Nifedipine Gastrointestinal Therapeutic System

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Citation
European Cardiology 2005;2005:1(1):1-6
DOI
http://dx.doi.org/10.15420/ecr.2005.1s
Introduction

Nifedipine, developed over 30 years ago, was the prototype dihydropyridine calcium channel blocker. It is available worldwide in various formulations for the therapeutic management of hypertension and angina pectoris. The first formulation available for clinical use contained the drug as a solution within a gelatine capsule.1 Following oral administration, peak plasma concentrations of nifedipine were attained within one to two hours and the elimination half-life was approximately two hours,1 resulting in the need to administer the drug every eight hours to maintain therapeutic concentrations. However, due to the rapid onset of action, short half-life and side effect profile, the need for pharmaceutical development was apparent.

This development initially resulted in the 'retardÔÇÖ formulation, which had a more extended duration of action. This tablet formulation contained nifedipine particles of differing surface area and the absorption rate was therefore determined by the dissolution rate of these particles. The resulting pharmacokinetics were characterised by peak plasma concentrations, which were attained within the first three to four hours after dosing, and the elimination half-life was approximately eight to 10 hours.2 Whilst the retard formulation was a significant advance over the original capsule formulation, it was still associated with a relatively rapid onset of action and often with profound falls in blood pressure with an associated reflex activation of the sympathetic nervous system. The most significant and unique development associated with nifedipine resulted in the Gastrointestinal Therapeutic System (GITS). This formulation consists of a two-layer core of nifedipine and osmotic polymer surrounded by a semi-permeable membrane. The membrane incorporates a precisely laser-drilled hole.3 When the tablet is swallowed, water is absorbed from the gastrointestinal (GI) tract through the semi-permeable membrane and the nifedipine-containing core forms a suspension, which is extruded through the laser-drilled hole at a constant rate by the expanding polymer core layer. The GITS formulation delivers nifedipine at a constant rate for approximately 18 to 22 hours and the resulting smooth and consistent plasma concentration profile is compatible with once-daily dosing.

This article largely focuses on the therapeutic benefits of the GITS formulation of nifedipine. However, it is important to appreciate that the distinctive pharmacology of the nifedipine molecule may well contribute to benefits beyond the well recognised antihypertensive and anti-ischaemic effects of the drug - these characteristics warrant discussion.

Pharmacological Characteristics of Nifedipine

Nifedipine selectively inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle cells, which interferes with the contractility process while producing no effect on serum calcium concentrations. At the cardiac level, nifedipine dilates the main coronary arteries in both normal and ischaemic regions. Furthermore, nifedipine is a powerful inhibitor of coronary artery spasm. Administration of nifedipine increases post-stenotic coronary blood flow, as well as myocardial oxygen delivery, while reducing total peripheral resistance and the requirement for oxygen. These properties account for the efficacy of nifedipine for chronic stable and vasospastic angina. The reduction of calcium influx in vascular smooth muscle cells causes arterial vasodilation and decreases peripheral vascular resistance. Nifedipine acts on both small and large arteries by increasing arterial compliance, resulting in a reduction of blood pressure.

Dihydropyridine calcium antagonists, and nifedipine in particular, appear to have anti-athreogenic properties mediated by their antioxidant properties and beneficial effects on both the vascular smooth muscle cells and the endothelium.4-6

It has been shown that nifedipine interferes with several of the disturbed mechanisms in endothelial dysfunction. The most dramatic effects of dihydropyridines have been observed on the release of nitric oxide from endothelial cells. The impaired vasodilation in hypertensive patients, patients with hypercholesterolaemia and patients with diabetes mellitus is rapidly restored after treatment with dihydropyridines - comparative analyses between different anti-hypertensive drugs have shown that nifedipine most potently enhances these effects.5,7 Other studies have shown that nifedipine has an effect on endothelial permeability and can reduce the increased flux of water and protein into the intima and the vessel wall. This protective effect diminishes intima oedema and reduces the growth and hypertrophy of vascular smooth muscle cells.8

The results of these experimental studies provide evidence of the cellular mechanisms of nifedipine in the pathogenesis of atherosclerosis and served as a basis for designing several clinical trials, which are discussed in this article.

Blood Pressure-lowering Effects of Nifedipine GITS

The anti-hypertensive and anti-anginal effects of nifedipine GITS have been well established for more than 15 years.

Nifedipine GITS has demonstrated a reduction of elevated blood pressure effectively in patients with mild to moderate hypertension in placebo-controlled and non-comparative clinical trials. Response rates were higher in elderly patients than in younger patients.9,10 No differences in blood pressure-lowering effects were observed with regards to gender, ethnic origin, body weight, and presence of diabetes.

