A comparison of the acute hypotensive of two different doses of nifedipine
effects
To determine whether a dose of 5 mg of nifedipine would be useful in the treatment of hypertensive emergencies, we compared the acute hypotensive effects of two different doses of nifedipine, 5 mg and IO mg, in patients with severe hypertension. In this prospective, randomized, double-blind study, 30 consecutive black patients with diastolic blood pressure that was equal to or greater than 115 mm Hg received either a 5 mg or 10 mg nifedipine capsule and a placebo capsule, which matched that of the alternative strength. Patients were asked to bite the capsules and swallow the contents. Blood pressure response over 4 hours and adverse effects were monitored. Mean systolic blood pressure was reduced from 191.7 mm Hg (95% confidence interval 170.8 to 212.7 mm Hg) to 157.9 mm Hg (137.0 to 178.9 mm Hg) and 206.1 mm Hg (185.1 to 227.0 mm Hg) to 153.7 mm Hg (132.8 to 174.7 mm Hg) in patients who were given 5 mg and 10 mg doses of nifedipine, respectively. Mean diastolic blood pressure in the group of patients that received 5 mg doses of nifedipine decreased from 128.2 mm Hg (115.6 to 140.7 mm Hg) to 105.2 mm Hg (92.7 to 117.7 mm Hg); the corresponding values in the group that received 10 mg doses of nifedipine were 129.9 mm Hg (117.4 to 142.5 mm Hg) and 97.5 mm Hg (85.0 to 110.1 mm Hg), respectively. The minimum mean systolic blood pressures occurred 20 and 25 minutes after administration of the 5 mg and 10 mg capsules, respectively; the minimum diastolic blood pressures were reached after 20 and 30 minutes, respectively. The mean basal and maximal post-treatment heart rates in patients who were given the 5 mg and 10 mg capsules were 65.5 beatslmin (95% confidence intervals; 56.8 to 74.3 beatslmin) and 71.6 beatslmin (62.7 to 80.5 beats/min), and 66.5 beatslmin (57.7 to 75.4 beatslmin) and 72 beatslmin (63 to 80 beatslmin), respectively. One patient who had fallen asleep between blood pressure measurements woke up restless and mildly agitated 25 minutes after he had been given IO mg of nifedipine; he settled down after reassurance was provided. There were no other adverse effects. These data indicate that both the 5 mg and the 10 mg doses of nifedipine, which were given in capsule form by the bite and swallow method, would be useful in the treatment of hypertensive emergencies. To avoid profound hypotension, it is advisable to use the lower dose (i.e., 5 mg of nifedipine). If a satisfactory response is not obtained, the dose may be repeated when the blood pressure has reached its nadir (usually within an hour). Thereafter, maintenance antihypertensive therapy will be needed and should be started 2 hours after patients have received 5 mg of nifedipine and 4 hours after they have received 10 mg of nifedipine. (AM HEART J 1992;124:720.)
Breminand
Maharaj,
MBChB,
FCP(SA),
MD, and Kenneth
van der Byl, BSc
Durban, South Africa
Sodium nitroprusside, diazoxide, labetalol, and hydralazine have been the drugs of choice for the therapy of hypertensive emergencies, but treatment requires careful monitoring, usually in an intensive care unit13 * The use of these drugs in many hospitals,
From the Department versity of Natal Medical Received Reprint Clinical Congella, 4/l/39269
720
for publication
of Experimental School, Durban, Dec.
10, 1991;
and Clinical Pharmacology, South Africa. accepted
Mar.
Uni-
25, 1992.
requests: Professor B. Maharaj, Department of Experimental & Pharmacology, University of Natal Medical School, P 0 Box 17039, 4013, South Africa.
especially those in developing countries, is limited by the lack of such facilities and inadequate staffing. Nifedipine in a dose of 10 mg given by the bite and swallow method, orally or sublingually, is also an effective means of treating hypertensive emergencies because of the ease of administration and the rapid reduction in blood pressurelm4; adverse effects are minimal, although marked decrease in blood pressure have been reported. 5-g Since more attention has been focused on the use of the lowest possible dose of drugs in the treatment of hypertension (it has been found that efficacy is often maintained and that adverse effects are reduced), we were interested in determining whether 5 mg of nifedipine would also
Volume
124
Number
3
Acute
effects of nifedipine
hypotensiue
721
Table I. Pretreatment, minimum, and final (4-hour) posttreatment blood pressures after 5 mg and 10 mg nifedipine Nifedipine Pressure
(mm Hg) Pretreatment Systolic Range Mean 95’2
CI
Diastolic Range Mean 957’
CI
Minimum Systolic Range Mean 95% CI Diastolic Range Mean 955 CI Final (l-hour) Systolic Range Mean 95% CI Diastolic Range Mean 95 1’; CI CI, Confidence
5 mg
10 mg
170-220 191.7 170.8-212.7
170-250 206.1 185.1-227.0
116-145 128.2 115.6-140.7
115-150 129.9 117.4-142.5
140-190 157.9 137.0-178.9
116-192 153.7 132.8-174.7
go-124 105.2 92.7-117.7
84-124 97.5 85.0-110.1
150-220 174.7 152.2-197.2
150-210 172.7 151.0-194.4
90-148 118.8 105.3-132.2
94-122 106.4 93.4-119.4
J
Tulle
interval.
rapidly reduce very high blood pressure in this setting while exposing the patient to a smaller risk of hypotension. Because this information was not available and because patients with hypertensive emergencies invariably have severe hypertension and the drugs that are used to treat this condition are those that reduce the high blood pressure acutely, a study was designed to compare the acute hypotensive effects of two single doses of nifedipine, 5 mg and 10 mg, in patients with severe hypertension. METHODS We asked colleagues to provide us male patients with severe hypertension who were older than 18 years of age and had been referred to them for evaluation and treatment. A total of 30 black male patients between the ages of 19 and 60 years (mean, 49.1 years) with a resting supine diastolic blood pressure of greater than or equal to 115 mm Hg after four measurements, each separated by 2 minutes, who were receiving no antihypertensive drugs or whosehypertension was inadequately controlled by antihypertensive therapy were entered into this double-blind randomized study after informed consent was obtained in a form that was ac-
Fig. with (n = 95 %
after
dose
lmmlms)
1. Mean systolic blood pressure changes in patients severe hypertension who were given either 5 mg 15) or 10 mg nifedipine (n = 15). Error bars indicate confidence intervals.
