During dynamic exercise, increases in diastolic pressure are inhibited, while maximum achievable systolic pressure is usually reduced. Chronic therapy with diltiazem produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem reduces the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio.

Intravenous diltiazem hydrochloride in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of 300 mg of diltiazem hydrochloride in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degree AV block. Diltiazem associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Chronic oral administration of diltiazem hydrochloride to patients in doses of up to 540 mg/day has resulted in small increases in PR interval, and on occasion produces abnormal prolongation (see WARNINGS).

Hypertension. In a randomized, double-blind, parallel-group, dose-response study involving 478 patients with essential hypertension, evening doses of CARDIZEM LA 120, 240, 360, and 540 mg were compared to placebo and to 360 mg administered in the morning. The mean reductions in diastolic blood pressure by ABPM at roughly 24 hours after the morning (4 AM to 8AM) or evening (6 PM to 10 PM) administration (i.e., the time corresponding to expected trough serum concentrations) are shown in the table below:

Mean Change in Trough Diastolic Pressure by ABPM Evening Dosing Morning Dosing
120 mg 240 mg 360 mg 540 mg 360 mg
-2.0 -4.4 -4.4 -8.1 -6.4

A second randomized, double-blind, parallel-group, dose-response study (N=258) eva luated CARDIZEM LA following morning doses of placebo or 120, 180, 300, or 540 mg. Diastolic blood pressure measured by supine office cuff sphygmomanometer at trough (7 AM to 9 AM) decreased in an apparently linear manner over the dosage range studied. Group mean changes for placebo, 120 mg, 180 mg, 300 mg and 540 mg were -2.6, -1.9, -5.4, -6.1, and -8.6 mm Hg, respectively.

Whether the time of administration impacts the clinical benefits of antihypertensive treatment is not known.

Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects.

Angina. The effects of Cardizem LA on angina were eva luated in a randomized, double-blind, parallel-group, dose-response trial of 311 patients with chronic stable angina. Evening doses of 180, 360, and 420 mg were compared to placebo and to 360 mg administered in the morning. All doses of Cardizem LA administered at night increased exercise tolerance when compared with placebo after 21 hours. The mean effect, placebo-subtracted, was 20 to 28 seconds for all thr