Nifedipine GITS is also effective in patients with severe hypertension. In a number of comparative trials with nifedipine GITS, compared with other drug classes, investigators have shown equal or superior anti-hypertensive efficacy of nifedipine GITS. These studies included calcium channel blockers (verapamil, diltiazem and felodipine), beta-blockers (atenolol, propranolol), and angiotensin-converting enzyme (ACE) inhibitors (enalapril and lisinopril).9,10 In comparison with co-amilozide (hydrochlorothiazide/amiloride), nifedipine GITS was demonstrated to be the equivalent in effectively lowering 24-hour blood pressure.9

Following the development of nifedipine GITS, studies demonstrated that patients could be switched from alternative formulations of nifedipine with comparable or improved efficacy, with a resulting improvement in the side effects profile.11 Subsequent studies suggested that nifedipine GITS had equivalent efficacy to diltiazem and atenolol in increasing exercise tolerance in chronic stable angina patients.12-14 Studies also suggested that the efficacy and tolerability of nifedipine GITS was superior to long-acting nitrates as second-line therapy to beta-blockade in the treatment of chronic stable angina15 and was particularly effective in patients with chronic stable angina inadequately controlled on beta-blockers alone.16,17 Nifedipine GITS has also been shown to have a sustained effect - a single daily dose was effective over 24 hours regardless of whether it was administered in the morning or evening.16

In addition to being efficacious and safe, nifedipine GITS is apparently able to maintain quality of life in patients with mild to moderate hypertension.9

Regression of Left Ventricular Hypertrophy and Activation of the Sympathetic Nervous System

There is a volume of evidence that left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular events18 and that regression of LVH improves prognosis.19 Studies of rapid, short-acting dihydropyridine calcium antagonists performed in the 1980s suggested that these agents were less effective than ACE inhibitors in decreasing left ventricular mass.20 A more recent meta-analysis comparing long-acting dihydropyridine calcium antagonists with other first-line anti-hypertensive agents has suggested that ACE inhibitors and dihydropyridines are equivalent in their ability to regress LVH.21 This is supported by studies directly comparing nifedipine GITS with other anti-hypertensives, which have shown a favourable effect of nifedipine GITS in regression of LVH.22,23 Furthermore, a recent direct comparison of enalapril, nifedipine GITS and felodipine extended release (ER) demonstrated equivalent efficacy between enalapril and nifedipine GITS with regard to LV mass regression whereas felodipine ER was less effective.24

The differential benefits (including regression of LVH) of long-acting dihydropyridine calcium antagonists compared with short-acting agents are partly associated with reflex activation of the sympathetic nervous system. Studies with both acute and long-term therapy with nifedipine GITS have elicited little or no clinical evidence of sympathetic activation based on both heart rate responses and circulating catecholamines.25

Evaluation of Nifedipine and Cerivastatin on Recovery of Endothelial Function (Encore I and Encore II)

The Evaluation of Nifedipine and Cerivastatin on Recovery of Coronary Endothelial Function (ENCORE I) and ENCORE II studies investigated changes in endothelial function as assessed by intracoronary infusion of acetylcholine,26,27 while ENCORE II also sought to investigate atherosclerotic vascular changes and their relation to endothelial dysfunction. The objectives of the studies were to determine the effects of a six-month treatment with nifedipine GITS (compared with cerivastatin and the combination nifedipine GITS/cerivastatin) on endothelium-dependent coronary vasomotion, to provide insight in atherosclerotic vascular changes, and to relate changes in endothelial function with those seen in the atherosclerotic process as assessed by quantitative coronary angiography. In ENCORE I, six monthsÔÇÖ treatment with nifedipine GITS significantly improved coronary endothelial function in the most constricted segment. The combination of nifedipine and cerivastatin tended to improve endothelial function; however, this only reached significance in an analysis of all coronary segments.26 It is important to appreciate that the assessment of endothelial function was performed 48 hours after drug withdrawal - therefore any beneficial effect reflects the long-term effects of the drugs and not the local effect of circulating drug concentrations, which are essentially undetectable at this time.

The conduct of the ENCORE II trial was compromised by the worldwide withdrawal of cerivastatin. Ultimately, 226 patients with stable angina were randomised to either placebo or nifedipine GITS. The study investigated the long-term (18 to 24 months) effects on the coronary endothelial function assessed by acetylcholine testing with quantitative coronary angiography, and atherosclerotic progression assessed by intravascular ultrasound (IVUS).27 Nifedipine GITS had a statistically significant beneficial effect on coronary vasomotion compared with placebo and the reduction in coronary vasoconstriction to acetylcholine was more pronounced after two years than after six months. Although plaque size as assessed by IVUS was not significantly affected by nifedipine there was a trend toward a beneficial effect of nifedipine on atheroma burden.

