Fundamentals of clinical cardiology Beta-adrenergic blockade in hypertension Lennart Hansson, M.D. Lars WerkS, M.D. Gbteborg, Sweden
Treatment of arterial hypertension with betaadrenergic blocking agents has become increasingly common in many countries during the last few years. In several European centers betaadrenergic blockers have even superseded diuretics as the first drug of choice when starting treatment in previously untreated hypertension. Much research has gone into this field, e.g., in order to clarify the antihypertensive mechanism of these agents. Moreover, the number of drugs with beta-receptor blocking effects t h a t are available for the treatment of hypertension has increased successively during the last years. The present review is an attempt to cover some of the aspects on the use of beta-adrenergic blockers in the therapy of hypertension seen against this background. During the few decades in which meaningful antihypertensive therapy has been available, a few important milestones are easily recognizable at which significant improvements of therapy have resulted, e.g., the introduction of the ganglionic blocking agents, the availability of reserpine, or the development of thiazide diuretics in the 1950's. The recent introduction of betaadrenergic blocking agents in the therapy of hypertension could be regarded as the latest step in this development. The first reports t h a t beta blockers lowered blood pressure in hypertensive patients were published in 1964 by SchrSder and Werk51 and Prichard and Gillam. 2During the following years a number of studies have confirmed these initial reports using propranolol, 3-1~ alprenolol, 12-~6practolol,17, 1~ pindolol,~ oxprenolol,~O and timolol. 1~ A contributing reason for the increasing use of From the Department of Intenaal Medicine I, Sahlgren's Hospital, G6teborg, Sweden. Received for publication June 5, 1975. Reprint requests: Lennart Hansson, M.D., Department of Internal Medicine I, Sahlgren's Hospital, G5teborg, Sweden.
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these agents has been their relative lack of serious side effects provided t h a t contraindications such as obstructive respiratory disease and impending heart failure have been observed. It has also been considered an important advantage that postural or exercise hypotension, as seen with sympatholytic agents, do not occur during treatment with beta-adrenergic blocking agents.S, Furthermore, there is no doubt t h a t considerable reductions of raised blood pressure can be achieved during treatment with beta blockers. Thus, the antihypertensive effect of propranolol has been reported as being at least as potent as that of, e.g., guanethidine. ~, 10 In long-term treatment almost 80 per cent of patients reacted favorably to the use of propranolol. 1~
Pharmacological properties Propranolol and most of the other betaadrenergic blocking agents t h a t are clinically available in many countries today could be regarded as "first-generation beta blockers." Thus, these agents block beta-1 receptors, e.g., in the myocardium, as well as beta-2 receptors, e.g., in the bronchi or peripheral blood vessels. As illustrated in Table I, many of these agents also have a membrane-stabilizing effect, which is sometimes referred to as a quinidine-like or local anesthetic action. This also implies some myocardial depression. The importance of the membrane-stabilizing effect should not be exaggerated, however, in the ordinary clinical use of these drugs. Even with the comparatively high doses of beta blockers that are frequently used in hypertension this effect hardly has to be taken into account, as approximately 100 times higher dosage is needed to demonstrate it in comparison with the dosage needed to demonstrate beta-receptor blockade. ~1 Some of the beta-adrenergic blocking agents
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Beta-adrenergic blockade in hypertension
also have a s y m p a t h o m i m e t i c action (Table I). This could be simply described as a weak agonist action of the c o m p o u n d in addition to its antagonistic action. I n the clinical situation beta blockers with s y m p a t h o m i m e t i c effect could be expected to cause a lesser reduction of resting heart rate 'and m y o c a r d i a l p e r f o r m a n c e t h a n agents devoid of this characteristic. During the last few years more specific beta-blocking agents have appeared. This "second generation" of beta-adrenergic blocking agents could be characterized as being cardioselective in their action since t h e y block beta-1 receptors specifically. Practolol, metoprolol, atenolol, and tolamolol (Table I) are all specific beta- 1 receptor blockers. Their specificity for beta-1 receptors is not absolute, however, b u t the affinity for blocking beta-1 receptors is 50 times higher or more t h a n the effect on beta-2 receptors. Clinically, this means t h a t patients with Obstructive respiratory disease could be t r e a t e d with considerably less risk of producing b r o n c h o c o n s t r i c tion.
Antihypertensive mechanisms From the onset of b e t a - r e c e p t o r blocking t h e r a p y in hypertension great interest has been focused on possible m e c h a n i s m s u n d e r l y i n g the antihypertensive action. In brief, h e m o d y n a m i e mechanisms, central nervous actions, reninangiotensin effects, as well as effects related to the local anesthetic effect have been discussed in this connection. Hemodynamic effects. I t is well k n o w n t h a t most forms of established h y p e r t e n s i o n are characterized by normal cardiac o u t p u t and elevated total peripheral resistanceY ~ Therefore it could seem unlogical to administer beta-adrenergic blocking agents in this condition in view of the predominantly cardiac effects of these agents, except m a y b e in the r a t h e r rare hyperkinetic forms of hypertension. Acute intravenous administration of beta blockers to hypertensive patients causes a significant reduction of cardiac o u t p u t b u t no c h a n g e of blood pressure due to a c o n c o m i t a n t rise of t o t a l peripheral resistance. TM ~4 L o n g - t e r m administration of propranolol with a c c o m p a n y i n g r e d u c t i o n of blood pressure was initially regarded as being effective m a i n l y t h r o u g h the chronic reduction of cardiac output. 7 L a t e r the Cleveland Clinic group has d e m o n s t r a t e d t h a t a gradual r e a d j u s t m e n t of
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Table I. P h a r m a c o l o g i c a l properties of some beta-receptor antagonists Blockers Beta Beta -1 -2
Propranolol Alprenolol Oxprenolol Sotalol Timolol Penbutolol Pindolo! Practolol H 93/26 metoprolol ICI 66.082 atenolol Toialnolol
+ + + + + + + + + + +
+ + + + + + + -----
Sympathomimetic effect
Membrane stabilizing effect
-+ + ---+ + ----
+ + + --+ + -----
total peripheral resistance down to the initial level or lower takes place during chronic treatm e n t with propranolol, ~5 a finding confirmed by our own studies. 24 A reduction of plasma v o l u m e during treatment with propranolol has been reported to occur in some patients 26 b u t this finding has not been confirmed in o t h e r studies, neither as regards propranoloI, 27 nor alprenolol, 26 or pindolol. 29 I t would therefore seem unlikely t h a t the antihypertensive action of beta blockers could be attributed to a reduction of plasma volume. Even an unchanged plasma volume could be an a d v a n t a g e during long-term therapy, however, as drug resistance due to salt and water retention, c o m m o n l y seen with other agents, 3~ should n o t be expected to occur. Central nervous effects. I t is well k n o w n from autoradiography studies in animals t h a t betaadrenergic blockers with few exceptions easily penetrate the blood-brain barrier and are accumulated in the central nervous system. Therefore it would be conceivable t h a t the antihypertensive effect of these agents could at least in part be explained by central nervous actions as has been suggested, e.g., by Dollery's group. T M ~2 On the other hand, practolol a n d atenolol do n o t penetrate the blood-brain barrier a n d still have a clear antihypertensive actionY. ~ T h e importance of central nervous effects is therefore uncertain at present. F u r t h e r difficulties arise from studies showing alprenolol to have a central nervous action, whereas p r o p r a n o l o l does not/4 in
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Table II. H y p o t e n s i v e effect reported with beta-adrenergic blocking drugs
Re[. No.
