Combined terazosin and verapamil therapy in essential hypertension. Hemodynamic and pharmacokinetic interactions.

alpha-Blockers and calcium antagonists are commonly used in the treatment of hypertension, but few data are available concerning first dose or steady state (SS) hemodynamic and pharmacokinetic effects of these drugs when they are used in combination therapy. To examine these interactions, we measured supine and standing blood pressure (BP), heart rate (HR), and cardiac index (CI) for 6 h in 24 hypertensive patients after 2 weeks of placebo, again after the first dose or 3 weeks of therapy (SS) with either 120 mg verapamil (V) twice a day, or 1 mg terazosin (T) titrated weekly to 5 mg daily, and finally when T was added to V (group VT) or V added to T (group TV), acutely and at SS. Changes in supine hemodynamics when T was added to V or when V was added to T were similar and included a further reduction in BP, a transient increase in HR, and little or no change in CI. Both groups experienced significant decreases in standing blood pressure, especially 0.5 to 2 h following initiation of combination therapy despite significant increases in standing HR and CI. Standing BP tended to be lower in group TV after the first dose, but minimum standing systolic BP was not significantly different between groups (group TV 97 mm Hg at 1 h; group VT 109 mm Hg at 1.5 h, P > .05). Four patients in group TV and two in group VT experienced symptomatic orthostatic hypotension with the first dose of double-agent treatment. Pharmacokinetic interactions, including an increase in the bioavailability of T when V was added, did not correlate with the degree of orthostasis. After 3 weeks of combined therapy, the orthostatic change in BP had attenuated and symptoms had improved in all patients. We conclude that T and V represent an effective combination for the treatment of essential hypertension, but that orthostasis may result when initiating combination therapy. The orthostasis seen in some patients appears to be due to the combined vasodilatory effects rather than negative ionotropic or chronotropic effects.

Analysis of adverse events in a dose titration study.

The authors have examined the analysis of adverse event data from an efficacy dose escalation trial. Unlike the analysis of efficacy data, the assumption that when a patient experiences an adverse event at a given dose, he or she will experience the same at a greater dosage level was not applicable in the analysis of adverse event data. Because the time effect is confounded with the dose effect in a dose escalation design, any assessment of a dose-effect relationship from such a scheme is found to be preliminary and suspect. For drugs that need to be dosed with a titration schedule, a time-dose-specific incidence of an adverse event provides more useful information than a dose-specific incidence. The pace of dose titration, which was found to be important in the manifestation of an adverse event, also needs to be specified. These aspects are illustrated with data from a specially designed trial. The entire study contained a placebo arm and three arms of an active drug randomized in a parallel comparative fashion. Within each of the three active drug arms, a forced titration scheme was used to raise the dose to different levels, which distinguished the three arms. With an efficacy dose titration design, the dose-response relationship for adverse events cannot be determined without incorporating a placebo arm and other arms with different maximum allowable doses. For drugs that need to be administered with a titration scheme, incidence of adverse events needs to be presented with the dosage, the time, and the pace of titration.

Terazosin: pharmacokinetics and the effect of age and dose on the incidence of adverse events.

Terazosin is a new, long-acting, selective, postsynaptic alpha 1-adrenergic receptor antagonist with a chemical structure similar to that of prazosin. In this article the pharmacokinetics of terazosin are reviewed, and the incidence of adverse events in a dose-response study and a meta-analysis of 20 placebo-controlled trials involving a total of 1814 patients is presented. Peak plasma concentrations of terazosin are achieved 1 to 2 hours after oral administration. The relatively long half-life of terazosin (12 hours) enables it to be administered in a once-a-day regimen. Dose and plasma levels of terazosin show a linear relationship. Terazosin is rapidly and completely absorbed after oral administration. The pharmacokinetics of terazosin are not significantly affected by food, age, hypertension, or renal impairment. Adverse events after the administration of terazosin are usually minor and not age related. The incidence of syncope after therapeutic dosages of terazosin is minimal. Terazosin's effectiveness, combined with its pharmacokinetics, safety profile, and potentially favorable lipid effect, makes it a highly appropriate choice for antihypertensive therapy.

Antihypertensive dose-response relationships: studies with the selective alpha 1-blocking agent terazosin.

