Nathaniel Winer

Kinetics and absolute bioavailability of atenolol

Twelve healthy volunteers received four single doses of atenolol (25‐, 25‐, and 100‐mg oral solutions and a 50‐mg intravenous infusion), each dose separated by at least one week. Blood and urine assayed for atenolol by a high pressure liquid chromatography (HPLC) method. Kinetic analysis of the intravenous data indicates a three‐compartment model with elimination from the central compartment. The mean ( ± SD) terminal elimination half‐life is 6.06 ± 2.02 hr, the mean volume of the central compartment is 0.173 L/kg, and 94.1 ± 8.0% of the intravenous dose is excreted in the urine. The mean value of the plasma clearance is 10.7 ± 1.27 L/hr and of the renal plasma clearance, 10.4 ± 1.14 L/hr. The mean absolute bioavailability for the 25‐, 25‐, and 100‐mg oral doses is 0.52 ± 0.18, 0.54 ± 0.12, and 0.58 ± 0.16, respectively. The maximum plasma concentration varies as a linear function of dose. Time to mean maximum plasma concentration (3.0 hr) and the time for half of the bioavailable dose to be absorbed (2.0 hr) do not differ significantly with dose. The mean renal plasma clearance after oral doses (9.49 ± 1.6 L/hr) is in the same range as renal clearance after intravenous doses.

Pharmacokinetics of oxprenolol in normal subjects.

The effect of oxprenolol administered intravenously (10 and 20 mg) and orally (20, 40, 80, and 160 mg) on plasma concentrations of the drug, resting heart rate, exercise‐induced tachycardia, and arterial blood pressure was assessed as a function of time in 6 healthy subjects. The pharmacokinetics of oxprenolol following intravenous administration are best described as 2‐compartnent open model with dose‐dependent parameters. The mean (±SD) plasma ha(f‐life for oral doses is 1.94 ± 0.37 and for intravenous doses is 2.31 ± 0.64 hr. After oral administration, peak plasma concentrations are reached within 30 to 90 min, and the area under the plasma concentration‐time curve varies linearly with the dose. Comparison of oral and intravenous data reveals the variation in bioavailabilty Qf orally administered oxprenolol to range from 19% to 74%. Unlike propranolol, oxprenolol does not show a saturable “first‐pass” elimination effect. Blockade of β‐receptors occurs at plasma levels in excess of 60 ng/ml as evidenced by significant reductions in resting heart rate and exercise‐induced tachycardia. Higher plasma concentrations of oxprenolol are required to lower blood pressure compared to those necessary to slow heart rate. These data suggest significant pharmacokinetic d(tferences between oxprenolol and other β‐adrenergic receptor allfagonists.

Effect of cold pressor stimulation on plasma norepinephrine, dopamine-β-hydroxylase, and renin activity

Abstract Changes in plasma levels of norepinephrine, dopamine-β-hydroxylase (DβH), and renin activity were observed in nine healthy volunteers during cold pressor stimulation. Increases in mean arterial blood pressure and heart rate during cold stimulation were accompanied by a sharp rise in plasma norepinephrine, while plasma DβH and renin activity showed little or no change. The results indicate that plasma norepinephrine accurately reflects acute activation of the sympathetic nervous system in contrast to plasma DβH and renin activity.

