Hypertensive crisis is a clinical condition after acute severe increase of arterial blood pressure (BP), which in most cases requires therapy toward immediate BP reduction, not necessarily to normal levels (1). In the treatment of hypertensive crisis, oral-sublingual administration of nifedipine capsules has been shown to be highly effective (2-7), and it has become one of the alternatives to parenteral antihypertensive drugs, particularly when careful hemodynamic monitoring is not available. Hypertension is particularly frequent and harmful in black populations (8-11), and the prognosis of hypertensive crisis is probably worse in black than in nonblack patients (12). In black patients with hypertension, it has been shown that calcium antagonists are particularly effective, both as long- and short-term treatment of hypertension, when compared with other classes of antihypertensive drugs (6,7,13). Although controversy still exists about the level to which BP should be reduced in patients with hypertensive crisis, a recent review of the literature (14) revealed some reports of serious adverse effects such as cerebral ischemia, stroke, and coronary events associated with acute and severe hypotension caused by the use nifedipine capsules. Thus there are concerns about the potential hazards of a rapid reduction of BP as induced by nifedipine capsules in such conditions. Therefore we hypothesized that for the treatment of hypertensive crisis, the administration of a slow-release preparation of nifedipine would be preferable because it would reduce BP for >10 h, while achieving a rapid enough effect without critical short-term decreases in BP. Such a formulation of nifedipine-retard has been shown to produce long-lasting plasma levels of the drug that correlated strongly with a prolonged reduction of BP for ∼12 h (15). Thus in our study, we compared for 12 h the short-term hypotensive effect of the slow-acting preparation of nifedipine-retard with that of the oral administration of nifedipine capsules in black patients with symptoms of hypertensive crisis.
PATIENTS AND METHODS
This was a randomized, parallel-group, placebo-controlled study, in which the short-term efficacy of two sublingual-oral doses of nifedipine capsules (10 mg) taken 6 h apart and of a single oral dose of nifedipine retard (20 mg, sustained-release) were evaluated for 12 h in two groups of 11 and 10 black patients with hypertensive crisis. In all patients, the short-term increase of BP was asymptomatic. After informed consent was given, all patients were submitted to a period of observation on placebo for 30 min. All subjects underwent a physical examination on admission, an electrocardiogram (ECG), standard blood chemical tests, and optic fundi evaluation. Subjects of both sexes were included if they were without any therapy for ≥2 weeks, aged 20-65 years, and with an average supine diastolic BP >120 mm Hg as a mean of the last three automatic readings over the placebo period. Exclusion criteria were aortic dissection, recent myocardial or cerebrovascular accident, renal artery stenosis, heart failure, and a serum creatinine value >2 times the upper limit of normal. After the placebo phase, if diastolic BP (DBP) was still >120 mm Hg, eligible patients were randomly assigned to either nifedipine capsules or nifedipine-retard treatments. A perforated capsule of nifedipine (10 mg) was put under the tongue, and the saliva was swallowed after 5 min. One capsule was given at the end of the placebo period and again 6 h later. In the other group, a single tablet of nifedipine retard (20 mg, sustained-release) was immediately swallowed at the end of the placebo period.
Blood pressure measurement
Blood pressure was measured every 5 min during the 30-min placebo phase with a Dinamap (Critikon 1846 SX). At the moment of administration of nifedipine capsules or nifedipine-retard, continuous BP recordings were started by using an automated noninvasive device (90207; SpaceLabs, Redmond, WA, U.S.A.). For each patient, BP readings were taken at 10-min intervals thereafter for the next 12 h with patients supine. When the instrument was fitted, automatic BP had to be within 5 mm Hg of three simultaneous readings obtained on the same arm with a standard mercury sphygmomanometer by using a t-tube connector. Recordings were accepted only if >80% of raw data were valid.
Results are expressed as mean ± SEM. We used Student's paired and unpaired t test with the Bonferroni correction for multiple comparisons when necessary, with specific software for analysis of Spacelabs 90207 data (16). Probability of 5% was the level adopted for statistical significance.
The demographic characteristics and baseline data of the study populations are summarized in Table 1. There were no significant differences between the treatment groups with respect to age, gender, plasma creatinine values, and BP values at the end of the placebo period. The decrease in BP induced by nifedipine capsules reached significance for systolic BP (SBP) at 20 min (from 224 ± 6 to 195 ± 6 mm Hg; p < 0.02) and for DBP at 10 min (from 153 ± 3 to 133 ± 3 mm Hg; p < 0.01) after administration. The decrease in BP induced by nifedipineretard reached significance for SBP at 20 min (from 228 ± 6 to 204 ± 6 mm Hg; p < 0.05) and for DBP at 30 min (from 152 ± 4 to 138 ± 4 mm Hg; p < 0.02) after administration. After this and up to 12 h after placebo, all the recorded BP values obtained with the two preparations were significantly lower than the respective pretreatment placebo values. Table 1 shows, for both treatments, the average BP and heart rate values at baseline, at the moment of the maximal effect, and at 2, 4, 6, 8, 10, and 12 h after drug administrations. Heart rate did not significantly change with nifedipine-retard throughout the study. With nifedipine capsules, a significant increase in heart rate was found ∼2 h after both administrations as compared with baseline placebo values. As shown in Table 1 and in Fig. 1, during the first 3 h after administration of the two preparations, the first dose of nifedipine capsules produced a faster and more pronounced decrease in both SBP and DBP compared with nifedipine-retard. At 2 h after administration, the BP levels reached by nifedipine capsules were significantly lower than the values obtained with nifedipine-retard. Both preparations induced a maximal BP decrease of ∼30% of the placebo values. The magnitude of the mean peak decrease in SBP/DBP of the first dose of nifedipine capsules (74 ± 4/57 ± 4 mm Hg) was similar to that of nifedipine-retard (62 ± 7/58 ± 77 mm Hg). In contrast, the time of peak decrease in SBP/DBP of nifedipine-retard occurred significantly later than that of the first dose of nifedipine capsules. Two hours after administration, nifedipine capsules produced a decrease in BP that was roughly similar to their peak effect, whereas at that time, the decrease in BP induced by nifedipine retard was only 70% of its maximal effect. Between the hours 4 and 6 after administration, the hypotensive effect of nifedipine capsules was blunted, and a second administration was necessary, whereas the BP values observed with nifedipine-retard continued to decrease slowly up to 12 h. No serious side effects were observed with either of the preparations. Four patients receiving nifedipine capsules had transient flush and headache. One patient treated with nifedipine-retard reported a mild transitory flush.
