Degree Of Intrinsic Sympathomimetic Activity Research Articles

Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well

Beta-adrenergic receptor blockers (β-blockers) are an appropriate treatment for patients having systemic hypertension (HTN) who have concomitant ischemic heart disease (IHD), heart failure, obstructive cardiomyopathy, aortic dissection or certain cardiac arrhythmias. β-Blockers can be used in combination with other antiHTN drugs to achieve maximal blood pressure control. Labetalol can be used in HTN emergencies and urgencies. β-Blockers may be useful in HTN patients having a hyperkinetic circulation (palpitations, tachycardia, HTN, and anxiety), migraine headache, and essential tremor. β-Blockers are highly heterogeneous with respect to various pharmacologic properties: degree of intrinsic sympathomimetic activity, membrane stabilizing activity, β1 selectivity, α1-adrenergic blocking effects, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific properties may be important in the selection of a drug for clinical use. β-Blocker usage to reduce perioperative myocardial ischemia and cardiovascular (CV) complications may not benefit as many patients as was once hoped, and may actually cause harm in some individuals. Currently the best evidence supports perioperative β-blocker use in two patient groups: patients undergoing vascular surgery with known IHD or multiple risk factors for it, and for those patients already receiving β-blockers for known CV conditions.

β-Adrenergic Blockers

KEY POINTS AND PRACTICAL RECOMMENDATIONS: • β-Blockers are appropriate treatment for patients with hypertension and those who have concomitant ischemic heart disease, heart failure, obstructive cardiomyopathy, or certain arrhythmias. • β-Blockers can be used in combination with other antihypertensive drugs to achieve maximal blood pressure control. Labetalol can be used in hypertensive emergencies and urgencies. • β-Blockers may be useful in patients having hyperkinetic circulation (palpitations, tachycardia, hypertension, and anxiety), migraine headache, and essential tremor. • β-Blockers are highly heterogeneous with respect to various pharmacologic effects: degree of intrinsic sympathomimetic activity, membrane-stabilizing activity, β(1) selectivity, α(1) -adrenergic-blocking effect, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific effects may be important in the selection of a drug for clinical use. • β-Blocker usage to reduce perioperative ischemia and cardiovascular complications may not benefit as many patients as was once hoped and may actually cause harm in some individuals. Currently the best evidence supports β-blocker use in two patient groups: patients undergoing vascular surgery with known ischemic heart disease or multiple risk factors for it and for patients already receiving β-blockers for known cardiovascular conditions.

Potential benefit of combination therapy with diuretics and beta blockers having intrinsic sympathomimetic activity

When combining a beta blocker with a diuretic in patients with hypertension, consideration should be given to the potential advantages of intrinsic sympathomimetic activity (ISA). During long-term administration of a beta blocker without ISA, total peripheral resistance stabilizes at or slightly above the pretreatment level. Since cardiac output is decreased, blood pressure falls. Thus, beta blockers without ISA may exacerbate the underlying haemodynamic abnormality of long-standing hypertension, increased systemic resistance. In contrast, the reduction in pressure which occurs with a beta blocker possessing a high degree of ISA, such as pindolol, is associated with a reduction in total peripheral resistance and little change in cardiac output. Thiazide diuretics and most beta blockers without ISA also have an adverse impact on the blood lipid profile, potentially increasing cardiovascular risk. With the exception of oxprenolol, monotherapy with beta blockers which possess ISA have generally had no adverse blood lipid changes. Indeed, pindolol has been shown to increase HDL-cholesterol and to reduce the ratio of total cholesterol to HDL-cholesterol. Pindolol administered in combination with several diuretics has not increased the adverse lipid effects of these agents and, in some studies, evidence suggests that pindolol may counteract some or all of these changes. The clinical significance of these differences between beta blockers with and without ISA remains uncertain. Nevertheless, the potential haemodynamic and metabolic benefit of agents with ISA mandate that they receive careful consideration when selecting a beta blocker to administer with a diuretic.

