Nifedipine and Systemic Hypertension Graham A. MacGregor, MA, FRCP

Nifedipine reduces Mood presswe predomin&tly by reducing systemic vascular resistance due to a direct vasodllating action on the arterioles. This pe- ripheral vasodilatii appears greater the more see- vere the hypertension. Studies have demonstrated an additive effect of fi blockers and converting-en- zyme inhibii in patients not controlled with ni- fediplm aione. Although there is a controversy about whether dk~retics have an additive effect on Mood pressure in patients already taking nifedi- pine, it would appear that the blood pressure-low- ering effect of thiazide is bktnted. Studies have shown that a high sodium intake may enhance the acute blood pressure-lowering effect of nifedipine. Niipine does cause a long-term reduction in so- dium balance.

(Am J Cardid 196@64546F-SlIF)

From the Blood Pressure Unit, Department of Medicine, Charing Cross and Westminster Medical School, London, England.

Address for reprints: Graham A. MacGregor, MA, FRCP, Depart- ment of Medicine, Charing Cross and Westminster Medical School, London W6 8RF, England.

T he development and introduction of the first cal- cium antagonists, verapamil and nifedipine, con- trasts to the planned development of angiotensin-

converting enzyme inhibitors such as captopril. Calcium entry antagonists were discovered by chance, and were found to dilate both renal and coronary arteries. These agents were introduced more than a decade ago without clear therapeutic indications. In pioneering studies, Fleckensteinl showed that verapamil and nifedipine in- hibited calcium-dependent excitation-contraction cou- pling of isolated cardiac papillary muscle. Studies in the late 1960s and 1970s clearly demonstrated that both drugs could reduce blood pressure in the setting of hyper- tension, and that the effect of the drug on blood pressure was much less pronounced in normotensive subjects. Rather than being considered a potential therapeutic in- dication for these drugs, the decrease in blood pressure was seen by many clinicians as a complication of treat- ment for patients with angina.*

FUNCTIONAL ABNORMALITY OF SMOOTH MUSCLE

One of the most intriguing aspects of the calcium entry antagonists is that they appear, at least in part, to lower blood pressure through their effect on the underly- ing mechanism that is responsible for the high blood pressure: a functional abnormality of the arteriolar smooth muscle. Independent studies by Robinson et al3 and Hulthen et al4 have shown that the infusion of vera- pamil into the brachial artery causes a greater increase in forearm blood flow in hypertensive patients than that seen in normotensive subjects. This difference in response to verapamil was more impressive when the investigators compared the results with those obtained with the admin- istration of nitroprusside. This latter finding makes it unlikely that a structural alteration in the arteriole could account for the greater response to verapamil. In further studies, Robinson5 demonstrated a significant correlation between the level of blood pressure before infusion of verapamil and the enhanced forearm response to verapa- mil (Fig. 1).

However, it is not clear what causes this functional abnormality of the smooth muscle cell as blood pressure increases. In essential hypertension, there is increasing evidence of an abnormality of either calcium transport across the cell membrane or binding of calcium to the cell membrane.3 There is also evidence in platelets that calci- um concentration may be increased with increasing blood pressure.6 Whatever abnormality of calcium transport in the smooth muscle cell is revealed by the calcium antago- nists, however, the clinical use of calcium entry antago- nists-like other blood pressure-lowering drugs-ulti- mately depends on clinical efficacy and tolerability.

46F THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64

FIGURE 1. klatien heween mean deli- ~praoare(MW~~rerponrivenea efreeMmtvemekefthefereaumtevera- pana-h127man,hchxl- hghethnemlal~jectsanllpa8entewith euenlidhypeMdmTheexcessdilate- lyre4mmsete~hasharbaan- izedhyNwh&ittethelwpen8etesedi- unnibopnroddainthesameeuhjects(r= o.!i5)(p@omoo1).(R~wiulper- midenhnJRJpden&g -4L

1 I I 1 I 80 100 120 140 160

MAP (mmHg)

