Nifedipine is a calcium ion influx inhibitor (calcium channel blocker or calcium ion antagonist).

The antianginal and antihypertensive actions of nifedipine are believed to be related to a specific cellular action of selectively inhibiting transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The contractile processes of these tissues are dependent upon the movement of extracellular calcium into the cells through specific ion channels. Nifedipine selectively inhibits the transmembrane influx of calcium through the slow channel without affecting, to any significant degree, the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within the muscle cells and an inhibition of the contractile processes. Nifedipine does not alter total serum calcium.

The specific mechanisms by which nifedipine relieves angina and reduces blood pressure have not been fully determined but are believed to be brought about largely by its vasodilatory action.

Nifedipine dilates the main coronary arteries and coronary arterioles both in normal and ischemic regions resulting in an increase in blood flow and hence in myocardial oxygen delivery.

Nifedipine by its vasodilatory action on peripheral arterioles, reduces the total peripheral vascular resistance. This reduces the workload of the heart and thus reduces myocardial energy consumption and oxygen requirements which probably accounts for the effectiveness of nifedipine in chronic stable angina.

The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilation and subsequent reduction in peripheral vascular resistance. The increased peripheral vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium.

The negative inotropic effect of nifedipine is usually not of major clinical significance because at therapeutic doses, nifedipine's vasodilatory property evokes a baroreceptor mediated reflex tachycardia which tends to counterbalance this negative inotropic effect. Continued administration of nifedipine to hypertensive patients has shown no significant increase in heart rate.

Although nifedipine causes a slight depression of sinoatrial node function and AV conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. In formal electrophysiologic studies, predominantly in patients with normal conduction systems, nifedipine has had no tendency to prolong AV conduction or sinus node recovery time, or to slow sinus rate.

The International Nifedipine GITS Study Intervention as a Goal in Hypertension Treatment trial called INSIGHT was a prospective double-blind trial with dynamic randomisation which enrolled mainly white hypertensive men and women. The primary endpoint was a composite of death from any cardiovascular or cerebrovascular cause, together with non-fatal stroke, myocardial infarction, and heart failure. The secondary endpoint included total mortality, death from a vascular cause, and non-fatal vascular events including transient ischemic attacks, angina (new or worsening) and renal failure. INSIGHT was designed to establish the superiority of Adalat XL over the diuretic combination co-amilozide (hydrochlorothiazide and amiloride). When the results of the Swedish Trial in Old Patients with Hypertension-2 study (STOP-2) became known and because these results suggested that calcium-channel blockade and diuretic treatment had similar efficacy in preventing complications, but before the patient code in INSIGHT was broken, a secondary, non-inferiority analysis was added.

INSIGHT randomized 6575 mild to moderate essential hypertensive or isolated systolic hypertensive patients, 55-80 years of age, with at least one other cardiovascular risk factor to nifedipine and co-amilozide. Patients were excluded if they had heart failure with low ejection fraction (< 40%), unstable angina, PTCA (Percutaneous Transluminal Coronary Angioplasty) or CABG (Coronary Artery Bypass Grafting) within 6 months prior to study start, or myocardial infarction or stroke in the 12 months prior to study start. Doses of each drug were titrated to achieve a target blood pressure of 140/90 mmHg (or drop of 20/10 mmHg) and if that target was not reached additional drugs could be added (atenolol and subsequently enalapril). On average patients were treated for 3.5 years. After placebo washout, the baseline blood pressure was 173/99 mmHg and decreased to 138/82 mmHg by the end of the trial in both groups. Heart rate was not different between the groups. At the end of the study 69 and 72% of patients on Adalat XL and hydrochlorothiazide/amiloride, respectively, were on monotherapy. All endpoints were assessed and adjudicated by the Critical Events Committee. The overall results of the study in Adalat XL show that Adalat XL was not inferior to the diuretic combination co-amilozide.