CLIN. EXPER. DIALYSIS AND APHERESIS, 6 ( 4 ) , 229-236 (1982)

T R E A " T OF HYF'ERTMSION IN DIALYSIS ANJJ

ESSESTIAL HYPERTENSION PATIENTS WITH NIFEDIPINE

H.E. Eliahou, A. Iaina, R. Schneider. D. Cohen, D. Goldfarb and M. Gross

Department of Rephrology, Chaim Sheba Medical Center Tel-Hashaner. Israel, 52621.

ABSTRACT

The immediate antihypertensive effect of l O m g nifedipine sublingually (nifedipine test), was measured in 19 chronic renal failure hypertensive patients on dialysis and 34 essential hypertensive patients normal kidney function. both groups. after the sublingual administration of nifedipine. The blood pressure decreased from 178f3.3 j 104.0f3.9 in dialysis patients and from 176.8t4.5 /107.1*2.4 to mm Hg in essential hypertension patients ( p < O . O O l ) . preasure during the test had a significant positive correlation with the pre-test values.

with The blood pressure decreased significantly in

The minimal values were observed between 30 and 60 minutes

to 136.0-4.7 j 87.0fS.1 mm Hg (p(O.001) 133.0f3.0 j 81.7f2.2 The decrease in blood

Thirteen hypertensive patients on dialysis and 20 essential hypertensive patients completed 2 weeks of daily oral nifedipine therapy, with a dose of 30 to 40 m g per day. treatment decreased from 179.524.5 j 108.525.3 mm Hg to 154.4f6.3 / 82.3f2.6 mm Hg (p<O.OOl) in dialysis patients, and fran 176.8f5.8 j 110.S2.9 to 151.3f5.3 j 93.5f2.6 mm Hg (p<O.OOl) in essential hypertension patients.

The mean blood pressure at the end of the 2 weeks of

The present results reveal that nifedipine has a powerful immediate as well as a long-term antihypertensive action in dialysis patients with high blood pressure. tensive patients.

This effect is similar to that obtained in essential hyper-

iNTRODUCTION

Antihypertensive therapy has recently been influenced by a new category of drugs, namely the slow channel blockers of transmembrane calcium transport (1-4). Nifedipine and verapamil. which are such clacium blockers, were discovered to possess a significant antihypertensive effect (5-9). because of its action as a coronary vasodilator without producing a significant negative inotropic effect ( h J 0 , l l ) . It la a potent vasodilator which promptly relaxes isolated arteries contracted by KC1, norepinephrine or serotonin (12). In healthy man, nifedipine decreases peripheral resistance by about 20% and increases cardiac index by about 40% (4.10).

Nifedipine seems to be promising

The purpose of this study was to evaluate nifedipine as an antihypertensive agent in hypertension occuring in patients on chronic maintenance dialysis. An attempt was

229

Copyright B 1983 by Mnrccl Dckkor. Ins.

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ELIAHOU ET AL. 230

made t o evaluate t h e immediate antihypertensive e f f ec t of sublingually adminiseered

nifedipine t o see whether it can serve as a t e s t fo r t h e prediction Of t h e success or f a i l u r e of t h i s form of therapy i n pa t i en t s on d i a lys i s with hypertension. when given

regularly.

pa t i en t s with normal kidney functions. A similar protocol was a l so used i n a group of e s sen t i a l hypertension

MATERIALS AND METHODS

Patients. The acute and chronic e f f ec t of nifedipine w a s studied i n 2 d i f f e ren t

groups of pat ients , nemely i n pat ients who a r e on chronic maintenance d i a lys i s for end

s tage kidney disease with hypertension and i n pa t i en t s with e s sen t i a l hypertension (M) with normal kidney functions. and 90 mm Hg d ia s to l i c on at l e a s t 3 occasions p r io r t o t h e use of nifedipine.

I n both groups blood pressures exceeded 150 mm Hg s y t o l i c

The m e d i a t e Antihmertensive Effect of Nifedipine (Nifedipine Test) . There were

19 hypertensive pa t i en t s on d i a lys i s and 34 EH pat ients who par t ic ipated i n t h e study.

All pat ients on d i a lys i s had stopped t h e i r previous antihypertensive therapy for a t l e a s t

10 days before t h e t e s t and were t e s t ed a few hours before t h e i r next scheduled dialysis .