PREDICTING BLOOD PRESSURE RESPONSE TO THERAPY

Clinical studies with nifedipine have demonstrated that the more severe the hypertension, the greater the decrease in blood pressure, and that there is little decrease in blood pressure in normotensive subjects within the dose range studuxL7 Our own studies in a group of age- matched normotensive and hypertensive subjects clearly confirmed this relation.8 Subjects were given a 5-mg cap- sule of nifedipine which was swallowed, and blood pres- sure was measured 30 minutes before and 2 hours after the administration of nifedipine. The results demon- strated that there was a greater decrease in blood pressure

in patients with essential hypertension (from 182 f 5.2/ 109 f 2.6 mm Hg to 160 f 4.5/96 f 1.9 mm Hg) compared with that in normotensive subjects (from 121 f 2.3/74 f 1.8 mm Hg to 117 f 1.6/69 f 1.1 mm Hg). There was a 10.4% decrease in mean arterial pressure 30 minutes after nifedipine administration in the hyperten- sive group compared with a 4.7% decrease in the normo- tensive subjects (p <O.OOl).

When blood pressure measurements obtained before nifedipine administration were related to the percent de- crease in blood pressure after nifedipine, a significant correlation was noted at both 30 minutes and 2 hours after treatment. Thus, the higher the initial blood nres- sure, the greater the decrease-m pressure with nifedipine administration. Because these correlations may be incor- rect since the decrease in blood pressure is, in part, calcu- lated from the pretreatment blood pressure, a more statis- tically correct method of analyzing the results was used (i.e., plotting the pretreatment blood pressure against the post-treatment blood pressure and comparing the slope of the line obtained against the line of identity), and the same finding was observed (Fig. 2). Studies in which nifedipine is given over a longer period of time have demonstrated a greater blood pressure-lowering effect the higher the initial pressure. These findings contrast with those observed with the administration of /3 blockers and converting-enzyme inhibitors.9

Supine mean blood presswe

tmmH$ 2 hours

post treatment Nifedioine t5mg tAPl

NIFEDIPINE Pre-treatment

supine mean blood pressure tmmHg)

80

:

100 120 140 160 180

(log scale)

o Normotensive fn =18) l Hypertensive fn = 281

1 Clog scale1 .-

COMBINATION THERAPY Although nifedipine is an effective long-term blood

pressure-lowering agent, not all patients respond to monotherapy. Several studies have now looked at the combination of nifedipine with other drugs for controlling hypertension.

Nifedipine and beta bladcers: Nifedipine has been nGuRE2Rela8mhetween --nphe- presuwh18mmabdvemd28hyperbdwst+ctsvs shown to have an additive effect on blood pressure when -ruphe-- 2howsafbruleaIbdadh combined with a /3 blocker. It is possible that the combi- ofamde5-mgmof-*(-ke-.)~ nation of a B blocker with nifedipine may actually reduce rkpaof- c4lmmenbfertiinbv#lll~ ~~~yf~rwofpathnb-aa

the acute vasodilating symptoms of nifedipine capsules. l l

less thn *zzL In patients with more resistant hypertension, nifedipine

u--m- has been shown to have an additive effect when added to Nghaths~bbedpramre.(R-~ the combination of /3 blocker and diuretic. In a double- parmbdonhPostg.radMJ.~ blind study, Bayley et alI2 clearly demonstrated both a

THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 19, 1989 47F

A SYMPOSIUM: CARDIOVASCULAR THERAPY-THE NEXT STEP

Supine

Blood

Pressure

mm Hg

180

160

140

120

100

80

***

I ***

N,fedipine

20 mg b.d.

1 month hr after Rx

Aceb”tolol

200 NJ b.d.

I manlh 2 hr after Rx

*

: **

Nikdipine

20 mq b.d.

Acebutolol

200 mg b.d.

1 month ! hr after Rx

:

***

[

***

Significant difference from pre-treatment BP

* P ( 0.05 ** P < 0.01 *** P < 0.001

ATENOLOL +NIFEOIPINE

PLACEBO 1 BENDROFLUAZIDE

FlGURE4.Changesinmeansqhbbodpewmure2~ 8Rerthelastdoseofatamlbld dledbhemd*1lnonth