Evaluation of isradipine (PN 200‐110) in mild to moderate hypertension

The efficacy and safety of isradipine (PN 200‐110), a new dihydropyridine calcium antagonist, was evaluated in 87 hypertensive patients in a placebo‐controlled, double‐blind, randomized multicenter trial. After a 3‐week single‐blind washout phase, isradipine (or matching placebo) was administered for 4 weeks, beginning at 2.5 mg b.i.d. with increments of 2.5 mg b.i.d. at weekly intervals if supine diastolic blood pressure remained ≥90 mm Hg. At the end of 1 week average supine blood pressure in the isradipine group (n = 45) fell from a baseline of 156 ± 13/104 ± 4 mm Hg to 146 ± 14/97 ± 7 mm Hg. By week 4 blood pressure was reduced by 19/14 mm Hg compared with 4/5 mm Hg in the placebo group (P < 0.001 between groups). Supine and standing pulse rates were slightly increased initially with isradipine therapy but returned to baseline with increasing isradipine doses. Blood pressure responses at week 4 were good or excellent (supine diastolic ≤90 mm Hg or ≥10 mm Hg decrease from baseline) in 87% of isradipine‐treated patients and in 26% of placebo‐treated patients. Headache, edema, abdominal discomfort, and constipation occurred slightly more frequently in isradipine‐treated patients than in placebo‐treated control subjects. The results indicate that isradipine, administered as monotherapy in doses of 2.5 to 10 mg b.i.d., is safe and effective in patients with mild to moderate essential hypertension.

Effects of atenolol on blood pressure, heart rate, renin, and norepinephrine during exercise.

A single oral 100‐mg dose of atenolol was given to 12 healthy subjects to evaluate the dynamic effects of the drug. Plasma atenolol, blood pressure, and heart rate were determined prior to dosing and during the subsequent 24 hr. After graded treadmill exercise (Bruce Stages 1 to 4) before and at 4, 8, and 24 hr after dosing, heart rate, blood pressure, plasma renin activity, and plasma norepinephrine at each 3‐min stage of exercise were measured. Mean (±SEM) plasma atenolol was 0 before dosing and 750 ± 66. 399 ± 34, and 51 ± 6 ng/ml at 4, 8, and 24 hr after dosing. Resting heart rate and blood pressure fell after atenolol. Systolic blood pressure at rest correlated inversely with plasma atenolol concentration and with the amount of drug calculated to be in the central compartment. Before dosing, heart rate, systolic blood pressure, plasma renin activity, and plasma norepinephrine increased progressively with each successive exercise stage. At 4 hr after dosing, exercise heart rate, systolic blood pressure, and plasma renin decreased, and plasma norepinephrine increased maximally. Smaller but significant changes in exercise heart rate, systolic blood pressure, and renin were present at 8 and 24 hr. Diastolic blood pressure during exercise was unchanged at 4 hr but was significantly reduced at 8 and 24 hr. During exercise the logarithm of the plasma atenolol concentration correlated positively with diastolic blood pressure and plasma norepinephrine and negatively with systolic blood pressure. The results demonstrate that dynamic effects of a single dose of atenolol closely parallel plasma drug concentrations and persist for at least one day. That atenolol does not stimulate resting heart rate suggests that it exerts little or no agonist effect. That atenolol does not lower exercise diastolic blood pressure at peak drug concentration as well as the correlation of diastolic blood pressure with plasma atenolol suggests that it exerts little peripheral vascular β2‐antagonist activity.

Placebo-controlled trial of once-a-day isradipine monotherapy in mild to moderately severe hypertension.

The efficacy and safety of once‐daily dosing of isradipine, a new calcium antagonist vasodilator, was evaluated in a multicenter, placebo‐controlled trial in hypertensive patients who had supine diastolic blood pressure (SDBP) 100–119 mm Hg. After a 3‐week single‐blind placebo washout patients randomly received either isradipine, 5 mg once daily, or a matching placebo; if SDBP remained ≥95 mm Hg or ≤10 mm Hg below baseline at four weekly clinic visits, isradipine was increased at weekly intervals by 5 mg once daily up to 20 mg and maintained during weeks 5 and 6. At week 6 mean supine blood pressure 24 hours after dosing had declined from 163 ± 20/105 ± 5 (N = 78) to 146 ± 17/92 ± 7 mm Hg (N = 60) on isradipine, 14.5 mg once daily, and from 163 ± 20/105 ± 6 (N = 85) to 157 ± 18/99 ± 10 mm Hg (N = 64) on placebo (P < .001 between groups). Standing blood pressure decreased from 159 ± 20/104 ± 8 to 144 ± 18/93 ± 11 mm Hg with isradipine and from 160 ± 22/105 ± 9 to 154 ± 19/101 ± 11 mm Hg with placebo (P < .001 between groups) without signs or symptoms of postural hypotension. A SDBP ≤ 90 mm Hg or a ≥ 10 mm Hg fall below baseline was achieved in 41 of 78 isradipine‐treated (53%) and 18 of 85 placebo‐treated subjects (21%). Four isradipine‐treated and 11 placebo‐treated patients were discontinued because of inadequate blood pressure control. Adverse effects in patients receiving isradipine and placebo included headaches (34.5% vs. 17.4%), weakness (7.1% vs. 0%), and palpitations (8.3% vs. 1.2%). Thus, isradipine, 5–20 mg once daily is safe and effective in lowering blood pressure over 24 hours in about one‐half of patients with mild to moderately severe hypertension.