Influence of beta blockade and intrinsic sympathomimetic activity on hemodynamics, inotropy and respiration at rest and during exercise

The degree of intrinsic Sympathomimetic activity (ISA) is reported to influence the effects of β blockade at rest, but the effects during exercise are not well documented. Heart rate, blood pressure and left ventricular (LV) function (as assessed by systolic time intervals) were measured at rest and during upright bicycle exercise as well as with flow-volume spirometry at rest in 13 healthy volunteers. The measurements were performed before and 4 and 24 hours after a single oral dose of pindolol (10 mg), nadolol (80 mg) and acebutolol (400 mg) in a double-blind, randomized, crossover manner. All drugs reduced heart rate, but nadolol had the most pronounced and longest bradycardic effect at rest. Diastolic blood pressure was only slightly influenced by the drugs, whereas systolic pressure was significantly lower compared with control values, especially during exercise (p < 0.001). Neither preejection period (PEP) nor LV ejection time (LVETc) was changed at rest after pindolol, but PEP increased and LVETc decreased significantly after nadolol (p < 0.05 for PEP and p < 0.01 for LVETc) and acebutolol (p < 0.05 for both). During exercise, PEP and LVET were significantly longer after all 3 drugs compared with control values. Only nadolol, which lacks ISA, significantly decreased expiratory flow values (p < 0.05). Thus, unlike the other β blockers, pindolol (with strong ISA) did not depress LV function at rest, while during exercise all 3 β blockers had equal adverse effects. The degree of ISA appears to be important in determining the hemodynamic effects of β-blocking drugs.

Immediate central hemodynamic effects of five different beta-adrenoceptor-blocking agents, acebutolol, atenolol, pindolol, practolol, and propranolol, in patients with ischemic heart disease

The hemodynamic effects of acebutolol were studied in six patients with ischemic heart disease. The changes in heart rate, cardiac output, and arterial blood pressure were determined after intravenous administration of six increasing doses of acebutolol to a cumulative dose of 0.64 mg/kg. After the sixth dose of acebutolol, cardiac output and heart rate were reduced 15% and 8%, respectively. Pulmonary artery pressure was increased by 4 mm Hg. Arterial blood pressure was not changed significantly. The effects of graded doses of acebutolol on heart rate and cardiac output were compared with earlier obtained results after atenolol (0.19 mg/kg), pindolol (0.025 mg/kg), practolol (0.64 mg/kg), and propranolol (0.19 mg/kg). The effects of increasing doses of acebutolol and practolol were very similar and significantly different from the effects of the other three drugs in spite having been administered at equipotent doses. The hemodynamic effects of acebutolol support the hypothesis that the hemodynamic response to beta-adrenoceptor antagonist drugs at rest is determined primarily by the degree of intrinsic sympathomimetic activity, whereas beta-1 selectivity does not modify the central hemodynamic response.

Basis for cardiovascular therapy with beta-blocking agents

Beta blockade is the cornerstone of the therapy for ischemic heart disease and is increasingly used as first-line therapy for hypertension. Three chief properties that distinguish among different beta blockers are cardioselectivity, intrinsic sympathomimetic activity (ISA) and pharmacokinetic differences. Cardioselectivity appears to confer some advantages, although there is a potential and serious danger in giving any beta blocker to patients with asthma, Heart failure or active peripheral disease. The degree of ISA in different beta blockers may vary. This property may diminish the degree of cardiac depression caused by beta blockade, influencing the response to exercise, but on the other hand, it may make the beta blocker less beneficial in minimizing the effects of myocardial ischemia. Beta blockers also differ in duration of action, vasodilating capacity and effect on renal blood flow. Several mechanisms may be involved in the antihypertensive effects of beta antagonists. In elderly hypertensive patients, beta blockade should be given cautiously, especially if combined with a diuretic, and pharmacokinetic differences in this age group must be considered.

Adrenergic beta receptor blockade: hemodynamic importance of intrinsic sympathomimetic activity at rest.

