Use of the calcium-channel blocker nifedipine in the management of hypertensive emergency

Use of the Calcium-Channel Blocker Nifedipine in the Management of Hypertensive Emergency JACOB I. HAFT, MD Niiedipine, a well-tolerated calcium-channel blocking drug, is known to produce a rapid and vigorous vasodilating effect on the peripheral vasculature. In order to determine its effectiveness in rapidly treating moderately severe hypertension, niiedipine was administered buccally to 63 patients. Ten-milligram capsules, perforated ten times with a 26-gauge needle, were chewed by patients to expel the viscous drug within them. Ii one capsule was not sufficiently effective within 20 to 30 minutes, a second capsule was administered similarly. The drug was administered to 63 patients with diastolic blood pressure of 120 mm Hg or greater, or systolic blood pressure of 200 mm Hg or greater with a diastolic blood pressure in excess of 90 mm Hg. Forty-two patients responded to 10 mg of niiedipine, with a drop in blood pressure from a mean (+-SD) of 205.5 2 24.41127.7 + 11.7 mm Hg to 158.6 f 24.7/88.8 f 10 mm Hg in 39.9 -c 13.0 minutes. Nineteen patients responded to two doses of niiedipine (20 mg), with a drop in blood pressure from 212.1 +- 27.1028.2 2 17.3 mm Hg to 165.4 + 24.5193.8 f 10.7 mm Hg after 66.0 + 17.8 minutes. There were no side effects and no hypotension, even among the 38 patients who had recently received other medications, including beta blockers, diuretics, hydralazine, methyldopa, captopril, and clonidine. It is our conclusion that the chewing of niiedipine capsules is a safe and effective method to lower blood pressure promptly without the use of parenteral medications. (Am J Emerg bled [Suppl] 1985;3:25-30)

Nifedipine is a calcium-channel blocking drug that has achieved widespread acceptance as a coronary dilator and coronary spasm inhibitor. However. even before it was understood that the drug’s ability to relax smooth muscle was caused by the blockage of calcium channels, nifedipine had already been shown to have a potent lowering effect on blood pressure in hypertensive patients. In 1971, Murakami and coworkers’ in Japan reported the use of lo-60 mg of nifedipine orally per day in 20 hypertensive patients. All patients had lowered blood pressures. Interestingly, those with very high blood pressures responded especially well. In 1972, Klutsch et al’ in Germany gave 1 mg of nifedipine IV to each of 20 hypertensives and noted a prompt but short-lived drop in systolic and diastolic blood pressures. Also in 1972, Kobayashi et al3 reFrom the Department of Cardiology, Center, Newark, New Jersey.

St. Michael’s

Medical

Address reprint requests to Dr. Haft: Department of Cardiology, St. Michael’s Medical Center, 306 Dr. Martin Luther King Jr. Blvd., Newark, NJ 07102.

ported on 47 patients with angina who received IO-60 mg of nifedipine orally per day. Of the six patients with diastolic blood pressures greater than 100 mm Hg, five patients’ pressures were lowered to less than 90 mm Hg after treatment with nifedipine. In 1976, Aoki et al4 administered nifedipine 30 mg sublingually to 19 patients with hypertension. They observed a potent blood pressure lowering effect that started at 15 minutes and continued for over four hours. Even with the high dose, no significant hypotension occurred. More recently, Beer et al” gave nifedipine sublingually in doses of 10 mg to 17 patients with diastolic blood pressures ranging from 90 to 110 mm Hg. and in doses of 20 mg to 26 patients with diastolic pressures greater than 1IO mm Hg. All but one patient responded. However, those patients given 20 mg had a significant increase in heart rate. In all of these early studies, no patient had recently received or was receiving other antihypertensive drugs at the time of nifedipine administration. To test the efficacy and safety of the emergency use of nifedipine in symptomatic patients with severe hypertension who might be on other antihypertensive agents, we chose to administer nifedipine by having each patient chew a perforated IO-mg nifedipine capsule as a first dose. Patients were given a second dose only if it was necessary.6 We were interested in finding out whether we could use nifedipine in a realistic clinical situation (one in which most of the patients were not free of other drugs and, as is the usual situation, had had drugs prescribed for them that they might or might not have been taking). METHODS The design of our study included only patients who had significant hypertension with diastolic blood pressure over 120 mm Hg or systolic blood pressure over 200 mm Hg and who had symptoms such as chest discomfort, shortness of breath, or headache. We did not use this regimen in patients who were asymptomatic or who had lesser degrees of hypertension. Baseline tests included physical examination, patient history, and repeated blood pressure determinations. When three blood pressure measurements were within 5 mm of each other, we administered nifedipine. Each IO-mg capsule of nifedipine was perforated ten times with a 26-gauge needle, and the patient was 25

AMERICAN

TABLE1.