The pat ients were asked t o be recumbent f o r 60 minutes.

pressure, they were given a capsule containing 10 mg nifedipine and were asked t o break

it by chewing and t o place it under the tongue.

They were monitored by EEC and t h e i r blood pressure w a s recorded every 10 minutes fo r t he

next hour.

After recording t h e i r blood

The pa t i en t s continued t o l i e down.

The same procedure was applied t o t h e M pat ients . Nine of them had no other

antihypertensive therapy while t he remaining 25 had stopped t h e i r antihypertensive therapy 3 days before t h e t e s t . .

The Antihypertensive Effect of Daily Nifedipine Therapy for 2 Weeks. Following t h e

the i n i t i a l sublingual nifedipine test, 14 hypertensive pa t i en t s on d i a lys i s and 22 EH pat ients were advised t o swallow a 10 mg capsule of nifedipine 3 t o 4 t imes daily.

Thirteen hypertensive pa t i en t s on d i a lys i s and 20 M pa t i en t s completed 2 weeks of o r a l

nifedipine therapy.

All pat ients on d i a lys i s were put on nifedipine alone, whereas nine of t h e M pa t i en t s

were on nifedipine alone,

antihypertensive medication, a be t a adrenergic blocker (oxprenolol or propranolol) , w a s obviously inadequate. comparison with the pretreatment values.

a f t e r t h e morning nifedipine dose.

The remaining 11 M pat ients continued taking t h e i r previous

which

The blood pressure measured2 weeks l a t e r WBS t h e one taken fo r This blood pressure was measured 2-3 hours

Mean, standard e r ro r of t h e mean (S54), student 's t - t e s t and correlat ion coeff ic ient

on t h e regression l i n e were calculated by t h e l e a s t squares method and t h e Bpeannan's

correlat ion coeff ic ient w a s computed for s t a t i s t i c a l analysis. s ignif icant .

A pCo.01 was considered

RESULTS Sublingual Nifedipine Test ( t ab le 1). In both hypertensive pa t i en t s on d i a lys i s

and those with EA, t h e administration of 10 mg nifedipine sublingually r su l t ed i n a

s ignif icant decrease i n blood pressure. The minimal blood pressure was observed a f t e r

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Tab

le 1

. B

lood

pre

ssur

e ch

ange

s af

ter

subl

ingu

al n

ifed

ipin

e te

st a

nd a

fter

2 w

eeks

of

dail

y ni

fedi

pine

adm

inis

trat

ion.

Hyp

erte

nsiv

e P

atie

nts

on D

ialy

sis

Nif

edip

ine

Subl

ingu

al

Tes

t :

n 19

Init

ial

bloo

d pr

essu

re(r

m Hg)

178.0+3.3/104.2*3.9

BP a

fter

60

min

utes

re

cum

benc

y 164.8*4.6*/99.1+3.2

Min

imal

BP a

fter

20-60 m

inut

es

of a

10

ng d

ose

136.4*4.7**/87.0+5.1**

Dai

ly 8

ifed

ipin

e fo

r 2

Uee

ks:

n 13

Init

ial

bloo

d pr

essu

re (

mn

Hg)

BP a

fter

2 w

eeks

179.5+4.5/1&3.9%.3

154.4%.

3/82.3*2.6

Ess

enti

al I

!ype

rtens

ion

Pat

ient

s

34

176. @4.5/107.1*2.4

160.4+3.8*/101.0*2.5*

133. 1*3.0**/81. 7*2.2**

20

176.@5.8/110.3*2.9

151.3f5.3**/93.5*2.6**

z

CI I

* pc

0.05

as

can

pare

d w

ith

the

init

ial

bloo

d pr

essu

re v

alue

s.

** ~(0.001

as c

ompa

red

wit

h th

e in

itia

l bl

ood

pres

sure

as

wel

l as

the

blo

od p

ress

ure

afte

r 60

min

utes

of

recu

mbe

ncy.

N

w e

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232 ELIAHOU ET AL.