Compound
16 14 8 10 19
Alprenolol Alprenolol Propranolol Propranolol Propranolol
19 19
Alprenolol Pindolol
19
No, of patients
7 (15) 41 82 (158) 232 {303) 20
Reduction of blood pressure (mm. Hg)
800 800 271 360 120-240
46/19 14/6 30/16 57/31 25/19
20 20
300-600 15-30
20/21 26/17
Timolol
20
15-30
24/14
17
Practolol
12 (48)
440
42/26
20 80
Oxprenolol Propranolol
20 (31) 17
280 320
22/14 46/25
62
Propranolol
1]
spite of the fact t h a t b o t h agents easily p e n e t r a t e into the central nervous system. It is conceivable t h a t the change of baroreceptor sensitivity t h a t h a s been suggested to t a k e place during prolonged t r e a t m e n t with b e t a blockers,~. 3~ and which could explain the previously m e n t i o n e d r e a d j u s t m e n t of t o t a l p e r i p h e r a l resistance, m a y depend on central n e r v o u s actions of the drugs. Effects on the renin-angiotensin system. T h a t beta-adrenergic blocking agents reduce renin release and p l a s m a renin activity in m a n h a s been d e m o n s t r a t e d in several studies26. 37 In a s t u d y t h a t has a t t r a c t e d m u c h a t t e n t i o n , L a r a g h ' s group in 1972 claimed t h a t the a n t i h y p e r t e n s i v e effect of propranolol was considerably m o r e m a r k e d in patients w i t h high p l a s m a renin activity in relation to their u r i n a r y sodium excretion28 Conversely, very little effect on blood pressure was seen in the p a t i e n t s with low p l a s m a renin activity. '~ L a r a g h a n d his co-workers have l a t e r d e m o n s t r a t e d the s a m e relation between initial p l a s m a renin a c t i v i t y and blood pressure response to p r o p r a n o l o l in a s t u d y comprising a group of p a t i e n t s with " p u r e " essential h y p e r t e n sion. :~'' T h e y h a v e also claimed t h a t t h e r e is a significant correlation b e t w e e n the change of blood pressure and the change of p l a s m a renin activity during p r o p r a n o l o l therapy.~' This finding m a y seem appealing from a logical
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Daily dosage (mgJ
80-240
29/24
Remarks
Standing BP + Diuretics + Diuretics in all; + methyldopa in 4 patients + Diuretics in all; + methyldopa in 4 patients + Diuretics in all; + methyldopa in 4 patients + Diuretics in 2 and hydralazine in 1 patient + Hydralazine (diuretics in 7 patients) + Minoxidil
point of view if one regards t h e elevated blood pressure and the high p l a s m a renin activity as expressions of increased s y m p a t h e t i c tone which are b o t h normalized by the a d m i n i s t r a t i o n of a beta-adrenergic r e c e p t o r blocker. T h e r e are no indications, however, t h a t the r e n i n - a n g i o t e n s i n s y s t e m has a direct influence on blood pressure in n o n m a l i g n a n t essential h y p e r t e n s i o n , except possibly during s t a t e s of severe salt depletion. T h e r e is also a growing n u m b e r of r e p o r t s which c a n n o t s u b s t a n t i a t e the finding t h a t t h e initial p l a s m a renin activity is of decisive i m p o r t a n c e for the antihypertensive response t o b e t a blockade or t h a t the change of renin is c o r r e l a t e d to the change of blood pressure2 T M However, r e c e n t l y it has been shown t h a t lowrenin p a t i e n t s initially unresponsive to p r o p r a n olol h a d a m a r k e d reduction of blood pressure following increased dosage2 ' T h i s seems to indicate t h a t b o t h opinions in this m a t t e r m a y in fact be correct. A n u m b e r of other variables t h a t could be expected to reflect s y m p a t h e t i c nervous activity, e.g., initial h e a r t rate, cardiac o u t p u t , or excretion of u r i n a r y catecholamines, h a v e been shown to be of little value in predicting the a n t i h y p e r t e n s i v e response to b e t a blockade2 ~..... Local anesthetic effect. Studies in r a b b i t s h a v e indicated t h a t the a n t i h y p e r t e n s i v e effect of propranolol was n o t related to t h e b e t a - r e c e p t o r blocking effect b u t r a t h e r to a n e u r o n - b l o c k i n g
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effect. 46 Clinical trials with the dextro-isomer of propranolol, which retains the local anesthetic effect of the racemic preparation but not the beta-receptor blocking capacity, have demonstrated no antihypertensive effect,47, 4s It therefore appears that the local anesthetic effect is w i t h o u t importance for the antihypertensive effect of beta-adrenergic blocking agents in man. In summary, it is difficult to provide an explanation of the antihypertensive mechanism of beta block.ers that would cover all the various agents presently available. Undoubtedly, in most cases the effect seems to be due to a chronic reduction of cardiac output with acompanying readjustment of total peripheral resistance to the initial or a lower level. It is conceivable, however, t h a t an index of cardiac peformance other than cardiac output, e.g., force of contraction (dp/dt), would be a better general denominator as the effect on cardiac output is known to be almost nonexistent with some beta blockers. It is also conceivable that central nervous effects do play a role at least in modifying the hemodynamic changes. The role of effects via the renin-angiotensin system seems to be rather small but certainly merits further research, e.g., along the lines of Frisk-Holmberg and Shand29 Selection of patients for treatment with beta blockers
It has been a common belief t h a t patients with a hyperkinetic circulation would be particularly responsive to treatment with beta-receptor blocking agents. Looking solely at the antihypertensive response, however, such patients do not respond more favorably to treatment than others. Thus, no correlation can be demonstrated between initial heart rate or cardiac output and blood pressure response2 ~ There is also no correlation between the change of cardiac output and the change of blood pressure during propranolol treatment. 2~ Undoubtedly, though, there is an extra benefit of treatment with beta blockers in patients with hyperkinetic circulation as palpitations or other similar symptoms usually disappear. Another common opinion is that older patients should not be given beta blockers. We do not wish to comment upon the need for antihypertensive therapy as such in the elderly,5~ but beta blockers
American Heart Journal
have been used successfully in the treatment of hypertensive patients over the age of 70 years. 51 Treatment with beta-receptor blockers in patients with renal insufficiency has recently caused debate due to a study in which three patients with moderate renal insufficiency showed rapidly deteriorating renal function during treatment with propranolol. 52 The results in these three patients are not in agreement with previous positive experience of beta blockade in uremic patients23, 54 Moreover, it should be noted that the negative report has been refuted by the group which probably has the widest experience of treatment with beta blockers in patients with renal insufficiency2~ Thus, it would appear t h a t the selection of patients for antihypertensive treatment with beta blockers does not have to be limited with respect to the hemodynamic picture, renal function, or age of the patient. We have drawn practical conclusions from this and have been using betaadrenergic blocking agents, mainly propranolol and alprenolol, as the first drugs of choice in the treatment of hypertension in our clinic since 1970. Contraindications and side effects
The beta-adrenergic blocking agents have certain contraindications that should be strictly observed. The importance of excluding patients with obstructive respiratory disease has already been touched upon, at least when treatment with nonselective beta-1 and beta-2~ blocking agents is considered. Another important (but maybe not absolute) contraindication is impending heart failure. Thus. in a study comprising 38 hypertensive patients with an average age of 72 years, only three patients developed heart failure during alprenolol therapy, two of whom could continue treatment after addition of digitalis21 In our own experience heart failure is extremely rare as a complication of beta-adrenergic blocking therapy when treating hypertensive patients. Further contraindications are A-V conduction blocks-at least A-V blocks II and I I I - a n d unstable diabetes mellitus requiring insulin therapy. Early in the era of beta-adrenergic blocking therapy it was already obvious t h a t side effects were' few and relatively mild. Thus, in a survey of 1,500 patients treated with propranolol, only 98