ceptable to the University of Natal Ethics Committee. Initial blood pressure was measured after patients had rested for I5 minutes in the supine position. Patients who had had a stroke or myocardial infarction in the 6 months preceding the study, female patients with hypertension, and patients with hypertensive encephalopathy or severe cardiac failure were not included in this study. Patients were randomized to receive either a 10 mg nifedipine capsule and a placebo that matched the 5 mg nifedipine capsule or a 5 mg nifedipine capsule and a placebo capsule that matched the 10 mg capsule. They were asked to bite the capsules and swallow the contents. Blood pressure and heart rate were measured every 5 minutes during the first half hour after administration. Additional measurements were made at 45 minutes, 1 hour, 2 hours, 3 hours, and 4 hours after administration. All blood pressure measurements were made by a single observer who used the same mercury sphygmomanometerfor each reading. Systolic and diastolic blood pressures corresponded to the pressures at which the Korotkoff’s sounds were first heard and at which they disappeared (first and fifth phase, respectively). The nature and frequency of any adverse effects that occurred were recorded. The patients returned to their attending physicians as soon as the last blood pressure measurement was made so that their laboratory evaluation and other special investigations could be completed and drug therapy could be initiated or modified. One-way analysis of variance was used to test all variables. Confidence intervals of 95% were also calculated. Linear regression analysis was used to examine the relationship between pretreatment and post-treatment systolic and diastolic blood pressures. RESULTS
The mean age in the group of patients that received 5 mg doses of nifedipine was 49.3 years (range, 41 to 64 years), and in the group that received 10 mg doses, the mean age was 49.0 years (range, 19 to 58 years). Seven patients in the first group were not receiving
722
Maharaj and van der By1
American
I 80’
0
30
60
120 Time afterdoselmnutes)
ItlO
240
Fig. 2. Mean diastolic blood pressurechangesin patients with severe hypertension who were given either 5 ma (n = 15) or 10 mg nifedipine (n = 15). Error bars indicate 955, confidence intervals.
any antihypertensive drugs before entry into the study, whereas seven were receiving combination therapy with two drugs, and one was receiving three antihypertensive agents. The medications used were hydrochlorothiazide (n = 3), furosemide (n = 3), reserpine (n = l), methyldopa (II = 4), captopril (n = 3), and prazosin (n = 1). In the group that was allocated to receive 10 mg nifedipine, five patients were not receiving any drugs, four were receiving monotherapy with captopril (n = l), enalapril (n = l), or methyldopa (n = 2), and four were receiving two antihypertensive drugs. One patient was given three drugs, and the last patient had been receiving four antihypertensive drugs. The medications that were prescribed for these patients were hydrochlorothiazide (n = 4), furosemide (n = l), reserpine (n = l), methyldopa (n = 6), captopril (n = 2), atenolol (n = l), prazosin (n = l), and hydralazine (n = 1). The baseline blood pressures, the minimum blood pressures after treatment, and the final (4-hour) post-treatment blood pressures are shown in Table I; both dosesof nifedipine produced acute reductions in systolic and diastolic blood pressure. The blood pressure changes are shown in Figs. 1 and 2, and the maximum decrease in blood pressure that was achieved with both dosesis shown in Table II. In spite of randomization, pretreatment systolic blood pressures were higher in the group that received 10 mg doses of nifedipine. Linear regression analysis revealed that the maximum decrease in systolic blood pressure correlated with the systolic blood pressure before treatment for both 5 mg and 10 mg doses of nifedipine (r = 0.65; p < 0.01 and r = 0.64; p < 0.05, respectively). The decrease in diastolic blood pressure correlated with
September 1992 Hearl Journal
pretreatment diastolic blood pressure for the 10 mg dose of nifedipine (r = 0.81; p < 0.001) but not for the 5 mg dose of nifedipine (r = 0.35; p = 0.19). The mean pretreatment heart rates in the 5 mg and 10 mg groups were 65.5 beatslmin (95% confidence intervals, 56.6 to 74.3 beats/min) and 66.5 beats/min (57.7 to 75.4 beats/min). Maximal heart rates after treatment were 71.6 beats/min (62.7 to 80.5 beats/min) and 72 beats/min (63 to 80 beats/min). One patient, who had been given 10 mg of nifedipine, fell asleep between blood pressure measurements and woke up in an agitated state 25 minutes after treatment. He settled down after reassurance was provided. No other adverse effects were noted. DISCUSSION
Hypertensive emergencies remain a clinical problem in developing countries in contrast to such emergencies in more developed countries. The problem is compounded by the limited availability or the unavailability of intensive care facilities and the shortage of nursing and medical staff; drugs that are usually used to treat this condition (e.g., sodium nitroprusside, diazoxide, labetalol, and hydralazine) are given intravenously and require careful supervision and monitoring to prevent the development of marked hypotension, which carries a substantial risk of serious complications that result from a reduction in regional cerebral, retinal, and myocardial blood flow; such complications include blindness, strokes, myocardial infarctions, and death.lO-‘” A drug that is easily administered (by either the oral or sublingual route), has a rapid onset of action, is efficacious, and has a low incidence of serious adverse effects would be advantageous in these countries. Nifedipine fulfils these criteria; in a number of clinical studies, nifedipine has been found to be effective and safe in patients with hypertensive criseswhen given orally or sublingually in dosagesthat range from 10 to 30 mg. l-4 It has been suggested that a potential drawback of this drug, as with any oral agent in this situation, is the lack of control over the degree to which blood pressure falls and the relatively long duration of effect, which may not permit the rapid reversal of hypotension if it occurs.2 This concern has been reinforced by the occasional reports of rapid and uncontrollable decreases in blood pressure that occur after administration of this drug.5-gAgainst this background and in view of the fact that there is an increasing tendency to use the lowest possible dose of an antihypertensive drug whenever possible so that efficacy is maintained and adverse effects are reduced, information was needed on the acute hypotensive effect of a dose of 5 mg nifedipine in this
Volume
124
Number
3
Table II. Maximum
Acute hypotensive
reduction in blood pressure after 5 mg and Maximum o-9
Systolic pressure No. of patients Nifedipine (5 mg) Nifedipine (10 mg) Diastolic pressure No. of patients Nifedipine (5 mg) Nifedipine (10 mg)
IO-19
20-29
5
1
2
6 1