Terazosin is a selective alpha 1-adrenergic-blocking agent indicated for the treatment of hypertension. The aim of this multicenter study, performed in 256 patients with mild to moderate essential hypertension, was to define the dosing characteristics of terazosin (in the range of 1 to 80 mg) administered once daily. Patients were randomly assigned to placebo or active treatment groups; each group received 3 months of treatment, which comprised three ascending doses of terazosin, each administered for a 1-month period. As determined by conventional office measurements of supine diastolic blood pressure and by automated ambulatory blood pressure monitoring, there was a clear antihypertensive dose-response relationship for terazosin in the range of 1 to 5 mg daily. Except for the 80 mg dose, none of the doses above 5 mg (10 to 40 mg) appeared to provide additional efficacy. Both the office measurements and the monitoring data indicated that the ratio of trough (effect at the end of the dosing interval) to peak (maximum effect during the dosing interval) was at least 50% or greater during treatment with the 5 mg dose. Thus the 5 mg dose appeared to provide meaningful clinical antihypertensive efficacy and to sustain its effects throughout the full 24-hour period.

The efficacy and safety of terazosin for the treatment of symptomatic BPH.

At least 16 clinical investigations have documented the effectiveness of alpha blockade for BPH. In the present review, four clinical studies evaluating the efficacy and safety of terazosin, a selective long-acting alpha 1 blocker, for symptomatic BPH are reviewed. The unique features of these clinical investigations are: the study designs established detailed inclusion and exclusion criteria, the outcome assessments were based upon quantitative outcome parameters, large cohorts of homogeneous patients were enrolled, and appropriate statistical methods were utilized. The dose of terazosin was titrated to maximal doses ranging between 5-20 mg. Only four of the 163 patients developed orthostatic hypotension. Overall, the peak and mean uroflow rates increased 50% and 46%, respectively (P less than 0.001). The cumulative improvement in the mean obstructive, irritative, and total symptom scores was 67%, 35%, and 54%, respectively (P less than 0.001). The present review of terazosin in males with symptomatic BPH supports the following conclusions: (1) the dose of terazosin can be safely titrated to 10 mg in normotensive and hypertensive patients with symptomatic BPH; (2) the adverse events associated with doses of terazosin up to 10 mg are relatively mild and reversible; and (3) the improvements in the outcome parameters (symptom scores and urinary flow rates) are clinically and statistically significant. Although the ultimate role of terazosin for symptomatic BPH will be determined by multi-center randomized placebo-controlled studies, the present review provides further evidence that selective alpha 1 blockers are effective and safe for the treatment of symptomatic BPH.

Efficacy of terazosin in the treatment of essential hypertension in blacks.

The antihypertensive effects of the selective alpha 1-adrenoceptor antagonist, terazosin, in black patients with uncomplicated, mild to moderate essential hypertension were examined retrospectively in seven randomized, double-blind, placebo-controlled trials conducted in the United States. Following 4 to 13 weeks of treatment with terazosin (2-40 mg, once daily), supine and standing systolic and diastolic blood pressures were decreased significantly from baseline, and these decreases were significantly greater than those observed in the placebo group (P less than 0.05). Blood pressure changes in the black and white patient subgroups were comparable. Terazosin was generally well tolerated with a low incidence of serious side effects. We conclude that terazosin is a safe and effective antihypertensive agent in black patients with essential hypertension.

Effects of terazosin on serum lipid levels in hypertensive blacks.

The effects of terazosin, a new, selective, alpha 1-adrenoceptor antagonist, on the serum lipid levels were examined in 103 black patients with uncomplicated, mild to moderate essential hypertension in six randomized, double-blind, placebo-controlled trials conducted in the United States. Terazosin produced statistically significant (P less than 0.05) reductions in total serum cholesterol and triglyceride levels and a marginally significant (P = 0.080) reduction in the combined low-density lipoprotein (LDL-C) and very-low-density lipoprotein (VLDL-C) cholesterol fraction when compared with placebo. We conclude that terazosin, unlike thiazide diuretics, has a favourable effect on the serum lipid profiles of hypertensive blacks.

Esmolol (Brevibloc) to assess dynamic subpulmonary stenosis in a child after repair of complete transposition: a case report.