A NS -

I

FlGURE3.Tl1eeffectofde41ined axebhbl~uldheom#utkn.su- phssYstdc-d-~- (RP)areslnmwlforthegraipdl2~- tknts2howsaftertheMdose.*p <0.05; **p <0.01; ***p <o.yM com- P-dwHh---. O?,~e~9--* Jfi

short- and long-term additive effect of nifedipine in pa- tients with hypertension resistant to diuretics and B blockers. In a randomized crossover study, we looked at the effect of nifedipine slow-release tablets, 20 mg twice daily (Adalat Retard@‘, Bayer), for 1 month compared with 4 weeks of the j3 blocker acebutolol, 200 mg twice daily, and then in combination for a further month.13 Comparing both drugs as monotherapy, there was a de- crease in blood pressure that was slightly greater with nifedipine (148 f 4/94 f 2 mm Hg) than acebutolol (157 f 6/101 f 3 mm Hg). However, when both drugs were combined, the decrease in blood pressure noted was greater than that seen with either drug alone (136 f 4/88 f 3 mm Hg) (Fig. 3).

Niipine and diuretics: Because of the vasodilatory effect of nifedipine, it had been assumed that the combi- nation of nifedipine and a diuretic would be additive, as is seen with hydralazine and minoxidil. However, Rosen- thal14 showed that when nifedipine and a thiazide diuretic were combined, there was no greater effect on blood pressure than with either drug alone. In contrast, a study from Sweden showed that nifedipine and bendrofluazide, first given alone and then combined at one-half the mono- therapy dose, decreased blood pressure more effectively as a combination than with either drug alone.15 Because some of the patients in the study were given the diuretic first, it is difficult to determine from this study whether a diuretic would be additive to patients already receiving nifedipine. To examine this question further, we studied the combination of nifedipine and diuretics. In our fast study, patients were treated with nifedipine slow-release

48F THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64

180

160

BLOOD PRESSURE mmtlg

Isupine 140

m standing

ESSENTIAL HYPERTENSION n = 9+SEM

120 120

100 100

80 80

PERCENTAGE FALL PERCENTAGE FALL

BEFORE NIFEDIPINE TREATMENT 20 mg bd

:::::>>: ::::::::: ::::::::: ::::::::: ::::::::: :::::: ::::::::: ::::::::: :::::::::

‘L

i:y::z . ..A.... :$g .gg ..:.:.:.:. ::::::::: A...... . ::::::::: ::::::::: .::::::::: 3

1112 2hrposl

. . . . . . . . . g$; i:$f# ::::::::: f:;:E c......; 2.s: :B

3

. . . . . . . . . $$g :m v.:.:.: ::::.:.:. H:; $33 y::::.:

13.4%

NIFEDIPINE 20 mg bd

CAPTOtPRlL 25 mgtds

1112 2 hrpost

*

::::::::: .A..... ::::::::: $$$$ ::::::::: y$# .A..... w .:.:.:.:.

,1[J

::::::::: m::::: w.v. .:.:q B 33$;:; . . ..A . . .:.:.:.:.

:*:sr:

I 22%

FlGURE5.Efkatmbbodprarrvhof-witl1~- pineferLmalihfe5owedbyule-of~for1 lllonul (*p <o.* **p <o.oog, idcatbg a sigdcid differ- mlcecanpuedwRh~ wRhdfelQheabne).sEM= ShldiUd~OftlWmCan.(ReproducedWRhpanniprkn fmn HyperenM.‘g

tablets, 20 mg twice daily, and then had added bendro- fluazide, 5 mg/day, for a further month.16 By the fourth week of treatment with nifedipine alone, average supine blood pressure had decreased from 168.5 f 4.2/106.2 f 1.4 mm Hg to 147.6 f 4.8/89.6 f 2.8 mm Hg. There was no further significant decrease in blood pressure noted with the addition of the diuretic. In a subsequent study, patients receiving either nifedipine tablets or atenolol were entered into a double-blind crossover study compar- ing the addition of 5 mg of bendrofluazide for 1 month to matching placebo for 1 month.17 In this study, we were unable to find any further decrease in blood pressure with the addition of the diuretic compared with the placebo (Fig. 4), suggesting that the blood pressure-lowering ef- fect of a diuretic is blunted in many patients taking nifedi- pine. Studies by Bayley et al-where patients whose blood pressure was well controlled with the combination of nifedipine, B blocker and diuretic subsequently had the latter agent withdrawn without loss of control of the blood pressure-also support this concept.