Dose-response curves for heart rate, cardiac output, arterial blood pressure, and pulmonary artery pressure were obtained in 37 patients with ischemic heart disease after intravenous administration of six increasing doses of propranolol, atenolol, practolol, pindolol, CPEP (1 -[2-cyanophenoxy]-3β-[3-phenylureido]-ethylamino-2-propanol), and BMMP (1-t-butylamino-3-[2-N-methylcarbamoyl-methoxyphenoxy]propan-2-ol-hydrochloride). The doses were equipotent, as indicated by reduction in exercise-induced tachycardia. The dose-response curves for cardiac output and heart rate can be divided into three groups according to the degree of intrinsic sympathomimetic activity. One group without intrinsic sympathomimetic activity included propranolol and atenolol, which reduced cardiac output (about 26% to 28%) and heart rate (about 15% to 17%). A second group with moderate intrinsic sympathomimetic activity, represented by practolol and BMMP, induced less reduction in cardiac output (about 12% to 17%) and heart rate (about 7% to 10%). A third group with pronounced intrinsic sympathomimetic activity, represented by pindolol and CPEP, did not reduce cardiac output and heart rate. Mean systemic blood pressure was essentially unchanged even after the largest dose of any of the drugs. Mean pulmonary artery pressure rose after atenolol, propranolol, and BMMP but not after pindolol, CPEP, and practolol. Atenolol, BMMP, and practolol are beta-1–selective drugs, it is concluded that the acute hemodynamic response to adrenergic beta receptor blocking drugs at rest is determined primarily by the degree of intrinsic sympathomimetic activity, whereas beta-1 selectivity did not modify the central hemodynamic responses to beta adrenoceptor blockade. Clinical Pharmacology and Therapeutics (1981) 29, 711–718; doi:10.1038/clpt.1981.100

The effects of pindolol and prazosin on hand blood flow in patients with cold extremities and on treatment with beta-blockers.

Hand blood flow and subjective sensitivity to cold were studied in nine hypertensive patients on treatment with beta-blockers. All patients complained of cold extremities. Neither hand blood flow nor sensitivity to cold changed after addition of prazosin, a well known vasodilator to the original beta-blocker. After changing to a beta-blocker with a high degree of intrinsic sympathomimetic activity (pindolol), hand blood flow increased and sensitivity to cold decreased in all patients, except one.

Immediate haemodynamic effects of propranolol, practolol, pindolol, atenolol and ICI 89,406 in healthy volunteers.

Changes in cardiac output, heart rate and arterial blood pressure were determined in 31 healthy volunteers after i. v. administration of equipotent doses of five different adrenergic betareceptor blocking drugs. Propranolol was given to seven subjects, atenolol to five, practolol to seven, pindolol to five, and (a new drug) ICI 89,406 to seven. Each drug was given in six logarithmically spaced doses. Propranolol is non-cardioselective and lacks intrinsic sympathomimetic activity. Atenolol, practolol, and ICI 89,406 are cardioselective. Practolol, pindolol, and ICI 89,406 have intrinsic sympathomimetic activity. Cardiac output was determined by impedance cardiography at supine rest. The dose-response curves for cardiac output and heart rate were of three different types: one obtained after administration of drugs without intrinsic activity, represented by propranolol and atenolol, both of which caused a maximal decrease in cardiac output of about 27%, and in heart rate of about 21%. A second type, obtained after drugs with moderate intrinsic sympathomimetic activity, represented by practolol, showed small but significant decreases in cardiac output of 12%, and in heart rate of 11 per cent. A third type, after drugs with marked intrinsic sympathomimetic activity, was represented by pindolol and ICI 89,406, which did not significantly reduce cardiac output or heart rate. The blood pressure was essentially unchanged in all subjects, even after the largest dose of any of the drugs. It was concluded that the degree of intrinsic sympathomimetic activity possessed by an adrenergic betareceptor blocking agent is responsible for acute changes in heart rate and cardiac output, and cardioselectivity is of no importance in this respect.