with a BP an increase in the incidence of side effects.I0 Meth- greater than 160/90mmHg (range 164-225192- yldopa though effective in the elderly is associated 118 mmHg) entered the study. Patients with car- with drowsiness," a particularly undesirable ad- diac conduction defects including sinus bradycar- verse effect in the aged. dia (< 50 beats per minute), abnormal liver function tests, or elevated serum creatinine levels were excluded. The study protocol was approved by the Correspondence: Prof. K. O'Malley MD, PhD, FRCP. hospital ethics committee and informed consent Accepted: 2 March 1988 was obtained. 0The Macmillan Press Limited, 1988 42 J. P. COX er al.

Study design chromatographic assay of verapamil and norverapamil, I ml specimens of plasma were made alka- Patients whose mean lying BP remained within the line (0.05 ml of 5N NaOH) and extracted with 5 ml limits 160-240/9&120mmHg after a four week diethyl ether. After removal and evaporation of run-in phase entered an open titration phase. The the organic layers, these were reconstituted in dose of verapamil (Veramila-Orion Pharmaceu- mobile phase (0.1 ml) and chromatographed. The tica) was titrated at weekly intervals (40 to 80 to column was 15 cm Sperisorb 50DS and the mobile 120 mg twice a day taken at 09.00 and 18.00 hours) phase contained methanol 450ml, water 50 ml, until clinic lying SBP was reduced to less than KH,PO, 34mg, and was adjusted to pH 3 with 160mmHg or there was a 20% reduction in SBP phosphoric acid. The flow rate was 2.5 ml/min and compared with the average SBP of the run-in the drugs were detected by fluorescence at wave- phase. Patients then entered a randomised double- lengths 275 nm excitation and 339 nm emission. blind placebo-controlled cross-over phase using ~eientiontimes for verapamil, norverapamil and the dose of verapamil as indicated on titration. internal standard (imipramine) were 3.1, 4.0 and During this phase they were seen after one, three, 5.2 minutes respectively. The elimination half-lives live and six weeks in each six week placebo and of verapamil and norverapamil were calculated treatment period for measurement of clinic BP, from the slope of the line derived by linear least heart rate and weight, and documentation of side squares regression analysis of the terminal part of eKects. At the end of each treatment period ambu- the log concentration time curve; the area under latory BP measurement, renal haemodynamic stu- the concentration time-curve was calcu- dies and psychometric testing were carried out. lated by the trapezoidal rule. Side effects were assessed by asking the patient Methods to report any symptoms experienced during treatment and by the response to a check list of 16 Clinic BP was measured between 10.00 and 12.00 questions put to the patient by the physician. hours with the Hawksley random zero sphygmo- Psychometric tests used in this study included manometer, Korotkoff phase V being taken for tests of psychomotor co-ordination, memory, con- DBP. BP and heart rate recordings were made centration, central nervous system arousal and with the patient lying after five minutes rest and mood. standing after two minutes with the arm supported at heart level.'' Ambulatory BP and heart rate Psychomotor Co-ordination This was assessed were measured non-invasively at half-hourly inter- with the number connection test (NCT) and the vals using a semi-automated portable recorder, the peg-board test (PBT) (Perdue Pegboarda-Sci- Remler M2000 (Remler Corp. San Francisco, ence Research Association, Inc. Illinois). The C.A.)." The Remler was operated by the patient NCT is a modified version of the Reitan trail from 09.00 to 22.00 hours. All Remler tapes were making testm in which patients were required to decoded by one operator. join up, in the correct sequence, a series of encir- Glomerular filtration rate and effective renal cled numbers, the test being scored as the time to plasma flow were estimated using plasma clear- completion. On the PBT, patients were required to ance of intravenously injected Cr5' EDTA and li2' transfer a set of small pegs from one row of holes hippuran (The Radiochemical Centre, Amersham) to another using the dominant hand, the score respectively. A single injection technique was being the time taken to complete the task. employed, using 50-75 microci of each isotope. Samples were taken from a venous cannula in the Concentration This was assessed with the digit opposite arm at intervals after injection (5, 10, 15, symbol substitution test (DSST) from the 30, 40, 50, 60, 80, 100, 140, 170, 180 and 240 Weschler adult intelligence scale (WAIS).2' In this minutes). Clearance values were calculated using a test patients are presented