JOURNAL

OF EMERGENCY

Use of Buccal

Patients

Nifedipine

MEDICINE

in Hypertension:

n Supplement

to Volume

3, Number

Group

A (10 mg)

6 n December

1985

Entry Data Group

B (20 mg)

at entry

Men (No.) Mean age (years) Women (No.)

22 58.6 ‘- 16.5 21

Mean age (years)

10 48.2 k 16.1 10 55.6 2 17.6

58.9 2 9.0

Blood pressure criteria for study entry Diastolic 2 120 mm Hg and systolic 2 200 mm Hg Only diastolic 2 120 mm Hg Systolic 2 200 mm Hg and diastolic Initial l

blood

pressure

P < 0.2 for group

20 4 9

2 90 mm Hg

(mm Hg)

A versus group

205.8 r 24.41122.9 ‘- 11.7

RESULTS Sixty-three consecutive patients were entered into the study. For purposes of analysis patients were divided into two groups. Group A received one IO-mg dose of nifedipine, and Group B received two IO-mg doses (Table I). There were 43 patients in Group A, of whom 22 were men. In Group B there were 20 patients, ten men and ten women. The mean age of the Results

of Use of Buccal

Nifedipine

in Hypertension

Responders (No.) Blood pressure: s 180/90 mm Hg (No.) c 170/100 mm Hg (No.) Reduced by 2 40/40 mm Hg (No.) (No.)

Final blood pressure (mm Hg) Mean time to desired endpoint

(min)

* P < 0.0001 for pre-treatment versus post-treatment t P < 0.2 for group A versus group B. * P < 0.001. 26

k 17.3’

patients in Group A was 49 years. Among the men, mean age was somewhat lower in Group B. Of the 43 patients in Group A, 20 had systolic blood pressures greater than 200 mm Hg and diastolic pressures greater than 120 mm Hg. Four patients had only diastolic pressures greater than 120 mm Hg, and nine patients had systolic blood pressures greater than 200 mm Hg with diastolic pressures greater than 90 mm Hg. In Group B, the proportion of patients meeting each of the blood pressure criteria was similar for both systolic and diastolic blood pressures, i.e., 13 patients fulfilled both entry criteria. Four patients had only diastolic blood pressures greater than 120 mm Hg. Overall, the mean blood pressure for Group B was minimally (less than 5%) but statistically significantly higher than that of Group A. Of the 43 patients who received one dose of nifedipine, 42 patients responded (Table 2). The single treatment failure was a patient who “eloped” from the emergency department approximately 10 minutes after receiving nifedipine-before his blood pressure had come down and before he was given a second dose. The diastolic blood pressures dropped to less than 90 mm Hg, and the systolic pressures dropped to less than 180 mm Hg in 36 of the 42 patients. Four patients had systolic blood pressures less

Group A (IO mg)

Non-responders

212.1 2 27.1’/128.2

B.

asked to chew the capsule. Nifedipine is formulated as soft gelatin capsules; the drug can be extruded from the capsule by having the patient chew the capsule after holes are made in it. We then examined the capsule to ensure that it had been emptied. We followed blood pressure levels every 5 minutes for the first 1.5 minutes and every 10 minutes thereafter. If we found the response achieved within 20 to 30 minutes inadequate, a second dose was administered. There have been one or two patients subsequently who have required third doses, but for the most part a second dose was sufficient. Of interest in our study was that there were no exclusions. Patients with severe chest pain, congestive heart failure with high levels of BUN, and severe headaches all were given nifedipine.

TABLE 2.

13 4 3

B (20 mg)

42

19

38 4 2

13 4 1

1 156.6 -t 24.7*/88.8 e 10’ 39.9 -c 13.0 values.

Group

165.4 i

1 24.5t$/93.8 2 10.7*$ 66.0 5 17.8

HAFT W NIFEDIPINE

than 170 mm Hg but diastolic pressures of 100 mm Hg or less. Two patients decreased both their systolic and diastolic blood pressures by greater than 40 mm Hg. Similar proportions of patients in Group B responded in the same way. Of the 20 patients, only one patient failed to respond. This patient had refractory hypertension with an elevated BUN and subsequently required three parenteral medications to lower blood pressure. Mean final blood pressures were approximately 160/89 mm Hg in Group A and 165/94 mm Hg in Group B, with no statistically significant difference between the groups. The mean time from the initial dose of nifedipine to therapeutic response was about 40 minutes in Group A and about 66 minutes in Group B. Typical responses of patients are illustrated in Figures l-9. Patient 1 (Fig. 1) arrived in the emergency department with a blood pressure of 21.51120mm Hg. He was given one dose of nifedipine and over the next 45 to 50 minutes demonstrated a gradual, gentle drop of blood pressure to 140180 mm Hg. Patient 2 (Fig. 2) presented mainly with diastolic hypertension. Blood pressure was 180/130 mm Hg. He responded to 10 mg of nifedipine with a gradual and gentle lowering of blood pressure within 60 minutes to 140/86 mm Hg. Patient 3 (Fig. 3) had mainly systolic hypertension of 2401110 mm Hg. After only one dose of nifedipine, the blood pressure decreased within 30 minutes to 140/90 mm Hg. Patient 4 (Fig. 4) presented with a blood pressure of 288/130 mm Hg. After a single dose of nifedipine, his pressure gradually decreased over the following 45 minutes to 210/90 mm Hg. Although his systolic pres-

