CURRENT DRUG THERAPY * DONALD G. VIDT, MD, AND ALAN BAKST, PharmD, EDITORS The hemodynamic effects of adrenergic blocking agents PROFESSOR PER LUND-JOHANSEN • The various antihypertensive agents reduce blood pressure by different mechanisms. Alpha-1 receptor blockers reduce vascular resistance and maintain cardiac output. Chronic treatment with beta blockers without intrinsic sympathomimetic activity produces a fall in blood pressure which is as- sociated with a fall in cardiac index and heart rate. Beta blockers with strong intrinsic sym- pathomimetic activity showed reduced heart rate during exercise. Labetalol reduces cardiac output and peripheral vascular resistance with little or no reduction in peripheral blood flow. Alpha-1 blockers are suitable for patients with active life-styles, with peripheral vascular disorders, or with high blood- cholesterol levels. Beta blockers are useful in patients who have tachycardia, palpitation problems, or angina pectoris, or who have survived a heart attack. They should not be used in patients with bronchial asthma, reduced peripheral blood flow, or heart failure. Labetalol reduces blood pressure in a somewhat larger fraction of patients than the pure alpha- or beta-blocking agents. It is hoped that its long-term results will include regression of cardiovascular damage, improved quality of life, and increased life expectancy. • INDEX TERMS: HEMODYNAMICS; HYPERTENSION; ADRENERGIC ALPHA RECEPTOR BLOCKERS; ADRENERGIC BETA RECEPTOR BLOCKERS • CLEVE CLIN ] MED 1992; 59:193-200 HE MAJOR hemodynamic factors control- In the early stages of hypertension, the sympathetic ling blood pressure are cardiac output and nervous system is overactive.4 Young subjects with total peripheral resistance. Hemodynamic mild hypertension have a characteristic hemodynamic alterations in hypertension differ in the early pattern during rest of high cardiac output, rapid heart Tand later stages of the disorder.1,2 In a 20-year follow-up rate, normal stroke volume, and total peripheral resis- study of 76 hypertensive patients, we demonstrated tance not different from normotensive controls. hemodynamic changes over time from a pattern of During exercise, however, the increase of the stroke high cardiac output and low resistance in young volume is limited, and although the heart rate tends to patients, to a pattern of low cardiac output and high be fast, cardiac output during submaximal exercise is resistance in older patients (Figure J).3 slightly reduced. Total peripheral resistance during ex- ercise does not fall to the same low levels found in From the Section of Cardiology, Haukeland Hospital, Bergen. normotensive controls. Address reprint requests to P.L-J., Section of Cardiology, Medical As the hypertensive patient grows older, structural Department, Haukeland Hospital, 5021 Bergen, Norway. changes in the heart and in the arterioles are probably This article was produced by Consultants in Medical Education, responsible for maintaining increased blood pressure. Inc., Manhasset, New York, under an educational grant from Schering-Plough International. In most patients over age 40 with established hyper- MARCH • APRIL 1992 CLEVELAND CLINIC JOURNAL OF MEDICINE 193 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. ADRENERGIC BLOCKERS • LUND-JOHANSEN commonly used antihyper- TPRI dyn s cnr5rrr2 HR beats/min tensive drugs. BP mmHg 4000 I- 6 EFFECTS OF ALPHA BLOCKERS 200 SAP 150 3000 - * 180 Alpha receptors in the 100 2000 peripheral blood vessels mediate sympathetic nerve 160 60 1000 stimulation and are impor- SI mL stroke"1 rrr2 CI L min-1m-2 tant for the regulation of 140 the local blood flow and for 70 10 the control of total periph- 120 eral resistance and, there- 50 by, the blood pressure. For 100 several decades, attempts 30 have been made to reduce Í—1—I I 1—1 I I I I I I—I—I I I I I the effect of increased sym- 1000 500 1000 500 1000 500 pathetic tone on the resis- 2 2 2 V02 mLymin-Vrrr VOp mUmin-Vm- V02 mL/min-Vm- tance vessel by using alpha blockade. The first alpha FIGURE 1. Hemodynamic alterations in essential hypertension over 20 years.3 Age at initial blockers were nonspecific study 17-29 yrs. Mean values and SEM. VO2, oxygen consumption; HR, heart rate; CI, car- and blocked both alpha-1 diac index; SI, stroke index; SAP, systolic arterial pressure; MAP, mean arterial pressure; and alpha-2 receptors at DAP, diastolic arterial pressure; TPRI, total peripheral resistance index. the nerve terminal and at the effector cells. Such tension, the characteristic hemodynamic pattern drugs (eg, phenoxybenzamine, dibenzyline) induced during rest is normal cardiac output and increased total vasodilatation, but when blood pressure fell, heart rate peripheral resistance. During exercise, cardiac output is and cardiac output increased markedly. Consequently, subnormal and total peripheral resistance is markedly the fall in blood pressure was modest, and these drugs elevated. could not be used for long-term treatment.12 In the later stages of severe essential