Beta-blocking drugs for arrhythmias, hypertension, and ischemic heart disease

Beta-Blocking Drugs for Arrhythmias, Hypertension, and lschernic Heart Disease

Varner J. Johns, MD, Loma Linda, California

It was in 1948 that Ahlquist [1] proposed that there were two distinct types of adrenergic receptors which he designated as alpha and beta. His conclusions were based on the observation that different sympathomimetic amines had different potencies and actions on different tissues. It was 10 years later that Powell and Slater [2] discovered dichloroisoproterenol, a drug that selectively blocked beta receptors. This discovery effectively opened the exciting era of beta blockade in all of its ramifications. In 1967, Lands et al [3] suggested the existence of two types of beta receptors: betai receptors, which mediate cardiac stimulation and lipolysis, and beta2 receptors, which mediate bronchodilation and a vasodepressor action. This concept has been supported by the identification of drugs that can selectively stimulate or block both of these mediators. In 1976, Ariens and Simonis [4] pointed out that beta-adrenergic receptors that respond to the neurotransmitter, noradrenalin, corresponded for the most part to betai receptors, whereas adrenaline could be related more to a betaz-adrenergic type of response. Exercise is a noradrenalin-producing stimulus, whereas mental stress and hypoglycemia are more likely to be associated with adrenaline-producing stimuli. Although the majority of betai receptors are in the heart and the majority of betas receptors are in the blood vessels and bronchi, there are a small number of beta2 receptors in the heart and a small number of betai receptors in the bronchi. This explains why small doses of betai- or betas-stimulating drugs, or betai- or betaz-adrenoreceptor-blocking drugs have activities that are more discrete, whereas large doees of these drugs tend to blur the differences between betai- and betas-stimulating or blocking FromLoma Linda lJniveu’sffySchool of Medkine. Loma Linda, California. RequestsfarrepfktsshoukibeaMessed to Van-w J. Johns, MD, Loma Linda University School of Medicine, Loma Linda, California 92354. Presented St the Nlnfh Annual Lymsn A. Brewer III Cardkthoracic Symposium, Los Angeles, California, December 7 and 8, 1983.

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drugs. Some of the actions that differentiate betablocking drugs are cardioselectivity, independent sympathomimetic activity, and membrane stabilizing activity. Betai responses result in cardiac stimulation, renin release, and lipolysis, whereas betas responses produce bronchodilation, vasodilation, and glycogenolysis. Cardioselective blockers are those that inhibit the cardiac betai receptors but have very little, if any, affect on the bronchial and vascular beta:! receptors. The standard for measuring cardioselectivity is the affect on exercise-induced tachycardia. The intrinsic sympathomimetic activity is the result of partial agonist activity as well as blocking activity on adrenergic receptors. Administration of drugs with this type of activity will result in less resting bradycardia and a greater decrease in systemic peripheral resistance than would occur with administration of drugs without intrinsic sympathomimetic activity. In some clinical situations, this reduction of resting bradycardia and reduction of peripheral resistance may provide a therapeutic advantage. In treating patients after myocardial infarction, however, intrinsic sympathomimetic activity would be a disadvantage. Membrane-stabilizing activity may also be referred to as the local anesthetic action or quinidine-like effect. It plays a very small, if any, role in the antiarrhythmic effect of beta blockers, since this action requires blood levels that are significantly higher than those obtained in vivo in order to have any effect on the inhibition of exercise-induced tachycardia [5]. It should also be noted that practolol, which has no membrane-stabilizing activity, is effective as an antiarrhythmic agent 161. Beta blockers with increased lipid solubility are more likely to be metabolized by the liver, whereas drugs with decreased lipid solubility are more apt to be excreted by the kidneys. There is wide variation