with a different code two-compartment model.I9 Effective renal plasma symbol for the numbers one to nine, and asked to flow was corrected for haematocrit to give renal write as many symbols as possible on numbered blood flow. sheets in 90 seconds, the score being the number of The pharmacokinetics of verapamil and its correct substitutions. major metabolite norverapamil were studied at the end of the titration phase from blood samples Memory Short term memory, learning, and taken before and at intervals after the last dose delayed recall (DR) performance were measured (15,30,45,60,90 minutes two, four, six, 12 and 24 by means of the 'shopping list test' (SLT)12and the hours). Plasma specimens were stored at - 20°C analagous 'pictures of objects test' (POT). In the prior to assay. For the high-performance liquid SLT, patients are shown 10 cards, each with the VERAPAMlL IN ELDERLY HYPERTENSIVES 43 name of a common grocery item printed on it, one hand side of the scale.24In order to reduce the VAS at a time in a fixed order at the rate of one card per data, only scores on alertness, calmness and con- second. The number of items remembered after the tentedness are reported. first presentation of the SLT gives a measure of short term verbal memory. The number of presen- All assessments were carried out by the same tations of the set of cards (up to a maximum of five observer under standardised conditions. Patients presentations) required before the patient can practised PBT, NCT, DSST, CFFT, and VAS on recall all the 10 items, provides an index of learn- four occasions prior to the start of the double- ing ability and is known as trials to criterion (TC). blind cross-over stage of the trial, in order to Delayed recall is assessed twenty minutes later by minimise learning effects during the study proper. asking patients to recall as many items as possible. Equivalent parallel forms of the DSST, NCT, Measurement of visual memory (POT) is identical DST, SLT and POT were used to prevent patients to that used for verbal memory (SLT) except that learning the material on repeated administration. pictures of common objects are used instead of Paper and pencil test forms were enlarged to words. Short term memory was also measured by facilitate this elderly population. means of the digit-span test (DST) administered The ambulatory BP data were analysed using a according to the WAIS man~al.~'Patients listen to computer programme designed to pair half-hourly a series of digits, presented at the rate of one per readings on verapamil with readings for the same second, and digit-span is taken as the longest time of day on placebo. Unpaired data were correctly remembered sequence. omitted. Student's paired t-test was used for all comparisons and the influence of treatment, order Central nervous system (CNS) arousal This was and interaction effects were determined by the assessed by critical flicker frequency (CFF),2' method appropriate for cross-over trails suggested measured on an activity profiler (Lord Medical by Hills and Armitage.25A probability value of less Ltd) under standard conditions of illumination. than 5% was taken to be significant. The psychophysical method for obtaining CFF thresholds used was the method of limits. Using this procedure the intensity of the flickering light Results source is held constant and the frequency is progressively increased (ascending thresholds) or One patient did not complete the study (see be- decreased (descending thresholds) until the subject low), leaving six females and three males, mean reports a change in his perception of the flicker age 75 years and range 65-83 years. Mean clinic (i.e. from flicker to fusion or from fusion to lying BP at the end of the run-in phase was 1911 flicker). Thresholds are reported in cycles per 103 mmHg. The daily doses of verapamil at the second (hertz) and the means of six ascending and end of the titration phase were 40mg (in 4 descending thresholds calculated separately. patients), 80mg (in l), and 120mg (in 4) twice daily. Verapamil reduced both SBP and DBP to a Subjective Mood Patients rated their subjective similar extent in the lying and standing positions state on bipolar visual analogue scales (VAS), (Table I) and there were no order or interaction scored as the distance in millimetres from the left effects. Heart rate was significantly reduced in the

Table I Clinic blood pressure, heart rate and weight (n = 9)

Placebo Verapamil Trearmenr 95% Conjidence (meun) (meun) d~yerence interval

Lying Systolic 186.9 166.7 20.2** BP (mmHg) Diastolic 99.8 86.4 13.2. Standing Systolic 190.0 BP (mmHg) Diastolic 104.5 Heart rate Lying. 82.8 (beatslmin) Stand~ng 89.0 Weight (kg) 66.6 44 J. P. COX er al.

