use of nifedipine as monotherapy in the management of hypertension

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Use of Nifedipine as Monotherapy in the Management of Hypertension WILLIAM A. LITTLER, M.D., F.R.C.P. Birmingham, United Kingdom Calcium antagonists are vasodilators and, therefore, they decrease the peripheral vascular resistance. Acute vasodilation invokes a re- flex increase in sympathetic activity that results in positive chrono- tropic and inotropic effects. These acute effects have been demon- strated both in patients with hypertension and subjects with normal blood pressure values. A theoretic objection to the use of nifedipine as monotherapy in patients with chronic hypertension was that cal- cium channel blockers would invoke a chronic sympathetic re- sponse and, in particular, chronic tachycardia. In this study, the ef- fects of calcium antagonists on ambulatory blood pressure were investigated in patients with essential hypertension who had no evi- dence of target organ damage. Direct arterial blood pressure meas- urements, monitored continuously over 24 hours, showed that ni- fedipine significantly reduced systolic and diastolic blood pressures throughout the day and at night. The variability in blood pressure values was not altered by nifedipine therapy, nor were there significant changes in heart rate. Estimations of left vehtricu- lar mass also demonstrated that successful control of blood pres- sure with nifedipine monotherapy resulted in a significant reduction ih the left ventricular mass similar to that achieved with beta block- ers ahd diuretics. Thus, nifedipine may be used effectively as mono- therapy in patients with essential hypertension, controlling blood pressure throughout the day and at night. Calcium antagonists are, therefore, useful drugs in the management of hypertension and, in light of the findings reported herein, should be seriously considered as initial therapy. From the Department of Cardiovascular Medicine, University of Birmingham, East Birmingham Hospi- tal, Birmingham, United Kingdom. Requests for reprints should be addressed to Professor W.A. Lit- tler, Department of Cardiovascular Medicine, Uni- versity of Birmingham, Bordesley Green East, Bir- mingham B9 5ST, United Kingdom. Calcium channel blockers are a chemically heterogeneous group of drugs that inhibit the entry of calcium into vascular smooth muscle. They act primarily by inhibiting the influx of extracellular calcium, probably through the slow calcium channel of the cell membrane. Their exact mechanisms of action are by no means clear and slow channel blockade may be an oversimplification. However, their major effect, both qualita- tively and quantitatively, is calcium antagonism. This chemical heteroge- nicity and the different sources of activator calcium in different vascular tissues may explain the variability of responses to calcium channel block- ers. Vasodilation is the most common theraoeutic characteristic of calcium channel blockers and is the basis of their gntihypertensive effect [l]. The calcium channel blockers that have received the most clinical attention as antihypertensive agents are nifedipine and verapamil.The antihyperten- sive effect of these two drugs is well documented in animal models of 36 October 11, 1965 The American Journal of Medicine Volume 79 (suppl 4A)

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Use of Nifedipine as Monotherapy in the Management of Hypertension

WILLIAM A. LITTLER, M.D., F.R.C.P.

Birmingham, United Kingdom

Calcium antagonists are vasodilators and, therefore, they decrease the peripheral vascular resistance. Acute vasodilation invokes a re- flex increase in sympathetic activity that results in positive chrono- tropic and inotropic effects. These acute effects have been demon- strated both in patients with hypertension and subjects with normal blood pressure values. A theoretic objection to the use of nifedipine as monotherapy in patients with chronic hypertension was that cal- cium channel blockers would invoke a chronic sympathetic re- sponse and, in particular, chronic tachycardia. In this study, the ef- fects of calcium antagonists on ambulatory blood pressure were investigated in patients with essential hypertension who had no evi- dence of target organ damage. Direct arterial blood pressure meas- urements, monitored continuously over 24 hours, showed that ni- fedipine significantly reduced systolic and diastolic blood pressures throughout the day and at night. The variability in blood pressure values was not altered by nifedipine therapy, nor were there significant changes in heart rate. Estimations of left vehtricu- lar mass also demonstrated that successful control of blood pres- sure with nifedipine monotherapy resulted in a significant reduction ih the left ventricular mass similar to that achieved with beta block- ers ahd diuretics. Thus, nifedipine may be used effectively as mono- therapy in patients with essential hypertension, controlling blood pressure throughout the day and at night. Calcium antagonists are, therefore, useful drugs in the management of hypertension and, in light of the findings reported herein, should be seriously considered as initial therapy.

From the Department of Cardiovascular Medicine, University of Birmingham, East Birmingham Hospi- tal, Birmingham, United Kingdom. Requests for reprints should be addressed to Professor W.A. Lit- tler, Department of Cardiovascular Medicine, Uni- versity of Birmingham, Bordesley Green East, Bir- mingham B9 5ST, United Kingdom.