hypertension, The situation changed completely when selective total peripheral resistance is greatly increased at rest alpha-1 receptor blockers were developed. These left and during exercise, often to more than twice the the alpha-2 receptors undisturbed, thus preserving the upper normal value. Heart pump function is markedly negative feedback system for noradrenalin at the nerve reduced with a fall in stroke volume when exercise load terminal. This produced vasodilatation without reflex increases. tachycardia.12'14 During the last decades of life, abnormalities in the heart are seen, including reduced compliance, reduced Acute and long-term effects filling rate, increased left ventricular thickness, and When an alpha-1 receptor blocker like doxazosin is left ventricular mass.5 Disturbances in the diastolic injected as a single dose, total peripheral resistance falls function probably are the first to occur. Recent echo- rapidly, with no significant changes in heart rate or Doppler studies also have demonstrated reduced pump cardiac output. This results in an immediate fall in function during exercise.6 The increased vascular resis- blood pressure, which is seen at rest and during exer- tance is found in most vascular beds, although to vary- cise.10 In some patients, the fall in blood pressure is ing degrees.7 excessive, and in ambulatory patients this can induce The various antihypertensive agents reduce blood the so-called "first-dose syncope reaction." In our series pressure by very different mechanisms. Drugs which on doxazosin, 3 of 15 patients had a marked reduction act via the adrenergic receptors may induce widely in vascular resistance and blood pressure in the supine different hemodynamic changes at rest and during ex- position after 1 mg of doxazosin was given intravenous- ercise.8*11 The following discussion briefly reviews the ly, while heart rate did not increase. When the dose was short- and long-term hemodynamic effects of these reduced, these hypotensive reactions were not seen.10 194 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 59 NUMBER 2 Downloaded from www.ccjm.org on October 1, 2021. For personal use only. All other uses require permission. ADRENERGIC BLOCKERS • LUND-JOHANSEN Our 1974 study14 dem- CI Umin-Vm-2 onstrated that prazosin in- 10 MAP mmHg duced normalization of TPRI dyn sec cm-5rrr2 central hemodynamics at 150 rest and during exercise (Figure 2). Significant reduction in total periph- 100 eral resistance was seen in 500 1000 500 1000 500 1000 2 V02 mUmirrVnr all patients. Blood pressure was reduced about 10% in HR x MAP beats/min mmHg HR beats/min patients with mild to 28000 moderately severe essential SI mL/stroke-Vnr2 hypertension. Heart rate 150 20000 did not change significant- y * ly, while exercise stroke index increased. As a con- 100 10000 sequence, the post-treat- 4000 500 1000 ment cardiac index was 500 1000 500 1000 higher than before treat- V O. , mLVmin-Vm-2 ment, inducing better total blood flow and normaliza- FIGURE 2. Central hemodynamics at rest and during exercise before (solid line) and during tion of arteriovenous (broken line)) 1 year treatment with prazosin (N=10). Mean values and SEM. *P < 0.05, **fP oxygen difference. Our < 0.01, ***P < 0.001. V02, oxygen consumption; HR, heart rate; CI, cardiac index; SI, more recent studies on stroke index; MAP, mean arterial pressure; TPRI, total peripheral resistance index. doxazosin and trimazosin have found the same effects.10,13 Our data have been output was counteracted by a 20% increase in total supported by studies from several other laboratories.12 peripheral resistance index. During the following 5 hours, total peripheral resistance fell towards pretreat- EFFECTS OF BETA BLOCKERS ment levels (for reasons still not quite understood), and the negative inotropic effect disappeared. The The hemodynamic changes induced by beta blockers negative chronotropic effect was still present after 4 are different in the acute stage compared with long- hours, when the fall in blood pressure was equivalent term use, and are different for beta blockers with vs to the reduction in cardiac index.18 without intrinsic sympathomimetic activity (ISA).9,15,16 With other beta blockers (eg, timolol, atenolol), the blood pressure fall after 4 to 5 hours is usually greater Acute effect than that achieved with epanolol.15 The classic study of Tarazi and Dustan in 197217 showed that, when propranolol was injected in a single Chronic effect dose, the initial response was a marked reduction in The typical response to chronic (1-year) treatment heart rate and cardiac output, a reflex increase in total with beta blockers without ISA is a fall in blood pres- peripheral resistance, and little immediate effect on sure at rest of about 15% to 20%, associated with a fall the blood pressure. But after 8 months, peripheral resis- in cardiac index and heart rate of approximately tance had fallen while cardiac output remained 25%.9,15 With cardioselective drugs such as atenolol reduced and blood pressure fell.