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between different beta blockers in their plasma protein-binding characteristics. The amount bound to plasma proteins affects the pharmacodynamics of the drugs since it is the free or unbound fraction of the drug that is pharmacologically active. Beta blockers tend to have relatively short half-lives, and those that are extensively metabolized have the shortest half-lives. Highly fat soluble drugs, like propranolol, are almost ‘completely eliminated by liver metabolism, whereas a drug such as practolol, with low lipid solubility and high water solubility, is excreted by the kidneys and has a longer half-life [7]. Blood levels of propranolol are increased in elderly persons as compared with young persons. Blood levels of the drug are also increased in patients with Crohn’s disease, Celiac disease, and uremia and are also higher when the drug is administered with food. This is probably due to saturation of the first pass effect with food [S]. Arrhythmias Although beta blockers are rarely used for sinus tachycardia per se, they may be very useful in treating sinus tachycardia that is secondary to heart disease or other disease processes, such as mitral stenosis with sinus rhythm, idiopathic hypertrophic subaortic stenosis, acute thyrotoxicosis, and coronary artery disease with angina pectoris. Paroxysmal atrial tachycardia with a reentrant arrhythmia may be benefitted by beta blockers. Digitalis is, of course, the indicated treatment for atria1 flutter or atria1 fibrillation; however, if digitalis has not slowed the heart adequately, beta blockade may provide additional slowing. Beta blockers are particularly helpful in cases of supraventricular arrhythmia since the sympathetic nerve supply to the atriums is greater than to the ventricles. Beta blockers are also helpful for some of the complex ventricular arrhythmias. They have been successful in suppressing chronic ventricular arrhythmias in approximately half of the patients studied [9-131. This form of therapy has been used in patients with arrhythmias due to coronary artery disease, mitral valve prolapse, idiopathic hypertrophic subaortic stenosis, and idiopathic ventricular premature contractions, but is also of use in those patients with digitalis-induced ventricular arrhythmia. When atenolol is used for suppressing ventricular arrhythmia; it should be given in a dose of at least 100 mg daily. It is noteworthy that its ability to suppress ventricular arrhythmia cannot be predicted on the basis of the blood level or the underlying type of heart disease. Anderson et al [14] demonstrated that five betablocking drugs caused, on average, a sixfold-increase in the ventricular fibrillation threshold in dogs under both nonischemic and ischemic conditions. The increased threshold for ventricular fibrillation and the reduced incidence of reinfarction are both logical mechanisms for reducing the death rate when pa-

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tients are treated with beta blockers after myocardial infarction. It has been well established that the cumulative death rate, the reinfarction rate, and the sudden death rate have been diminished in such patients [15-201. Beta-adrenoreceptor-blocking drugs have their primary antiarrhythmic properties as a result of the ability to antagonize the effects of catecholamines on cardiac automaticity and reentry [Zl’]. In one study [22], the arrhythmias that responded favorably to beta-adrenergic blockade with nadolol included extra systoles, ventricular bigeminy, ventricular trigeminy, paroxysmal atrial tachycardia, and sinus tachycaidia. Although atria1 flutter and fibrillation did not convert to sinus rhythm, they were favorably influenced by slowing. Nadolol is a potentially valuable betaadrenoreceptor-blocking agent because of its long half-life, since compliance is a greater problem with frequently administered drugs. When used to control arrhythmia, angina pectoris, or hypertension, this may be a valuable advantage for ensuring compliance in selected patients. Hypertension Beta-adrenergic blockade has become an important adjunct in the treatment of hypertension. It has proved to be more effective in treating hypertension in young patients than in elderly patients [23,24]. The mechanism by which beta-adrenergic blockade produces a diminution in blood pressure in hypertensive patients has not been definitely established, but it may be some combination of the following factors: a reduction in cardiac output, decreased plasma volume, action on the central beta adrenoreceptors that reduce sympathetic nervous tone, or an inhibition of renin secretion [25-291. There is a great deal of conflicting evidence regarding the role of beta blockade in the treatment of hypertension through its inhibition of renin activity. There have been, however, a few reports that have shown better control of hypertension in patients with high, as compared to low, renin levels [30-321. It has also been noted that marked suppression of plasma renin activity can be obtained at plasma propranolol concentrations that have a trivial hypotensive effect. This suggests that mechanisms other than the suppression of renin activity are important contributors to the hypotensive effect of propranolol[33,34].There is also some evidence that beta blockers are more effective in the treatment of patients with hypertension associated with diuretic therapy if the diuretic therapy has resulted in an increase in the plasma renin activity of more than 2 ng/ml per hour than in those patients receiving diuretic therapy who do not have such an increase [35]. From a review of all of the evidence on the usage of b&a blockers alone in the treatment of hypertension, it must be concluded that their effect is usually independent of their affect on renin. In hypertensive patients who