Table 11 Renal haemodynamics (n = 9). GFR = glomerular filtration rate; RBF = renal blood flow

Placebo Verapamil Trearnrent 95% Conjidence (mean) (mean) dgerence inlervol

GFR (mllmin) 68.8 65.9 2.3 - 6.2: 10.8 RBF (mllmin) 388.2 388.1 - 1.0 - 36.5: 34.5

lying position only. Body weight was unchanged with treatment. , Systolic Mean ambulatory SBP from 09.00 to 22.00 hours was significantly reduced from 174 to 169 mmHg, (treatment difference, 5.2 mmHg; 95% CI, 1.9: 8.5; P < 0.01; 168 paired readings) and DBP from 95 to 90 mmHg (treatment difference 4.4 mmHg; 95% C1,2.3: 6.4; P < 0.001; 169 paired readings) with treatment (Figure 1). Ambulatory heart rate was unaffected. Neither glomerular filtration rate nor renal blood flow were significantly different on active treatment compared with placebo (Table 11). Table I11 summarises the pharmacokinetic findings. The mean elimination half-life for verapamil Diastolic was 6.9 f I. I hours. Pre-dose and maximum post- dose (C,,,) concentrations of verapamil increased with increasing doses of the drug. Times to C,,,, did not differ substantially between doses. Areas under the plasma concentration-time curves over a dose interval (AUC 0-12 hours, final dose) were dose-related. Data for norverapamil were similar in trend. Note, however, that the values of norverapamil half-life are apparent values and probably 8oJ ? 1b 1'2 ib 16 ib 2b 212 over-estimate the elimination half-life because of a.m. p.m. continuing formation of norverapamil from vera- dose dose pamil during the verapamil elimination process. Hours No impairment of mental function was found Figure 1 Curves derived from the means of hourly on any of the performance indices measured values of ambulatory systolic and diastolic blood pres- (Table IV). These findings were not influenced by sure on placebo ( A ) and verapamil (A) after 6 weeks of either order or interaction effects, confirming that treatment (n = 9).

Table 111 Verapamil and norverapamil pharmacokinetics

Verapamil dose 40 mg twice daily (n = 4) 80 mg twice daily (n = I) 120 mg twice daily (n = 4)

Parameter Verapamil Norverapamil Verapamil Norverapamil Verapamil Norverapamil t 112 B (hr) 5 2.6 16.5f 17.0 4.4 11.0 10.1 f 0.7 14.6 f 3.6 AUC 0-12 (ng/ml/hr) 507.0 f 275.2 1133.1 f 328.7 2345.0 4148.1 1914.2 f 285.4 3778.2 f 1325.5 c,, (ng/ml) 15.5 f 27.8 43.3 f 24.7 25.0 92.0 68.3 f 29.6 210.8 f 128.3 c,., (nJml) 133.0 f 50.9 162.5 f 20.6 344.0 493.0 349.0 f 80.4 500.0 f 215.8 I,,,,, (hr) 1.2~0.4 1.3f 0.6 1.5 6.0 1.6 f 0.8 3.3 f 2.2

Data are mean f SD;t 112 B = elimination half-life; AUC, 0-1 2 = area under plasma concentration-timecurve during a dose interval: C,, - pre-dose drug plasma concentration; C,, - peak drug plasma concentration; I,,, = time to C,,. VERAPAMIL IN ELDERLY HYPERTENSIVES 45

Table IV Psychometric test scores (n = 9)