Calcium channel blockers are a chemically heterogeneous group of drugs that inhibit the entry of calcium into vascular smooth muscle. They act primarily by inhibiting the influx of extracellular calcium, probably through the slow calcium channel of the cell membrane. Their exact mechanisms of action are by no means clear and slow channel blockade may be an oversimplification. However, their major effect, both qualita- tively and quantitatively, is calcium antagonism. This chemical heteroge- nicity and the different sources of activator calcium in different vascular tissues may explain the variability of responses to calcium channel block- ers.

Vasodilation is the most common theraoeutic characteristic of calcium channel blockers and is the basis of their gntihypertensive effect [l]. The calcium channel blockers that have received the most clinical attention as antihypertensive agents are nifedipine and verapamil.The antihyperten- sive effect of these two drugs is well documented in animal models of

36 October 11, 1965 The American Journal of Medicine Volume 79 (suppl 4A)

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-LITTLER

TABLE I Characteristics of Three Groups of Patients with Hypertension Treated with Different Drug Regimens

Characteristics Timolol Nifedipine lndapamide

Age (years) 39k14 40 t 7 40t11 Male:female ratio 9:o 7~2 4:4 Casual systolic pressure 170~13 173214 164k 16

(mm Hg) Casual diastolic pressure 107512 109r7 97 i 10

(mm W) Casual heart rate a2 i a 77-+13 76i.13

(beats per minute)

hypertension and in humans with the condition. When given acutely, both nifedipine and verapamil produce a decline in blood pressure that is associated with a reduc- tion in the peripheral vascular resistance. However, these drugs differ from one another in the rapidity and potency of their relaxant effect on vascular smooth muscle. Nifedi- pine acts more quickly and profoundly on smooth muscle than does verapamil and is associated with more obvious evidence of reflex sympathetic activation, such as tachy- cardia and increases in plasma catecholamine and renin levels. Such changes are less marked with verapamil, which has a slower onset of action.

The reduction in blood pressure induced by acute ad- ministration of nifedipine is offset, to a greater or lesser extent, by the baroreceptor-activated reflexes. In addition to the increases in heart rate and cardiac output, in- creased sympathetic tone is reflected by increased levels of circulating norepinephrine and increased plasma renin activity [I]. In patients with poor reflex responses, such as the elderly and those with hypertension, there sometimes may be a pronounced decrease in arterial pressure after acute administration of nifedipine.

When compounds such as nifedipine and verapamil were first introduced into clinical practice, they were thought to be unsuitable for use as monotherapy since they produced changes in sympathetic activity. Because of these changes, it was originally advised that beta block- ers be used in combination with calcium channel blockers like nifedipine. To determine the effect of chronic nifedi- pine monotherapy in patients with essential hypertension, studies were conducted to assess the effect of nifedipine on chronic ambulatory intra-arterial blood pressure and its variability and on heart rate.

Hypertrophy of the left ventricle is the principal adapta- tion of the heat-l in response to systemic hypertension, and its presence may predict a greater risk of morbidity and mortality. However, the etiology of this hypertrophy is uncertain. Traditional teaching states that hypertrophy is a direct result of pressure overload, but the means by which this hemodynamic stimulus is translated into a biochemi- cal response that produces ventricular hypertrophy is un-

clear. Experiments in animals have suggested that hu- moral factors may be involved [2] and, in humans, there is some evidence that factors other than pressure overload may be responsible [3]. Various factors have been impli- cated in ventricular hypertrophy, including plasma cate- cholamines and plasma renin [4].

A statistically significant correlation between the left ventricular mass index and blood pressure measured over a 24-hour period has been reported previously; however, no correlation was found between the mass index and humoral factors, such as plasma renin activity or plasma noradrenaline [5].

PATIENTS AND METHODS

Chronic Monotherapy with Nifedipine and Ambulatory Blood Pressure (Study I). Ten patients, eight men and two women, with moderate essential hypertension were studied; the average casual blood pressure was 173 i 141109 + 7 mm Hg. The mean age was 40 years, with a range of 33 to 53 years. There was no evidence of target organ damage in any patient, and underlying causes of hypertension had been excluded. No patient was receiving medication at the time of entry into the study. Informed consent was obtained from all patients, and the studies were approved by the hospital’s eth- ical committee.

Patients participated in two separate 24-hour studies: one during the control period and one during active treatment with nifedipine. At the completion of the first intra-arterial blood pressure study, patients began taking lo-mg oral doses of nifedipine three times a day. The patients were initially evalu- ated at two-week intervals and then monthly for a period of 16 weeks. The dosage of nifedipine was increased to 20 mg three times a day if the blood pressure reduction was less than 1017 mm Hg.