The American Journal of Surgery

have a significant increase in their plasma renin activity, the antihyperteneive effects &fdiuretics is,‘tb a significant degree, due to the suppression of renin release by beta-adrenergic blockade [35]. Labetalol is not only a beta-blocking drug, it also has alpha-adrenergic-blocking properties. Although the beta-blocking potency is much greater than the alpha blocking activity, it is, nevertheless, one of the few beta blockers that decreases peripheral vascular resistance and causes some peripheral vasodilation. The effect of this drug on systolic blood pressure has been found to be more pronounced with the patient in the standing position, but it did not cause postural hypotension [36]. Nadolol had the longest plasma half-life of any of the beta blockers that are now on the market and therefore can be administered once a day; thus it is associated with high patient compliance [37]. This medication has important hypotensive properties that make it effective for hypertension. Its mechanism for lowering blood pressure is apparently the same as other beta blockers [21]. Nadolol has decreased plasma renin activity by 50 percent. It carries a potentially greater risk in patients who have renal failure since approximately 70 percent of the absorbed dose is excreted by the kidneys [38]. Another effective antihypertensive and potent beta blocker is pindolol. Pindolol has intrinsic sympathomimetic activity that decreases peripheral vascular resistance, but it may also be associated with some paradoxical loss of blood pressure control when given in high doses. Metoprolol (Lopressor@) is a cardioeelective beta blocker which is an effective, well-tolerated antihypertensive agent. It is noteworthy that all beta blockers are antihypertensive. If beta blockers are to be administered to potentially.asthmatic patients, it is certainly better to employ a cardioselective agent, although the cardioselectivity may be lost at high doses. In addition, drugs with intrinsic sympathomimetic activity or partial agonist activity cause less bradycardia. Propranolol in a dose of 40 mg three times a day was successful in reducing the blood pressure while recumbent by 20/10 mm Hg. The effect was as great after 2 weeks of therapy as after 4 weeks [39]. Small doses of atenolol(50 mg/day) and metroprolol(lO0 mg/day) were effective in reducing blood pressure levels with patients in both sitting and standing positions [40]. Atenolol, when given once a day, is more effective in reducing blood pressure than pindolol given twice a day if they are given in dosage levels that provide comparable levels of betai blockade. It should alao be noted that side effects, including insomnia, dizx&ss, and impotence, were less frequent with atenolol(16.6 percent) than with pindolol(36.8 percent) [41]. It was also noted by Creminger et al [42] that 100 mg of atenolol produced a more pronounced diastolic blood pressure reduction than 20 mg of pindolol using the sustained release form. Forty-four percent of the patients who did not revobma 147, Jum le84

spond to pindolol showed good blood pressure control tiih atenolol, whereas only 10 percent of those who did not respond to Atenolol showed good blood pressure control with pindolol[42]. Angina Pectoris

