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Role of calcium antagonists in systemic hypertension
Role of CalciumAntagonists in Systemic Hypertension ALBERT0
ZANCHETTI,
Despite the physiologic rationale of their use in hypertension, traditional vasodilators such as hydralazine and minoxidil are often relegated to the second and, more often, to the third and fourth steps of step-care programs. Although they are powerful blood pressure-lowering agents, they cause tachycardia, excessive renin stimulation and sodium retention, and cannot be used as the only antihypertensive agent. The characteristics of the antihypertensive action of calcium antagonists make them suitable for monotherapy. Indeed, all calcium antagonists, while effectively lowering blood pressure through vasodilatation, either do not affect heat-l rate (verapamil and its analogs) or cause a moderate and transient heart rate increase (dihydropyridine compounds). Dihydropyridines also possess a natriuretic effect, probably due to inhibition of tubular sodium transport. The natriuretic effect is
T
1 o discuss the place calcium antagonists have and are going to have in the treatment of hypertension, I should like to start by describing some of the therapeutic guidelines that have been widely used in the last few years. The reasons that underlie these guidelines and whether the same reasons may now justify the use of new classes of antihypertensive agents, in particular the calcium antagonists, will then be discussed. Figure 1 illustrates the stepped-care program formulated by a World Health Organization Expert Committee in 1978.l These guidelines suggest as the first step either a diuretic or a p blocker, and as a second step either the combination of the two or the addition of other antihypertensive compounds. For many years the American approach to antihypertensive therapy has been to use diuretics as the only first choice. Recently, however, the step-care recommendations From the Istituto di Clinica Mcdica Generale e Terapia Medica, IJniversit5 di Milano, and Centro di Fisiologia Clinica e Ipertensione, Ospcdale Ma&ore, Milano, Italy. Address for reprints: Albert0 Zanchetti, MD, Centro di Fisiologia Clinica e Ipertensione, Universita di Milano, Ospedale Maggiore, Via F. Sforza, 35, 20122 Milano, Italy. 1308
MD
evident during the first 2 days of administration, but a small negative sodium balance persists for at least 1 week. There is no increase in body weight or fluid volumes with long-term administration of calcium antagonists with a marked acute natriuretic response, such as dihydropyridines, and those antagonists with a very moderate immediate natriuretic response, such as verapamil. All calcium antagonists, therefore, appear capable of preventing the sodium and water retention that vasodilatation would otherwise entail. More liberal step-care guidelines are now possible to find the agent most suitable for the individual patient. In these guidelines, calcium antagonists, as well as angiotensin converting enzyme inhibitors, are considered as possible first-choice agents along with diuretics and /3 blockers. (Am J Cardiol 1987;59:130B-136B)
made by the U.S. Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure2 recognized the role of p blockers in addition to that of diuretics, and very closely reproduce the recommendations made by the World Health 0rganization.l The main consideration upon which current stepcare programs of antihypertensive therapy are based is that what really matters in antihypertensive therapy is blood pressure (BP] reduction, not the means or mechanisms by which BP is reduced: therefore preference should be given to those drugs that can effectively lower BP with a minimum of untoward reactions (including symptoms) and that can often act as monotherapy, in such a way as to facilitate the patient’s compliance.lz3 Within this framework diuretics and ,6blockers are considered as first-choice drugs. They are undoubtedly effective as monotherapy in a sizable number of patients with mild to moderate hypertension and they have long been thought to induce minor and infrequent untoward effects, or at least less untoward effects than most of the other traditional antihypertensive agents.l
January 30. 1987
FIGURE 1. Stepped-care program as formulated by the World Health Organization in 1978. Reproduced with permission from the World Health Organization.’
Missing in this approach is achievement of a precise correction of the hemodynamic derangement. Hypertension is usually characterized by an increased BP, associated with no change or even a slight decrease in cardiac output and with a widespread increase in peripheral vascular resistance.” On the other hand, most of the p blockers are known to reduce BP by decreasing cardiac output with a further increase of the already elevated peripheral vascular resistance, which persists through several years of treatment.” Despite the physiologic rationale of their use in hypertension, vasodilators such as hydralazine and minoxidil are relegated to the second and, more often, to the third and fourth steps of step-care programs1 Although they are powerful in lowering BP, they cause tachycardia, excessive renin stimulation and sodium retention. Therefore, they cannot be used effectively on a long-term basis as monotherapy; they must be associated with both a /3 blocker and a diuretic in socalled “triple therapy.”
Characteristics of the AntihypertensiveAction of Calcium Antagonists To determine the place that calcium antagonists have in the treatment of hypertension we should first consider the characteristics of their antihypertensive action, and examine whether calcium antagonists present advantages over traditional vasodilators that make them suitable for monotherapy or for a less complicated therapeutic association.