Esmolol (Brevibloc), a new, ultra-short acting, cardioselective beta-adrenergic blocking agent with half-life of 9.2 min following i.v. administration was given to a 4-year-old child with known dynamic and fixed sub-pulmonary stenosis post Senning repair for complete transposition of the great vessels. The left ventricular systolic pressure increased from 48 to 100 mmHg, heart rate showed an increase from 65 to 140 bpm, the right femoral arterial pressures decreased from 115/58 to 77/35 mmHg following an infusion of Isoprel. Infusion of esmolol partially relieved the dynamic sub-pulmonary stenosis. There were no adverse effects and esmolol was tolerated well by the child. Esmolol might thus play a role in the pediatric catheterization laboratory during investigational procedures, electrophysiological studies and in the control of rapid supraventricular tachycardia, especially in adolescents with WPW pre-excitation. Esmolol would also be beneficial in emergency treatment of epinephrine or isoproterenol overdosage.

Effect of intracoronary nicardipine on methylergonovine-induced coronary artery spasm in patients with variant angina.

In a double-blind, randomized placebo controlled study, the effect of intracoronary (IC) nicardipine (0.4 mg) on methylergonovine (0.4 mg) induced coronary artery spasm was assessed in 16 patients with a history of variant angina. Reversal of the methylergonovine-induced coronary artery spasm was observed in 100% of patients treated with IC nicardipine and 25% of patients treated with placebo (p less than 0.01). There were no significant differences between the nicardipine and placebo treatment groups with respect to heart rate, blood pressure, proportion of patients experiencing chest pain or ST segment changes. These findings demonstrate that IC nicardipine is safe and could be effective in the reversal of coronary artery spasm in patients with variant angina.

The effects of esmolol on the hemodynamics of acute theophylline toxicity.

The effects of esmolol, a beta 1-selective adrenergic receptor antagonist with a short duration of action, were studied in a canine model of the hemodynamics of theophylline toxicity. Animals were anesthetized, then given 50 mg/kg aminophylline IV over 20 minutes followed by a continuous infusion of 1.75 mg/kg/hr. Hemodynamic parameters, including heart rate, cardiac output, systemic blood pressure, pulmonary arterial pressure, and pulmonary artery wedge pressure, were measured every 30 minutes along with plasma catecholamines and theophylline levels. Marked tachycardia was seen in the intoxicated state, with heart rate rising from a baseline of 128.0 +/- 8.3 beats per minute (BPM) to 179.0 +/- 7.4 BPM (P = .012). This was associated with increases in catecholamines (baseline norepinephrine .04 +/- .04 ng/mL plasma rose to .42 +/- .21 ng/mL plasma after intoxication, P = .048). The average serum theophylline level during the experiment was 44.0 +/- 1.1 micrograms/mL serum. Esmolol then was given by IV infusion in these animals in doses of 25, 50, and 100 micrograms/kg/min. It returned the heart rate to the preintoxication baseline in a dose-related manner. Esmolol did not decrease cardiac output or lower blood pressure.

Esmolol-digoxin drug interaction.

An open-label baseline-controlled study was conducted in 11 healthy male subjects to study the possible interaction between the cardioselective, short-acting beta blocker esmolol and digoxin when administered concurrently under steady-state conditions. Steady-state concentration, elimination half-life, and the total body clearance of esmolol were not changed significantly (P greater than .05) by digoxin. Digoxin peak concentration and the time to reach the peak concentration were not affected by esmolol. However, the digoxin AUC during the six-hour esmolol infusion increased from 2.60 +/- 0.59 to 2.88 +/- 0.75 ng.hr/mL (P less than .05). There were no clinically significant changes in the heart rate and blood pressure during this drug interaction study. The PR intervals were similar between digoxin monotherapy and esmolol plus digoxin combined treatment. Although digoxin did not influence the kinetics of esmolol, the small increase seen in digoxin serum concentration during the combination therapy warrants that caution be exercised during concurrent administration of esmolol and digoxin to patients.

Safety and efficacy of flestolol, a new ultrashort-acting beta-adrenergic blocking agent, for supraventricular tachyarrhythmias.

