Corey B. Toal

Long-acting dihydropyridine calcium-channel blockers and sympathetic nervous system activity in hypertension: A literature review comparing amlodipine and nifedipine GITS

Abstract 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 pharmacokinetic 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.

Dietary sodium restriction, blood pressure and sympathetic activity in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were started at birth on sodium diets ranging from severely deficient (9 mumol) to a regular intake (101 mumol Na+/g food). Blood pressure and sympathetic activity were assessed at 6 and 16 weeks of age. At either age, SHR on 9 mumol Na+ failed to develop hypertension. Spontaneously hypertensive rats on 17 mumol Na+ exhibited significant blunting of the hypertension; SHR on 26 mumol showed a small amelioration. At 6 weeks, basal plasma noradrenaline was similar in SHR and WKY on 9 and 101 mumol Na+, whereas plasma adrenaline was increased in SHR at the lowest sodium level. At 16 weeks, both catecholamines were significantly increased in SHR on the 9 and 17 mumol sodium diet versus SHR on the control diet. Blood pressure responsiveness to noradrenaline was significantly decreased on 9 mumol Na+, but to a similar extent in both strains. In contrast, the blood pressure lowering effect of ganglionic blockade was markedly blunted in SHR on 9 mumol Na+ and to a lesser extent on 17 mumol Na+ (both for percentage and absolute decrease) and 26 mumol Na+ (only for absolute fall); however, this did not occur in WKY over the diet-range used. We conclude that a sodium-deficient diet from birth prevents/blunts the development of hypertension in SHR, at least partly by decreasing the pressor effect of the sympathetic nervous system.

Body fluid volumes during development of hypertension in the spontaneously hypertensive rat.

Body fluid volumes were measured in conscious spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats from four to 16 weeks of age. Plasma volume was elevated in four-week-old SHR, similar at five weeks, and decreased at all other ages compared with WKY controls. Blood volume showed a similar pattern. Extracellular fluid volume was found not to be different between the two strains in age-matched animals, except at four and five weeks where the SHR exhibited lower values than the WKY. The plasma/interstitial fluid volume ratio was significantly elevated at four weeks, but decreased from six weeks on in SHR compared with WKY controls. Sodium space tended to be increased in young SHR (four to six weeks), but was similar at eight and 16 weeks for the two strains. These results indicate that: (1) intravascular volume expansion may be involved in the development of hypertension in SHR in the very early stages; (2) intravascular volume changes do not appear to be related to overall volume expansion or contraction.

Dietary sodium restriction and the renin-angiotensin system in young spontaneously hypertensive rats.

Severe dietary sodium restriction initiated early in life is required to prevent development of hypertension in spontaneously hypertensive rats (SHR). Moderate sodium restriction does not affect hypertension development. This relative insensitivity to sodium restriction may be related to compensatory increases in other pressor mechanisms, specifically the renin-angiotensin system. We evaluated this possibility by measuring plasma renin activity, the blood pressure response to the angiotensin converting enzyme inhibitor captopril as well as blood pressure responsiveness to exogenous angiotensin II in SHR and Wistar-Kyoto rats (WKY) raised from birth until 6 or 16 weeks on control (101 mumol Na+/g food), moderate (26 mumol/g) or two severe (17 or 9 mumol/g) sodium-restricted diets. Moderate sodium restriction did not affect development of hypertension, but also did not cause significant increases in PRA or the blood pressure response to captopril in SHR or WKY. In contrast, severe sodium restriction blunted or prevented the development of hypertension in SHR and was associated with (1) marked increases in plasma renin activity (2) increased maintenance of blood pressure by the renin-angiotensin system (as assessed by captopril), and (3) a marked decrease in the blood pressure response to angiotensin II. We conclude that the relative insensitivity of hypertension development in SHR to dietary sodium restriction does not relate to a compensatory increase in the activity of the renin-angiotensin system. The moderate sodium restriction employed (26 mumol/g) may rather represent the lower end of the normal range.

Blood pressure control in patients with mild to moderate essential hypertension switched from nifedipine gastrointestinal therapeutic system (GITS) 30 mg to nifedipine GITS 20 mg