IN HYPERTENSIVE

EMERGENCY

190 180

,

l&

170

-\

160 150 140

Systolic e-4 Diastolic w . 'k

f

')-~.l*~"l

.

-8 l

i

240 230 220 210

-q - ', ‘, -

Systolic e-4 Diastolic w

200 190 180 170 160 mm

Hg

-

?

\ \ \ \

140 150 130 120 -

i

-+-w-*

240 230 c Systolic e--0 Diastolic O--O

5

0

10

15

30

lhr. 2hr..3hr

Min FIGURE

70 I-

190/106

148/88

140/80

2151120

,

18019a

,

148/E!o

'

0

10

20

30

40

50

lW88 '":v-t~

60 120 180

Min FIGURE

1.

Blood pressure

in patient

1.

3.

Blood pressure in patient 3.

sure remained elevated, he was out of danger and felt symptomatically improved. This patient was treated in the earlier portion of our study; if he had been entered later in the study, he would have received a second dose of nifedipine, which might have successfully reduced his systolic pressure as well. As we became more experienced with nifedipine, we used the second dose more readily. In patient 5 (Fig. 5) there was not much change in the initial blood pressure of 2401120 mm Hg after 20 minutes. However, a second dose, given at 20 minutes, promptly reduced his blood pressure to an acceptable level (140/90 mm Hg). 21

AMERICAN

JOURNAL

OF EMERGENCY

n Supplement

MEDICINE

to Volume

6 n December

3, Number

1985

230-

Systolic Diastolic

e-4 m

200 mm Hg

180 180

160 -

170 1

140 120 -

mm Hg

160150-

100 -

140-

0

5

FIGURE 4.

230-

10

20 Min

25

30.. 45

60

Blood pressure in patient 4.

?

220-

15

I I I I I

I I I I I I I I I I I I

210200-

190180-

systolic *

- l

1st

2nd dose

dose

Diastok W

FIGURE 6.

Min

Blood pressure in patient 6.

\

I I

210

170.

200

mm Hg

190

160150-

‘,**

180

. ‘)__

8

8.

Systolic Diastolic

170 160

1401

150 140

130

mm Hg

130 120 110 100 90

i->_L

80 70 2Gub,,a

r

0

~4o’Qo

,70,110 ,Eo,,cQ Emw

I

I

I

I

10

20

30

40

50

1st dose FIGURE 5. 28

23m20

I

2nd dose

15oml

lm30

1-m 60 90

140!90

I

180

Min

Blood pressure in patient 5.

dose FIGURE 7.

dose Blood pressure in patient 7.

* - 4 _

HAFT W NIFEDIPINE

Patient 6’s (Fig. 6) blood pressure ievelled off after a minimal response to the first dose of nifedipine. After 1.5 minutes, he was given a second dose to which he promptly responded. Patient 7 (Fig. 7) also had an inadequate response to 10 mg of nifedipine. His systolic blood pressure decreased from 200 to 190 mm Hg, and his diastolic pressure went from 130 to I10 mm Hg. At 20 minutes, he received another dose of nifedipine, at which time his blood pressure decreased steadily and satisfactorily. Patient 8 (Fig. 8) started to show a decrease in blood pressure but then levelled off after reaching 200/120 mm Hg. After the second dose, this patient’s response was adequate. Rarely did we see the type of response illustrated by patient 9 (Fig. 9). Within 20 minutes of his initial response, blood pressure started to drift up again. After a second dose, the patient’s blood pressure was reduced satisfactorily. The mean blood pressures with standard deviations of all patients are illustrated in Figure 10. Of key importance in our study was the fact that most patients had been taking other drugs (Table 3). Of the 63 patients, only 25 were not receiving at least one other antihypertensive drug when they entered the study. The typical history was of a patient who had been previously diagnosed as hypertensive and had been prescribed medication, but who had either not been followed closely by his physician or had not been compliant with his medication regimen. When he started to feel ill with headache, chest pain, or shortness of breath (about two days before his arrival at the emergency department), the patient restarted his medication and may even have doubled the dose prescribed for him. It is frequently difficult to unravel what medications the patient has actually taken, and it is often 260 250 240 230 220 210 200 190 rIxn Hg

Systolic

e--0

Diastolic e t b-+-a

l‘,-+*

l.

