Brian A. Gould

Nifedipine tablets for systemic hypertension: A study using continuous ambulatory intraarterial recording

The action of nifedipine tablets was examined in 17 patients with essential hypertension focusing particularly on the profile of blood pressure (BP) reduction over 24 hours resulting from both twice-daily and once-daily therapy (dose range 40 to 120 mg daily). This new formulation of nifedipine has a more prolonged and lower peak plasma level than an equivalent dose of nifedipine capsules. Our patients were fully ambulant and studied by continuous intraarterial recording techniques. BP responses during isometric and dynamic exercise testing were also observed. Within-patient comparisons of consecutive mean hourly systolic and diastolic BP showed a highly significant effect from twice-daily therapy (p less than 0.001) for nearly the entire day. Also, significantly lower BP was maintained during isometric and dynamic exercise. Mean hourly heart rates were not significantly altered. The profile of action of the single morning dose was initially similar, but its efficacy diminished from 6 P.M. to 8 A.M. on the following day. Side effects were not unduly troublesome and did not cause any patient withdrawals. Four patients developed mild ankle edema. Two others had facial flushing. Nifedipine given twice daily in tablet form, therefore, is an effective antihypertensive drug capable of lowering BP consistently over 24 hours in ambulant patients and during formal exercise testing. We suggest that this agent may be useful as initial therapy for systemic hypertension, although the tablets are not as yet widely available.

Evaluation of the Remler M2000 blood pressure recorder. Comparison with intraarterial blood pressure recordings both at hospital and at home.

The Remler M2000 is a semiautomated device that has been used to collect epidemiological data and assess blood pressure variability. It has been subjected to limited evaluation in operation, however, and no studies of its accuracy away from the hospital or office environment have been undertaken. We recruited a group of 28 patients with essential hypertension who were undergoing intraarterial ambulatory blood pressure monitoring and compared the intraarterial recordings with those made with the Remler instrument both at home and in the hospital. The Remler recordings were also compared with simultaneous indirect blood pressure measurements made with the random zero sphygmomanometer. The mean difference between the Remler and intraarterial blood pressure recordings was -3/7 in the hospital and 7/0 at home. All standard deviations were greater than 10 mm Hg, indicating large between-subject variability. Overall, the relationship of the Remler M2000 readings to intraarterial pressures was as close if not closer than standard indirect sphygmomanometry and thus might provide useful data for epidemiological surveys or drug trials. It would appear that for accurate measurement of short-term blood pressure variation and 24-hour recording, intraarterial recording is the method of choice.

Propranolol versus verapamil for the treatment of essential hypertension

Recent reports have confirmed that slow calcium channel inhibitors have useful antihypertensive properties because they produce dilatation of the peripheral arterioles without reflex tachycardia. Their clinical place in the management of hypertension has yet to be clearly defined, and thus we have performed an open crossover trial to compare the 24-hour profiles of blood pressure reduction after chronic therapy with propranolol and verapamil. Nineteen patients were studied by continuous ambulatory intraarterial recording and the order of drug administration was decided by random allocation. Drug dosage was twice daily and titrated according to casual clinic pressures (propranolol, 40 to 240 mg twice a day; verapamil, 120 to 240 mg twice a day). Mean hourly blood pressure and heart rate values were obtained over a 24-hour cycle, and the responses to isometric and dynamic exercise were also examined. Both drugs were shown to produce a uniform and comparable reduction in blood pressure throughout the whole day, together with a reduction in heart rate, which was greater with propranolol. Comparable effects were also seen on the pressor responses to exercise. Both drugs were equally well tolerated and caused no patient withdrawals. We conclude that oral verapamil given twice daily showed a similar degree of efficacy to propranolol and provided 24-hour blood pressure control. This slow calcium channel inhibitor may be useful as initial therapy for hypertension, particularly for those patients in whom beta-adrenoreceptor blockers are contraindicated.

An evaluation of self-recorded blood pressure during drug trials.