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side effects were reported, e.g., vertigo, fatigue, and nausea, a n d only 19 p a t i e n t s h a d to stop medication due to side effects2 ~ In a l o n g - t e r m s t u d y comprising m o r e t h a n 300 h y p e r t e n s i v e patients, 67 tolerable side effects were r e p o r t e d and 29 p a t i e n t s had to be t a k e n off the b e t a blocker t h e r a p y . 1~ Usually side effects give subjective s y m p t o m s and t h e y also t e n d to occur early during t r e a t ment. T h i s m a k e s it possible to a d j u s t dosage or withdraw t h e r a p y if needed during an early phase of t r e a t m e n t . T h e s e f e a t u r e s of b e t a - a d r e n e r g i c blocking t h e r a p y m u s t be considered p r e f e r a b l e to the slow onset t y p e of m e t a b o l i c d i s t u r b a n c e s w i t h o u t subjective s y m p t o m s t h a t are seen w i t h several other t y p e s of a n t i h y p e r t e n s i v e drugs. Beta blockers in combination with other antibypertensive agents It has been pointed out t h a t the c o m b i n a t i o n of beta-adrenergic blockade and v a s o d i l a t a t i o n offers a new aspect on the drug t r e a t m e n t of hypertension27 Several reports h a v e also confirmed the usefulness of such c o m b i n a t i o n s , e.g., between beta blockers a n d h y d r a l a z i n e ~~ ~1 or newer m o r e p o t e n t vasodilators such as minoxidi162 and guancydine. ~3 T h e relaxation of v a s c u l a r s m o o t h muscle with ensuing r e d u c t i o n of peripheral vascular resistance and blood pressure leads to a b a r o r e c e p t o r - m e d i a t e d increase of h e a r t r a t e and cardiac o u t p u t w h e r e b y t h e antihypertensive effect of the v a s o d i l a t o r is all b u t nullified. A d m i n i s t r a t i o n of a b e t a - r e c e p t o r blocker in this s i t u a t i o n breaks this chain of c o m p e n s a t o r y m e c h a n i s m s , thus u n m a s k i n g the full a n t i h y p e r t e n s i v e p o t e n t i a l of the vasodilator, as can be clearly d e m o n s t r a t e d in h e m o d y n a m i c studies. ~4 A n o t h e r way of achieving peripheral vasodilatation would be to reduce v a s o c o n s t r i c t o r activity by alpha-adrenergic r e c e p t o r blockade. Also in this setting b e t a - r e c e p t o r blockade is desirable in order to prevent reflex-induced i n c r e m e n t s of h e a r t r a t e and cardiac output. Initial clinical trials with c o m b i n e d alpha- and b e t a - r e c e p t o r blockade were not successful due to t h e limiting side effects of alpha-adrenergic blockade25 M o r e positive reports have been published, e.g., on t h e use of oxprenolol and p h e n t o l a m i n e 2 ~ Our own limited experience with a new c o m p o u n d (AH 5158) which exhibits b o t h alpha- and b e t a -
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receptor blocking capability is also quite favorable. A f u r t h e r w a y of obtaining r e l a x a t i o n of precapillary resistance vessels would be b y specific s t i m u l a t i o n of v a s c u l a r beta-2 receptors. T h e initial clinical experience with c o m b i n e d beta-2 receptor s t i m u l a t i o n a n d beta-1 r e c e p t o r blockade in h y p e r t e n s i o n h a s n o t seemed to offer practical advantages, however. 67 Needless to say, the c o m b i n e d use of a b e t a blocker and a diuretic also offers a useful m e a n s b y which elevated blood pressure can be reduced. T h e c o m b i n a t i o n with a diuretic is not a s essential as, e.g., during t r e a t m e n t w i t h s y m p a t h o l y t i c drugs, since b e t a blockers do n o t cause p l a s m a volume expansion as discussed above. An a d v a n tage with combined beta b l o c k a d e and diuretic t r e a t m e n t , though, would be t h a t the doses of each drug could be reduced significantly while maintaining an a d e q u a t e a n t i h y p e r t e n s i v e effect. This could positively affect m a i n l y the thiazideinduced h y p o k a l e m i a and hyperuricemia28 Additional benefits of beta-receptor blockade A n u m b e r of additional benefits have been reported f r o m t h e use of b e t a - b l o c k i n g t h e r a p y , e.g., the relief of angina pectoris and migraine. Of interest are also the r e p o r t s on reduction of anxiety, as h y p e r t e n s i v e p a t i e n t s have been reported as being m o r e anxious t h a n n o r m o t e n sives29 During the first years of b e t a - b l o c k i n g t h e r a p y it was reported t h a t beta b l o c k a d e reduced anxiety in neurotic patients. TM Later, great interest has been focused on the effects of beta blockers in situations of stress and it has been shown t h a t oxprenolol given to race drivers before a race will abolish the t a c h y c a r d i a as well as the rise of blood glucose a n d free f a t t y acids. ~1 A normalization of the E C G a n d h e a r t r a t e could also be d e m o n s t r a t e d when a group of lecturers, m o s t of w h o m were physicians, were given a b e t a blocker prior to their p r e s e n t a tion. ~ In 1966 W a a l ~ speculated on the possibility t h a t beta-receptor blockers given to h y p e r t e n s i v e patients m i g h t in the long r u n reduce d e a t h s f r o m myocardial infarction due to t h e a n t i a r r h y t h m i c effect of these agents. In retrospective a n a l y s e s it has also been shown t h a t propranolol drastically reduced infarct d e a t h s in p a t i e n t s with k n o w n ischemic h e a r t disease. ~3 F u r t h e r m o r e , h y p e r t e n -
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sive patients treated with beta blockade seemed to have a three to four times lower risk of suffering a fatal infarct or sudden death. TM T h e reduced risk of sudden death has recently been confirmed in a prospective double-blind study in which alprenolQ1 was given to postinfarction patients/5 Obviously, these findings require further confirmation, particularly as regards the beneficial effect of beta blockers in the t r e a t m e n t of hypertension. If, however, it c a n be shown in prospective and controlled studies t h a t deaths from ischemic heart disease can be reduced by treatment with beta blockers this would constitute a significant advantage for this type of treatment over conventional antihypertensive treatment, which does not seem to reduce infarct deaths/~ Practical considerations affecting the choice of drug When treating mild to moderately severe hypertension there seems to be little difference between various beta-receptor blockers as regards their antihypertensive potency and side effects.l~. 18, 19. ~ In severe hypertension, however, beta blockers devoid of sympathomimetic properties may prove to be more effective/~. 7s Regarding dosage, it has been claimed t h a t an antihypertensive effect can always be expected provided that a sufficiently large dose is p r e scribed, which has led to the administration of up to 4 Gm. of propranolol a day2 It has also been demonstrated in a small number of patients t h a t increasing the daily dosage of propranolol also increases the antihypertensive effect. TM From a practical point of view extremely large doses of any drug are never desirable. Our own policy for many years has been to use combined therapy mainly with hydralazine or diuretics if a sufficient antihypertensive effect is not seen with propranolol, 300 to 600 mg. daily, or alprenolol, 1,000 to 1,200 mg. daily. When it comes to choosing between different beta-receptor blockers, we feel t hat long-term experience with, e.g., propranolol and alprenolol is such that this in itself constitutes a reason for selecting one of these "older" beta blockers r at her than any of the more recently introduced "firstgeneration" agents. The situation becomes somewhat different when the new "second-generation" beta blockers are taken into consideration, e.g.,
American Heart Journal
metoprolol and atenolol, as they offer certain advantages that have been discussed above. T h e recent experience with practolol, which after a few years of clinical use suddenly was found to cause serious side effects, warrants carefulness and observance when newer agents are taken into use. Regarding the number of daily doses that are required in order to maintain good control of the blood pressure, it is obvious t h a t the fewer doses needed and the simpler the administration of the drug the better the patient adherance to the prescribed regimen. 81 In this regard several beta blockers have been shown to maintain a stable level of blood pressure when given twice daily. This is true not only of alprenolol, which can be prescribed in Durules, but also of propranolol. 8~ 82 The long duration of beta blockers as regards their effect on blood pressure can also be illustrated by the slow rise of blood pressure if treatment is stopped. I~ It has also been demonstrated that the pharmacological half-life of several betareceptor blockers is considerably longer than their plasma half-life. 83 Regarding onset of action it has been claimed that up to six to eight weeks of t r e a t m e n t would be required in order to see the full antihypertensive effect of propranolol. 5 Obviously, this report of a slow onset of action could be explained by a low starting dose and a gradual buildup of dosage. Our own experience indicates a much faster lowering of blood pressure during propranolol treatment 3~ and, in reference to pindolol, it has been claimed that a significant reduction of blood pressure is seen within 20 minutes after oral administration. 84 T reat m ent with beta blockers and anesthesia has caused some concern. The extreme opinion that beta blockers should be withdrawn 4 weeks prior to coronary bypass surgery has been based upon postoperative cardiogenic shock in five patients in a report from the Cleveland Clinic. 8~ Obviously, one cannot exclude the possibility that the ischemic heart disease in these patients and not the t reat m ent with a beta blocker was the main contributing factor to their myocardial failure postoperatively. Our own policy regarding withdrawal or continuation of beta-blocking therapy in the preoperative situation has not been uniform. Undoubtedly, anesthesia can be performed in most cases without previous with-
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and Werk5
d r a w a l o f b e t a - b l o c k i n g t r e a t m e n t . If, h o w e v e r , d i s c o n t i n u a t i o n o f t h e r a p y is d e s i r e d , we h a v e u s u a l l y d o n e so 2 d a y s p r e o p e r a t i v e l y . T h i s w i l l n o t b r i n g b l o o d p r e s s u r e b a c k to t h e u n t r e a t e d level in m o s t p a t i e n t s , a s h a s a l r e a d y b e e n discussed, b u t r e s t i n g h e a r t r a t e w i l l rise t o t h e i n i t i a l level (or h i g h e r ) , i n d i c a t i n g t h a t b e t a b l o c k a d e is n o t p r e s e n t .