Nifedipine and convertingsnzyme inhibitors: Nifedi- pine is known, at least acutely, to cause an increase in renin release and, therefore, in angiotensin II. In patients with severe hypertension, the combination of nifedipine and captopril was found particularly useful in controlling blood pressure. We therefore decided to perform a ran- domized study of the effect of nifedipine and captopril

HYPERTENSIVES (n=lO)+ SEM ACUTE RESPONSE TO 5mg (capsuled NIFEDIPINE

SUPINE 13

MEAN BLOOD 120

PRESSURE mmHg 110

103

FlGURE6.Chagesinmemsqinebloodpresswebefore (Re)d50midesaRera5-mgr-mQ’ef~in10 M----l hypdemhonthcfiRhdayda higil-,llomd-lmdiew~dlet.5EM=--of ttmmean.

alone and then in combination in patients with moderate essential hypertension who were receiving no other treat- ment. l8 Blood pressure measurements were taken 2 hours after the last dose. Ten patients received captopril, 25 mg 3 times a day for 4 weeks; mean arterial pressure de- creased by 9.5%. Nifedipine retard tablets, 20 mg twice a day, were added and patients were studied 4 weeks later; mean arterial blood pressure decreased by 17.3%. In a separate group of 9 patients treated with the same dose of each agent, mean arterial pressure decreased by 13.4% with nifedipine treatment alone; when captopril was add- ed to the nifedipine therapy for an additional month, mean arterial pressure decreased by an additional 22% (Fig. 5).

NIFEDIPINE AND SODIUM BALANCE Most blood pressure-lowering agents are potentiated

by a reduction in salt intake. In view of our previous finding that diuretics did not appear to have additive effects when combined with nifedipine therapy, the effect of nifedipine in patients with differing salt intakes was examined.19 Ten patients with essential hypertension were studied while receiving a normal sodium intake of approximately 150 mmols/day, on the fifth day of a high sodium intake of approximately 350 mmols/day, and on the fifth day of a low sodium intake of 10 mmols/day. On the fifth day of each sodium intake, blood pressure was measured before and 30 minutes after oral administra- tion of a 5-mg capsule of nifedipine. Nifedipine caused a significant reduction in blood pressure with the 3 diets. However, with the high-salt diet both the absolute and percent decrease in blood pressure was greater than with the low- or normal-sodium diet (p <0.05) (Fig. 6). These results show that in contrast to other antihypertensive agents, the acute blood pressure-lowering effect of nifedi- pine is not blunted by a high salt intake and, in fact, its action may possibly be enhanced.

Several previous studies have demonstrated that ni- fedipine acutely causes an increase in sodium and water

THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 19, 1989 49F

A SYMPOSIUM: CARDIOVASCULAR THERAPY-THE NEXT STEP

excretion, but most investigators assumed that there was no long-term effect on sodium balance.20 To examine this further, 8 patients who had been receiving chronic nifedi- pine therapy for at least 6 weeks (range 6 to 234) were studied.21 Each patient while taking nifedipine was given a constant dietary intake of sodium (150 mmols) and potassium (80 mmols). After 11 days on this controlled diet, the nifedipine was withdrawn and replaced with a matching placebo in a single-blind fashion for 7 days. Mean 24-hour urinary sodium excretion during the con- trol phase was 138 f 5 mmols (& standard error of the mean) and decreased significantly to 75 f 9 mmols (p <O.Ol) on the first day of nifedipine withdrawal, and to 106 f 11 mmols (p <0.05) on the second day. The mean cumulative positive sodium balance for the 7 nifedipine- free days was 146 f 26 mmols. This retention of sodium upon cessation of nifedipine therapy demonstrates that nifedipine has a long-term effect on sodium balance. This may play an important additive role in its blood pressure- lowering effect and contrasts with other peripheral vaso- dilators-such as minoxidil and hydralazine-in which there is sodium retention that, in the long term, may offset the decrease in blood pressure caused by the vasodi- lator.