To our knowledge, there have been no published comparisons of different techniques for measuring blood pressure during clinical trials. We undertook a comparison during clinical trials with verapamil and prazosin. During an open trial of verapamil we compared the treatment-induced blood pressure reductions as measured by clinic, intra-arterial, and self-recorded methods. The mean reduction in blood pressure was 38 +/- 13.6/20 +/- 10.1 mm Hg for clinic blood pressure, 24 +/- 17.9/16 +/- 7.3 mm Hg for self-recorded blood pressure, and 23 +/- 12.3/19 +/- 10.1 mm Hg for mean daytime intra-arterial blood pressure. During prazosin treatment the mean reduction in blood pressure was 28 +/- 21.5/18 +/- 8.5 mm Hg for clinic blood pressure, 21 +/- 20.5/6 +/- 13.7 mm Hg for self-recorded blood pressure, and 18 +/- 19.2/5 +/- 9.6 mm Hg for mean daytime intra-arterial blood pressure. There was little agreement between methods within individual patients and for group comparisons of intra-arterial or clinic methods. There was, however, good agreement between intra-arterial and self-recorded methods. This study suggests that self-recorded blood pressure recording is suitable for monitoring efficacy of antihypertensive agents in a group of patients, although caution must be exercised when interpreting the effects of therapy when measured by indirect methods in an individual patient.

Twice-daily verapamil for hypertension: A comparison with propranolol

Recent reports have confirmed that some slow calcium channel inhibitors have useful antihypertensive properties because they produce dilatation of the peripheral arterioles without reflex tachycardia. Verapamil is such a drug, but its clinical role in the management of hypertension is not clear. An open crossover trial was performed to compare the 24-hour profiles of blood pressure reduction after long-term therapy with a standard beta-adrenoceptor blocker, propranolol, and verapamil. Nineteen patients were studied by continuous ambulatory intraarterial recording and the order of drug administration was determined by random allocation. The drugs were administered 2 times a day and titrated according to casual clinic pressures (propranolol, 40 to 240 mg 2 times a day; verapamil, 120 to 240 mg 2 times a day). Mean hourly blood pressure and heart rate values were obtained over a 24-hour cycle and the responses to isometric and dynamic exercise were also examined. The drugs produced a uniform and comparable reduction in blood pressure throughout the day, together with a reduction in heart rate, which was greater with propranolol. Comparable effects were also seen on the pressor responses to exercise. Both drugs were equally well tolerated and caused no patient withdrawals. Thus, oral verapamil given 2 times a day shows a degree of efficacy similar to that of propranolol and provides 24-hour blood pressure control. This slow calcium channel inhibitor was well tolerated and may be used as initial therapy for hypertension.

Ambulatory blood pressure — direct and indirect

Ambulatory blood pressures help characterise the behavior of blood pressure away from the hospital environment and may aid in the diagnosis and management of hypertensive patients. These measurements have been obtained either by patient-recorded blood pressures or with automated recorders such as the Remler M2000 and Avionics 1978 Pressurometer. We have evaluated these techniques against indirect pressures measured with the random zero sphygmomanometer and intraarterial blood pressures recorded with the “Oxford” sytem for ambulatory monitoring. The mean discrepancy for home BP-intra arterial BP was 0/3 mmHg whilst for clinic BP-intra-arterial BP it was −13/1 mmHg. There was a mean error of 3/2 mmHg for Remler-intra-arterial BP and of −2/4 for clinic BP-Remler. There was a mean error of −2/11 mmHg for Avionics -intra-arterial BP and of 3/8 mmHg for clinic BP-Avionics. Morning and evening self-recorded blood pressures (as used by epidemiologists) did not relate well to mean daytime ambulatory pressures. During a clinical trial the observed reductions in blood-pressure, as recorded by intra-arterial and self-recorded pressures, showed good agreement for a group of patients but not for the individual.

Prazosin alone and combined with a beta-adrenoreceptor blocker in treatment of hypertension.