DIALYSIS

81

61

- 4

E E

I

2 4

1

sy BP

r = 0.72 P<O.001

/ 150 200

mm Hg

Dia BP

r = 0.48 p<0.05 n = 19

/ m * b

m . . . 100 150

mm Hg

Fig. 1. NIFEDIPINE TEST I N DIALYSIS PATIENTS.

THE CORRELATION BETWEEN THE DECREASE I N SYSTOLIC

AND DIASTOLIC BLOOD PRESSURE AND THE PFIE TEST VALUE.

SY BP and Dia BP : SYSTOLIC AND DIASTOLIC BLOOD PRESSURE.

30-60 minutes.

the average blood pressure of 178-+3.3/lOb.O-+3.9 mm Hg obtained after 60 minutes of recumbe- ncy before the nifedipine was taken.

both systolic and diastolic mean values.

In EH patients the blood pressure which averaged 176.82b.5/107.122.4 mm Hg on an out

patient basis and 160.4t3.8/101.0+2.5 mm Hg after 60 minutes of recumbency, began decrea- sing within 10-15 minutes and reached B minhun of 133.1 +3.0/81.?+2.2 mm Hg within 30-60

minutes, p<O.OOl for both systolic and diastolic as compared with the values after 60 minutes of recumbency.

In the dialysis patients it averaged 136+4.7/87.0+5.1 nun Hg compared with

This difference is significant with a p<0.001 for

The decrease in blood pressure during the test had a positive significant correlation to the pre-test values for both systolic and diastolic pressures in both groups of patients (figures 1 & 2).

The antihypertensive Effect of Daily Bifedipine Therauy for 2 weeks (table 1). The blood pressure decreased significantly in dialysis patients from an average of 179.52 h.5/108.925.3 mm Hg to an average of 15b.b+6.3/82.322.6 mm Hg, ptO.001 for both systolic and diastolic values, The initial

average blood pressure which was 176.8+5.8/110.3+2.9 m Hg decreased significantly after 2 weeks to an average of 151.3+5.3/93.5'2.6 mm Hg, p<O.OOl for both systolic and diastolic

A similar decrease was observed in patients with M.

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HYPERTENS ION PAT 1 ENTS WITH N IFEDIP I N E

OUTPATlENTb I Dia BP

f

6 0 -

E

= 0.63 n = 34

. . '4 c . . . * / I .

. 1

120 150 2 0 0 10 1 0 0 130

mm Hg mm Hg

Fig. 2. N I F m I P I N E TEST I N ESSENTIAL HYPERTENSIVE PAT1I:PiTS.

THE CORRELATION BETdEEPI 'P IE DECREASE Il? SYSTOLIC

AND DIASTOLIC BLOOD PRESSURE AND ?'HE PRE TEST VALUE.

s y BP and D i a EP: SYSTOLIC AND DIASTOLIC BLOOD PRESSURE.

pressures.

between t h e amount of blood pressure decrease during the n i fed ip ine t e s t and the decrease

obtained a f t e r 2 weeks of n i fed ip ine o ra l therapy. r=0.22. p>0.05 for sys to l i c and r=0.07.

p>0.05 fo r d i a s t o l i c blood pressures.

No co r re l a t ion could be demonstrated by the Spearman coe f f i c i en t of cor re la t ion

Complications. Transient headaches, ver t igo , dizziness and f a c i a l f lushing occured t o

d i f fe ren t degrees i n 2 of t he pa t i en t s on d i a lys i s and i n 3 EH pa t ien ts . Headaches and

dizziness were the cause of t he abandonment of t he treatment i n 2 other Eli pa t ien ts .

One pa t ien t on d i a lys i s stopped the treatment because of marked l eg edema.

DISCUSSION

The r a t iona le behind the use of calcium ion blockers i n t he treatment of hyper-

tension is based on the reduction i n systemic vascular tone with the r e su l t i ng decrease

i n peripheral res i s tance and reduction i n blood pressure, as w e l l a s t h e i r promising

card iopro tec t ive e f f ec t .

mented i n the coronary c i r cu la t ion without adversely a f fec t ing myocardial con t r ac t l i t y .

thus preventing inappropriate coronary vasoconstriction and myocardial ischemia (2-4,

10.11.13.14).