The results obtained in these two studies confirmed the benefits of nifedipine GITS in improving endothelial function and the potential to slow the atherosclerotic process.

Outcome Trials with Nifedipine GITS

Prior to the completion of the Intervention as a Goal in Hypertension Treatment (INSIGHT) study, the efficacy regarding morbidity and mortality of antihypertensive drugs other than diuretics and beta-blockers had not been established. The primary objective of INSIGHT was the comparison of cardiovascular and cerebrovascular morbidity and mortality in high-risk hypertensive patients treated with either with nifedipine GITS (30mg or 60mg), or with the diuretic combination co-amilozide (amiloride/ hydrochlorothiazide 2.5/25mg or 5/50mg).28 The primary study outcome was a composite end-point defined as stroke, intra-cerebral haemorrhage, subarachnoid haemorrhage, myocardial infarction (MI), heart failure (HF) and death of cerebrovascular or cardiovascular origin including sudden cardiac death. When compared with the gold standard of combined diuretic treatment by co-amilozide, nifedipine GITS was found to be equally as effective in preventing cardiovascular complications based on the primary end-point (see Figure 1A), and the groups did not differ for all-cause mortality, non-fatal end-points, or the combined primary and secondary end-points (see Figure 1B).28

Pre-specified sub-group analyses showed that the long-term protective effects of nifedipine GITS extended to hypertensive patients with diabetes mellitus,29 with previous MI,30 and patients with isolated systolic hypertension.31 New onset diabetes during the course of the study was lower in patients treated with nifedipine GITS than in those treated with co-amilozide.29

Two sub-studies of INSIGHT looked for a difference between nifedipine and diuretic therapy on the progression of atherosclerosis in high-risk hypertensive patients. In one study, double-helix computerised tomography (CT) was used as a non-invasive technique to detect, measure and compare calcifications in the coronary arteries.32 In the other study ultrasonography was used to measure intimamedia thickness (IMT) of the carotid arteries.33 The overall treatment effect of nifedipine demonstrated significant inhibition of coronary calcium progression over a three-year period (see Figure 2A).32 Co-amilozide was associated with a significant progression of IMT in the right common carotid artery far wall, whereas no progression was observed with nifedipine GITS treatment33 (see Figure 2B).

Both sub-study results give an indication that nifedipine GITS has a more favourable profile than co-amilozide in the patient population studied. Since there was no difference between the two treatments with regard to the extent of blood pressure-lowering, this confirms the earlier findings that the anti-atherosclerotic effect of nifedipine GITS is independent of its anti-hypertensive effect.

A coronary disease trial investigating outcome with nifedipine GITS (ACTION) was the largest ever randomised outcome trial of an anti-anginal drug in patients with symptomatic stable angina. Nifedipine GITS or placebo were added to existing anti-anginal therapy in a double-blind manner in 7,665 patients who were then followed-up for a mean period of 4.9 years.34 The primary end-point for efficacy (all-cause death, acute MI, refractory angina, new overt HF, debilitating stroke and peripheral revascularisation) and primary end-point for safety (all-cause death, acute MI and debilitating stroke) did not differ between the two treatment groups. With nifedipine GITS the rate of death and any cardiovascular event or procedure was significantly less than with placebo. The summarising results, including selected individual end-points, are presented in Figure 3A.

A sub-group analysis of the 52% of ACTION patients who were hypertensive at baseline35 demonstrated a significant benefit with nifedipine GITS for the primary end-point for efficacy, all cardiovascular events, death and any cardiovascular event or procedure and vascular events or revascularisation. The summarising results, including selected individual end-points, are presented in Figure 3B.

Overall, the ACTION trial conclusively demonstrates that nifedipine GITS can be used safely for the long-term treatment of coronary artery disease (CAD) patients because, in addition to providing symptomatic benefit, it prolongs cardiovascular event and procedure-free survival.

Conclusion

Nifedipine GITS has proven and well-established anti-hypertensive and anti-anginal effects. The nifedipine GITS formulation provides 24-hour efficacy on a once-daily basis, with the advantages of improving adherence to therapy and minimising the variability in the blood pressure-lowering and anti-ischaemic effects. The results of the INSIGHT and ACTION studies provide definitive evidence that nifedipine GITS has beneficial effects on morbidity and mortality. Moreover, these and other studies provide further evidence of nifedipineÔÇÖs anti-atherosclerotic effects. Ôûá

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