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OF CARDIOLOGY
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Effects on blood pressure and heart rate: Among the first demonstrations of the antihypertensive action of calcium antagonists was our study of verapamil.5 We showed that oral doses of verapamil(80 to 160 mg 3 times daily) effectively lowered systolic and diastolic BP without affecting heart rate, which exhibited a slight tendency to decrease rather than increase [Fig. 2). Even during exercise verapamil did not cause any disproportionate increase in heart rate.5 As far as the dihydropyridine class is concerned, the antihypertensive action of nifedipine was first found by Aoki, fi Olivari7 and their co-workers. As shown in Figure 3, the antihypertensive effect of a single dose of nifedipine is accompanied by a consistent increase in heart rate: this is never very large, however, and usually lasts for a shorter period than the hypotensive effecL8 Figure 4 is from a recent work by our group” on another dihydropyridine, felodipine. In 11 hypertensive patients there was a prompt decrease in systolic and diastolic BP, both lying down and standing; this effect was seen after the first 10-mg dose of felodipine, and was maintained throughout the week during which 10 mg of felodipine was administered twice daily. Also there was a moderate increase in heart rate. On interruption of treatment, there was neither a rebound effect nor a brisk return of BP to hypertensive levels: BP gradually increased, and heart rate decreased during the 5 days of washout. That the BP reduction induced by calcium antagonists is due to peripheral vasodilatation accompanied by cardiac activation, which gradually attenuates with the passage of time, is also shown by our current study on nitrendipine? the BP decrease after the first dose of this calcium antagonist is accompanied by a rather marked increase in cardiac output, but after 1 week of
BP
mmHg 180 160 140
80’
b/
HR
min
110
1
I 100 i
1
90.
i
P-
601 Vl
VP
i-----
P
1 Vl
--1 v2
o---a Upright Supine FIGURE 2. Systolic (S), mean (M) and diastolic (D) blood pressure (BP) leff, and heart rate (HR) right, during administration of placebo (P), during the first period of verapamil administration (V,: 80 mg 3 times daily for 5 days) and during the second period of verapamil administration (V,: 160 mg 3 times daily in 9 of 12 patients, 80 mg 3 times daily in the remaining 3 for 5 days). All symbols are mean f standard error of the mean of values measured in 12 patients. Reproduced with permission from Eur J Clin Pharmacol.5
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pounds; dihydropyridines have a greater immediate natriuretic response than verapamil or gallopamil.15 Figure 5 shows that in hypertensive subjects tested on different days with placebo, a 16-mg dose of nifedipine or a 160-mg dose of verapamil, the 2 calcium antagonists caused a similar decrease in BP: nifedipine also induced a marked increase in diuresis and natriuresis in the subsequent 6 hours, whereas verapamil increased diuresis and natriuresis to a much smaller extent.* This indicates that the diuretic and natriuretic action of calcium antagonists is not directly related to the lowering in BP, although it must be noted that both the BP and the renal effects of the 2 calcium antagonists were almost entirely absent in normotensive subjects8 Three aspects of the natriuretic effect of calcium antagonists are worthy of discussion: the mechanism(s) of this effect, the duration of the effect and the importance of the natriuretic effect in the antihypertensive action of calcium antagonists. Figure 6 shows that in our experience the natriuretic effect of a lo-mg dose of the dihydropyridine compound, felodipine, is observed in the absence of any change in glomerular filtration rate, but that renal
BP mmlig 1
OPPORTUNITIES
-,
80
70
mm Hg
BLOOD
PRESSURE
180, r
0
I
I
I
I
r
I
1
1
2
3
4
5
6h
o--o
placebo
M
nifedipine
M
verapamil
* * *
S
160.
p < 0.005 pc
0.001
FIGURE 3. Blood pressure (BP) and heart rate (HR): effects of a single placebo tablet (0), a single lo-mg dose of nifedipine (0) and a single 160-mg dose of verapamil (A) on 3 different days in 14 hypertensive patients. Reproduced with permission from J Cardiovast Pharmacol.*
140-
801 60 j ,
continuous therapy, although the same BP decrease is maintained, cardiac output has reverted to approximately normal values. Calcium antagonists are also known to attenuate the vascular responses to cu-adrenergic agonists? Our recent work suggests that calcium antagonists might also attenuate the pressor response to angiotensin II infusion, while a mild hypotensive effect of potassium infusion may become evident after treatment with a calcium antagonist.12 Renal effects: An important characteristic by which calcium antagonists differ from traditional vasodilators is their natriuretic rather than antinatriuretic action Evidence of a natriuretic effect of all classes of calcium antagonists has been provided by intravenous administration in animal experiments.13J4 This presentation will concentrate on responses to oral administration in hypertensive patients. Acutely, on single dose administration, all calcium antagonist compounds have some natriuretic effect, but this is of a different extent with different com-
,
,
,
,
,
, HEART
b/min
,
,
,
,
,
,
,
,
RATE
loogo8070601 PLACEBO CI
supine
1
FELODIPINE
IWASH-OUT)
-upright
FIGURE 4. Supine ( l ) and upright (0) systolic (S) and diastolic (D) blood pressure and heart rate during placebo, felodipine and washout periods. Each circle is the average of all values measured in each subject on each day (10 measurements on last placebo day, on first and seventh felodipine day and on first, third and fifth washout day, 3 measurements on all other days). Reproduced with permission from J Cardiovasc Pharmacol.g