Future lines of development Future development of antihypertensive therap y c a n b e e x p e c t e d t o f o l l o w t h r e e m a i n lines. A further refinement of central nervous system-acting d r u g s of t h e c l o n i d i n e t y p e c a n b e e x p e c t e d , l e a d i n g t o d r u g s t h a t give less s e d a t i o n . A s e c o n d p o s s i b l e line of d e v e l o p m e n t w o u l d b e t h e p r o d u c t i o n of m o r e p o t e n t v a s o d i l a t o r s , a n d s o m e o f t h e s e , e.g., m i n o x i d i l a n d g u a n c y d i n e , h a v e already been touched upon here. However, with m o r e p o t e n t v a s o d i l a t o r s i t will b e c o m e m a n d a tory to administer both a beta blocker and a d i u r e t i c t o p r e v e n t reflex t a c h y c a r d i a a n d fluid r e t e n t i o n . T h u s , t h e v a s o d i l a t o r s c a n n o t be exp e c t e d t o serve as t h e first d r u g s of c h o i c e as t h e y s h o u l d b e r e s e r v e d for c a s e s n e e d i n g m u l t i p l e d r u g therapy. Finally, a refinement of the beta-receptor blockers can be foreseen and some of the "secondgeneration" beta blockers already look promising as r e g a r d s t h e i r a n t i h y p e r t e n s i v e effect. T h u s , a t e n o l o l ~3.86-~ a n d m e t o p r o l o P 9-~~ h a v e b e e n shown to have a useful blood pressure-lowering effect a n d c o m p a r a t i v e l y few a n d m i l d side effects. T h e a d v a n t a g e o f s e l e c t i v e b e t a - 1 r e c e p t o r b l o c k a d e is t h a t b r o n c h i a l b e t a - 2 r e c e p t o r s a r e not blocked, thereby reducing the risk of bronchoc o n s t r i c t i o n . I t is a l s o c o n c e i v a b l e t h a t t h e unblocked vascular beta-2 receptors may cont r i b u t e t o less p r o n o u n c e d rises o f b l o o d p r e s s u r e during episodes of increased release of catechol a m i n e s , e.g., d u r i n g m e n t a l s t r e s s o r p h y s i c a l exercise. F u r t h e r m o r e , t h e l a c k of a s y m p a t h o m i m e t i c effect w i t h b o t h a t e n o l o l a n d m e t o p r o l o l c o u l d b e a n a d v a n t a g e , a t least w h e n t r e a t i n g severe hypertension. S e e n a g a i n s t t h i s b a c k g r o u n d i t is p o s s i b l e t h a t f u t u r e t r e a t m e n t of h y p e r t e n s i o n will b e e v e n more dependent upon drugs with a beta-receptor b l o c k i n g a c t i v i t y t h a n is t h e c a s e t o d a y . W e w i s h to s t r e s s once a g a i n t h o u g h t h a t t h e p o s i t i v e experience with some of the newer agents should
400
b e c o n f i r m e d in l a r g e r series w i t h l o n g p e r i o d s o f follow-up before one can state that these agents a r e as safe as " f i r s t - g e n e r a t i o n " b e t a b l o c k e r s . REFERENCES
1. SchrSder, G., and WerkS, L.: Nethalide, a betaadrenergic blocking agent, Clin. Pharmacol. Ther. 5:159, 1964. 2. Prichard, B. N. C., and Gillam, P. M. S.: The use of propranolol in the treatment of hypertension, Br. Med. J. 2:725, 1964. 3. Paterson, J. W., and Dollery, C. T.: Effect of propranolol in mild hypertension, Lancet 2:1148, 1966. 4. Prichard, B. N. C., and Gillam, P. M. S.: Propranolol in hypertension, Am. J. Cardiol. 18:387, 1966. 5. Prichard, B. N. C., and Gillam, P. M. S.: Treatment of hypertension with propranolol, Br. Med. J. 1:7, 1969. 6. Waal, H. J.,: Hypertensive action of propranolol, Clin. Pharmacol. Ther. 7:588, 1966. 7. Frohlich, E. D., Tarazi, R. C., Dustan, H. P., and Page, I. H.: The paradox of beta-adrenergic blockade in hypertension, Circulation 37:417, 1968. 8. Hansson, L., Ma!mcrona, R., Olander, R., Rosenhall, L., Westerlund, A., Aberg, H., and Hood, B.: Propranolol in hypertension. Report on 158 patients treated up to one year, Klin. Wochenschr. 50:364, 1972. 9. Karlberg, B.; and HSrnkvist, P. E.: Propranolol in treatment of hypertension, Opusc. Med. 8:296, 1971. 10. Zacharias, F. J., Cowen, K. J., Prestt, J., Vickers, J., and Wall, B. G.: Propranolol in hypertension: A study of long-term therapy, 1964-1970, AM. HEART J. 83:755, 1972. ll. Lydtin, H., Kusus, T., Daniel, W., Schierl, W., Ackenheil, M., Kempter, H., LohmSller, G., Niklas, M., and Walter, I.: Propranolol therapy in essential hypertension, AM. HEART J. 83:589, 1972. 12. Furberg, C., and Michaelson, G.: Effect of Aptin, a betaadrenergic blocking agent in arterial hypertension, Acta Med. Scand. 186:447, 1968. 13. Tibblin, G., and Ablad, B.: Antihypertensive therapy with alprenolol, a beta-adrenergic antagonist, Acta Med. Scand. 186:451, 1968. 14. Bengtsson, C.: Comparison between alprenolol and chlorthalidone as antihypertensive agents, Acta Med. Scand. 191:433. 1972. 15. Beng~sson, C.: Comparison between alprenolol and propranolol as antihypertensive agents, Acta Med. Scand. 192:415. 1972. 16. Vedin. A., Wilhelmsson. C.. and WerkS. L.: Comparative study of alprenolol and methyldopa m previously untreated essential hypertension. Br. Heart J. 35:1285, 1973. 17. Prichard, B. N. C.. Boakes, A. J., and Day, G.: Practolol in the therapy of hypertension. Postgrad. Med. J. 47 (Suppl.):84. 1971 18. Andersson, O.. and Berglund. G.: Practolol-propranolol: Comparison of the antihypertensive effect. Acta Med. Scand. 1974. 19. Morgan. T. O.. Sabro. J., Anavekar. S. N.. Louis. W. J.. and Doyle, A. E.: A comparison of beta-adrenergic blocking drugs in the treatment of hypertension. Postgrad. Med. J. 50:253, 1974. 20. Dorph, S.. and Binder. C.: Evaluation of the hypotensive effect of beta-adrenergic blockade in hypertension. Acta Med. Scand. 185:443, 1968. 21. Coltart. D. J.: Assessment of beta-adrenergic blocking
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22. 23.
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effects of propranolol. Observations on predictability, Folia Med. Neerl. 14:67, 1971. George, C. F.: Round table on renin suppression and the hypotensive effect of beta-adrenergic blocking agents, in Third meeting of the International Society of Hypertension, Milano, 1974. Clin. Sci. Mol. Med. 48(Suppl. 2):1975. Hansson, L., and Zweifler, A. J.: The effect of propranolol on plasma renin activity and blood pressure in mild essential hypertension, Acta Med. Scand. 195:397, 1974. Morgan, T. 0.: Round table on renin suppression and the hypotensive effect of beta-adrenergic blocking agents, in Third meeting of the International Society of Hypertension, Milano, 1974. Clin. Sci. Mol. Med. 48(Suppl. 2):1975. Stokes, G. S., Weber, M. A., and Thornell, I. R.: Betablockers and plasma renin activity in hypertension, Br. Med. J. 1:60, 1974. Hansson, L., Zweifler, A. J., Julius, S., and Ellis, C. N.: Propranolol therapy in essential hypertension. Observations on predictability of therapeutic response, Int. J. Clin. Pharmacol. 10:79, 1974. Eliash, S., and Weinstock, M.: Role of adrenergic neurone blockade in the hypotensive action of propranolol, Br. J. Pharmacol. 43:287, 1971. Waal-Manning, H. J.: Lack of effect of d-propranolol on blood pressure and pulse rate in hypertensive patients, Proc. Univ. Otago Med. School 48:80, 1970. Rahn, K., Hawlina, A., Kersting, F., and Planz, G.: Studies on the antihypertensive action of the optical isomers of propranolol in man, Naunyn-Schmiedeberg Arch. Pharmacol. 286:319, 1974. Frisk-Holmberg, M., and Shand, D. G.: A dual antihypertensive mechanism for propranolol, in Berglund, G., Hansson, L., and WerkS, L., editors: The pathophysiology and management of arterial hypertension, Astra Int., Ltd., Copenhagen, 1975. Fry, J.: Natural history of hypertension, Lancet 2:431, 1974. Eisalo, A., and Munter, J.; The effect of alprenolol in elderly patients with raised blood pressure, Acta Med. Scand. 554(Suppl.):23, 1974. Warren, D. J., Swainson, C. P., and Wright, N.: Deterioration in renal function after beta-blockade in patients with chronic renal failure and hypertension, Br. Med. J. 2:193, 1974. Jameson, S.: Effekten av Inderal vid behandling av uremisk hypertension, Nord. Med. 44:1282, 1971. Franzfin, P., and Pasternack, A.: Propranolol in renal failure, Br. Med. J. 2:763, 1972. Kincaid-Smith, P., and Hua, A. S. P.: Beta-adrenergic blocking agents in renal failure, Br. Med. J. 3:520, 1974. Stephen, S. A.: Unwanted effects of propranolol, Am. J. Cardiol. 18:463, 1966. WerkS, L.: New t r e a t m e n t for hypertension, Eur. J. Clin. Pharmacol. 3:61, 1971. Hansson, L., Olander, R., Malmcrona, R., and Westerlund, A.: Treatment of hypertension with propranolol and hydralazine, Acta Med. Scand. 190:531, 1971. Gottlieb, T. B., Katz, F. H., and Chidsey, C. A.: Combined therapy with vasodilator drugs and betaadrenergic blockade in hypertension, Circulation 45:571, 1972. Hansson, L., and Zweifler, A. J.: Combined treatment of hypertension with vasodilation and beta-adrenergic blockade, Mich. Med. 72:695, 1973.