Angina pectoris occurs whenever there is significant narrowing of one or more coronary arteries by a significant fixed atherosclerotic lesion or by coionary spasm. Angina is usually precipitated by something that increases myocardial oxygen utilization. It may, however, be the result of a decrease in the myocardial oxygen supply caused by such mechanisms as spasm or a reduction in the diastolic blood pressure. The principal determinants of myocardial oxygen utilization include heart rate, contractility of the myocardium, left ventricular muscle mass, and tension in the wall of the left ventricle. The latter is effected by the systemic arterial pressure (afterload) and by the preload, which is dependent on the venous return. The treatment of angina, at the present time, is centered around the use of nitrates, calcium channel blockers, and beta blockers. The mechanism of action of the beta blockers as a class is through their effect in reducing myocardial oxygen utilization. This reduction is achieved by decreasing the heart rate, the systemic arterial blood pressure, and myocardial contractility. If the patient has left ventricular failure, beta blockers should ordinarily not be used. If the patient is on the verge of left ventricular failure, then the use of beta blockers may increase the patient’s angina by reducing myocardial contractility, resulting in an increase in heart size which causes an increase in tension in the left ventricular kall and, hence, an increase in myocardial oxygen utilization. In such a setting, the patient’s angina might increase rather than decrease. In the absence of bradycardia, hypotension, or left ventricular failure, beta-blockade treatment of angina pectoris is a dependable method for the reduction of chest pain. The effect of exercise on angina pectoris is also primarily through reduction of heart rate. The amount of exercise that achieves the heart rate that caused angina pectoris before the initiation of a regular exercise program will again result in angina pectoris, although a higher level of exercise would be required to reach the same heart rate. Long-term therapy with atenolol has been shown to decrease the frequency of chest pain, reduce the amount of nitroglycerin required to control chest pain, increase exercise tolerance, reduce heart rate, and reduce the peak double product (heart rate multiplied by systolic blood pressure) [#I. Although all beta blocking drugs are effective in the treatment of angina pectoris, it is interesting to compare the relative effect of a drug like pindolol that has significant intrinsic sympathomimetic activity and propranolol, a drug without such activity. They both 727

have comparable effects in reducing the incidence of anginal attacks and in increasing exercise tolerance. Pindolol, however, does not decrease the resting heart rate or the ejection fraction or increase the left ventricular end-diastolic volume to the same extent that propranolol does [44,45]. Myocardial Infarction In 1967, it was first suggested by Braunwald [46] that if the balance between the myocardial oxygen supply and demand could be altered, the size of a myocardial infarct might be reduced. In 1967, Snow [20] reported that orally administered propranolol, when given for 3 weeks after acute myocardial infarction, reduced mortality. His findings were not confirmed by Balcon et al [47] in a controlled trial shortly thereafter, in which propranolol was given in the 24 hour period after the onset of chest pain. Although propranolol has been quite successful in dogs in the experimental laboratory, the evidence in human subjects after an acute myocardial infarction has been unsatisfactory in many studies and, therefore, it must still be considered investigational. In a laboratory study on dogs, Miura et al [48] noted that when propranolol was given before coronary occlusion occurred, there was a 53 percent reduction in infarct size; when it was given 3 hours after occlusion occurred, the infarct size was reduced by 28 percent; but if it was not given until 6 hours after occlusion occurred, there was no effect. In light of this information, only when beta blockers are given during the first 3 hours after myocardial infarction should a reduction in the size of the infarct be expected. All studies regarding the reduction in myocardial infarct size should be disregarded if the time of administration of the beta blocker is longer than 3 to 5 hours after the onset of pain. There is no definite evidence that early intervention after acute myocardial infarction using beta blockers reduces mortality. If this form of therapy is to be beneficial in human subjects, it would require the intravenous administration of a cardioselective beta blocker without intrinsic sympathomimetic activity within 3 hours after the onset of chest pain. Such a study that is both randomized and doubleblind should be carried out. For short-term administration of beta blockers after myocardial infarction, one must be careful to avoid employing these drugs in situations where they are definitely contraindicated, such as asthma, severe hypotension, acute left ventricular failure, marked bradycardia, and heart block. On the other hand, there is strong evidence that supports the use of cardioselective beta-blocking drugs without intrinsic sympathomimetic activity during the period from 1 to 36 months after myocardial infarction. There is an impressive array of supportive data from several randomized doubleblind studies which have utilized large numbers of patients and a variety of beta blocking drugs. These