Summary We recorded intra-arterial ambulatory blood pressure in 13 patients with essential hypertension before and after long-term twice-daily prazosin therapy (mean dosage 13.8 mg, SD 4.2 mg). Nine other patients with essential hypertension inadequately controlled with (β-adrenoreceptor blocking drugs were studied before and after the addition of long-term twice-daily prazosin therapy (mean dosage 8.8 mg, SD 6.7 mg). Ten patients, responders from both groups, then received once-daily prazosin, and intraarterial monitoring was repeated for a third time. Circadian curves from pooled hourly data showed no significant reduction of intra-arterial ambulatory blood pressure with prazosin alone. There was a slight reflex tachycardia. Nine patients receiving combination therapy showed a daytime reduction in blood pressure averaging 24/6 mm Hg (p < 0.001). Postural hypotension was recorded in both groups. Once-daily prazosin failed to control the blood pressure after 1700 h in the group of 10 patients defined as responders. Following combination therapy the blood pressure was reduced by 19/14 mm Hg at the peak of isometric hand grip and by 25/9 mm Hg on dynamic bicycle exercise. These data indicate that prazosin as an antihypertensive agent is best used in combination therapy with β-adrenoreceptor blockade.

An intra‐arterial profile of methyldopa

The “Oxford” system for intra‐arterial ambulatory blood pressure monitoring was used to monitor the blood pressure profile in 24 patients with essential hypertension who had received no therapy for 4 wk. The responses to tilt and isometric and dynamic bicycle exercise were recorded. Following the baseline study patients received methyldopa 125 mg t.i.d., which was titrated to a maximum of 500 mg t.i.d. according to blood pressure responses. The mean daily dosage was 1359 mg. Six weeks after the last dosage increment the experiment was repeated. Each patient was asked to take the total daily dosage once a day and the intra‐arterial monitoring program was repeated after another 6 wk. Mean daytime intra‐arterial blood pressure during three‐times‐daily dosing was reduced by 27/15 mm Hg; circadian curves were clearly separated during the day but not at night. Once‐daily dosing did not control blood pressure as well. There was no evidence of postural hypotension and the absolute pressure response was lowered during both isometric and dynamic exercise. These results are comparable to those from similar studies with α‐ and β‐adrenoreceptor–blocking drugs.

Alpha-adrenoreceptor blockade with indoramin in hypertension.

We have evaluated the effects of indoramin, an alpha-adrenoreceptor blocking drug, used as sole therapy in a group of 27 patients with essential hypertension. Blood pressure and heart rate were measured continuously over prolonged ambulatory periods using an established invasive technique before and after six weeks of therapy. The protocol was randomised, double-blind, and with double-dummy placebo control. A standardised programme of physiological stress testing was also performed during each study. Placebo produced no appreciable change in the levels or patterns of blood pressure over 24-h periods, but indoramin produced a significant reduction, which was particularly marked during the night. Physiological testing did not reveal any postural hypotension, and the response to dynamic and isometric exercise was modified in level but not in degree of change. There were many unwanted effects, which may limit the clinical value of this drug.

Intra-arterial ambulatory blood pressure monitoring in the assessment of antihypertensive drugs

Direct measurement of blood pressure in ambulatory patients was performed with the intra-arterial “Oxford System” to assess the effectiveness of differing antihypertensive agents. The betablocker, metoprolol (200 mg daily), decreased daytimed blood pressure from 174/95 mmHg to 158/85 mmHg; the combination of metoprolol and chlorthalidone (25 mg daily) further decreased the mean daytime pressure to 143/78 mmHg (p < 0.001 systolic, p < 0.005 diastolic). The calcium channel blockers, nifedipine (20–40 mg twice daily) and verapamil (120–160 mg three times daily), each significantly decreased the nifedipine, but decreased significantly with verapamil. The angiotensin converting enzyme inhibitor, enalopril (20–40 mg daily), significantly decreased blood pressure for 18 of 24 hours, the antihypertensive effect being most pronounced during the daytime period. These experiences indicate that the technique of direct ambulatory blood pressure monitoring is of value in studying both the efficacy and the duration of antihypertensive treatment.mean hourly blood pressure during most of the day (23 of 24 hours with nifedipine, 15 of 24 hours of verapamil). Heart rate did not change with nifedipine, but decreased significantly with verapamil. The angiotensin converting enzyme inhibitor, enalopril (20–40 mg daily), significantly decreased blood pressure for 18 of 24 hours, the antihypertensive effect being most pronounced during the daytime period. These experiences indicate that the technique of direct ambulatory blood pressure monitoring is of value in studying both the efficacy and the duration of antihypertensive treatment.