Rate of increase in the plasma concentration of nifedipine as a major determinant of its hemodynamic effects in humans

Abstract

The relevance of the rate of increase in the plasma concentration of nifedipine for the drug's hemodynamic effect was investigated in healthy volunteers. Nifedipine was given intravenously according to two regimens, each designed to produce the same steady-state concentration, but attained gradually (within 5 to 7 hours) with one regimen and rapidly (within 3 minutes) with the other. The mean steady-state concentrations obtained were 31.7 +/- 5.2 (SD) ng/ml and 29.4 +/- 9.8 ng/ml, respectively (not significant). With the gradual regimen, heart rate was unchanged and diastolic blood pressure was lowered gradually by approximately 10 mm Hg. With the rapid regimen, heart rate increased immediately and remained elevated for the duration of the infusion, whereas diastolic blood pressure did not change significantly. At the end of the gradual-rise regimen, the infusion rate was increased tenfold for 10 minutes, promptly resulting in tachycardia and a paradoxical rise in diastolic blood pressure. These divergent hemodynamic responses of the gradual- and rapid-rise regimens could well be related to differences in baroreceptor activation. It is concluded that the hemodynamic response to nifedipine is influenced by the rate of increase of its concentration in plasma.

Evaluation of the Method for Nifedipine Administration for a Rapid Onset of Clinical Effect: A Clinical Study in Normal Volunteers.

“…Nifedipine usually shows no marked antihypertensive eŠect in normal individuals, because the diastaltic sympathicotonia through pressoreceptor with decreases of peripheral arterial resistance induces the increases of heart rate, and prevents blood pressure decreases. 20) However, there have been reports [21][22][23][24][25][26][27][28] that nifedipine signiˆcantly reduced the blood pressure by oral and sublingual administration and that the serum nifedipine concentration was correlated with the antihypertensive eŠect in normal individuals. In our study, also, the serum concentration was correlated with blood pressure, especially DBP, by each administration method.…”

Oral absorption profile of nitrendipine in healthy subjects: a kinetic and dynamic study.

“…The rate of increase of the nitrendipine plasma concentration, calculated as Cmax/tmax for the Osmet (0.69 ± 0.42 ng ml-1 h) was much lower and less variable than for the tablet (6.4 + 12.5 ng ml-1 h). This low rate of rise of the plasma concentration may enhance the efficacy and reduce side-effects of nitrendipine, as has been shown for nifedipine (Kleinbloesem et al, 1987). With the Osmet, the plasma concentation of nitrendipine remained above 50% of Cmax for 10.7 ± 3.2 h, whereas with the tablet this was only 2.3 ± 1.3 h. The controlled-release character of the Osmets is also reflected in the MAT of 8.4 ± 1.3 h compared with 3.7 ± 2.7 h for the tablet.…”

“…It has also been shown that the reflex tachycardia caused by intravenous nifedipine is determined principally by a rapid rate of increase of the plasma concentration rather than by the absolute height of the plasma concentration (Kleinbloesem et al, 1987). In fact, the blood pressure lowering effect could be dissociated from its accompanying reflex tachycardia by choosing a low rate of increase of the nifedipine plasma concentration (Kleinbloesem et al, 1987). The same principle may apply to other vasodilating agents, including nitrendipine, and therefore in the present study the kinetic and haemodynamic effect profile of this drug was investigated when given by a tablet formulation and by an osmotic pumping device from which nitrendipine is released at zero-order rate for 13 h. Such a device has been used in previous studies both orally and rectally in man (Davis, 1983;Davis et al, 1984;de Leede et al, 1982de Leede et al, , 1984Kleinbloesem etal., 1984a) and its usefulness as an experimental tool in clinical pharmacology has been reviewed Urquhart, 1985).…”

Calcium Antagonists in Clinical Practice: Focus on Metabolic and Vascular Effects

“…Вторая подгруппа -увеличивающие ча-стоту пульса антагонисты кальция, или дигидропири-дины. У этих препаратов преобладает способность вы-зывать дилатацию периферических артерий, в резуль-тате чего рефлекторно повышается тонус СНС и увели-чивается ЧСС [23]. В связи с этим, как свидетельствуют результаты многочисленных исследований, наблю-даются различия в эффективности дигидропиридино-вых и недигидропиридиновых АК в разных клинических ситуациях.…”