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61, Katila, M., and Frick, M. H.: Combined dihydralazine and propranolol in the treatment of hypertension, Int. J. Clin. Pharmacol. 4:111, 1970. 62. Gilmore, E., Well, J., and Chidsey, C.: Treatment of essential hypertension with a new vasodilator in combination with beta-adrenergic blockade, N. Engl. J. Med. 282:521, 1970. 63. Hansson, L., Vedin, A., WerkS, L., and Wilhelmsson, C.: Controlled study of guancydine in hypertension, 1974. 64. Sannerstedt, R., Stenberg, J., Johnsson, G., and WerkS, L.: Hemodynamic interference of alprenolol with dihydralazine in normal and hypertensive man, Am. J. Cardiol. 28:316, 1971. 65. Beilin, L. J., and Juel-Jensen, B. E.: Alpha-and betaadrenergic blockade in hypertension, Lancet 1:979, 1972. 66. Majid, P. A,, Meeran, M. K., Benaim, M. E., Sharma, B., and Taylor, S. H.: Alpha- and beta-adrenergic receptor blockade in the treatment of hypertension, Br. Heart J. 36:588, 1974. 67. Andersson, O., and Berglund, G.: Combined therapy with beta-2-receptor stimulation and beta-l-receptor blockade in hypertension. Acta Med. Scand. 197:495, 1975. 68. Angervall, G., and Bystedt, U.: The effect of alprenolol in combination with saluretics in hypertension, Acta Med. Scand. 554(Suppl.):39, 1974. 69. Wheatly, D.: Psychiatric aspects of hypertension, Psychopharmacol. Bull. 10:4, 1974. 70. Granville-Grossman, K.L., and Turner, P.: The effect of propranolol on anxiety. Lancet 1:788, 1966. 71. Taggart, P., and Carruthers, S. M.: Suppression by oxprenolol of adrenergic response to stress, Lancet 2:256, 1972. 72. Taggart, P., Carruthers, S. M., and Somerville, W.: Electrocardiogram, plasma catecholamines and lipids and their modification by oxprenolol when speaking before an audience, Lancet 2:341, 1973. 73. Lambert, D. M. D.: Beta-blockers and life expectancy in ischemic heart disease, Lancet 1:793, 1972. 74. Lambert, D. M. D.: Hypertension and myocardial infarction, Lancet 2:685, 1974. 75. Wilhelmsson, C., Vedin, A., Wilhelmsen, L., Tibblin, G., and WerkS, L.: Reduction of sudden deaths after myocardial infarction by t r e a t m e n t with alprenolol, Lancet 2:1157, 1974. 76. Veterans Administration Co-operative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension, J. A. M. A. 213:1143, 1970.
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77. Kincaid-Smith, P.: Management of severe hypertension, Am. J. Cardiol. 32:575, 1973. 78. Berglund, G., and Hansson, L.: A within-patient comparison of alprenolol and propranolol in hypertension, Acta Med. Scand. 193:547, 1973. 79. Kincaid-Smith, P., Fang, P , and Laver, M.: A new look at the treatment of severe hypertension, Clin. Sci. Mol. Med. 45(Suppl. 1):75P, 1973. 80. Hansson, L., Olander, R., and Aberg, H.: Twice-daily propranolol treatment for hypertension, Lancet 2:713, 1971. 81. Malahy, B.: The effect of instruction and labelling on the number of medication errors made by patients at home, Am. J. Hosp. Pharm. 23:283, 1966. 82. Berglund, G., Andersson, O., Hansson, L., and Olander, R.: Propranolol given twice daily in hypertension, Acta Med. Scand. 194:513, 1973. 83. Carruthers, S. G., Kelly, J. G., McDevitt, D. G., Shanks, R. G., and Walsh, M. J.: Duration of action of betablocking drugs, Br. Med. J. 2:177, 1973. 84. Doyle, A. E.: in Berglund, G., Hansson, L., and WerkS, L., editors: The pathophysiology and management of arterial hypertension, Copenhagen, 1975, Astra Int. Ltd. 85. Viljoen, J. F., Estafanous, F. G., and Kellner, G. A.: Propranolol and cardiac surgery, J. Thorac. Cardiovasc. Surg. 64:826, 1972. 86. Amery, A., Billiet, L., Joosens, J. V., Meekers, J., Reybrouckt, T., and van Mieghem, W.: Preliminary report on the haemodynamic response of hypertensive patients treated with a beta blocker (ICI 66.082), Acta Clin. Belg. 28:358, 1973. 87. Hansson, L., Henningsen, N. C., Karlberg, B. E., Aberg, H., Jameson, S., Malmcrona, R., and Hersvall, C.: Hypotensive action of ICI 66.082, a new beta-adrenergic blocking agent, Int. J. Clin. Pharmacol. 10:206, 1974. 9 88. Hansson, L., Aberg, H., Karlberg, B. E., and Westerlund, A.: Controlled study of Tenormin (ICI 66.082) in the treatment of hypertension, Br. Med. J. 2:367, 1975. 89. Bengtsson, C.: The effect of the cardioselective betablocker metoprolol in essential hypertension, 1974. (To be published) 90. Berglund, G., Bergstrand, R., Vedin, A.I and Wilhelmsson, C.: A comparative study of the efficacy of the cardioselective beta-blocker metoprolol and alphamethyldopa in previously untreated patients with essential hypertension, 1974. (To be published)
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Treatment of arterial hypertension with betaadrenergic blocking agents has become increasingly common in many countries during the last few years. In several European centers betaadrenergic blockers have even superseded diuretics as the first drug of choice when starting treatment in previously untreated hypertension. Much research has gone into this field, e.g., in order to clarify the antihypertensive mechanism of these agents. Moreover, the number of drugs with beta-receptor blocking effects t h a t are available for the treatment of hypertension has increased successively during the last years. The present review is an attempt to cover some of the aspects on the use of beta-adrenergic blockers in the therapy of hypertension seen against this background. During the few decades in which meaningful antihypertensive therapy has been available, a few important milestones are easily recognizable at which significant improvements of therapy have resulted, e.g., the introduction of the ganglionic blocking agents, the availability of reserpine, or the development of thiazide diuretics in the 1950's. The recent introduction of betaadrenergic blocking agents in the therapy of hypertension could be regarded as the latest step in this development. The first reports t h a t beta blockers lowered blood pressure in hypertensive patients were published in 1964 by SchrSder and Werk51 and Prichard and Gillam. 2During the following years a number of studies have confirmed these initial reports using propranolol, 3-1~ alprenolol, 12-~6practolol,17, 1~ pindolol,~ oxprenolol,~O and timolol. 1~ A contributing reason for the increasing use of From the Department of Intenaal Medicine I, Sahlgren's Hospital, G6teborg, Sweden. Received for publication June 5, 1975. Reprint requests: Lennart Hansson, M.D., Department of Internal Medicine I, Sahlgren's Hospital, G5teborg, Sweden.
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these agents has been their relative lack of serious side effects provided t h a t contraindications such as obstructive respiratory disease and impending heart failure have been observed. It has also been considered an important advantage that postural or exercise hypotension, as seen with sympatholytic agents, do not occur during treatment with beta-adrenergic blocking agents.S, Furthermore, there is no doubt t h a t considerable reductions of raised blood pressure can be achieved during treatment with beta blockers. Thus, the antihypertensive effect of propranolol has been reported as being at least as potent as that of, e.g., guanethidine. ~, 10 In long-term treatment almost 80 per cent of patients reacted favorably to the use of propranolol. 1~
Pharmacological properties Propranolol and most of the other betaadrenergic blocking agents t h a t are clinically available in many countries today could be regarded as "first-generation beta blockers." Thus, these agents block beta-1 receptors, e.g., in the myocardium, as well as beta-2 receptors, e.g., in the bronchi or peripheral blood vessels. As illustrated in Table I, many of these agents also have a membrane-stabilizing effect, which is sometimes referred to as a quinidine-like or local anesthetic action. This also implies some myocardial depression. The importance of the membrane-stabilizing effect should not be exaggerated, however, in the ordinary clinical use of these drugs. Even with the comparatively high doses of beta blockers that are frequently used in hypertension this effect hardly has to be taken into account, as approximately 100 times higher dosage is needed to demonstrate it in comparison with the dosage needed to demonstrate beta-receptor blockade. ~1 Some of the beta-adrenergic blocking agents
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Beta-adrenergic blockade in hypertension
also have a s y m p a t h o m i m e t i c action (Table I). This could be simply described as a weak agonist action of the c o m p o u n d in addition to its antagonistic action. I n the clinical situation beta blockers with s y m p a t h o m i m e t i c effect could be expected to cause a lesser reduction of resting heart rate 'and m y o c a r d i a l p e r f o r m a n c e t h a n agents devoid of this characteristic. During the last few years more specific beta-blocking agents have appeared. This "second generation" of beta-adrenergic blocking agents could be characterized as being cardioselective in their action since t h e y block beta-1 receptors specifically. Practolol, metoprolol, atenolol, and tolamolol (Table I) are all specific beta- 1 receptor blockers. Their specificity for beta-1 receptors is not absolute, however, b u t the affinity for blocking beta-1 receptors is 50 times higher or more t h a n the effect on beta-2 receptors. Clinically, this means t h a t patients with Obstructive respiratory disease could be t r e a t e d with considerably less risk of producing b r o n c h o c o n s t r i c tion.