Flestolol, a new ultrashort-acting (half-life 6.9 minutes) beta-blocking drug, was administered by intravenous infusion to 18 patients with new-onset atrial fibrillation or flutter and rapid ventricular response (120 beats/min or more for at least 30 minutes). Drug dose of flestolol was progressively increased until at least 1 of 3 endpoints was achieved: at least a 20% reduction in heart rate from baseline, heart rate 100 beats/min or less, or conversion to normal sinus rhythm. Flestolol was then administered as a maintenance infusion up to 24 hours. When flestolol was discontinued, patients were monitored for 1 additional hour. The mean ventricular response at baseline of 133 +/- 12 beats/min decreased to 103 +/- 20 beats/min at the end of flestolol titration (p less than 0.0001). Fourteen patients (78%) achieved defined endpoints. All 14 patients who continued to receive maintenance infusion had a sustained response. When flestolol was discontinued, ventricular response increased 33 +/- 23% within 60 minutes. The only adverse effect seen was hypotension in 2 patients. Flestolol is effective in slowing ventricular response in new-onset atrial fibrillation and flutter, maintains a therapeutic effect during continuous infusion and rapidly loses therapeutic effect when discontinued.

Cardiovascular and neuromuscular effects of esmolol during induction of anesthesia.

Sixteen subjects scheduled for surgical procedures under general anesthesia participated in an investigation of the effects of esmolol on the transient hypertension and tachycardia that was observed during endotracheal intubation and on the duration of succinylcholine-induced neuromuscular blockade. In eight subjects, infusion of esmolol was begun five minutes before induction of anesthesia and continued for 12 minutes after induction. In the remaining subjects, an equivalent volume of solvent (D5W) was infused for 12 minutes. Infusion of esmolol significantly attenuated the cardioacceleration observed during intubation without any significant effect on the pressor effects of the procedure. Esmolol delayed the recovery from succinylcholine-induced neuromuscular blockade by less than three minutes. The mechanism of this delay remains to be investigated, although such a delay does not have clinical significance. Esmolol-induced attenuation of the tachycardia seen during intubation may offer a protective effect on the myocardium, especially in elderly subjects and patients with coronary artery disease.

Clinical experience with esmolol, a short-acting beta-adrenergic blocker in cardiac arrhythmias and myocardial ischemia.

The efficacy and safety of esmolol, an ultra-short-acting beta-adrenergic blocking agent (elimination half-life, 9 min), was investigated in 358 patients with supraventricular tachyarrhythmias (SVTs) in three multicenter studies (placebo-controlled, propranolol-controlled, and open-label baseline-controlled) and in 19 patients with myocardial ischemia (acute myocardial infarction or unstable angina) in a single-center, open-label study. Esmolol was infused intravenously in doses ranging from 25 micrograms/kg/min to 300 micrograms/kg/min. In SVT studies, efficacy was judged by one or more of the following: a reduction of at least 15% to 20% from the average baseline heart rate, heart rate less than 100 beats/min, or conversion to normal sinus rhythm (NSR). Results revealed that esmolol was superior to placebo and equal to propranolol in controlling heart rate in SVT patients. Conversion to NSR was comparable in patients treated with esmolol (14%) and in those treated with propranolol (16%). The majority of patients achieved therapeutic response at esmolol doses of 200 micrograms/kg/min or less. Among esmolol-treated patients, recovery from beta blockade (i.e., heart rate approaching baseline levels) was achieved within ten minutes after discontinuation of infusion, indicating a brief duration of action of esmolol. In contrast, beta blockade persisted 4.5 hours after discontinuation of propranolol. In patients with myocardial ischemia, esmolol effectively reduced heart rate and blood pressure, thereby decreasing rate-pressure product. The most frequent adverse effect in patients treated with esmolol was hypotension. No clinically significant laboratory abnormalities were reported in esmolol-treated patients. Esmolol was well tolerated in patients infused for durations of up to 24 hours and in patients with conditions for which treatment with beta blockers is inappropriate. These results suggest that esmolol effectively and rapidly controls the heart rate in patients with SVT and in patients with acute myocardial ischemia. Furthermore, because of its short half-life, esmolol offers excellent benefits as compared with the currently available beta-adrenergic blockers in the treatment of critically ill patients. Esmolol was well tolerated by patients for whom beta blockers in general would be unsuitable.

Esmolol and the adrenergic response to perioperative stimuli.