January 30, 1987
blood flow is simultaneously increased.“*‘” That an increase in renal blood flow, although regularly observed during administration of a calcium antagonist, is not necessarily associated with a natriuretic effect is also illustrated in Figure 6 by the finding that, on the seventh consecutive day of administration of felodipine 10 mg twice daily, the natriuretic effect has disappeared but the increase in renal blood flow is still observed. The most likely mechanism is a direct inhibition of tubular reabsorption, as shown in animal experiments with the micropuncture technique.17z1” The duration of the natriuretic effect has been explored in some recent experiments of our group, in which we studied sodium and potassium balances before and during administration of felodipine 10 mg
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JOURNAL
OF CARDIOLOGY
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80GFR ml/min 60-
lOOO-
800RPF ml/min
NORMOTENSIVES n 10
HYPERTENSIVES n 14
600-
170 150
130-
mmHg
SBP
130 llO110
Na+ excretion m mol/24
h go-
90 1200
70 3
800 ml ‘6 h
H20
400
-I
St
th
1 day 7 day Pl FIGURE 6. Effects of felodipine (10 mg on first day and 10 mg twice daily for the subsequent 6 days) on glomerular filtration rate (GFR), renal plasma flow (RPF) and sodium (Na+) excretion in 11 patients with essential hypertension. Mean f standard error of the mean on the last day of placebo period (pl) and on days 1 and 7 of felodipine administration ( l p 10.05, “p 10.01). Reproduced with permission from J Hypertension.16
0
Na+
0
Placebo
m
Ntfedlplne
* p -z 0.005
**
p
m
Verapamll
FIGURE 5. Maximum decrease in systolic blood pressure (SBP) and water and sodium excretion during the 6 hours after oral administration of placebo, nifedipine, 10 mg, or verapamil, 160 mg in different days in 10 normotensive and 14 hypertensive subjects ( l p <0.05, ““p 50.01). Reproduced with permission from J Cardiovasc Pharmacol.*,i3
once daily on the first day and then 10 mg twice daily for 6 additional daysS1,“’At these doses, which had a definite hypotensive effect, felodipine significantly increased sodium excretion on the first and second day inducing a negative sodium balance, averaging slightly more than 80 mmol; no further significant natriuretic effect was observed from the third day onward but a negative sodium balance was maintained until the last day of felodipine administration [Fig. 7). Although a statistically significant increase in potassium excretion did not occur on any single day, a small daily increase in potassium excretion continued throughout the week of felodipine administration, so that a negative potassium balance of about 50 mmol developed. Whether a slightly negative sodium and water balance is maintained under long-term therapy with a calcium antagonist, or whether the natriuretic properties simply result, on long term, in preventing the sodi-
1348
A SYMPOSIUM:
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ANTAGONISTS-EMERGING
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mmol 150 1
0
+1
2
3
4
5
6
+7
days
FIGURE 7. Sodium (Na+) and potassium (K+) balance during felodipine therapy. Sodlum and potassium balances were calculated by adding daily urinary excretion of sodium (or potassium) minus the excretion during the last day of placebo administration. Reproduced with permission from J Cardiovasc Pharmacol.g
251
Men
*
1
Women
FIGURE 8. Cumulative percent withdrawals from randomized treatment in the Medical Research Council study caused by suspected adverse reactions to antihypertensive therapy. l = propranolol; A = bendrofluazide; 0 = placebo. Reproduced with permission from Br Med J.24
urn and water retention that vasodilatation would otherwise entail, cannot be assessed by balance studies. There are, however, indications that body weight does not increase under prolonged treatment with calcium antagonists, and that this is true both for calcium antagonists with a marked acute natriuretic response, such as nifedipine,lg and for those with a very moderate acute natriuretic response, such as verapami15JD That the acute natriuretic effect of calcium antagonists is not immediately relevant for their antihypertensive action is also suggested by recent investigations of Leonetti et al. 21 Subjects with moderate essential hypertension were given a single dose of 10 mg of nifedipine and placebo in random order during a normal sodium diet (100 mmol/day) and again during sodium depletion (20 mmol/day for 7 days plus 25 mg of furosemide for 3 days]. During both the normal
OPPORTUNITIES
and low sodium diets nifedipine significantly reduced BP, despite the conspicuous natriuretic effect during sodium repletion, and its marked blunting during sodium depletion. On the whole, it appears that the natriuretic action of calcium antagonists is more important in preventing sodium retention and therefore in maintaining the antihypertensive effect long term than in contributing to the short-term antihypertensive effect. Further, we also have some evidence that, with excessive doses, the natriuretic effect of calcium antagonists may turn into an antinatriuretic one.22 When we used large doses of felodipine (12.5,25 and 50 mg 3 times daily) in preliminary experiments, no natriuretic response was observed, and, particularly with the highest dose, sodium excretion appeared to be somewhat decreased, and some decrease in glomerular filtration rate occurred simultaneously. In summary, the characteristics of the antihypertensive action of calcium antagonists, verapamil, its analogs and the dihydropyridine compounds-particularly the absence or mildness of reflex sympathetic activation as well as the natriuretic properties of these compounds that avoid the building-up of sodium and water retention-make them suitable for use in antihypertensive monotherapy.