setting. Because such information was not available, because patients with hypertensive crises invariably have very high blood pressure, and because the drugs that are used in this situation are those that acutely reduce blood pressure, we embarked on a doubleblind, randomized study to compare the efficacy and safety of 5 mg and 10 mg doses of nifedipine in the acute reduction of blood pressure in patients with severe hypertension. Both doses produced acute blood pressure reductions. After administration of 5 mg of nifedipine, mean systolic blood pressure was reduced by 18% from 191.7 mm Hg to 157 mm Hg and mean diastolic blood pressure by 18% from 128.2 to 105.2 mm Hg; the corresponding values for 10 mg of nifedipine were 206.1 to 153.7 mm Hg and 129.9 to 97.5 mm Hg (i.e., reductions of 26 % and 25 % , respectively). The data also indicate that there is a dose-response relationship for nifedipine within the dose range of 5 to 10 w There is a paucity of data on the use of a single dose of 5 mg of nifedipine to produce acute reductions in blood pressure in adults. When 5 mg of nifedipine was given to 33 patients with hypertension, both mean systolic and diastolic blood pressures were reduced by 12 “C from 182/109 mm Hg to 160/95 mm Hg.17 In an article in which outpatients with severe hypertension were given 10 mg of nifedipine sublingually, mention is made of the fact that elderly patients were excluded from the study and that in a small number of patients (figures were not given) 5 mg of nifedipine was safely given, and the expected hypotensive effect was achieved.18 Also, the possibility of a dose-response relationship when nifedipine is used acutely has not been adequately explored. The results of published reports suggest that a dose-response relationship exists within the dosage range of 10 to 20 mg for systolic but not diastolic blood pressure,lg that the relationship is flat in the dosage range of 10 to 30
10
723
mg
decrease 30-39
effects of nifedipine
in blood 40-49
pressure 50-59
(mm
Hg) 60-69
3 2
3 1
2 4
1 2
3 5
3 7
1
1
ws20and
70- 79
80+
1 3
3
that a dose of 20 mg has nearly maximal antihypertensive activity.21 The changes in heart rates that were noted with both doses of nifedipine were not clinically significant. With the exception of one patient in the 10 mg group who on one measurement (at 10 minutes) had a heart rate of 96 beats/min, the maximum heart rates in patients that were entered into this study did not exceed 90 beatslmin at any stage during the investigation. The heart rate response after administration of 10 to 30 mg of nifedipine in previous studies has been variable.3* I8 Our results with both doses of nifedipine are consistent with the observations in previous studies that the onset of action is rapid (within 5 to 10 minutes),4 that the time to peak effect ranges from 15 to 60 minutes, that after peak effect, blood pressure rises gradually and reaches pretreatment levels within 6 to 10 hours (usually within 3 to 5 hours) after administration,3> 2oa21 and that the duration of action is doserelated.21 Our findings also concur with those of other investigators who have noted that response correlated with blood pressure values before treatment17g lg, 22 and that the drug was effective both in untreated patients and in those whose hypertension was inadequately controlled or in those who were currently receiving a variety of other antihypertensive medications, including calcium channel blockers. 18,23-25Response does not correlate with age, gender, or type of hypertensive emergency.lgs 26 As previously mentioned, one patient who had fallen asleep between blood pressure measurements woke up restless and mildly agitated 25 minutes after he had been given 10 mg of nifedipine; he settled down after reassurance was provided. This patient experienced no other adverse effects. The adverse effects that have been encountered in this setting include headaches, palpitations, dizziness, facial flushing, and hypotension3; their frequency in other
724
Maharaj
and van der By1
studies has varied considerably.* Although the dose of nifedipine that produced the marked decrease in blood pressure in the patients in these studies is not always given, it is apparent from the published case reports that the lowest dose that has been used thus far to produce acute reductions in blood pressure (i.e., 10 mg of nifedipine) can cause this adverse effect.‘,’ The maximum reductions in systolic blood pressure in the present investigation indicate that the risk of hypotension could be lower with a 5 mg dose of nifedipine, although the possibility that the hypotension is a class-related and not dose-related event cannot be discounted. In spite of the foregoing, the results of the present investigation, and indeed, those of the studies that are cited above indicate that the absolute decrease in blood pressure is not uniform; that is, some patients may not respond even if they have markedly elevated blood pressures, whereas others may have marked blood pressure reductions that are disproportionate to pretreatment levels. A small proportion of patients may fail to respond to nifedipine (6 Pi in one study)ls even after the administration of a second dose (2% in another study).24 Nifedipine has emerged as the drug of choice for the treatment of hypertensive emergencies in developing countries because of the easeof administration, efficacy, safety, and reduced need for intensive monitoring. The sublingual route is not recommended because of poor absorption from the buccal mucosa; the bite and swallow method is preferable because higher serum levels are achieved.28-“0 There is a small but clinically important risk of hypotension when nifedipine is used to produce acute reductions in blood pressure. Accordingly, it should only be used for treatment of hypertensive emergencies. In the present study, both the 5 mg and the 10 mg doses produced rapid and safe reductions in blood pressure in patients with severe hypertension. Since patients with hypertensive emergencies invariably have severe high blood pressure and since the drugs that are used to treat this condition are those that reduce blood pressure acutely, both strengths of nifedipine given by the bite and swallow technique would be useful in the treatment of hypertensive emergencies. With 5 mg of nifedipine, the maximal reduction in blood pressure occurred earlier, its magnitude was lower, and the duration of action was shorter. Accordingly, the risk of hypotension is reduced, and if it were to occur, it would not be prolonged. Against this background, preference should be given to the use of the lower dose (i.e., 5 mg). It is noteworthy that some authors have either
American
suggested31or recommended4 the use of 5 mg of nifedipine; it is not clear whether these recommendations were based on their personal experience. Patients who do not respond adequately will require a second dose. It would be safer to base this decision on two blood pressure measurements, the first, 20 to 30 minutes after administration of the first dose and the second 5 to 10 minutes later. These measurements will indicate whether the blood pressure has reached its nadir or is still decreasing. When the nadir has been reached and target blood pressure has not been achieved, the second dose can be given. Thereafter, maintenance antihypertensive therapy will be needed because blood pressure begins to rise after the peak effect has occurred. Maintenance therapy should be started 2 hours after patients have received 5 mg of nifedipine and 4 hours after they have received 10 mg of nifedipine. We thank Frances Pithouse, RN, Sundrapragasen Pillay, MBChB, and Shaun M. Khedun, MMedSci, for their assistance during the study. We also thank all colleagues who referred patients to us, Mr. Albert Hirasen for preparing the figures, and Mrs. Marlene Bryer for preparing the manuscript. We acknowledge the support of Bayer-Miles (South Africa).