REFERENCES 1. Fleckenstein A. History of calcium antagonists. Circ Res 1983;52:suppl I:3-16. 2. MacGregor GA. Hypertension. In: Krebs R, ed. Treatment of Cardiovascular Diseases by Adalat. New York: Schattauer, 1986;231-258. 3. Robinson BF, Dobbs BJ, Bayley S. Response of forearm resistance vessels to verapamil and sodium nitroprusside in normotensive and hypertensive men: evi- dence for a functional abnormality of vascular smooth muscle in primary hyper- tension. Clin Sci 1982.3r33-42. 4. H&hen UL, Bolli P, Amann FW, Kiowski W, Buhler FR. Enhanced vasodila- tation in essential hypertension by calcium channel blockade with verapamil. Hypertension 1982;4:suppl 2:26-31. 5. Robinson BF. Altered calcium handling as a cause of primary hypertension. J Hypertetw 1984;2:453-460. 6. Erne P, Bolli P, Burg&r E, Buhler FR. Correlation of platelet calcium with

blood pressure: effect of antihypertensive therapy. N Engl J Med 1984;310:1084- 1088. 7. LederballePedersen 0, Mikkelsen E. Acute and chronic effects of nifedipine in arterial hypertension. Ear .I Clin Pharmacol 1978;14:375-381. 3. MacGregor GA, Markandu ND, Rotellar C, Smith SJ, Sagnella GA. The acute response to nifedipine is related to pre-treatment blood pressure. Postgrad Med J 1983;59:suppl 2:91-94. 9. MacGregor GA, Sagnella GA, MacRae KD. Misleading paper about mislead- ing statistics. Lancet 1985;1:926-927. 10. Yagil Y, Kobrin I, Stessman .I, Ghanem J, Leibel B, Ben&hay D. Effective- ness of combined nifedipine and propranolol treatment in hypertension. Hyperten- sion 1983;5:suppl lI:lI-113~II-117. 11. Hustcd SE, Nielson HK, Christensen CK, Lederballe-Pedersen 0. Long- term therapy of arterial hypertension with nifedipine given alone or in combina- tion with a beta-adrenoceptor blocking agent. Ear J Clin Pharmacol 1982;22: 101-103. 12. Bayley S, Dobbs RJ, Robinson BF. Nifedipine in the treatment of hyperten- sion: report of a doubleblind controlled trial. Br J Clin Pfiarmacol1982;14:509- 512. 13. Singer DRJ, Markandu ND, Shore AC, MacGregor GA. Nifedipine and acebutolol in combination for the treatment of moderate to severe essential hyper- tension. J Human Hypertens 1987;1:31-37. 14. Rosenthal J. Antihypertensive effects of nifedipine, mefruside, and a combi- nation of both substances in patients with essential hypertension. In: Kaltenback M, Neufeld HN, cds. New Therapy of Ischemic Heart Disease and Hypertension. Amsterdam, Oxford, Prittcetotz Excerpta Medica, 1982;175-181. 15. Halhn L, Andren L, Hansson L. Controlled trial of nifedipine and bcndroflu- methiazide in hypertension. J Cardiwarc Pharmacol 1983;5:1083-1085. 16. Cappuccio FP, Markandu ND, Tucker F, Sagnella GA, MacGregor GA. Does a diuretic cause a further fall in blood pressure in hypertensive patients already on nifedipine? J Clin Hypertetw 1986;4:346-353. 17. Cappuccio FP, Markandu ND, Tucker FA, Shore AC, MacGregor GA. A double-blind study of the blood pressure-lowering effect of a thiazide diuretic in hypertensive patients already on nifedipine and a beta blocker. J Hyperteas 1987;5:733-738. 13. Singer DRJ, Markandu ND, Shore AC, MacGregor GA. Captopril and nifedipine in combination for moderateto-severe essential hypertension. Hyper- tenrion 1987,9.629633. 19. Cappuccio FP, Markandu ND, MacGregor GA. Calcium antagonists and sodium balance. J Cardiowsc Pharmacol (in press). 20. Leonetti G, Cuspidi C, Sampieri L, Terzoli L, Zanchetti A. Comparison of cardiovascular, renal, and humoral effects of acute administration of two calcium channel blockers in normotensive and hypertensive subjects. J Cardiouasc Phar- macol 1982;4:suppl 3:S319-S324. 21. Pevahouse JB, Markandu ND, Cappuccio FP, Singer DRJ, Buckley MG, Sugoen AL, Sagnema GA, MacGregor GA. Long-term nifedipine therapy, plas- ma atria1 natriuretic peptide and sodium balance in hypertensive patients (abstr). J Hypertens 1987;5(6):767.

SOF THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 64