Antihypertensive mechanisms From the onset of b e t a - r e c e p t o r blocking t h e r a p y in hypertension great interest has been focused on possible m e c h a n i s m s u n d e r l y i n g the antihypertensive action. In brief, h e m o d y n a m i e mechanisms, central nervous actions, reninangiotensin effects, as well as effects related to the local anesthetic effect have been discussed in this connection. Hemodynamic effects. I t is well k n o w n t h a t most forms of established h y p e r t e n s i o n are characterized by normal cardiac o u t p u t and elevated total peripheral resistanceY ~ Therefore it could seem unlogical to administer beta-adrenergic blocking agents in this condition in view of the predominantly cardiac effects of these agents, except m a y b e in the r a t h e r rare hyperkinetic forms of hypertension. Acute intravenous administration of beta blockers to hypertensive patients causes a significant reduction of cardiac o u t p u t b u t no c h a n g e of blood pressure due to a c o n c o m i t a n t rise of t o t a l peripheral resistance. TM ~4 L o n g - t e r m administration of propranolol with a c c o m p a n y i n g r e d u c t i o n of blood pressure was initially regarded as being effective m a i n l y t h r o u g h the chronic reduction of cardiac output. 7 L a t e r the Cleveland Clinic group has d e m o n s t r a t e d t h a t a gradual r e a d j u s t m e n t of
American Heart Journal
Table I. P h a r m a c o l o g i c a l properties of some beta-receptor antagonists Blockers Beta Beta -1 -2
Propranolol Alprenolol Oxprenolol Sotalol Timolol Penbutolol Pindolo! Practolol H 93/26 metoprolol ICI 66.082 atenolol Toialnolol
+ + + + + + + + + + +
+ + + + + + + -----
Sympathomimetic effect
Membrane stabilizing effect
-+ + ---+ + ----
+ + + --+ + -----
total peripheral resistance down to the initial level or lower takes place during chronic treatm e n t with propranolol, ~5 a finding confirmed by our own studies. 24 A reduction of plasma v o l u m e during treatment with propranolol has been reported to occur in some patients 26 b u t this finding has not been confirmed in o t h e r studies, neither as regards propranoloI, 27 nor alprenolol, 26 or pindolol. 29 I t would therefore seem unlikely t h a t the antihypertensive action of beta blockers could be attributed to a reduction of plasma volume. Even an unchanged plasma volume could be an a d v a n t a g e during long-term therapy, however, as drug resistance due to salt and water retention, c o m m o n l y seen with other agents, 3~ should n o t be expected to occur. Central nervous effects. I t is well k n o w n from autoradiography studies in animals t h a t betaadrenergic blockers with few exceptions easily penetrate the blood-brain barrier and are accumulated in the central nervous system. Therefore it would be conceivable t h a t the antihypertensive effect of these agents could at least in part be explained by central nervous actions as has been suggested, e.g., by Dollery's group. T M ~2 On the other hand, practolol a n d atenolol do n o t penetrate the blood-brain barrier a n d still have a clear antihypertensive actionY. ~ T h e importance of central nervous effects is therefore uncertain at present. F u r t h e r difficulties arise from studies showing alprenolol to have a central nervous action, whereas p r o p r a n o l o l does not/4 in
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Table II. H y p o t e n s i v e effect reported with beta-adrenergic blocking drugs
Re[. No.
Compound
16 14 8 10 19
Alprenolol Alprenolol Propranolol Propranolol Propranolol
19 19
Alprenolol Pindolol
19
No, of patients
7 (15) 41 82 (158) 232 {303) 20
Reduction of blood pressure (mm. Hg)
800 800 271 360 120-240
46/19 14/6 30/16 57/31 25/19
20 20
300-600 15-30
20/21 26/17
Timolol
20
15-30
24/14
17
Practolol
12 (48)
440
42/26
20 80
Oxprenolol Propranolol
20 (31) 17
280 320
22/14 46/25
62
Propranolol
1]
spite of the fact t h a t b o t h agents easily p e n e t r a t e into the central nervous system. It is conceivable t h a t the change of baroreceptor sensitivity t h a t h a s been suggested to t a k e place during prolonged t r e a t m e n t with b e t a blockers,~. 3~ and which could explain the previously m e n t i o n e d r e a d j u s t m e n t of t o t a l p e r i p h e r a l resistance, m a y depend on central n e r v o u s actions of the drugs. Effects on the renin-angiotensin system. T h a t beta-adrenergic blocking agents reduce renin release and p l a s m a renin activity in m a n h a s been d e m o n s t r a t e d in several studies26. 37 In a s t u d y t h a t has a t t r a c t e d m u c h a t t e n t i o n , L a r a g h ' s group in 1972 claimed t h a t the a n t i h y p e r t e n s i v e effect of propranolol was considerably m o r e m a r k e d in patients w i t h high p l a s m a renin activity in relation to their u r i n a r y sodium excretion28 Conversely, very little effect on blood pressure was seen in the p a t i e n t s with low p l a s m a renin activity. '~ L a r a g h a n d his co-workers have l a t e r d e m o n s t r a t e d the s a m e relation between initial p l a s m a renin a c t i v i t y and blood pressure response to p r o p r a n o l o l in a s t u d y comprising a group of p a t i e n t s with " p u r e " essential h y p e r t e n sion. :~'' T h e y h a v e also claimed t h a t t h e r e is a significant correlation b e t w e e n the change of blood pressure and the change of p l a s m a renin activity during p r o p r a n o l o l therapy.~' This finding m a y seem appealing from a logical
396
Daily dosage (mgJ
80-240
29/24
Remarks
Standing BP + Diuretics + Diuretics in all; + methyldopa in 4 patients + Diuretics in all; + methyldopa in 4 patients + Diuretics in all; + methyldopa in 4 patients + Diuretics in 2 and hydralazine in 1 patient + Hydralazine (diuretics in 7 patients) + Minoxidil
point of view if one regards t h e elevated blood pressure and the high p l a s m a renin activity as expressions of increased s y m p a t h e t i c tone which are b o t h normalized by the a d m i n i s t r a t i o n of a beta-adrenergic r e c e p t o r blocker. T h e r e are no indications, however, t h a t the r e n i n - a n g i o t e n s i n s y s t e m has a direct influence on blood pressure in n o n m a l i g n a n t essential h y p e r t e n s i o n , except possibly during s t a t e s of severe salt depletion. T h e r e is also a growing n u m b e r of r e p o r t s which c a n n o t s u b s t a n t i a t e the finding t h a t t h e initial p l a s m a renin activity is of decisive i m p o r t a n c e for the antihypertensive response t o b e t a blockade or t h a t the change of renin is c o r r e l a t e d to the change of blood pressure2 T M However, r e c e n t l y it has been shown t h a t lowrenin p a t i e n t s initially unresponsive to p r o p r a n olol h a d a m a r k e d reduction of blood pressure following increased dosage2 ' T h i s seems to indicate t h a t b o t h opinions in this m a t t e r m a y in fact be correct. A n u m b e r of other variables t h a t could be expected to reflect s y m p a t h e t i c nervous activity, e.g., initial h e a r t rate, cardiac o u t p u t , or excretion of u r i n a r y catecholamines, h a v e been shown to be of little value in predicting the a n t i h y p e r t e n s i v e response to b e t a blockade2 ~..... Local anesthetic effect. Studies in r a b b i t s h a v e indicated t h a t the a n t i h y p e r t e n s i v e effect of propranolol was n o t related to t h e b e t a - r e c e p t o r blocking effect b u t r a t h e r to a n e u r o n - b l o c k i n g
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Beta-adrenergic blockade in hypertension
effect. 46 Clinical trials with the dextro-isomer of propranolol, which retains the local anesthetic effect of the racemic preparation but not the beta-receptor blocking capacity, have demonstrated no antihypertensive effect,47, 4s It therefore appears that the local anesthetic effect is w i t h o u t importance for the antihypertensive effect of beta-adrenergic blocking agents in man. In summary, it is difficult to provide an explanation of the antihypertensive mechanism of beta block.ers that would cover all the various agents presently available. Undoubtedly, in most cases the effect seems to be due to a chronic reduction of cardiac output with acompanying readjustment of total peripheral resistance to the initial or a lower level. It is conceivable, however, t h a t an index of cardiac peformance other than cardiac output, e.g., force of contraction (dp/dt), would be a better general denominator as the effect on cardiac output is known to be almost nonexistent with some beta blockers. It is also conceivable that central nervous effects do play a role at least in modifying the hemodynamic changes. The role of effects via the renin-angiotensin system seems to be rather small but certainly merits further research, e.g., along the lines of Frisk-Holmberg and Shand29 Selection of patients for treatment with beta blockers
It has been a common belief t h a t patients with a hyperkinetic circulation would be particularly responsive to treatment with beta-receptor blocking agents. Looking solely at the antihypertensive response, however, such patients do not respond more favorably to treatment than others. Thus, no correlation can be demonstrated between initial heart rate or cardiac output and blood pressure response2 ~ There is also no correlation between the change of cardiac output and the change of blood pressure during propranolol treatment. 2~ Undoubtedly, though, there is an extra benefit of treatment with beta blockers in patients with hyperkinetic circulation as palpitations or other similar symptoms usually disappear. Another common opinion is that older patients should not be given beta blockers. We do not wish to comment upon the need for antihypertensive therapy as such in the elderly,5~ but beta blockers
American Heart Journal
have been used successfully in the treatment of hypertensive patients over the age of 70 years. 51 Treatment with beta-receptor blockers in patients with renal insufficiency has recently caused debate due to a study in which three patients with moderate renal insufficiency showed rapidly deteriorating renal function during treatment with propranolol. 52 The results in these three patients are not in agreement with previous positive experience of beta blockade in uremic patients23, 54 Moreover, it should be noted that the negative report has been refuted by the group which probably has the widest experience of treatment with beta blockers in patients with renal insufficiency2~ Thus, it would appear t h a t the selection of patients for antihypertensive treatment with beta blockers does not have to be limited with respect to the hemodynamic picture, renal function, or age of the patient. We have drawn practical conclusions from this and have been using betaadrenergic blocking agents, mainly propranolol and alprenolol, as the first drugs of choice in the treatment of hypertension in our clinic since 1970. Contraindications and side effects