Placebo Verapamil Treatment 95% Conjidence (mean) (mean) difrerence interval

PBT (seconds to completion) NCT (seconds to completion) DSST (number correct/90 seconds) SLT TC (number of presentations) DR (number of items recalled) POT TC (number of presentations) DR (number of items recalled) DST (longest sequence recalled) CFF Ascending (Hertz) Descending (Hertz) VAS I. Alert-Drowsy (mm) 2. Happy-Sad (mm) 3. Calm-Excited (mm)

PBT = peg board test; NCT = number connection test; DSST = digit symbol substitution test; SLT = shopping list test; TC = trials to criterion; DR = delayed recall; POT = pictures of objects test; DST = digit span test; CFF = critical flicker frequency; VAS = visual analogue scale.

the learning plateau was achieved in the pre-study years) using a higher average dose of verapamil phase. (165 mg twice daily). One patient with a history of epilepsy left the Renal haemodynamics were unchanged in the study because of a grand ma1 seizure which oc- face of a fall in BP in keeping with animal studies28 curred in the double-blind phase while on placebo. and data in younger subjects.w3' The maintenance Two patients reported headaches and one com- of renal function in patients who might be plained of leg cramps on verapamil. expected to have decreased renal perfusionJ2J3 suggests that verapamil may have a useful role in this age group. Discussion The elimination half-life for verapamil of 6.9 * 1.1, hours is similar to that of 6.7 * 2.0 hours Verapamil exerts its BP lowering effect by reducing reported in a younger population after 3 days on peripheral resistance, without causing reflex tachy- veraparnil." An average peak verapamil plasma cardia, an increase in plasma renin activity or fluid concentration of 280 f 56.0 ng/ml after 160 mg of retention,I2 as occurs with other vasodilator drugs verapamil was reported in the same study." such as hydrala~ine.'~In this study verapamil in an whereas our values after 120mg were higher at averge dose of 80mg twice daily lowered BP 349.0 f 80.4 nglml. This difference may be due to effectively in elderly hypertensives with few side- a reduction in-first pass metabolism of verapamil effects. Reductions in lying and standing BP were in the elderly as has been observed with proprano- similar and postural hypotension did not occur. IOI'~and labetal~l.~~ Heart rate was significantly reduced only in the The possibility that antihypertensive agents lying position. The effects of verapamil in these might have adverse effects on mental function has elderly patients are similar to those found in been investigated in several studies. Beta-adreno- studies of younger hypertensives, the main dif- receptor blocking drugs have central effects which ference being that doses in the range, 80 to 240 mg/ can be demonstrated by psychomotor tests." Solo- day controlled BP in this study whereas considera- mon el aP8 comparing mental function in patients bly higher doses, up to a total of 720 mg, were used on diuretic therapy alone with patients taking to obtain control in the younger patients.I2-l4.I6 methyldopa or propranolol, showed impairment Mean ambulatory BP was significantly lower on of verbal memory with methyldopa and proprano- verapamil from 09.30 to 22.00 hours, although this lo1 but not with diuretic therapy. Lichter el effect seemed to wane six hours after the 09.00 hrs using tests of memory similar to those used in the dose (Figure I). These findings are similar to those present study, showed a significant memory of Hornung er al.,2' who showed that twice-daily impairmant with atenolol but not enalapril. The verapamil achieved significant reduction in intra- absence of impairment in mental function in the arterial BP consistently throughout the day and presence of BP reduction with verapamil is of night in younger hypertensives (mean age 49.3 particular relevance to the elderly. It would appear 46 J. P. COX et al. from the evidence to date that impairment of monotherapy in the management of the elderly mental function is more closely related to the drug hypertensive patient. used than to a reduction in BP. In conclusion twice-daily verapamil lowers BP Acknowledgements with few side effects in elderly hypertensives. The This study was supported by the Research Committee of ambulatory data show that the BP lowering elfect the Royal College of Surgeons in Ireland and a grant is reasonably well maintained throughout the in- from the Medical Research Council of Ireland. Orion terval between doses. Thus, verapamil in the pres- Pharmaceutica provided supplies of verapamil and ent formulation appears both safe and efTective as placebo.

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