Patients underwent a 24-hour period of continuous intra- arterial ambulatory blood pressure monitoring as previously described [6]. This study was performed under standardized conditions [7]. Frequency histograms of pressures at one- hour intervals were plotted. The mean and standard devia- tions in the data were used to determine variability in mean systolic and diastolic pressures [7]. Effect on Left Ventricular Hypertrophy of Nifedipine as Monotherapy in Hypertension (Study II). In this investiga- tion [5], 26 patients with essential hypertension were studied. The patient demographics are presented in Table I. At the time of entry into the study, the mean casual untreated blood pressure was 168 t 16/l 01 -t 12 mm Hg. Patients were se- lected from among those presenting at an outpatient clinic and had casual blood pressures exceeding 140195 mm Hg on three occasions that were separated by at least a one-month period. Patients had not received any other antihypertensive agent prior to this study, nor were they taking any other medi- cation. Causes of secondary hypertension were excluded. The patients were randomly assigned to one of three regi- mens for 16 weeks: IO mg of timolol (a nonselective beta blocker) three times a day; 10 mg of nifedipine (a calcium antagonist) three times a day; or 2.5 mg of indapamide (a diuretic with perhaps some calcium antagonist properties) daily.

Patients underwent 24-hour continuous intra-arterial am-

October 11, 1985 The American Journal of Medicine Volume 79 (suppl 4A) 37

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-LITTLER

140- 140-

130- 130-

MAP lm- MAP lm- (mm W llo. (mm W llo.

lOO= lOO=

90= 90=

809 809

($& 70. ($& 70.

60- 60-

50. 50.

- MAP ‘c SE control l = P<O.OS 0 =P<O.Ol A = P<O.O005 C--C MAP z SE nifedipine o = PcO.025 l =P<O.O05

l Or*OrO*oo*oooo*oo’AAoO

- - - HR nifedipine

4oJ , , , , , , , , , , , , , , , , , , , . , , , 13 14 15 16 17 18 19 20 21 22 23 0 1 2 3 4 5 6 7 8 9 10 11

mm (h)

Figure 1. Mean arterial pressure (MAP) and heart rate (HR) averaged for each hour throughout the day and at night during the control period and after 16 weeks of treatment with 10 mg of nifedipine every eight hours in patients with hypertension. There was a significant reduction in blood pressure for all observations, but heart rates were not significantly different during the two study periods.

bulatory monitoring of blood pressure as previously de- scribed [6]. These measurements were made under stand- ardized conditions. M-mode echocardiography was performed before both the control and the chronic intra-arte- rial studies using an SK1 Ekoline 20 E20A ultrasonoscope with tracings recorded on ultraviolet paper by a Cambridge multichannel physiologic recorder. Satisfactory echocardio- grams were obtained in 23 patients. The echocardiograms were obtained by the same observer with the same appara- tus on each occasion, and were analyzed by an observer “blind” to the nature and duration of treatment. Only M-mode

.echocardiograms showing continuous endocardial echoes were used, and the measurements were averaged over three to five beats. Left ventricular (LV) mass was calculated by the following formula: LV = 1.04 ([Dd+Pw+S13 - [Dd13) - 13.6 g, in which Dd is the left ventricular end-diastolic dimension; Pw is the left ventricular posterior wail thickness; and S is the intraventricular septal thickness [8,9]. The left ventricular mass index was derived by dividing the calculated left ventric- ular mass by the patient’s body surface area.

Venous blood samples were drawn through an indwelling cannula after patients had rested in a supine position for 60 minutes. Samples were drawn at the same time of day and assayed by the same technician to determine plasma renin activity and catecholamine levels. Plasma renin activity was measured by a modification of the method of Waite [IO]; plasma catecholamines were analyzed by the method of

Henry et al [1 11. Statistical analysis was performed using Stu- dent paired t tests. Nonparametric data were analyzed by Wilcoxon’s sign rank sum test. Results were expressed as mean ? standard deviation.

RESULTS

Study I. Indirect measurements showed that the mean systolic and diastolic blood pressures were significantly reduced after two weeks of treatment with nifedipine (sys- tolic, 173 t: 14 mm Hg at baseline versus 138 i 11 mm Hg after treatment, p <O.OOl ; diastolic, 109 -I 7 mm Hg versus 84 1 14 mm Hg, p ~0.05). This reduction was maintained throughout the 16-week period. Intra-arterial ambulatory blood pressure was also significantly reduced during the 24-hour monitoring period (153/98 t 19111 mm Hg to 133185 +- 1318 mm Hg, p <O.OOl) (Figure 1). The significant decline in blood pressure was present during both awake and sleeping states (awake, 159/l 03 -r- 18/l 2 mm Hg to 140189 +- 18/8 mm Hg; p co.01 for systolic blood pressure, p <O.OOl for diastolic blood pressure; sleeping, 136/88 2 23113 mm Hg to 122/80 2 13/8 mm Hg; p co.02 for systolic blood pressure, p co.05 for dia- stolic blood pressure). The blood pressure variability val- ues between the total awake and asleep periods were not significantly altered by nifedipine therapy.