DoWeNeedMore First-Choice AntihyflertensiveAgents? As mentioned one of the main principles upon which current stepped-care programs are basedl,” is that preference should be given to those drugs that can effectively lower BP with a minimum of untoward reactions, and that diuretics and /3 blockers have long been thought to induce only minor and infrequent untoward effects. The latter statement has been partly disputed by the recently published results of the Medical Research Council Trial on Mild Hypertensionz3J4 As shown in Figure 8, during the 5 years of this trial (which enrolled about 18,000 patients) about 23% of men and 13% of women had to be withdrawn from treatment with bendrofluazide, and 19% of men and 20% of women from treatment with propranolol because of untoward effects ascribed to treatment. Concern has also been expressed about the metabolic effects of diuretics and, to some extent, of ,6 blockers.25 Although the Medical Research Council tria123J4has shown these metabolic changes to be rather small with prolonged therapy, there is a consensus now that diuretics should be used in smaller doses than previously suggested.3,2fi An additional reason why p blockers were placed in the foreground of antihypertensive therapy was that they were said to exert some “cardioprotective” action, i.e., a more effective prevention of coronary morbidity in hypertension. This promise has not been fulfilled by the Medical Research Councilz4 and the International Prospective Primary Prevention Study in HypertensionZ7trials, with the possible exception of male nonsmokers, a subgroup in which both studies reported some possible advantages.
January 30, 1987
DIURETICS
lNHIBITORSorANTAGONIST,S
\ lnh,b,tors)
program. Reproduced
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indications or limited indications, perhaps on consideration of age and race, sometimes on cost consideration and often on the experience of the physician. Small doses of any agent should be used to commence therapy and the doses should not subsequently be increased beyond what is suggested by dose-response curves or the appearance of disturbances. In case of symptoms the physician has the choice of either switching to another first-step compound or of decreasing the dose of the first agent and combining it with one of the other agents as indicated in the scheme. As far as the calcium antagonists are concerned, a distinction is made between verapamil and nifedipine and other dihydropyridines. Only dihydropyridines can safely be combined with a p blocker, while verapamil can be associated with a diuretic. Finally, according to recent studies, all types of calcium antagonists can advantageously be administered with an angiotensin converting enzyme inhibitor.‘”
or
FIGURE 9. Outline of proposed step-care permission from Raven Press.30
THE AMERICAN
with
This does not mean diuretics and p blockers have lost their place as first-choice agents in the treatment of hypertension; they simply indicate that diuretics and /3 blockers have lost their prominence or uniqueness as the only agents available as first choice in antihypertensive therapy, in view of the characteristics of 2 new classes of antihypertensive agents, the calcium antagonists and the angiotensin converting enzyme inhibitors.
liberal Versus Rigid Approachesto Stepped Care The most important advantage of having a wide spectrum of antihypertensive drugs available is that this choice now makes it possible to find the most suitable agent for the individual patient. In clinical practice the choice of a drug should be seen as tentative, to be confirmed, corrected or abandoned on the basis of the patient’s response.20Most aspects of a patient’s response are susceptible to clinical measurement: not only the BP reduction, but the subjective and metabolic adverse effects and the arrest or reversal of secondary cardiovascular changes2” More liberal guidelines than the ones suggested up to now are shown in Figure 9.30The philosophy of a step-wise procession from simple to more complicated means of lowering BP is preserved, but is associated with the concept of multiple choices for the physician and the patient. Graphically, the step design seems lost but is substantially preserved. The physician has a choice to start not only with a thiazide diuretic or a /3 blocker, but also with a calcium antagonist or an angiotensin converting enzyme inhibitor. The choice among the various classes (sometimes including other classes as well, such as (Yblockers or centrally acting drugs) is made on simple clinical evaluation of existing contra-
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sion 1983;S:Yfi-102. 20. Semplicini A. Pessina AC, Rossi GP, Padrini R. Tagliafierro R, Quintarelli GF, Ferrari M, Dal Palti C. Plasma levels of veropamil and its effeocts on blood pressure. body fluid volumes and renal function in hypertensive patients. fnt 1 Clin Phoromocol Res 1982;2:suppl 1:81-t& 21. Leonetti G, Rupoli L. Sangiorgi P, Gradnik R. Cuspidi C, Bolla G. Zanchetti A. Effects of different sodium intakes on the antihypertensive and renal effects of single oral doses of nifedipine in hypertensive patients [obstr). Eleventh Scientific Meeting, fnternotionol Society of ffypertension, Heidelberg. 1986. 22. Leonetti G, Gradnik R, Terzoli L, Fruscio M. Rupoli L, Zanchetti A. Felodipine, a new vosodiloting drug: blood pressure, cordioc. renal, and humoral effects in hypertensive patients. [ Cardiovosc Pharmocol 1984;6: 392-398.
23. Medical Research Council Working Party on Mild to Moderate Hypertension. Adverse reactions to bendrofluozide and propronolol for the treatment of mild hypertension. Loncet 1981;2:539-543.
OPPORTUNITIES
24. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med / 3985;291:97-104. 25. Hansson L, Lowenstein ), Zanchetti A, eds. Coronary heart disease: hy2A. pertension ond other risk factors. Am [ Med 1984;76:supp~ 26. Zanchetti A. A re-examination of stepped-core: o retrospective ond o prospective. [ Cardiovasc Phormocol 1985;7:suppl l:S126-S131. 27. The IPPPSH Collaborative Group. Cardiovosculor risk and risk factors in o randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (fPPPSH). [ Hypertension 1985;34:379-392. 28. Zanchetti A. Which drug to which patient? [ Hypertension 1985;3:suppf 3:S57-S63.
29. Hansson L. Assessment of the patient’s response. [ Hypertension 1985; 3:suppf 2:X5-S69. 30. Zanchetti A. Step-wise treatment: which step first? In: Strasser T. Canten D. eds. Mild Hypertension. Proceedings ofo WHO/fSH faint Meeting. New York: Raven Press. 1986. in press.