Esmolol, an ultra-short-acting, cardioselective, beta-receptor blocking agent, has been developed for use in clinical conditions requiring controlled beta-receptor blockade. Its esterase-induced rapid metabolic inactivation and resulting brief pharmacologic effect provides control over the magnitude and duration of beta-receptor blockade. In placebo-controlled clinical trials, the effects of infusion of esmolol on the sympathetically mediated hemodynamic responses to stressful events during the perioperative period were evaluated in patients scheduled for surgical procedures under general anesthesia. In patients undergoing either noncardiac or cardiac surgical procedures, esmolol was effective in attenuating tachycardia that is normally seen during induction of anesthesia, laryngoscopy and endotracheal intubation, or sternotomy and aortic dissection by reducing the hemodynamic stress on the heart with negligible adverse effects. This much-desired cardioprotective effect of esmolol will be of special value to patients with coronary artery disease and patients with an unstable cardiovascular status who are undergoing major surgical procedures with general anesthesia.

Flestolol: an ultra-short-acting beta-adrenergic blocking agent.

Flestolol (ACC-9089) is a nonselective, competitive, ultra-short-acting beta-adrenergic blocking agent, without any intrinsic sympathomimetic activity. Flestolol is metabolized by plasma esterases and has an elimination half-life of approximately 6.5 minutes. This agent was well tolerated in healthy volunteers at doses up to 100 micrograms/kg/min. In long-term infusion studies, flestolol was well tolerated at the effective beta-blocking dose (5 micrograms/kg/min) for up to seven days. Flestolol blood concentrations increased linearly with increasing dose and good correlation exists between blood concentrations of flestolol and beta-adrenergic blockade. Flestolol produced a dose-dependent attenuation of isoproterenol-induced tachycardia. Electrophysiologic and hemodynamic effects of flestolol are similar to those of other beta blockers. In contrast with other beta blockers, flestolol-induced effects reverse rapidly (within 30 minutes) following discontinuation because of its short half-life. Flestolol effectively reduced heart rate in patients with supraventricular tachyarrhythmia. In patients with unstable angina, flestolol infusion was found to be safe and effective in controlling chest pain. It is concluded that flestolol is a potent, well-tolerated, ultra-short-acting beta-adrenergic blocking agent. Use of flestolol in the critical care setting is currently undergoing investigation.

Antiarrhythmic activity of esmolol (ASL-8052)--a novel ultra-short acting beta-adrenoreceptor blocking agent.

In a single-blind, placebo-controlled study, esmolol was administered intravenously to 12 patients with chronic atrial fibrillation. Esmolol produced a significant dose-dependent decrease in the ventricular rate without conversion to normal sinus rhythm in any of the patients. For most patients, a correlation was observed between the blood levels of esmolol and reductions in heart rate. There were no significant adverse effects. We conclude that esmolol is an effective and safe agent for the control of heart rate in patients with supraventricular tachycardia.

Comparison of the antiarrhythmic effects of acebutolol and propranolol in the treatment of ventricular arrhythmias.

This study was designed to assess the relative antiarrhythmic activity of fixed doses of 2 beta-adrenergic blocking agents, propranolol and acebutolol, in a prospective double-blind crossover trial. Twenty-one patients who had at least 30 premature ventricular contractions (PVCs) per hour while receiving placebo were entered into the study. Ten patients were randomized to initially receive propranolol, 40 mg every 8 hours, and 11 were assigned to receive acebutolol, 300 mg every 8 hours. After 6 weeks of treatment, patients were weaned off medication for 1 week and then placed on placebo for 1 week. Eighteen patients were available and eligible for crossover to the alternative regimen for an additional 6 weeks. All 21 patients completed courses with propranolol and 17 completed courses with acebutolol. The mean number of PVCs per hour during placebo, propranolol and acebutolol treatment were 267, 87 and 119, respectively. Using paired t test statistics on observation differences, both propranolol and acebutolol significantly reduced the number of PVCs per hour compared with placebo, whereas similar analysis revealed no significant difference in the antiarrhythmic effect. However, with the current sample size the power of the test is too low for the latter conclusion to be stated with confidence. Side effects were mild and infrequent, requiring discontinuation of acebutolol in 2 patients and discontinuation of propranolol in 1. Thus, acebutolol is a safe and effective antiarrhythmic agent and compares favorably with propranolol.