38 October 11, 1985 The American Journal of Medicine Volume 79 (suppl 4A)

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-LITTLER

TABLE II Results of 16 Weeks of Treatment with Three Drug Regimens in Patients with Hypertension

Timolol Nifedipine lndapamide

Control Treated Control Treated Control Treated

24-Hour blood pressure 142190 t 918 120173 2 %17t 153198 rt 19111 133185 i 13187 144187 i- I 3110 127182 -+ 9/l Ot

(mm W Left ventricular mass index

Wm) Heart rate

(beats per minute) Supine plasma renin activity

(nmoliliterlhour) Noradrenaline level

(nmol/liter) Adrenaline level

(nmol/liter)

115 + 15 107 t 20 126 + 31 117k27 107 i 21 101 * 22*

75 -+ 8 62 i ? 79 17 75 k 9 79 f 7 78 t 10

1.8 + 1.1 0.8 5 0.2* 1 .o 2 0.7 1 .O t- 0.8 1.2 * 1.3 2.3 2 1.8*

2.02 f 0.71 1.84 -+ 0.83 1.93 t 1.06 1.60 -+ 1.36 1.57 i 0.66 1.62 i 0.22

0.21 z!z 0.11 0.15 ” 0.04 0.20 I 0.09 0.14 k 0.11 0.28 i 0.09 0.39 IL 0.16

*p <0.05. tp 10.01.

Over the 16-week period, heart rate, which was meas- [15] to increase left ventricular mass despite adequate ured in the clinic, did not change significantly (77 +- 13 reductions in blood pressure. It has been suggested that it beats per minute versus 80 +- 19 beats per minute). There is the increase in sympathetic activity [16] and plasma was no significant difference in 24-hour heart rates after renin activity [9] produced by these vasodilators that pre- chronic nifedipine therapy (control, 80 t 9 beats per min- vents regression and that may cause further increases in ute versus nifedipine-treated, 77 f 9 beats per minute). hypertrophy of the left ventricle. However, calcium antag- Study II. The results of this study are presented in Table onists, as well as vasodilators, have been shown by sev- II. All three antihypertensive agents produced a satisfac- eral groups to reduce left ventricular mass with chronic tory reduction in blood pressure over a 24-hour period at use. More recently, enalapril, an angiotensin converting the end of the 16-week observation period. However, the enzyme inhibitor, was shown to produce a reduction in left three drugs produced markedly different effects on the ventricular mass without any evidence of sympatholytic other measured parameters, and no consistent pattern activity or suppression of circulating catecholamine levels emerged. 117).

COMMENTS

Study I. The results of this study confirmed the hypoten- sive action of nifedipine monotherapy in patients with es- sential hypertension [12]. Similar methods of recording ambulatory blood pressure have been reported in studies utilizing verapamil [13] and nifedipine tablets [14]. How- ever, in the case of verapamil, the diastolic blood pressure during the late evening and at night was not significantly reduced. This phenomenon may reflect, in part, the lack of standardization of activities in that particular study.

The variability in blood pressure values was not af- fected by nifedipine therapy. It has previously been shown that the level of pressure and the degree of physical activ- ity produce the most potent effects on blood pressure vari- ability during continuous intra-arterial recording [7].

Heart rates did not change significantly after 16 weeks of nifedipine therapy, in contrast with previous observa- tions from acute and short-term studies. Study II. Long-term blood pressure control has been associated with regression of left ventricular hypertrophy in the case of most, but not all, antihypertensive agents. In particular, powerful vasodilators such as minoxidil and hydralazine have been shown in animals [2] and humans

In this study of three different antihypertensive agents with differing modes of action, a successful reduction in blood pressure, but no consistent or statistically significant change in plasma catecholamine levels or, by inference, significant change in sympathetic tone was demonstrated. Despite this, statistically significant reductions in the left ventricular mass index were found in all groups. These data do not support the hypothesis that the sympathetic nervous system is responsible for left ventricular hypertro- phy, and I believe that the most likely cause of the de- crease in the left ventricular mass index is the effective reduction of blood pressure over prolonged periods of time. Furthermore, these data demonstrated that not only does nifedipine, used as monotherapy, have a significant effect on blood pressure, but it also has a significant effect on one of the principal target organs in hypertension, the left ventricle.

In conclusion, these investigations have shown that ni- fedipine may be used effectively as monotherapy over long periods of time to reduce blood pressure during the day and at night. This prolonged reduction in blood pres- sure is associated with a significant reduction in ,the left ventricular mass similar to that seen with beta blockers and diuretics.

October 11, 1985 The American Journal of Medicine Volume 79 (suppl 4A) 39

SYMPOSIUM ON CALCIUM CHANNEL BLOCKERS-LITTLER

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