REFERENCES
5.
6. 7.
8.
9.
10.
11.
12.
13. 14.
*References
3, 8, 9, 19. 22, and 27.
September 1992 Heart Journaf
Bertel 0, Marx BE. Hypertensive emergencies. Nephron 1987;47(suppl 11:51-6. Garcia JY, Vidt DG. Current management of hypertensive emergencies. Drugs 1987;34:263-78. Houston MC. Treatment of hypertensive urgencies and emergencies with nifedipine. AM HEART J 1986;i11:963-9. Houston MC. The comnarative effects of clonidine hvdrochloride and nifedipine in the treatment of hypertensive crises. AM HEART J 1988;115:152-9. O’Mailia JJ, Sander GE, Giles TD. Nifedipine-associated myocardial ischaemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 1987;107:185-6. Leavitt AD, Zweifler AJ. Nifedipine, hypotension and myocardial injury. Ann Intern Med i988;108:305. Wachter RM. Svmntomatic hvnotension induced bv nifedipine in the acute treatment of severe hypertension. Arch Intern Med 1987;147:556-8. Hannedouche T, Josse S, Godin M, Fillastre JP. Efficacy of sublingual nifedipine in the acute treatment of hypertension in haemodialysis patients. Curr Ther Res 1985;38:383-5. Erbel R, Brand G, Meyer J, Effert S. Emergency treatment of hypertensive crisis with sublingual nifedipine. Postgrad Med J 1983;59(suppl 3):134-6. Ledingham JGG, Rajagopalan B. Cerebral complications in the treatment of accelerated hypertension. Q J Med 1979;48:2541. Haas DC, Streeten DHP, Kim RC, Naalbandian AN, Obeid AI. Death from cerebral hypoperfusion during nitroprusside treatment of acute angiotension-dependent hypertension. Am J Med 1983;75:1071-6. Montoliu J, Botey A, Pons JM, Revert L. Fatal hypotension in normal-dose nitroprusside therapy. AM HEART J 1979: 97:541-L Kumar GK, Dastoor FC, Robaya JR, Razzaque MA. Side effects of diazoxide. J Am Med Assoc 1976;235:275-6. Wilson DJ, Wallin JD, Vlachakis ND, Freis E, Vidt DG, Michelson EL, Langford HG, Flamenbaum W, Poland MP. I
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“-
Volume Number
15.
16. 17.
18.
19.
20.
21.
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Intravenous labetalol in the treatment of severe hypertension and hypertensive emergencies. Am J Med 1983;75(suppl 4A3:95-102. Krogsgaard AR, Hilden T, McNair A, Nielsen PE. Cerebral svmptoms and blood pressure during parenteral administration of chlorpromazine, dihydralazine and diazoxide. Danish Multicenter Study on Acute Severe Hypertension. Acta Med Stand 1983;678(supp1)51-60. Hulse JA, Taylor DSI, Dillon MJ. Blindness and paraplegia in severe childhood hypertension. Lancet 1979;2:553-6. MacGregor GA, Markandu ND, Roteller C, Smith SS. The acute response to nifedipine is related to pretreatment blood pressure. Postgrad Med J 1983;59(suppl 2):91-4. Jennings AA, Jee LD, Smith JA, Commerford PJ, Opie LH. Acute effect of nifedipine on blood pressure and left ventricular ejection fraction in severely hypertensive outpatients: predictive effects of acute therapy and prolonged efficacy when added to existing therapy. AM HEART J 1986;111:557-63. Ellrodt AG, Ault MJ, Riedinger MS, Murata GH. Efficacy and safety of sublingual nifedipine in hypertensive emergencies. Am J Med 1985;79(suppl 4A):19-25. Aoki K, Kondo S, Mochizuki A, Yoshida T, Kato S, Kato K, Takikawa K. Antihypertensive effect of cardiovascular Caztantagonist in hypertensive patients in the absence and presence of beta-adrenergic blockade. AM HEART J 1978;96:218-26. Masotti G, Morettini A, Galanti G, Paoli G, Poggesi L. Antihypertensive action of nifedipine: effects on arteries and veins. J Clin Pharmacol 1985;25:27-35.
Acute hypotensive
22. Bertel 0, Conen D, Radu Nifedipine in hypertensive .T.
effects of nifedipine
EW, Muller emergencies.
725
J, Lang C, Dubach UC. Br Med J 1983;286:19-
23. Adler AG, Leahy JJ, Cressman MD. Management of perioperative hypertension using sublingual nifedipine. Experience in elderly patients undergoing eye surgery. Arch Intern Med 1986;146:1927-30. 24. Haft JI, Litterer WE. Chewing nifedipine to rapidly treat hypertension. Arch Intern Med 1984;144:2357-9. MA, Rovang KS, Mohiuddin SM, Mooss AN, Hille25. Malesker man DE, Sketch MH. Nifedipine in the treatment of hypertensive episodes in the coronary care unit. DICP 1989;23:855-8. 26. Pedersen OL, Mikkelsen E. Acute and chronic effects of nifedipine in arterial hypertension. Eur J Clin Pharmacol 1978; 14:375-81. 27. Beer N, Gallegos 1, Cohen A, Klein N, Sonnenblick E, Frishman W. Efficacy of sublingual nifedipine in the acute treatment of systemic hypertension. Chest 1981;79:571-4. DE, Forbes WP, Kohl1 D. Nifedipine in hypertensive 28. Hilleman emergencies. DICP 1987;21:1013-14. 29. McAllister RG. Kinetics and dynamics of nifedipine after oral and sublingual doses. Am J Med 1986;81(suppl 6A):2-5. 30. van Harten J, Burggraaf K, Danhof M, van Brummelen P, Breimer DD. Negligible sublingual absorption of nifedipine. Lancet 1987;2:1363-5. 31. Bertel 0. Symptomatic hypotension induced by nifedipine in the acute treatment of severe hypertension. Arch Intern Med 1987;147:1683.