In this study, we compared in black patients with hypertensive crisis the short-term hypotensive effect of a single tablet of the slow-acting preparation of nifedipine (20 mg) with that of two single oral administrations (6 h apart) of nifedipine capsules (10 mg). Over the last 25 years, nifedipine in the form of short-acting capsules given by the oral-sublingual route has been widely used in the treatment of hypertensive crisis either in black (5-7) or in nonblack patients (2-4,7). Although in that context, the use of nifedipine capsules has been generally considered to be highly effective and safe (1-7), it is now clear that serious neurologic and cardiac adverse events may occur in a few patients treated with nifedipine capsules, the majority of which may be attributed to an abrupt vasodilatation and to a rapid decrease in BP within the first 2-4 h after administration (14). Although the level to which BP should be reduced in patients with hypertensive crisis is still controversial, some patients may suffer from the consequences of a critical decrease in cerebral blood flow when systemic BP is reduced abruptly (17). With nifedipine capsules, this has been related to the rapid absorption and increase in blood levels of the substance, because good correlation has been found between the rapid increase of blood levels of nifedipine and the time-course of its pharmacodynamic effects (18). Thus it is conceivable that a preparation that could effectively decrease BP within 12-24 h with a minimal risk of abrupt short-term decreases in BP would be preferable for treatment of hypertensive crisis. Compared with nifedipine capsules, the slow-release preparation of nifedipine-retard has been shown to produce a significant delay in peak concentrations and a much smaller range of peak plasma levels, along with a smaller interindividual variation of plasma drug levels (19). In this study, we found that the hypotensive effect of nifedipine capsules was more rapid and more pronounced than that of nifedipine-retard and that a single administration of nifedipine retard reduced BP slowly and continuously ≤12 h after administration and more smoothly compared with nifedipine capsules. During the first 2 h after administration, the BP decrease induced by nifedipine capsules was significantly greater, and the BP was maintained at a significantly lower level than that with nifedipine-retard. With nifedipine capsules, after the initial rapid decrease of BP, its hypotensive effect was substantially lost between the fourth and the sixth hours, thus leading to a second administration of the drug, which produced another deep short-term decrease in BP. Although both preparations produced a similar maximal BP decrease (∼30% of the placebo values), there was a marked difference in the time of the peak decrease of BP. With nifedipine capsules, the peak decrease in BP occurred within the first 3 h after administration, whereas with nifedipine capsules, it was only achieved 6-7 h after administration. This difference on the time to peak probably explains the lower incidence of side effects (flushing, headache) that were found with nifedipine-retard compared with nifedipine capsules, because these effects are commonly related to the intensity of the vasodilatory effects of nifedipine. Although we did not detect any symptoms of cerebral hypoperfusion with nifedipine capsules, some serious adverse effects, such as cerebrovascular and myocardial ischemia caused by severe hypotension, have been reported after administration of nifedipine capsules in patients with hypertensive crisis. Thus there still is a major concern that the rapid and short-term decrease of BP observed with nifedipine capsules may lead in some patients to a critical reduction in organ blood flow. The pharmacodynamic characteristics, particularly the absence of abrupt decreases in BP that we have found with nifedipine-retard, are consistent with a safer profile of this preparation in comparison with nifedipine capsules, so that the likelihood of these severe adverse effects is substantially less. Because in hypertensive crisis, the aim is to achieve BP control within 12-24 h, our data support a rapid enough BP-reducing effect of nifedipine-retard for hypertensive crisis that is achieved more gradually and with a safer profile compared with nifedipine capsules. We conclude that in black patients with hypertensive crisis, nifedipine capsules produce an abrupt decrease in BP that may be potentially harmful. For patients suitable for treatment with nifedipine, the slow- release form of nifedipine-retard seems to be quite preferable because it reduces BP effectively and smoothly for ≥12 h while achieving a rapid enough effect without critical abrupt decreases in BP.
Acknowledgment: This study was supported by PRAXIS XXI-SAU-1302/95 and by a grant from Reitoria da Universidade do Porto, Portugal.
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