Effects of pindolol and methyldopa on blood pressure and plasma norepinephrine.

Thirty patients with essential hypertension (supine diastolic blood pressure 100 to 115 mm Hg) were treated in a randomized, double-blind study with either pindolol (mean dose 28 +/- 5 mg twice a day) or methyldopa (673 +/- 158 mg three times a day) for 12 weeks after a 3-week, single-blind placebo period. In 17 pindolol-treated patients mean supine blood pressure was 163 +/- 3/106 +/- 1 during the placebo period and 155 +/- 3/99 +/- 2 mm Hg (p less than 0.01) during the high-dose period. In 13 patients treated with methyldopa mean supine blood pressure fell from 160 +/- 4/104 +/- 1 to 156 +/- 5/97 +/- 2 mm Hg. Mean standing heart rate was reduced during pindolol therapy from 84 +/- 2 to 79 +/- 2 bpm (p less than 0.05) but was unchanged during methyldopa treatment. Mean supine pretreatment plasma norepinephrine fell from 379 +/- 40 to 337 +/- 33 pg/ml in patients on pindolol therapy and from 448 +/- 76 to 223 +/- 39 pg/ml (p less than 0.02) in the methyldopa-treated group. Although norepinephrine generally decreased in pindolol responders and not in nonresponders, changes in supine diastolic blood pressure and supine plasma norepinephrine did not correlate. In contrast, norepinephrine declined consistently in methyldopa-treated patients regardless of the blood pressure response; changes in diastolic blood pressure and norepinephrine correlated (r = 0.59; p less than 0.05). The results suggest that suppression of sympathetic nervous system activity may play a role in the hypotensive effect of both pindolol and methyldopa.

Comparison of intravenous dilevalol with placebo in moderate hypertension

Dilevalol, an agent that combines nonselective β‐blocking and β2‐mediated vasodilating properties, was compared with placebo in 16 subjects with moderate hypertension in a double‐blind crossover study. Dilevalol or a placebo was administered intravenously in bolus injections of 25, 50, and 50 mg at 15‐minute intervals. Fifteen minutes after a cumulative dose of 125 mg, the blood pressure was lowered by 11/9 mm Hg, compared with 2/1 mm Hg after placebo (p < 0.01 between groups for systolic and diastolic blood pressure), an effect that persisted for at least 105 minutes. Standing systolic blood pressure was also lowered in dilevalol‐treated patients without orthostatic symptoms. No significant effects on heart rate were noted. Fifteen minutes after the last dose of dilevalol, plasma norepinephrine levels increased from a baseline of 200 ± 24 to 495 ± 44 pg/ml (p < 0.01), compared with a nonsignificant rise from 262 ± 21 to 306 ± 28 pg/ml with placebo vehicle. Dilevalol also increased α‐human atrial natriuretic factor by 5.4 pg/ml, compared with 0.5 pg/ml after placebo (p < 0.01 between groups). Plasma renin activity and plasma epinephrine, aldosterone, and cyclic guanosine monophosphate levels were unchanged by dilevalol. There were no significant adverse effects with dilevalol administration. Compared with placebo, dilevalol given intravenously appears to be safe and effective antihypertensive treatment.