effects
To determine whether a dose of 5 mg of nifedipine would be useful in the treatment of hypertensive emergencies, we compared the acute hypotensive effects of two different doses of nifedipine, 5 mg and IO mg, in patients with severe hypertension. In this prospective, randomized, double-blind study, 30 consecutive black patients with diastolic blood pressure that was equal to or greater than 115 mm Hg received either a 5 mg or 10 mg nifedipine capsule and a placebo capsule, which matched that of the alternative strength. Patients were asked to bite the capsules and swallow the contents. Blood pressure response over 4 hours and adverse effects were monitored. Mean systolic blood pressure was reduced from 191.7 mm Hg (95% confidence interval 170.8 to 212.7 mm Hg) to 157.9 mm Hg (137.0 to 178.9 mm Hg) and 206.1 mm Hg (185.1 to 227.0 mm Hg) to 153.7 mm Hg (132.8 to 174.7 mm Hg) in patients who were given 5 mg and 10 mg doses of nifedipine, respectively. Mean diastolic blood pressure in the group of patients that received 5 mg doses of nifedipine decreased from 128.2 mm Hg (115.6 to 140.7 mm Hg) to 105.2 mm Hg (92.7 to 117.7 mm Hg); the corresponding values in the group that received 10 mg doses of nifedipine were 129.9 mm Hg (117.4 to 142.5 mm Hg) and 97.5 mm Hg (85.0 to 110.1 mm Hg), respectively. The minimum mean systolic blood pressures occurred 20 and 25 minutes after administration of the 5 mg and 10 mg capsules, respectively; the minimum diastolic blood pressures were reached after 20 and 30 minutes, respectively. The mean basal and maximal post-treatment heart rates in patients who were given the 5 mg and 10 mg capsules were 65.5 beatslmin (95% confidence intervals; 56.8 to 74.3 beatslmin) and 71.6 beatslmin (62.7 to 80.5 beats/min), and 66.5 beatslmin (57.7 to 75.4 beatslmin) and 72 beatslmin (63 to 80 beatslmin), respectively. One patient who had fallen asleep between blood pressure measurements woke up restless and mildly agitated 25 minutes after he had been given IO mg of nifedipine; he settled down after reassurance was provided. There were no other adverse effects. These data indicate that both the 5 mg and the 10 mg doses of nifedipine, which were given in capsule form by the bite and swallow method, would be useful in the treatment of hypertensive emergencies. To avoid profound hypotension, it is advisable to use the lower dose (i.e., 5 mg of nifedipine). If a satisfactory response is not obtained, the dose may be repeated when the blood pressure has reached its nadir (usually within an hour). Thereafter, maintenance antihypertensive therapy will be needed and should be started 2 hours after patients have received 5 mg of nifedipine and 4 hours after they have received 10 mg of nifedipine. (AM HEART J 1992;124:720.)
Breminand
Maharaj,
MBChB,
FCP(SA),
MD, and Kenneth
van der Byl, BSc
Durban, South Africa
Sodium nitroprusside, diazoxide, labetalol, and hydralazine have been the drugs of choice for the therapy of hypertensive emergencies, but treatment requires careful monitoring, usually in an intensive care unit13 * The use of these drugs in many hospitals,
From the Department versity of Natal Medical Received Reprint Clinical Congella, 4/l/39269
720
for publication
of Experimental School, Durban, Dec.
10, 1991;
and Clinical Pharmacology, South Africa. accepted
Mar.
Uni-
25, 1992.
requests: Professor B. Maharaj, Department of Experimental & Pharmacology, University of Natal Medical School, P 0 Box 17039, 4013, South Africa.
especially those in developing countries, is limited by the lack of such facilities and inadequate staffing. Nifedipine in a dose of 10 mg given by the bite and swallow method, orally or sublingually, is also an effective means of treating hypertensive emergencies because of the ease of administration and the rapid reduction in blood pressurelm4; adverse effects are minimal, although marked decrease in blood pressure have been reported. 5-g Since more attention has been focused on the use of the lowest possible dose of drugs in the treatment of hypertension (it has been found that efficacy is often maintained and that adverse effects are reduced), we were interested in determining whether 5 mg of nifedipine would also
Volume
124
Number
3
Acute
effects of nifedipine
hypotensiue
721
Table I. Pretreatment, minimum, and final (4-hour) posttreatment blood pressures after 5 mg and 10 mg nifedipine Nifedipine Pressure
(mm Hg) Pretreatment Systolic Range Mean 95’2
CI
Diastolic Range Mean 957’
CI
Minimum Systolic Range Mean 95% CI Diastolic Range Mean 955 CI Final (l-hour) Systolic Range Mean 95% CI Diastolic Range Mean 95 1’; CI CI, Confidence
5 mg
10 mg
170-220 191.7 170.8-212.7
170-250 206.1 185.1-227.0
116-145 128.2 115.6-140.7
115-150 129.9 117.4-142.5
140-190 157.9 137.0-178.9
116-192 153.7 132.8-174.7
go-124 105.2 92.7-117.7
84-124 97.5 85.0-110.1
150-220 174.7 152.2-197.2
150-210 172.7 151.0-194.4
90-148 118.8 105.3-132.2
94-122 106.4 93.4-119.4
J
Tulle
interval.
rapidly reduce very high blood pressure in this setting while exposing the patient to a smaller risk of hypotension. Because this information was not available and because patients with hypertensive emergencies invariably have severe hypertension and the drugs that are used to treat this condition are those that reduce the high blood pressure acutely, a study was designed to compare the acute hypotensive effects of two single doses of nifedipine, 5 mg and 10 mg, in patients with severe hypertension. METHODS We asked colleagues to provide us male patients with severe hypertension who were older than 18 years of age and had been referred to them for evaluation and treatment. A total of 30 black male patients between the ages of 19 and 60 years (mean, 49.1 years) with a resting supine diastolic blood pressure of greater than or equal to 115 mm Hg after four measurements, each separated by 2 minutes, who were receiving no antihypertensive drugs or whosehypertension was inadequately controlled by antihypertensive therapy were entered into this double-blind randomized study after informed consent was obtained in a form that was ac-
Fig. with (n = 95 %
after
dose
lmmlms)
1. Mean systolic blood pressure changes in patients severe hypertension who were given either 5 mg 15) or 10 mg nifedipine (n = 15). Error bars indicate confidence intervals.
