The transient increase in norepinephrine levels observed with NPA and the sustained increases in norepinephrine levels observed after chronic treatment with amlodipine suggest that sympathetic activation occurs with those two drugs. The lack of increase in norepinephrine levels after administration of NGITS suggests that this formulation does not activate the sympathetic system. The lowering of epinephrine levels after administrations of NGITS and amlodipine suggests that inhibition of release of epinephrine by the adrenal medulla occurs with longer-acting dihydropyridine formulations.

Calcium-channel blockers (CCBs) constitute a diverse group of compounds but are often referred to as a single homogeneous class of drug and the clinical responses indiscriminately summarized. Even within the dihydropyridine subgroup, there are significant differences in formulations, pharmacokinetics, durations of action and their effects on blood pressure, heart rate, end organs and the sympathetic nervous system. Amlodipine and nifedipine in the gastrointestinal therapeutic system (GITS) formulation are the most studied of the once-daily CCBs. Amlodipine has an inherently long pharma-cokinetic half-life, whereas, in contrast, nifedipine has an inherently short half-life but in the GITS formulation the sophisticated delivery system allows for once-daily dosing. This article is derived from a systematic review of the published literature in hypertensive patients. The following search terms in three main databases (MEDLINE, Embase, Science Citation Index) from 1990 to 2011 were utilized: amlodipine, nifedipine, sympathetic nervous system, sympathetic response, sympathetic nerve activity, noradrenaline, norepinephrine and heart rate. More than 1500 articles were then screened to derive the relevant analysis. As markers of sympathetic nervous system activation, studies of plasma norepinephrine concentrations, power spectral analysis, muscle sympathetic nerve activity and norepinephrine spillover were reviewed. Overall, each drug lowered blood pressure in hypertensive patients in association with only small changes in heart rate (i.e. < 1 beat/min). Plasma norepinephrine concentrations, as the most widely reported marker of sympathetic nervous system activity, showed greater increases in patients treated with amlodipine than with nifedipine GITS. The evidence indicates that both these once-daily dihydropyridine CCBs lower blood pressure effectively with minimal effects on heart rate. There are small differences between the drugs in the extent to which each activates the sympathetic nervous system with an overall non-significant trend in favour of nifedipine GITS.

This was an open-label, randomized, 3-way crossover study that compared in 25 healthy male subjects, the pharmacokinetics of a single 60-mg dose of nifedipine GITS tablet versus (1) 20-mg doses of nifedipine prolonged action tablets given q12h for a total of two doses and (2) 2 x 10 mg doses of nifedipine capsules given q8h for a total of three doses. Following capsule administration, there was a rapid rise in plasma concentration of drug achieving a peak concentration of 196(35) ng/mL (mean and coefficient of variation) within 0.7 (105) hours and an AUC(infinity) of 973(39) ng.hr/mL. After nifedipine PA there was also a rapid rise in plasma concentration of drug achieving a Cmax of 85.5 (36) ng/mL with a tmax of 1.7(58) hours and an AUC(infinity) of 879(46) ng.hr/mL. For the nifedipine GITS formulation, there was a lag in the plasma concentration time profile for approximately 2 to 3 hours, then it rose gradually achieving a Cmax of of 686(54) 30.5(63) ng/mL with a tmax of 15.0(50) hours and an AUC(infinity) ng.hr/mL. The AUC(infinity) and Cmax were significantly (P = 0.0001) greater in the capsule and PA formulations than for the GITS; however, the tmax for the GITS formulation was significantly (P = 0.001) longer than for the other formulations. This study suggests marked formulation-dependent pharmacokinetics, which may have important clinical implications.

Blood pressure and body weight of conscious spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were measured up to 16 wk of age in animals started at birth on five different sodium-containing diets. SHR on 9 mumol sodium/g food did not show a rise in basal blood pressure; however, when stressed the SHR still exhibited slightly higher blood pressures than WKY. In SHR on 17 mumol sodium/g food the development of hypertension was blunted compared with that of control (101 mumol/g) diet animals. SHR on 26 or 44 mumol sodium/g diet exhibited a development of hypertension similar to that of SHR on control diet. The 26 mumol/g, 44 mumol/g, and control sodium diet groups, regardless of strain, had similar growth rates. By contrast, on 17 mumol sodium/g food both SHR and WKY showed a substantially reduced growth rate, and all animals on 9 mumol sodium/g diet were severely retarded in growth. The results indicate that dietary sodium restriction can ameliorate the development of hypertension in SHR, but only when the sodium levels are so low as to affect overall growth.

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Pharmacokinetic and pharmacodynamics studies are usually carried out separately with theoretical linking or interpretations.• The pharmacokinetics of short-vs.long-acting formulations of nifedipine is well known, but the pharmacokinetics of different once-a-day formulations of nifedipine is generally not well known by the practising physician. WHAT THIS STUDY ADDS• This study provides practical patient-based information linking pharmacokinetics to pharmacodynamics in one of the target populations of patients, those with hypertension, who might receive the two different drugs. AIMSThe haemodynamic responses to nifedipine vary between short-and long-acting formulations. However, the latter have not been compared despite marked differences in their constitution. Our 1-month randomized, crossover study was designed to compare the 30-mg osmotic, constant-release nifedipine gastrointestinal therapeutic system (N-GITS) with an encapsulated mini-tablet Coracten XL. METHODSForty-four hypertensive patients aged 63 Ϯ 7 years were studied. The formulation was changed on day 15 and (for a single dose) day 30. At days 0, 14, 15, 29 and 30, patients were monitored for 6 h after dosing, during which blood pressure (BP), heart rate (HR) and plasma levels of norepinephrine (NE) and nifedipine were measured. The primary outcome was the difference in plasma NE between formulations at the time of peak nifedipine level. RESULTSSystolic BP decreased rapidly after the first dose of Coracten, achieving nadir at 5 h. HR rose by 1.2 Ϯ 8.8 beats min -1. After N-GITS HR fell by 2.4 Ϯ 7.7 beats min -1 (P = 0.159). Plasma NE was higher in the Coracten-(480 Ϯ 38.3 pg ml -1 ) than N-GITS-treated patients (343 Ϯ 75.0 pg ml -1 ) at the time of peak nifedipine concentrations (4 and 5 h, respectively) and their change from baseline was significantly (P = 0.0046) different. A similar difference between the drugs was seen again at days 15 and 30, at 5 h after switching formulations. CONCLUSIONSThis study suggests that two different formulations of once-daily nifedipine result in different BP and plasma NE responses, and that switching between formulations causes opposite effects upon the sympathetic nervous response to falling BP.

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