ZANCHETTI,
Despite the physiologic rationale of their use in hypertension, traditional vasodilators such as hydralazine and minoxidil are often relegated to the second and, more often, to the third and fourth steps of step-care programs. Although they are powerful blood pressure-lowering agents, they cause tachycardia, excessive renin stimulation and sodium retention, and cannot be used as the only antihypertensive agent. The characteristics of the antihypertensive action of calcium antagonists make them suitable for monotherapy. Indeed, all calcium antagonists, while effectively lowering blood pressure through vasodilatation, either do not affect heat-l rate (verapamil and its analogs) or cause a moderate and transient heart rate increase (dihydropyridine compounds). Dihydropyridines also possess a natriuretic effect, probably due to inhibition of tubular sodium transport. The natriuretic effect is
T
1 o discuss the place calcium antagonists have and are going to have in the treatment of hypertension, I should like to start by describing some of the therapeutic guidelines that have been widely used in the last few years. The reasons that underlie these guidelines and whether the same reasons may now justify the use of new classes of antihypertensive agents, in particular the calcium antagonists, will then be discussed. Figure 1 illustrates the stepped-care program formulated by a World Health Organization Expert Committee in 1978.l These guidelines suggest as the first step either a diuretic or a p blocker, and as a second step either the combination of the two or the addition of other antihypertensive compounds. For many years the American approach to antihypertensive therapy has been to use diuretics as the only first choice. Recently, however, the step-care recommendations From the Istituto di Clinica Mcdica Generale e Terapia Medica, IJniversit5 di Milano, and Centro di Fisiologia Clinica e Ipertensione, Ospcdale Ma&ore, Milano, Italy. Address for reprints: Albert0 Zanchetti, MD, Centro di Fisiologia Clinica e Ipertensione, Universita di Milano, Ospedale Maggiore, Via F. Sforza, 35, 20122 Milano, Italy. 1308
MD
evident during the first 2 days of administration, but a small negative sodium balance persists for at least 1 week. There is no increase in body weight or fluid volumes with long-term administration of calcium antagonists with a marked acute natriuretic response, such as dihydropyridines, and those antagonists with a very moderate immediate natriuretic response, such as verapamil. All calcium antagonists, therefore, appear capable of preventing the sodium and water retention that vasodilatation would otherwise entail. More liberal step-care guidelines are now possible to find the agent most suitable for the individual patient. In these guidelines, calcium antagonists, as well as angiotensin converting enzyme inhibitors, are considered as possible first-choice agents along with diuretics and /3 blockers. (Am J Cardiol 1987;59:130B-136B)
made by the U.S. Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure2 recognized the role of p blockers in addition to that of diuretics, and very closely reproduce the recommendations made by the World Health 0rganization.l The main consideration upon which current stepcare programs of antihypertensive therapy are based is that what really matters in antihypertensive therapy is blood pressure (BP] reduction, not the means or mechanisms by which BP is reduced: therefore preference should be given to those drugs that can effectively lower BP with a minimum of untoward reactions (including symptoms) and that can often act as monotherapy, in such a way as to facilitate the patient’s compliance.lz3 Within this framework diuretics and ,6blockers are considered as first-choice drugs. They are undoubtedly effective as monotherapy in a sizable number of patients with mild to moderate hypertension and they have long been thought to induce minor and infrequent untoward effects, or at least less untoward effects than most of the other traditional antihypertensive agents.l
January 30. 1987
FIGURE 1. Stepped-care program as formulated by the World Health Organization in 1978. Reproduced with permission from the World Health Organization.’
Missing in this approach is achievement of a precise correction of the hemodynamic derangement. Hypertension is usually characterized by an increased BP, associated with no change or even a slight decrease in cardiac output and with a widespread increase in peripheral vascular resistance.” On the other hand, most of the p blockers are known to reduce BP by decreasing cardiac output with a further increase of the already elevated peripheral vascular resistance, which persists through several years of treatment.” Despite the physiologic rationale of their use in hypertension, vasodilators such as hydralazine and minoxidil are relegated to the second and, more often, to the third and fourth steps of step-care programs1 Although they are powerful in lowering BP, they cause tachycardia, excessive renin stimulation and sodium retention. Therefore, they cannot be used effectively on a long-term basis as monotherapy; they must be associated with both a /3 blocker and a diuretic in socalled “triple therapy.”