This i s suggested by t h e i r potent vasodi la tory e f f ec t docu-

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ELIAHOU ET AL. 234

The calcium ion inhibitors. verapamil and nifedipine, were used clinically as Verapamil was tried in essential hypertension, secondary

However, the use antihypertensive agents. hypertension, as well as in malignant hypertensive crises (6.15-21).

of verapazuil has not become popular because of its deleterious effects on the myocardium

when taken with the widely used beta adrenergic blockers (22).

Nifedipine, which is a long-acting vasodilator, was found to exert no myocardial depressant effect and was found to be safe when combined with other beta adrenergic

receptor blocking agent (23).

as early as 1972 by Klutsch et a1 ( 7 ) . Kobayashi et al (8) and Murakami et a1 (5). Guazzi et a1 found nifedipine to be an effective antihypertensive drug alone (24) or in combination with methyl dopa (25).

nation was as effective as in the short term trial (25). Aoki et a1 (23) reported that the combined administration of nifedipine with propranolol achieved a decrease in blood pressure of 7% more than the nifedipine alone and prevented the nifedipine-induced increase in heart rate.

The hypotensive effect of nifedipine has been reported

The long-term follow up showed that the combi-

Olivary et a1 (26) monitored the hernodynamic effect of a single dose of nifedipine.

10 mg in 27 primary hypertensive patients. blood pressure after 30 minutes and a 16% reduction after 120 minutes as compared with the control values.

They found a 21% reduction in mean arterial

The reduction in both systolic and diastolic arterial pressures

associated with reduced peripheral vascular resistance and increased cardiac index.

There were no changes in systolic and diastolic pulmonary pressures nor in plasma volume.

At the end of 3 weeks of treatment, these patients did not develop drug resistance. Circulatory measurements, repeated at the end of the trial, demonstrated that the hypo-

tensive effect was still mediated through reduction of peripheral vascular resistance and increased cardiac output. The side effects which included headache, palpitations

without arrhythmia and a burning sensation in the face and legs, were usually short-lived.

The sublingual administration of nlfedipine has an important antihypertensive

effect in almost all the patients tested in our study. tensive patients on dialysis and M patients. effect of a 10 mg nifedipine dose sublingually could not predict the exact blood

pressure response of the patient after a 2 week period of daily therapy a8 given in the present study.

Thjs was true in both hyper-

However, the immediate hypotensive

In all patients, the higher the initial blood pressure the greater the antihyper-

tensive effect of sublingual nifedipine. drug in hypertensive episodes during dialysis

suggeet that nifedipine can be used sublingually in hypertensive spikes in dialysis

patients.

in chronic dialysis patients a8 well as In M patients. with minimal transient side effects. Theee findings favor the hypothesis that calcium ion blockers act through

the reduction of vascular tone of whatever etiology. thus suggesting that it may be

acting at the cormon pathway in the production of increased prripheral resistance. Moreover, this treatment brought out certain problems in the practical management of the patients. the most important of which is the short action of the drug. This disadvantage can at present be minimized by taking the nifedipine in 4 or even more doees during the day or by the addition of a beta adrenergic blocker, such as propra- nolol. which could cover the periods in which the action of nifedipine is low. et al (27) found that the action of nifedipine and propranolol are additive, giving

This observation makes nifedipine an important

as well as in M patients. These findings

Daily therapy with nifedipine was a180 effective in reducing blood pressure

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HYPERTENSION PATIENTS WITH NIFEDIPINE 235

an extra advantage t o t h i s combination.

i n combination with propranolol was a l so observed i n our pat ients who were taking an

inadequately effect ive dose of be t a blockers, who responded t o t h e addition of nifedipine

by an effect ive reduction i n blood pressure.

The hypotensive addi t ive e f f ec t on nifedipine

In summary, t h e present r e s u l t s revealed tha t nifedipine has a powerful immediate

antihypertensive act ion i n d i a lys i s pat ients with hypertension, which can be maintained

adequately by repeated dai ly doses.

pat ients , indicat ing t h a t t h e calcium ion blockers reduce high b l m d pressures of d i f f e ren t

e t iologies , most probably through t h e i r act ion at t h e c e l l u l a r level .

nifedipine t a b l e t s seem necessary t o develop 80 as t o maintain a more s t ab le long term

antihypertensive effect .

This e f fec t is similar t o t h a t obtained i n M

Slow-release

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