ceptable to the University of Natal Ethics Committee. Initial blood pressure was measured after patients had rested for I5 minutes in the supine position. Patients who had had a stroke or myocardial infarction in the 6 months preceding the study, female patients with hypertension, and patients with hypertensive encephalopathy or severe cardiac failure were not included in this study. Patients were randomized to receive either a 10 mg nifedipine capsule and a placebo that matched the 5 mg nifedipine capsule or a 5 mg nifedipine capsule and a placebo capsule that matched the 10 mg capsule. They were asked to bite the capsules and swallow the contents. Blood pressure and heart rate were measured every 5 minutes during the first half hour after administration. Additional measurements were made at 45 minutes, 1 hour, 2 hours, 3 hours, and 4 hours after administration. All blood pressure measurements were made by a single observer who used the same mercury sphygmomanometerfor each reading. Systolic and diastolic blood pressures corresponded to the pressures at which the Korotkoff’s sounds were first heard and at which they disappeared (first and fifth phase, respectively). The nature and frequency of any adverse effects that occurred were recorded. The patients returned to their attending physicians as soon as the last blood pressure measurement was made so that their laboratory evaluation and other special investigations could be completed and drug therapy could be initiated or modified. One-way analysis of variance was used to test all variables. Confidence intervals of 95% were also calculated. Linear regression analysis was used to examine the relationship between pretreatment and post-treatment systolic and diastolic blood pressures. RESULTS
The mean age in the group of patients that received 5 mg doses of nifedipine was 49.3 years (range, 41 to 64 years), and in the group that received 10 mg doses, the mean age was 49.0 years (range, 19 to 58 years). Seven patients in the first group were not receiving
722
Maharaj and van der By1
American
I 80’
0
30
60
120 Time afterdoselmnutes)
ItlO
240
Fig. 2. Mean diastolic blood pressurechangesin patients with severe hypertension who were given either 5 ma (n = 15) or 10 mg nifedipine (n = 15). Error bars indicate 955, confidence intervals.
any antihypertensive drugs before entry into the study, whereas seven were receiving combination therapy with two drugs, and one was receiving three antihypertensive agents. The medications used were hydrochlorothiazide (n = 3), furosemide (n = 3), reserpine (n = l), methyldopa (II = 4), captopril (n = 3), and prazosin (n = 1). In the group that was allocated to receive 10 mg nifedipine, five patients were not receiving any drugs, four were receiving monotherapy with captopril (n = l), enalapril (n = l), or methyldopa (n = 2), and four were receiving two antihypertensive drugs. One patient was given three drugs, and the last patient had been receiving four antihypertensive drugs. The medications that were prescribed for these patients were hydrochlorothiazide (n = 4), furosemide (n = l), reserpine (n = l), methyldopa (n = 6), captopril (n = 2), atenolol (n = l), prazosin (n = l), and hydralazine (n = 1). The baseline blood pressures, the minimum blood pressures after treatment, and the final (4-hour) post-treatment blood pressures are shown in Table I; both dosesof nifedipine produced acute reductions in systolic and diastolic blood pressure. The blood pressure changes are shown in Figs. 1 and 2, and the maximum decrease in blood pressure that was achieved with both dosesis shown in Table II. In spite of randomization, pretreatment systolic blood pressures were higher in the group that received 10 mg doses of nifedipine. Linear regression analysis revealed that the maximum decrease in systolic blood pressure correlated with the systolic blood pressure before treatment for both 5 mg and 10 mg doses of nifedipine (r = 0.65; p < 0.01 and r = 0.64; p < 0.05, respectively). The decrease in diastolic blood pressure correlated with
September 1992 Hearl Journal
pretreatment diastolic blood pressure for the 10 mg dose of nifedipine (r = 0.81; p < 0.001) but not for the 5 mg dose of nifedipine (r = 0.35; p = 0.19). The mean pretreatment heart rates in the 5 mg and 10 mg groups were 65.5 beatslmin (95% confidence intervals, 56.6 to 74.3 beats/min) and 66.5 beats/min (57.7 to 75.4 beats/min). Maximal heart rates after treatment were 71.6 beats/min (62.7 to 80.5 beats/min) and 72 beats/min (63 to 80 beats/min). One patient, who had been given 10 mg of nifedipine, fell asleep between blood pressure measurements and woke up in an agitated state 25 minutes after treatment. He settled down after reassurance was provided. No other adverse effects were noted. DISCUSSION
Hypertensive emergencies remain a clinical problem in developing countries in contrast to such emergencies in more developed countries. The problem is compounded by the limited availability or the unavailability of intensive care facilities and the shortage of nursing and medical staff; drugs that are usually used to treat this condition (e.g., sodium nitroprusside, diazoxide, labetalol, and hydralazine) are given intravenously and require careful supervision and monitoring to prevent the development of marked hypotension, which carries a substantial risk of serious complications that result from a reduction in regional cerebral, retinal, and myocardial blood flow; such complications include blindness, strokes, myocardial infarctions, and death.lO-‘” A drug that is easily administered (by either the oral or sublingual route), has a rapid onset of action, is efficacious, and has a low incidence of serious adverse effects would be advantageous in these countries. Nifedipine fulfils these criteria; in a number of clinical studies, nifedipine has been found to be effective and safe in patients with hypertensive criseswhen given orally or sublingually in dosagesthat range from 10 to 30 mg. l-4 It has been suggested that a potential drawback of this drug, as with any oral agent in this situation, is the lack of control over the degree to which blood pressure falls and the relatively long duration of effect, which may not permit the rapid reversal of hypotension if it occurs.2 This concern has been reinforced by the occasional reports of rapid and uncontrollable decreases in blood pressure that occur after administration of this drug.5-gAgainst this background and in view of the fact that there is an increasing tendency to use the lowest possible dose of an antihypertensive drug whenever possible so that efficacy is maintained and adverse effects are reduced, information was needed on the acute hypotensive effect of a dose of 5 mg nifedipine in this
Volume
124
Number
3
Table II. Maximum
Acute hypotensive
reduction in blood pressure after 5 mg and Maximum o-9
Systolic pressure No. of patients Nifedipine (5 mg) Nifedipine (10 mg) Diastolic pressure No. of patients Nifedipine (5 mg) Nifedipine (10 mg)
IO-19
20-29
5
1
2
6 1