Characteristics of the AntihypertensiveAction of Calcium Antagonists To determine the place that calcium antagonists have in the treatment of hypertension we should first consider the characteristics of their antihypertensive action, and examine whether calcium antagonists present advantages over traditional vasodilators that make them suitable for monotherapy or for a less complicated therapeutic association.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 59
1318
Effects on blood pressure and heart rate: Among the first demonstrations of the antihypertensive action of calcium antagonists was our study of verapamil.5 We showed that oral doses of verapamil(80 to 160 mg 3 times daily) effectively lowered systolic and diastolic BP without affecting heart rate, which exhibited a slight tendency to decrease rather than increase [Fig. 2). Even during exercise verapamil did not cause any disproportionate increase in heart rate.5 As far as the dihydropyridine class is concerned, the antihypertensive action of nifedipine was first found by Aoki, fi Olivari7 and their co-workers. As shown in Figure 3, the antihypertensive effect of a single dose of nifedipine is accompanied by a consistent increase in heart rate: this is never very large, however, and usually lasts for a shorter period than the hypotensive effecL8 Figure 4 is from a recent work by our group” on another dihydropyridine, felodipine. In 11 hypertensive patients there was a prompt decrease in systolic and diastolic BP, both lying down and standing; this effect was seen after the first 10-mg dose of felodipine, and was maintained throughout the week during which 10 mg of felodipine was administered twice daily. Also there was a moderate increase in heart rate. On interruption of treatment, there was neither a rebound effect nor a brisk return of BP to hypertensive levels: BP gradually increased, and heart rate decreased during the 5 days of washout. That the BP reduction induced by calcium antagonists is due to peripheral vasodilatation accompanied by cardiac activation, which gradually attenuates with the passage of time, is also shown by our current study on nitrendipine? the BP decrease after the first dose of this calcium antagonist is accompanied by a rather marked increase in cardiac output, but after 1 week of
BP
mmHg 180 160 140
80’
b/
HR
min
110
1
I 100 i
1
90.
i
P-
601 Vl
VP
i-----
P
1 Vl
--1 v2
o---a Upright Supine FIGURE 2. Systolic (S), mean (M) and diastolic (D) blood pressure (BP) leff, and heart rate (HR) right, during administration of placebo (P), during the first period of verapamil administration (V,: 80 mg 3 times daily for 5 days) and during the second period of verapamil administration (V,: 160 mg 3 times daily in 9 of 12 patients, 80 mg 3 times daily in the remaining 3 for 5 days). All symbols are mean f standard error of the mean of values measured in 12 patients. Reproduced with permission from Eur J Clin Pharmacol.5
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pounds; dihydropyridines have a greater immediate natriuretic response than verapamil or gallopamil.15 Figure 5 shows that in hypertensive subjects tested on different days with placebo, a 16-mg dose of nifedipine or a 160-mg dose of verapamil, the 2 calcium antagonists caused a similar decrease in BP: nifedipine also induced a marked increase in diuresis and natriuresis in the subsequent 6 hours, whereas verapamil increased diuresis and natriuresis to a much smaller extent.* This indicates that the diuretic and natriuretic action of calcium antagonists is not directly related to the lowering in BP, although it must be noted that both the BP and the renal effects of the 2 calcium antagonists were almost entirely absent in normotensive subjects8 Three aspects of the natriuretic effect of calcium antagonists are worthy of discussion: the mechanism(s) of this effect, the duration of the effect and the importance of the natriuretic effect in the antihypertensive action of calcium antagonists. Figure 6 shows that in our experience the natriuretic effect of a lo-mg dose of the dihydropyridine compound, felodipine, is observed in the absence of any change in glomerular filtration rate, but that renal
BP mmlig 1
OPPORTUNITIES
-,
80
70
mm Hg
BLOOD
PRESSURE
180, r
0
I
I
I
I
r
I
1
1
2
3
4
5
6h
o--o
placebo
M
nifedipine
M
verapamil
* * *
S
160.
p < 0.005 pc
0.001
FIGURE 3. Blood pressure (BP) and heart rate (HR): effects of a single placebo tablet (0), a single lo-mg dose of nifedipine (0) and a single 160-mg dose of verapamil (A) on 3 different days in 14 hypertensive patients. Reproduced with permission from J Cardiovast Pharmacol.*
140-
801 60 j ,
continuous therapy, although the same BP decrease is maintained, cardiac output has reverted to approximately normal values. Calcium antagonists are also known to attenuate the vascular responses to cu-adrenergic agonists? Our recent work suggests that calcium antagonists might also attenuate the pressor response to angiotensin II infusion, while a mild hypotensive effect of potassium infusion may become evident after treatment with a calcium antagonist.12 Renal effects: An important characteristic by which calcium antagonists differ from traditional vasodilators is their natriuretic rather than antinatriuretic action Evidence of a natriuretic effect of all classes of calcium antagonists has been provided by intravenous administration in animal experiments.13J4 This presentation will concentrate on responses to oral administration in hypertensive patients. Acutely, on single dose administration, all calcium antagonist compounds have some natriuretic effect, but this is of a different extent with different com-
,
,
,
,
,
, HEART
b/min
,
,
,
,
,
,
,
,
RATE
loogo8070601 PLACEBO CI
supine
1
FELODIPINE
IWASH-OUT)
-upright