180 170 160 150 140

0

5

10

15

20

1st dose (min) FIGURE

8.

Blood pressure

0

5

10

15

20 1Hr

2nd dose (min) in patient

8.

w

IN HYPERTENSIVE

EMERGENCY

i--w-+

170 1 160 1

mm Hg

210 120 220 120

I

0

185125 190130

m

200

200125 205 170 190100 17090

I

I

I

1

5

10

15

I

20

25 Min

1 St dose FIGURE

9.

Blood

pressure

I

17080

no:0

II 35 mo

30 2nd dose

in patient

9.

with trepidation that another drug is added to the regimen. Eleven of the 63 patients were taking one drug, 15 were taking two drugs, eight were taking three drugs, two were taking four drugs, and one was taking five drugs at the time we added the buccal nifedipine. The most common concurrent drug was a diuretic; the second most common was methyldopa. There were also many patients using beta blockers and a number using nitrates, prazosin. hydralazine, captopril, and guanethidine. One patient in each group was already receiving nifedipine for the treatment of angina. At the start of the study, we were concerned that the presence of other drugs, especially drugs that interfered with catecholamines, might cause the patients to be sensitive to the potent vasodilating effects of nifedipine and therefore might reduce their blood pressure excessively. (Such events have been reported with intravenous diazoxide, another rapidly acting, potent vasodilator.) This did not happen in any of our patients, regardless of what type of concomitant antihypertensive medicines they had been receiving when they were given nifedipine. We must emphasize, however, that all of our patients had severely elevated blood pressures at the time of study. Patients with lesser degrees of hypertension were not studied. 29

AMERICAN

JOURNAL

OF EMERGENCY

MEDICINE

H Supplement

to Volume

3, Number

6 w December

1985

2401 230 240

220

230

210. 200. 190180170. 2 E

160.

L

150-

ti

140.

1609

1

130.

150-

120. 110loogo90-

80-

1

80

7oJ

70

I

I

I

I

I

I

I

I

I

I

0

I

I

I

I

20

30

40

50

60

70

80

90

0

I

10

I

I

I

1

10

20

30

40

50

60

I

70

80

90

Min

Min

FIGURE 10. Mean blood pressures (with standard deviations) of patients in group A (left) and group B (r$zt). TABLE 3.

Additional

Medications Number Group

No. of additional None One Two Three Four Five

A

of Patients Group

B

(to mg)

(20 mg)

18 8 6 7 2 1

7 3 9 1 0 0

16 12 9 9 4 2 2 3 1 1

9 4 3 1 1 0 2 1 1 1

drugs

Type of drug(s) being taken Diuretics Methyldopa Beta blockers Nitrates Prazosin hydrochloride Hydralazine hydrochloride Captopril Clonidine hydrochloride Nifedipine Guanethidine sulfate

CONCLUSION

Nifedipine, when administered buccally in one chewed perforated IO-mg capsule (and in some cases

two capsules), is an effective and safe method for lowering blood pressure promptly and smoothly in patients with diastolic pressures over 120 mm Hg or systolic pressures over 200 mm Hg, or both. It is valuable to note that this regimen can be used in patients who have been or are taking other antihypertensive drugs. REFERENCES 1. Murakami M, Murakami E, Takekoshi N, et al. Antihypertensive effect of 4(2’-nitrophenyl)-2-6-dimethyl-1, 4-dihydropyridine-3, 5-dicarbonic acid dimethyl ester (Nifedipine BAY a 1040): A new coronary dilator. Jpn Heart J 1972;13:128-135. 2. Klutsch VK, Schmidt P, Grosswendt J. Der Einfluss von BAY a 1040 auf die Nierenfunktion des Hypertonikers. Arzneimittelforsch 1972;22:377-380. 3. Kobayashi T, Ito Y, Tawara I. Clinical experiences with a new coronary active substance (BAY a 1040). Arzneimittelforsch 1972;22:380-389. 4. Aoki K, Yoshida T, Kato S, et al. Hypotensive action and increased plasma renin activity by calcium antagonist (nifedipine) in hypertensive patients. Jpn Heart J 1976;17:479-484. 5. Beer N, Gallegos I, Cohen A, et al. Efficacy of sublingual nifedipine in the acute treatment of systemic hypertension. Chest 1981;79:571-574. 6. Haft JI, Litterer WE. Chewing nifedipine to rapidly treat hypertension. Arch Int Med 1984;144:2357-2359.