setting. Because such information was not available, because patients with hypertensive crises invariably have very high blood pressure, and because the drugs that are used in this situation are those that acutely reduce blood pressure, we embarked on a doubleblind, randomized study to compare the efficacy and safety of 5 mg and 10 mg doses of nifedipine in the acute reduction of blood pressure in patients with severe hypertension. Both doses produced acute blood pressure reductions. After administration of 5 mg of nifedipine, mean systolic blood pressure was reduced by 18% from 191.7 mm Hg to 157 mm Hg and mean diastolic blood pressure by 18% from 128.2 to 105.2 mm Hg; the corresponding values for 10 mg of nifedipine were 206.1 to 153.7 mm Hg and 129.9 to 97.5 mm Hg (i.e., reductions of 26 % and 25 % , respectively). The data also indicate that there is a dose-response relationship for nifedipine within the dose range of 5 to 10 w There is a paucity of data on the use of a single dose of 5 mg of nifedipine to produce acute reductions in blood pressure in adults. When 5 mg of nifedipine was given to 33 patients with hypertension, both mean systolic and diastolic blood pressures were reduced by 12 “C from 182/109 mm Hg to 160/95 mm Hg.17 In an article in which outpatients with severe hypertension were given 10 mg of nifedipine sublingually, mention is made of the fact that elderly patients were excluded from the study and that in a small number of patients (figures were not given) 5 mg of nifedipine was safely given, and the expected hypotensive effect was achieved.18 Also, the possibility of a dose-response relationship when nifedipine is used acutely has not been adequately explored. The results of published reports suggest that a dose-response relationship exists within the dosage range of 10 to 20 mg for systolic but not diastolic blood pressure,lg that the relationship is flat in the dosage range of 10 to 30
10
723
mg
decrease 30-39
effects of nifedipine
in blood 40-49
pressure 50-59
(mm
Hg) 60-69
3 2
3 1
2 4
1 2
3 5
3 7
1
1
ws20and
70- 79
80+
1 3
3
that a dose of 20 mg has nearly maximal antihypertensive activity.21 The changes in heart rates that were noted with both doses of nifedipine were not clinically significant. With the exception of one patient in the 10 mg group who on one measurement (at 10 minutes) had a heart rate of 96 beats/min, the maximum heart rates in patients that were entered into this study did not exceed 90 beatslmin at any stage during the investigation. The heart rate response after administration of 10 to 30 mg of nifedipine in previous studies has been variable.3* I8 Our results with both doses of nifedipine are consistent with the observations in previous studies that the onset of action is rapid (within 5 to 10 minutes),4 that the time to peak effect ranges from 15 to 60 minutes, that after peak effect, blood pressure rises gradually and reaches pretreatment levels within 6 to 10 hours (usually within 3 to 5 hours) after administration,3> 2oa21 and that the duration of action is doserelated.21 Our findings also concur with those of other investigators who have noted that response correlated with blood pressure values before treatment17g lg, 22 and that the drug was effective both in untreated patients and in those whose hypertension was inadequately controlled or in those who were currently receiving a variety of other antihypertensive medications, including calcium channel blockers. 18,23-25Response does not correlate with age, gender, or type of hypertensive emergency.lgs 26 As previously mentioned, one patient who had fallen asleep between blood pressure measurements woke up restless and mildly agitated 25 minutes after he had been given 10 mg of nifedipine; he settled down after reassurance was provided. This patient experienced no other adverse effects. The adverse effects that have been encountered in this setting include headaches, palpitations, dizziness, facial flushing, and hypotension3; their frequency in other
724
Maharaj
and van der By1
studies has varied considerably.* Although the dose of nifedipine that produced the marked decrease in blood pressure in the patients in these studies is not always given, it is apparent from the published case reports that the lowest dose that has been used thus far to produce acute reductions in blood pressure (i.e., 10 mg of nifedipine) can cause this adverse effect.‘,’ The maximum reductions in systolic blood pressure in the present investigation indicate that the risk of hypotension could be lower with a 5 mg dose of nifedipine, although the possibility that the hypotension is a class-related and not dose-related event cannot be discounted. In spite of the foregoing, the results of the present investigation, and indeed, those of the studies that are cited above indicate that the absolute decrease in blood pressure is not uniform; that is, some patients may not respond even if they have markedly elevated blood pressures, whereas others may have marked blood pressure reductions that are disproportionate to pretreatment levels. A small proportion of patients may fail to respond to nifedipine (6 Pi in one study)ls even after the administration of a second dose (2% in another study).24 Nifedipine has emerged as the drug of choice for the treatment of hypertensive emergencies in developing countries because of the easeof administration, efficacy, safety, and reduced need for intensive monitoring. The sublingual route is not recommended because of poor absorption from the buccal mucosa; the bite and swallow method is preferable because higher serum levels are achieved.28-“0 There is a small but clinically important risk of hypotension when nifedipine is used to produce acute reductions in blood pressure. Accordingly, it should only be used for treatment of hypertensive emergencies. In the present study, both the 5 mg and the 10 mg doses produced rapid and safe reductions in blood pressure in patients with severe hypertension. Since patients with hypertensive emergencies invariably have severe high blood pressure and since the drugs that are used to treat this condition are those that reduce blood pressure acutely, both strengths of nifedipine given by the bite and swallow technique would be useful in the treatment of hypertensive emergencies. With 5 mg of nifedipine, the maximal reduction in blood pressure occurred earlier, its magnitude was lower, and the duration of action was shorter. Accordingly, the risk of hypotension is reduced, and if it were to occur, it would not be prolonged. Against this background, preference should be given to the use of the lower dose (i.e., 5 mg). It is noteworthy that some authors have either
American
suggested31or recommended4 the use of 5 mg of nifedipine; it is not clear whether these recommendations were based on their personal experience. Patients who do not respond adequately will require a second dose. It would be safer to base this decision on two blood pressure measurements, the first, 20 to 30 minutes after administration of the first dose and the second 5 to 10 minutes later. These measurements will indicate whether the blood pressure has reached its nadir or is still decreasing. When the nadir has been reached and target blood pressure has not been achieved, the second dose can be given. Thereafter, maintenance antihypertensive therapy will be needed because blood pressure begins to rise after the peak effect has occurred. Maintenance therapy should be started 2 hours after patients have received 5 mg of nifedipine and 4 hours after they have received 10 mg of nifedipine. We thank Frances Pithouse, RN, Sundrapragasen Pillay, MBChB, and Shaun M. Khedun, MMedSci, for their assistance during the study. We also thank all colleagues who referred patients to us, Mr. Albert Hirasen for preparing the figures, and Mrs. Marlene Bryer for preparing the manuscript. We acknowledge the support of Bayer-Miles (South Africa).