BACKGROUND Nifedipine gastrointestinal therapeutic system (GITS) is a once-daily formulation of nifedipine that provides sustained plasma nifedipine concentrations throughout the 24-hour dosing interval. OBJECTIVE This study was undertaken to determine if adult patients with mild to moderate essential hypertension whose blood pressure had been controlled for > or = 3 months with nifedipine GITS 30 mg could be successfully switched to a 20-mg daily dose with continued antihypertensive efficacy. METHODS This was a randomized, double-blind, parallel-group study. Patients entered a 1-week run-in period during which they continued to receive their usual antihypertensive medication, including nifedipine GITS 30 mg. After baseline assessment, patients entered a 6-week treatment period during which they were randomly assigned to receive nifedipine GITS 30 or 20 mg. Men and women were eligible to participate if they were > or = 55 years of age, had received a diagnosis of mild to moderate essential hypertension (sitting diastolic blood pressure [DBP] 95-114 mm Hg), and had exhibited good blood pressure control (sitting DBP < or = 90 mm Hg) while taking nifedipine GITS 30 mg once daily for > or = 3 months. Systolic blood pressure (SBP), DBP, and heart rate were recorded at baseline and after 1, 3, and 6 weeks of treatment. Adverse events were reported by patients. The responder rate was defined as the percentage of patients whose sitting DBP was < 95 mm Hg at the final study assessment. Results were based on the intent-to-treat analyses, which included data for all patients who received > or = 1 dose and had 1 postbaseline blood pressure assessment. Statistical significance was set at P < 0.05. RESULTS Seventy-five patients entered the 1-week run-in period; 71 patients (94.7%) were randomized to treatment. Twenty-four patients received nifedipine GITS 30 mg for 43.0 +/- 3.3 days, and 47 patients received nifedipine GITS 20 mg for 42.5 +/- 6.7 days. Both groups exhibited a sustained decrease in blood pressure throughout the study; minor variations were not statistically significant. End-point SBP and DBP for the 30- and 20-mg groups were 135.5 +/- 9.8/81.7 +/- 5.4 mm Hg and 138.6 +/- 11.8/82.9 +/- 7.6 mm Hg, respectively. Changes from baseline in end-point SBP and DBP did not differ significantly between groups. At the end of treatment, goal DBP (< 95 mm Hg) was achieved by 24 of 24 patients (100%) receiving the 30-mg dose and 45 of 47 patients (95.7%) receiving the 20-mg dose. Blood pressure control (sitting DBP < 90 mm Hg) was achieved by 21 of 24 (87.5%) patients in the 30-mg group and 35 of 47 (74.5%) patients in the 20-mg group. The most commonly reported adverse event was headache; 2 patients discontinued the study because of adverse events. Overall, 9 of 24 patients (37.5%) in the 30-mg group and 14 of 47 patients (29.8%) in the 20-mg group experienced > or = 1 treatment-related adverse event. CONCLUSIONS Patients whose mild to moderate essential hypertension is controlled with nifedipine GITS 30 mg once daily may be able to switch to 20 mg once daily with continued antihypertensive efficacy. In addition to safety and economic advantages, such a switch may be a reasonable alternative in patients with lower body weight or as an adjunct to existing antihypertensive therapy.

V-011 ONCE DAILY NIFEDIPINE: THE FORMULATION DICTATES THE PHARMACO KINETIC CHARACTERISTICS AND THE THERAPEUTIC RESPONSES

Background Nifedipine has been available worldwide since the early 1980s as a treatment for hypertension and angina pectoris. However, over time, the drug formulation has undergone a number of modifications to improve the pharmacokinetic profile and achieve a once daily dosing régimen. Nifedipine in the GITS formulation is the most studied of the once daily formulations and it is registered in most major countries worldwide. Nifedipine GITS employs osmotic push pull technology but there is a wide range of alternative drug delivery systems including, for example, erosive tablet technology, hydrophilic matrix tablets, a monolithic enteric coated like tablet with an erosive polymer matrix, an eroding matrix and a monolayer matrix tablet. Results This presentation is derived from a comprehensive review of the published literature to date. Pharmacokinetic and bioequivalence studies have failed to show that any of the other formulations is consistently bioequivalent to nifedipine GITS. With respect to pharmacodynamics, limited data from comparative clinical studies show significant differences in favour of the nifedipine GITS formulation in terms of blood pressure control and activation of the sympathetic nervous system. For example, in the study by Brown and Toal (2007) when patients were switched from Nifedipine GITS to Coractennifedipine a rapid decline in blood pressure was noted accompanied by an increase in heart rate and plasma norepinephrine at the time of peak plasma drug concentration. Finally, nifedipine GITS is the only once daily formulation with clinical trial outcome evidence in both hypertension (INSIGHT) and angina pectoris (ACTION). Conclusions The evidence base confirms that Nifedipine GITS should be considered to be the “reference” formulation. Furthermore, for both pharmacokinetic and therapeutic reasons, the evidence indicates that patients should not be switched between once daily formulations of nifedipine.

C-001 EFFECTS OF LONG ACTING DIHYDROPYRIDINE CALCIUM CHANNEL BLOCKERS ON SYMPATHETIC ACTIVITY IN HYPERTENSION: A COMPARISON OF AMLODIPINE AND NIFEDIPINE GITS

Background Calcium channel blockers (CCBs) constitute a diverse group of compounds, with three principal subgroups and multiple variations in formulation. CCBs are often referred to as a single homogeneous class of drug and the clinical responses indiscriminately summarized. Even within the main subgroup, 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 GITS formulation are the most studied of the once daily CCBs and are registered in most major countries worldwide. Amlodipine has an inherently long pharmacokinetic 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. Methods This presentation is derived from a systematic review of the published literature in hypertensive patients to date. 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 1,500 articles were then screened to derive the relevant analysis. Results As markers of sympathetic nervous system activation, plasma norepinephrine, power spectral analysis, muscle sympathetic nerve activity and norepinephrine spillover studies were reviewed. Although direct comparisons of the two drugs in one study would present the ideal this was rarely reported. Durations of treatment with either drug ranged from 1 week to 52 weeks. Doses of amlodipine ranged from 2.5 to 10 mg once a day and 20 to 150 mg once a day for nifedipine GITS. Each drug lowered blood pressure in patients with small changes in heart rate (i.e. < 1 b/min). Plasma norepinephrine measurements were the most reported marker of sympathetic nervous system activity and showed a greater increase in patients treated with amlodipine than nifedipine GITS. Conclusions The evidence indicates that both these once daily dihydropyridine CCBs lower blood pressure effectively with minimal effects on heart rate. However, there are small differences between the drugs in the extent to which each activates the sympathetic nervous system: overall, the available evidence favours nifedipine GITS.