The beta-adrenergic blocking agents have certain contraindications that should be strictly observed. The importance of excluding patients with obstructive respiratory disease has already been touched upon, at least when treatment with nonselective beta-1 and beta-2~ blocking agents is considered. Another important (but maybe not absolute) contraindication is impending heart failure. Thus. in a study comprising 38 hypertensive patients with an average age of 72 years, only three patients developed heart failure during alprenolol therapy, two of whom could continue treatment after addition of digitalis21 In our own experience heart failure is extremely rare as a complication of beta-adrenergic blocking therapy when treating hypertensive patients. Further contraindications are A-V conduction blocks-at least A-V blocks II and I I I - a n d unstable diabetes mellitus requiring insulin therapy. Early in the era of beta-adrenergic blocking therapy it was already obvious t h a t side effects were' few and relatively mild. Thus, in a survey of 1,500 patients treated with propranolol, only 98
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side effects were reported, e.g., vertigo, fatigue, and nausea, a n d only 19 p a t i e n t s h a d to stop medication due to side effects2 ~ In a l o n g - t e r m s t u d y comprising m o r e t h a n 300 h y p e r t e n s i v e patients, 67 tolerable side effects were r e p o r t e d and 29 p a t i e n t s had to be t a k e n off the b e t a blocker t h e r a p y . 1~ Usually side effects give subjective s y m p t o m s and t h e y also t e n d to occur early during t r e a t ment. T h i s m a k e s it possible to a d j u s t dosage or withdraw t h e r a p y if needed during an early phase of t r e a t m e n t . T h e s e f e a t u r e s of b e t a - a d r e n e r g i c blocking t h e r a p y m u s t be considered p r e f e r a b l e to the slow onset t y p e of m e t a b o l i c d i s t u r b a n c e s w i t h o u t subjective s y m p t o m s t h a t are seen w i t h several other t y p e s of a n t i h y p e r t e n s i v e drugs. Beta blockers in combination with other antibypertensive agents It has been pointed out t h a t the c o m b i n a t i o n of beta-adrenergic blockade and v a s o d i l a t a t i o n offers a new aspect on the drug t r e a t m e n t of hypertension27 Several reports h a v e also confirmed the usefulness of such c o m b i n a t i o n s , e.g., between beta blockers a n d h y d r a l a z i n e ~~ ~1 or newer m o r e p o t e n t vasodilators such as minoxidi162 and guancydine. ~3 T h e relaxation of v a s c u l a r s m o o t h muscle with ensuing r e d u c t i o n of peripheral vascular resistance and blood pressure leads to a b a r o r e c e p t o r - m e d i a t e d increase of h e a r t r a t e and cardiac o u t p u t w h e r e b y t h e antihypertensive effect of the v a s o d i l a t o r is all b u t nullified. A d m i n i s t r a t i o n of a b e t a - r e c e p t o r blocker in this s i t u a t i o n breaks this chain of c o m p e n s a t o r y m e c h a n i s m s , thus u n m a s k i n g the full a n t i h y p e r t e n s i v e p o t e n t i a l of the vasodilator, as can be clearly d e m o n s t r a t e d in h e m o d y n a m i c studies. ~4 A n o t h e r way of achieving peripheral vasodilatation would be to reduce v a s o c o n s t r i c t o r activity by alpha-adrenergic r e c e p t o r blockade. Also in this setting b e t a - r e c e p t o r blockade is desirable in order to prevent reflex-induced i n c r e m e n t s of h e a r t r a t e and cardiac output. Initial clinical trials with c o m b i n e d alpha- and b e t a - r e c e p t o r blockade were not successful due to t h e limiting side effects of alpha-adrenergic blockade25 M o r e positive reports have been published, e.g., on t h e use of oxprenolol and p h e n t o l a m i n e 2 ~ Our own limited experience with a new c o m p o u n d (AH 5158) which exhibits b o t h alpha- and b e t a -
398
receptor blocking capability is also quite favorable. A f u r t h e r w a y of obtaining r e l a x a t i o n of precapillary resistance vessels would be b y specific s t i m u l a t i o n of v a s c u l a r beta-2 receptors. T h e initial clinical experience with c o m b i n e d beta-2 receptor s t i m u l a t i o n a n d beta-1 r e c e p t o r blockade in h y p e r t e n s i o n h a s n o t seemed to offer practical advantages, however. 67 Needless to say, the c o m b i n e d use of a b e t a blocker and a diuretic also offers a useful m e a n s b y which elevated blood pressure can be reduced. T h e c o m b i n a t i o n with a diuretic is not a s essential as, e.g., during t r e a t m e n t w i t h s y m p a t h o l y t i c drugs, since b e t a blockers do n o t cause p l a s m a volume expansion as discussed above. An a d v a n tage with combined beta b l o c k a d e and diuretic t r e a t m e n t , though, would be t h a t the doses of each drug could be reduced significantly while maintaining an a d e q u a t e a n t i h y p e r t e n s i v e effect. This could positively affect m a i n l y the thiazideinduced h y p o k a l e m i a and hyperuricemia28 Additional benefits of beta-receptor blockade A n u m b e r of additional benefits have been reported f r o m t h e use of b e t a - b l o c k i n g t h e r a p y , e.g., the relief of angina pectoris and migraine. Of interest are also the r e p o r t s on reduction of anxiety, as h y p e r t e n s i v e p a t i e n t s have been reported as being m o r e anxious t h a n n o r m o t e n sives29 During the first years of b e t a - b l o c k i n g t h e r a p y it was reported t h a t beta b l o c k a d e reduced anxiety in neurotic patients. TM Later, great interest has been focused on the effects of beta blockers in situations of stress and it has been shown t h a t oxprenolol given to race drivers before a race will abolish the t a c h y c a r d i a as well as the rise of blood glucose a n d free f a t t y acids. ~1 A normalization of the E C G a n d h e a r t r a t e could also be d e m o n s t r a t e d when a group of lecturers, m o s t of w h o m were physicians, were given a b e t a blocker prior to their p r e s e n t a tion. ~ In 1966 W a a l ~ speculated on the possibility t h a t beta-receptor blockers given to h y p e r t e n s i v e patients m i g h t in the long r u n reduce d e a t h s f r o m myocardial infarction due to t h e a n t i a r r h y t h m i c effect of these agents. In retrospective a n a l y s e s it has also been shown t h a t propranolol drastically reduced infarct d e a t h s in p a t i e n t s with k n o w n ischemic h e a r t disease. ~3 F u r t h e r m o r e , h y p e r t e n -
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Beta-adrenergic blockade in hypertension
sive patients treated with beta blockade seemed to have a three to four times lower risk of suffering a fatal infarct or sudden death. TM T h e reduced risk of sudden death has recently been confirmed in a prospective double-blind study in which alprenolQ1 was given to postinfarction patients/5 Obviously, these findings require further confirmation, particularly as regards the beneficial effect of beta blockers in the t r e a t m e n t of hypertension. If, however, it c a n be shown in prospective and controlled studies t h a t deaths from ischemic heart disease can be reduced by treatment with beta blockers this would constitute a significant advantage for this type of treatment over conventional antihypertensive treatment, which does not seem to reduce infarct deaths/~ Practical considerations affecting the choice of drug When treating mild to moderately severe hypertension there seems to be little difference between various beta-receptor blockers as regards their antihypertensive potency and side effects.l~. 18, 19. ~ In severe hypertension, however, beta blockers devoid of sympathomimetic properties may prove to be more effective/~. 7s Regarding dosage, it has been claimed t h a t an antihypertensive effect can always be expected provided that a sufficiently large dose is p r e scribed, which has led to the administration of up to 4 Gm. of propranolol a day2 It has also been demonstrated in a small number of patients t h a t increasing the daily dosage of propranolol also increases the antihypertensive effect. TM From a practical point of view extremely large doses of any drug are never desirable. Our own policy for many years has been to use combined therapy mainly with hydralazine or diuretics if a sufficient antihypertensive effect is not seen with propranolol, 300 to 600 mg. daily, or alprenolol, 1,000 to 1,200 mg. daily. When it comes to choosing between different beta-receptor blockers, we feel t hat long-term experience with, e.g., propranolol and alprenolol is such that this in itself constitutes a reason for selecting one of these "older" beta blockers r at her than any of the more recently introduced "firstgeneration" agents. The situation becomes somewhat different when the new "second-generation" beta blockers are taken into consideration, e.g.,
American Heart Journal
metoprolol and atenolol, as they offer certain advantages that have been discussed above. T h e recent experience with practolol, which after a few years of clinical use suddenly was found to cause serious side effects, warrants carefulness and observance when newer agents are taken into use. Regarding the number of daily doses that are required in order to maintain good control of the blood pressure, it is obvious t h a t the fewer doses needed and the simpler the administration of the drug the better the patient adherance to the prescribed regimen. 81 In this regard several beta blockers have been shown to maintain a stable level of blood pressure when given twice daily. This is true not only of alprenolol, which can be prescribed in Durules, but also of propranolol. 8~ 82 The long duration of beta blockers as regards their effect on blood pressure can also be illustrated by the slow rise of blood pressure if treatment is stopped. I~ It has also been demonstrated that the pharmacological half-life of several betareceptor blockers is considerably longer than their plasma half-life. 83 Regarding onset of action it has been claimed that up to six to eight weeks of t r e a t m e n t would be required in order to see the full antihypertensive effect of propranolol. 5 Obviously, this report of a slow onset of action could be explained by a low starting dose and a gradual buildup of dosage. Our own experience indicates a much faster lowering of blood pressure during propranolol treatment 3~ and, in reference to pindolol, it has been claimed that a significant reduction of blood pressure is seen within 20 minutes after oral administration. 84 T reat m ent with beta blockers and anesthesia has caused some concern. The extreme opinion that beta blockers should be withdrawn 4 weeks prior to coronary bypass surgery has been based upon postoperative cardiogenic shock in five patients in a report from the Cleveland Clinic. 8~ Obviously, one cannot exclude the possibility that the ischemic heart disease in these patients and not the t reat m ent with a beta blocker was the main contributing factor to their myocardial failure postoperatively. Our own policy regarding withdrawal or continuation of beta-blocking therapy in the preoperative situation has not been uniform. Undoubtedly, anesthesia can be performed in most cases without previous with-
399
Hansson
and Werk5
d r a w a l o f b e t a - b l o c k i n g t r e a t m e n t . If, h o w e v e r , d i s c o n t i n u a t i o n o f t h e r a p y is d e s i r e d , we h a v e u s u a l l y d o n e so 2 d a y s p r e o p e r a t i v e l y . T h i s w i l l n o t b r i n g b l o o d p r e s s u r e b a c k to t h e u n t r e a t e d level in m o s t p a t i e n t s , a s h a s a l r e a d y b e e n discussed, b u t r e s t i n g h e a r t r a t e w i l l rise t o t h e i n i t i a l level (or h i g h e r ) , i n d i c a t i n g t h a t b e t a b l o c k a d e is n o t p r e s e n t .