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September 1992 Heart Journaf
Bertel 0, Marx BE. Hypertensive emergencies. Nephron 1987;47(suppl 11:51-6. Garcia JY, Vidt DG. Current management of hypertensive emergencies. Drugs 1987;34:263-78. Houston MC. Treatment of hypertensive urgencies and emergencies with nifedipine. AM HEART J 1986;i11:963-9. Houston MC. The comnarative effects of clonidine hvdrochloride and nifedipine in the treatment of hypertensive crises. AM HEART J 1988;115:152-9. O’Mailia JJ, Sander GE, Giles TD. Nifedipine-associated myocardial ischaemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 1987;107:185-6. Leavitt AD, Zweifler AJ. Nifedipine, hypotension and myocardial injury. Ann Intern Med i988;108:305. Wachter RM. Svmntomatic hvnotension induced bv nifedipine in the acute treatment of severe hypertension. Arch Intern Med 1987;147:556-8. Hannedouche T, Josse S, Godin M, Fillastre JP. Efficacy of sublingual nifedipine in the acute treatment of hypertension in haemodialysis patients. Curr Ther Res 1985;38:383-5. Erbel R, Brand G, Meyer J, Effert S. Emergency treatment of hypertensive crisis with sublingual nifedipine. Postgrad Med J 1983;59(suppl 3):134-6. Ledingham JGG, Rajagopalan B. Cerebral complications in the treatment of accelerated hypertension. Q J Med 1979;48:2541. Haas DC, Streeten DHP, Kim RC, Naalbandian AN, Obeid AI. Death from cerebral hypoperfusion during nitroprusside treatment of acute angiotension-dependent hypertension. Am J Med 1983;75:1071-6. Montoliu J, Botey A, Pons JM, Revert L. Fatal hypotension in normal-dose nitroprusside therapy. AM HEART J 1979: 97:541-L Kumar GK, Dastoor FC, Robaya JR, Razzaque MA. Side effects of diazoxide. J Am Med Assoc 1976;235:275-6. Wilson DJ, Wallin JD, Vlachakis ND, Freis E, Vidt DG, Michelson EL, Langford HG, Flamenbaum W, Poland MP. I
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Intravenous labetalol in the treatment of severe hypertension and hypertensive emergencies. Am J Med 1983;75(suppl 4A3:95-102. Krogsgaard AR, Hilden T, McNair A, Nielsen PE. Cerebral svmptoms and blood pressure during parenteral administration of chlorpromazine, dihydralazine and diazoxide. Danish Multicenter Study on Acute Severe Hypertension. Acta Med Stand 1983;678(supp1)51-60. Hulse JA, Taylor DSI, Dillon MJ. Blindness and paraplegia in severe childhood hypertension. Lancet 1979;2:553-6. MacGregor GA, Markandu ND, Roteller C, Smith SS. The acute response to nifedipine is related to pretreatment blood pressure. Postgrad Med J 1983;59(suppl 2):91-4. Jennings AA, Jee LD, Smith JA, Commerford PJ, Opie LH. Acute effect of nifedipine on blood pressure and left ventricular ejection fraction in severely hypertensive outpatients: predictive effects of acute therapy and prolonged efficacy when added to existing therapy. AM HEART J 1986;111:557-63. Ellrodt AG, Ault MJ, Riedinger MS, Murata GH. Efficacy and safety of sublingual nifedipine in hypertensive emergencies. Am J Med 1985;79(suppl 4A):19-25. Aoki K, Kondo S, Mochizuki A, Yoshida T, Kato S, Kato K, Takikawa K. Antihypertensive effect of cardiovascular Caztantagonist in hypertensive patients in the absence and presence of beta-adrenergic blockade. AM HEART J 1978;96:218-26. Masotti G, Morettini A, Galanti G, Paoli G, Poggesi L. Antihypertensive action of nifedipine: effects on arteries and veins. J Clin Pharmacol 1985;25:27-35.
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23. Adler AG, Leahy JJ, Cressman MD. Management of perioperative hypertension using sublingual nifedipine. Experience in elderly patients undergoing eye surgery. Arch Intern Med 1986;146:1927-30. 24. Haft JI, Litterer WE. Chewing nifedipine to rapidly treat hypertension. Arch Intern Med 1984;144:2357-9. MA, Rovang KS, Mohiuddin SM, Mooss AN, Hille25. Malesker man DE, Sketch MH. Nifedipine in the treatment of hypertensive episodes in the coronary care unit. DICP 1989;23:855-8. 26. Pedersen OL, Mikkelsen E. Acute and chronic effects of nifedipine in arterial hypertension. Eur J Clin Pharmacol 1978; 14:375-81. 27. Beer N, Gallegos 1, Cohen A, Klein N, Sonnenblick E, Frishman W. Efficacy of sublingual nifedipine in the acute treatment of systemic hypertension. Chest 1981;79:571-4. DE, Forbes WP, Kohl1 D. Nifedipine in hypertensive 28. Hilleman emergencies. DICP 1987;21:1013-14. 29. McAllister RG. Kinetics and dynamics of nifedipine after oral and sublingual doses. Am J Med 1986;81(suppl 6A):2-5. 30. van Harten J, Burggraaf K, Danhof M, van Brummelen P, Breimer DD. Negligible sublingual absorption of nifedipine. Lancet 1987;2:1363-5. 31. Bertel 0. Symptomatic hypotension induced by nifedipine in the acute treatment of severe hypertension. Arch Intern Med 1987;147:1683.