FIGURE 4. Supine ( l ) and upright (0) systolic (S) and diastolic (D) blood pressure and heart rate during placebo, felodipine and washout periods. Each circle is the average of all values measured in each subject on each day (10 measurements on last placebo day, on first and seventh felodipine day and on first, third and fifth washout day, 3 measurements on all other days). Reproduced with permission from J Cardiovasc Pharmacol.g
January 30, 1987
blood flow is simultaneously increased.“*‘” That an increase in renal blood flow, although regularly observed during administration of a calcium antagonist, is not necessarily associated with a natriuretic effect is also illustrated in Figure 6 by the finding that, on the seventh consecutive day of administration of felodipine 10 mg twice daily, the natriuretic effect has disappeared but the increase in renal blood flow is still observed. The most likely mechanism is a direct inhibition of tubular reabsorption, as shown in animal experiments with the micropuncture technique.17z1” The duration of the natriuretic effect has been explored in some recent experiments of our group, in which we studied sodium and potassium balances before and during administration of felodipine 10 mg
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80GFR ml/min 60-
lOOO-
800RPF ml/min
NORMOTENSIVES n 10
HYPERTENSIVES n 14
600-
170 150
130-
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SBP
130 llO110
Na+ excretion m mol/24
h go-
90 1200
70 3
800 ml ‘6 h
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400
-I
St
th
1 day 7 day Pl FIGURE 6. Effects of felodipine (10 mg on first day and 10 mg twice daily for the subsequent 6 days) on glomerular filtration rate (GFR), renal plasma flow (RPF) and sodium (Na+) excretion in 11 patients with essential hypertension. Mean f standard error of the mean on the last day of placebo period (pl) and on days 1 and 7 of felodipine administration ( l p 10.05, “p 10.01). Reproduced with permission from J Hypertension.16
0
Na+
0
Placebo
m
Ntfedlplne
* p -z 0.005
**
p
m
Verapamll
FIGURE 5. Maximum decrease in systolic blood pressure (SBP) and water and sodium excretion during the 6 hours after oral administration of placebo, nifedipine, 10 mg, or verapamil, 160 mg in different days in 10 normotensive and 14 hypertensive subjects ( l p <0.05, ““p 50.01). Reproduced with permission from J Cardiovasc Pharmacol.*,i3
once daily on the first day and then 10 mg twice daily for 6 additional daysS1,“’At these doses, which had a definite hypotensive effect, felodipine significantly increased sodium excretion on the first and second day inducing a negative sodium balance, averaging slightly more than 80 mmol; no further significant natriuretic effect was observed from the third day onward but a negative sodium balance was maintained until the last day of felodipine administration [Fig. 7). Although a statistically significant increase in potassium excretion did not occur on any single day, a small daily increase in potassium excretion continued throughout the week of felodipine administration, so that a negative potassium balance of about 50 mmol developed. Whether a slightly negative sodium and water balance is maintained under long-term therapy with a calcium antagonist, or whether the natriuretic properties simply result, on long term, in preventing the sodi-
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mmol 150 1
0
+1
2
3
4
5
6
+7
days
FIGURE 7. Sodium (Na+) and potassium (K+) balance during felodipine therapy. Sodlum and potassium balances were calculated by adding daily urinary excretion of sodium (or potassium) minus the excretion during the last day of placebo administration. Reproduced with permission from J Cardiovasc Pharmacol.g
251
Men
*
1
Women
FIGURE 8. Cumulative percent withdrawals from randomized treatment in the Medical Research Council study caused by suspected adverse reactions to antihypertensive therapy. l = propranolol; A = bendrofluazide; 0 = placebo. Reproduced with permission from Br Med J.24
urn and water retention that vasodilatation would otherwise entail, cannot be assessed by balance studies. There are, however, indications that body weight does not increase under prolonged treatment with calcium antagonists, and that this is true both for calcium antagonists with a marked acute natriuretic response, such as nifedipine,lg and for those with a very moderate acute natriuretic response, such as verapami15JD That the acute natriuretic effect of calcium antagonists is not immediately relevant for their antihypertensive action is also suggested by recent investigations of Leonetti et al. 21 Subjects with moderate essential hypertension were given a single dose of 10 mg of nifedipine and placebo in random order during a normal sodium diet (100 mmol/day) and again during sodium depletion (20 mmol/day for 7 days plus 25 mg of furosemide for 3 days]. During both the normal
OPPORTUNITIES
and low sodium diets nifedipine significantly reduced BP, despite the conspicuous natriuretic effect during sodium repletion, and its marked blunting during sodium depletion. On the whole, it appears that the natriuretic action of calcium antagonists is more important in preventing sodium retention and therefore in maintaining the antihypertensive effect long term than in contributing to the short-term antihypertensive effect. Further, we also have some evidence that, with excessive doses, the natriuretic effect of calcium antagonists may turn into an antinatriuretic one.22 When we used large doses of felodipine (12.5,25 and 50 mg 3 times daily) in preliminary experiments, no natriuretic response was observed, and, particularly with the highest dose, sodium excretion appeared to be somewhat decreased, and some decrease in glomerular filtration rate occurred simultaneously. In summary, the characteristics of the antihypertensive action of calcium antagonists, verapamil, its analogs and the dihydropyridine compounds-particularly the absence or mildness of reflex sympathetic activation as well as the natriuretic properties of these compounds that avoid the building-up of sodium and water retention-make them suitable for use in antihypertensive monotherapy.