Future lines of development Future development of antihypertensive therap y c a n b e e x p e c t e d t o f o l l o w t h r e e m a i n lines. A further refinement of central nervous system-acting d r u g s of t h e c l o n i d i n e t y p e c a n b e e x p e c t e d , l e a d i n g t o d r u g s t h a t give less s e d a t i o n . A s e c o n d p o s s i b l e line of d e v e l o p m e n t w o u l d b e t h e p r o d u c t i o n of m o r e p o t e n t v a s o d i l a t o r s , a n d s o m e o f t h e s e , e.g., m i n o x i d i l a n d g u a n c y d i n e , h a v e already been touched upon here. However, with m o r e p o t e n t v a s o d i l a t o r s i t will b e c o m e m a n d a tory to administer both a beta blocker and a d i u r e t i c t o p r e v e n t reflex t a c h y c a r d i a a n d fluid r e t e n t i o n . T h u s , t h e v a s o d i l a t o r s c a n n o t be exp e c t e d t o serve as t h e first d r u g s of c h o i c e as t h e y s h o u l d b e r e s e r v e d for c a s e s n e e d i n g m u l t i p l e d r u g therapy. Finally, a refinement of the beta-receptor blockers can be foreseen and some of the "secondgeneration" beta blockers already look promising as r e g a r d s t h e i r a n t i h y p e r t e n s i v e effect. T h u s , a t e n o l o l ~3.86-~ a n d m e t o p r o l o P 9-~~ h a v e b e e n shown to have a useful blood pressure-lowering effect a n d c o m p a r a t i v e l y few a n d m i l d side effects. T h e a d v a n t a g e o f s e l e c t i v e b e t a - 1 r e c e p t o r b l o c k a d e is t h a t b r o n c h i a l b e t a - 2 r e c e p t o r s a r e not blocked, thereby reducing the risk of bronchoc o n s t r i c t i o n . I t is a l s o c o n c e i v a b l e t h a t t h e unblocked vascular beta-2 receptors may cont r i b u t e t o less p r o n o u n c e d rises o f b l o o d p r e s s u r e during episodes of increased release of catechol a m i n e s , e.g., d u r i n g m e n t a l s t r e s s o r p h y s i c a l exercise. F u r t h e r m o r e , t h e l a c k of a s y m p a t h o m i m e t i c effect w i t h b o t h a t e n o l o l a n d m e t o p r o l o l c o u l d b e a n a d v a n t a g e , a t least w h e n t r e a t i n g severe hypertension. S e e n a g a i n s t t h i s b a c k g r o u n d i t is p o s s i b l e t h a t f u t u r e t r e a t m e n t of h y p e r t e n s i o n will b e e v e n more dependent upon drugs with a beta-receptor b l o c k i n g a c t i v i t y t h a n is t h e c a s e t o d a y . W e w i s h to s t r e s s once a g a i n t h o u g h t h a t t h e p o s i t i v e experience with some of the newer agents should
400
b e c o n f i r m e d in l a r g e r series w i t h l o n g p e r i o d s o f follow-up before one can state that these agents a r e as safe as " f i r s t - g e n e r a t i o n " b e t a b l o c k e r s . REFERENCES
1. SchrSder, G., and WerkS, L.: Nethalide, a betaadrenergic blocking agent, Clin. Pharmacol. Ther. 5:159, 1964. 2. Prichard, B. N. C., and Gillam, P. M. S.: The use of propranolol in the treatment of hypertension, Br. Med. J. 2:725, 1964. 3. Paterson, J. W., and Dollery, C. T.: Effect of propranolol in mild hypertension, Lancet 2:1148, 1966. 4. Prichard, B. N. C., and Gillam, P. M. S.: Propranolol in hypertension, Am. J. Cardiol. 18:387, 1966. 5. Prichard, B. N. C., and Gillam, P. M. S.: Treatment of hypertension with propranolol, Br. Med. J. 1:7, 1969. 6. Waal, H. J.,: Hypertensive action of propranolol, Clin. Pharmacol. Ther. 7:588, 1966. 7. Frohlich, E. D., Tarazi, R. C., Dustan, H. P., and Page, I. H.: The paradox of beta-adrenergic blockade in hypertension, Circulation 37:417, 1968. 8. Hansson, L., Ma!mcrona, R., Olander, R., Rosenhall, L., Westerlund, A., Aberg, H., and Hood, B.: Propranolol in hypertension. Report on 158 patients treated up to one year, Klin. Wochenschr. 50:364, 1972. 9. Karlberg, B.; and HSrnkvist, P. E.: Propranolol in treatment of hypertension, Opusc. Med. 8:296, 1971. 10. Zacharias, F. J., Cowen, K. J., Prestt, J., Vickers, J., and Wall, B. G.: Propranolol in hypertension: A study of long-term therapy, 1964-1970, AM. HEART J. 83:755, 1972. ll. Lydtin, H., Kusus, T., Daniel, W., Schierl, W., Ackenheil, M., Kempter, H., LohmSller, G., Niklas, M., and Walter, I.: Propranolol therapy in essential hypertension, AM. HEART J. 83:589, 1972. 12. Furberg, C., and Michaelson, G.: Effect of Aptin, a betaadrenergic blocking agent in arterial hypertension, Acta Med. Scand. 186:447, 1968. 13. Tibblin, G., and Ablad, B.: Antihypertensive therapy with alprenolol, a beta-adrenergic antagonist, Acta Med. Scand. 186:451, 1968. 14. Bengtsson, C.: Comparison between alprenolol and chlorthalidone as antihypertensive agents, Acta Med. Scand. 191:433. 1972. 15. Beng~sson, C.: Comparison between alprenolol and propranolol as antihypertensive agents, Acta Med. Scand. 192:415. 1972. 16. Vedin. A., Wilhelmsson. C.. and WerkS. L.: Comparative study of alprenolol and methyldopa m previously untreated essential hypertension. Br. Heart J. 35:1285, 1973. 17. Prichard, B. N. C.. Boakes, A. J., and Day, G.: Practolol in the therapy of hypertension. Postgrad. Med. J. 47 (Suppl.):84. 1971 18. Andersson, O.. and Berglund. G.: Practolol-propranolol: Comparison of the antihypertensive effect. Acta Med. Scand. 1974. 19. Morgan. T. O.. Sabro. J., Anavekar. S. N.. Louis. W. J.. and Doyle, A. E.: A comparison of beta-adrenergic blocking drugs in the treatment of hypertension. Postgrad. Med. J. 50:253, 1974. 20. Dorph, S.. and Binder. C.: Evaluation of the hypotensive effect of beta-adrenergic blockade in hypertension. Acta Med. Scand. 185:443, 1968. 21. Coltart. D. J.: Assessment of beta-adrenergic blocking
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22. 23.
24.
25.
26. 27.
28.
29.
30. 31. 32. 33.
34.
35.
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March, 1977, Vol. 93, No. 3