DoWeNeedMore First-Choice AntihyflertensiveAgents? As mentioned one of the main principles upon which current stepped-care programs are basedl,” is that preference should be given to those drugs that can effectively lower BP with a minimum of untoward reactions, and that diuretics and /3 blockers have long been thought to induce only minor and infrequent untoward effects. The latter statement has been partly disputed by the recently published results of the Medical Research Council Trial on Mild Hypertensionz3J4 As shown in Figure 8, during the 5 years of this trial (which enrolled about 18,000 patients) about 23% of men and 13% of women had to be withdrawn from treatment with bendrofluazide, and 19% of men and 20% of women from treatment with propranolol because of untoward effects ascribed to treatment. Concern has also been expressed about the metabolic effects of diuretics and, to some extent, of ,6 blockers.25 Although the Medical Research Council tria123J4has shown these metabolic changes to be rather small with prolonged therapy, there is a consensus now that diuretics should be used in smaller doses than previously suggested.3,2fi An additional reason why p blockers were placed in the foreground of antihypertensive therapy was that they were said to exert some “cardioprotective” action, i.e., a more effective prevention of coronary morbidity in hypertension. This promise has not been fulfilled by the Medical Research Councilz4 and the International Prospective Primary Prevention Study in HypertensionZ7trials, with the possible exception of male nonsmokers, a subgroup in which both studies reported some possible advantages.
January 30, 1987
DIURETICS
lNHIBITORSorANTAGONIST,S
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program. Reproduced
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indications or limited indications, perhaps on consideration of age and race, sometimes on cost consideration and often on the experience of the physician. Small doses of any agent should be used to commence therapy and the doses should not subsequently be increased beyond what is suggested by dose-response curves or the appearance of disturbances. In case of symptoms the physician has the choice of either switching to another first-step compound or of decreasing the dose of the first agent and combining it with one of the other agents as indicated in the scheme. As far as the calcium antagonists are concerned, a distinction is made between verapamil and nifedipine and other dihydropyridines. Only dihydropyridines can safely be combined with a p blocker, while verapamil can be associated with a diuretic. Finally, according to recent studies, all types of calcium antagonists can advantageously be administered with an angiotensin converting enzyme inhibitor.‘”
or
FIGURE 9. Outline of proposed step-care permission from Raven Press.30
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This does not mean diuretics and p blockers have lost their place as first-choice agents in the treatment of hypertension; they simply indicate that diuretics and /3 blockers have lost their prominence or uniqueness as the only agents available as first choice in antihypertensive therapy, in view of the characteristics of 2 new classes of antihypertensive agents, the calcium antagonists and the angiotensin converting enzyme inhibitors.
liberal Versus Rigid Approachesto Stepped Care The most important advantage of having a wide spectrum of antihypertensive drugs available is that this choice now makes it possible to find the most suitable agent for the individual patient. In clinical practice the choice of a drug should be seen as tentative, to be confirmed, corrected or abandoned on the basis of the patient’s response.20Most aspects of a patient’s response are susceptible to clinical measurement: not only the BP reduction, but the subjective and metabolic adverse effects and the arrest or reversal of secondary cardiovascular changes2” More liberal guidelines than the ones suggested up to now are shown in Figure 9.30The philosophy of a step-wise procession from simple to more complicated means of lowering BP is preserved, but is associated with the concept of multiple choices for the physician and the patient. Graphically, the step design seems lost but is substantially preserved. The physician has a choice to start not only with a thiazide diuretic or a /3 blocker, but also with a calcium antagonist or an angiotensin converting enzyme inhibitor. The choice among the various classes (sometimes including other classes as well, such as (Yblockers or centrally acting drugs) is made on simple clinical evaluation of existing contra-
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sion 1983;S:Yfi-102. 20. Semplicini A. Pessina AC, Rossi GP, Padrini R. Tagliafierro R, Quintarelli GF, Ferrari M, Dal Palti C. Plasma levels of veropamil and its effeocts on blood pressure. body fluid volumes and renal function in hypertensive patients. fnt 1 Clin Phoromocol Res 1982;2:suppl 1:81-t& 21. Leonetti G, Rupoli L. Sangiorgi P, Gradnik R. Cuspidi C, Bolla G. Zanchetti A. Effects of different sodium intakes on the antihypertensive and renal effects of single oral doses of nifedipine in hypertensive patients [obstr). Eleventh Scientific Meeting, fnternotionol Society of ffypertension, Heidelberg. 1986. 22. Leonetti G, Gradnik R, Terzoli L, Fruscio M. Rupoli L, Zanchetti A. Felodipine, a new vosodiloting drug: blood pressure, cordioc. renal, and humoral effects in hypertensive patients. [ Cardiovosc Pharmocol 1984;6: 392-398.
23. Medical Research Council Working Party on Mild to Moderate Hypertension. Adverse reactions to bendrofluozide and propronolol for the treatment of mild hypertension. Loncet 1981;2:539-543.
OPPORTUNITIES
24. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal results. Br Med / 3985;291:97-104. 25. Hansson L, Lowenstein ), Zanchetti A, eds. Coronary heart disease: hy2A. pertension ond other risk factors. Am [ Med 1984;76:supp~ 26. Zanchetti A. A re-examination of stepped-core: o retrospective ond o prospective. [ Cardiovasc Phormocol 1985;7:suppl l:S126-S131. 27. The IPPPSH Collaborative Group. Cardiovosculor risk and risk factors in o randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (fPPPSH). [ Hypertension 1985;34:379-392. 28. Zanchetti A. Which drug to which patient? [ Hypertension 1985;3:suppf 3:S57-S63.
29. Hansson L. Assessment of the patient’s response. [ Hypertension 1985; 3:suppf 2:X5-S69. 30. Zanchetti A. Step-wise treatment: which step first? In: Strasser T. Canten D. eds. Mild Hypertension. Proceedings ofo WHO/fSH faint Meeting. New York: Raven Press. 1986. in press.