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studies have demonstrated the value of long term beta-blocker therapy (duration of at least 1 to 3 years after myocardial infarction). Drugs that have been studied include oxprenolol, sotalol alprenolol, timolol, metoprolol, propranolol, and practolol [15-17,19,49-531. The decreased mortality associated with beta-blocking drugs is likely, at least partially, to be the result of a higher threshold for ventricular fibrillation [14]. Stimulation of the cardiac sympathetic nerves has been shown to decrease the threshold for ventricular fibrillation [54,55]. Beta-blocking drugs also reduce mortality by reducing the rate of reinfarction. They may also affect mortality through the same mechanisms that reduce the incidence of angina pectoris. Propranolol may lessen platelet aggregation, although it affects platelet function much less than does aspirin [56]. There also may be some benefit from an inhibition of lipolysis [57], which affects myocardial metabolism in a manner that spares oxygen. In 1974 Wilhelmsson et al [52] demonstrated a 50 percent reduction in total mortality with alprenolol for a period of 2 years. In a multicenter international study in 1975 [19], practolol was employed, and total mortality was reduced from 7.7 to 6.2 percent. Because of the incidence of side effects, practolol has been withdrawn from the market, and therefore, the study is of help only in demonstrating the general benefit of beta blockers. In 1979, Andersen et al [53] demonstrated a reduction in mortality of patients 65 years of age or younger from 20 to 9 percent when they employed alprenolol for a period of 1 year. In 1981, the Norwegian Multicenter Study Group [15] reported on the use of timolol for reduction in mortality and reinfarction in patients who survived myocardial infarction. They started treatment 7 to 28 days after infarction occurred. When they compared the cumulative sudden death rate over 33 months, they found a 13.9 percent rate in the placebo group and a 7.7 percent rate in the timolol group (a reduction of 44.6 percent). The cumulative reinfarction rate was 20.1 percent in the placebo group and 14.4 percent in the timolol group. These were impressive differences and involved a large number of patients: placebo group 939 patients, timolol group 945 patients. In 1981, Hjalmarson et al [IS] showed a beneficial effect of metoprolol when it was given for a period of 3 months. There was an 8.9 percent mortality rate in the placebo group and a 5.7 percent rate in the metroprolol group (a reduction of 36 percent). The P-Blocker Heart Attack Trial Research Group [17] studied 3,837 patients during a 25 month period who were given propranolol. In the placebo group, the mortality rate was 9.8 percent, and in the propranolol group, it was 7.2 percent. Sudden cardiac deaths occurred in 4.6 percent of the patients in the placebo group and in 3.3 percent of those in the propranolol group. The mortality rate from arteriosclerotic heart disease was 8.5 percent in the placebo group and 6.2

The American Journal at %qgefy

Beb-Mcking Drugs

percent in the propranolol group. In 1982, in a preliminary report of the Norwegian MGlticentre Trial, Hansteen et al [Ss] also reported benefits from propranolol when given for a period of 1 year. In summary, there is now extensive evidence that supports the use of beta blockade to reduce the death rate in patients after their recovery from an acute myocardial infarction for a period of at least 1 to 3 years. Patients, of course, should be excluded from treatment who have major contraindications, including impaired myocardial function, asthma, insulin-dependent diabetes mellitus, peripheral vascular disease, or conduction disorders [59]. The therapy may need to be stopped if there are side effects that are not well tolerated by the patient, including hypotension, dizziness, bradycardia, decreased sexual activity, congestive heart failure, psychiatric manifestations, cold extremities, and gastrointestinal tract complaints [15,17,58,60]. Some of the beta blockers that are clinically beneficial are not yet available in the United States. The beta blocker that will become the eventual drug of choice has not been definitely determined but will likely be cardioselective without intrinsic sympathomimetic activity. Whether beta blockade will continue to be beneficial if given more than 2 to 3 years after the myocardial infarction has also not been established. If there are subgroups with low mortality rates that can be eliminated from therapy without losing the demonstrated benefits in groups with high mortality, this would be desirable. A very promising avenue for future study has been presented by Theroux et al [61]. They used the exercise electrocardiogram to study patients 1 day before hospital discharge after they suffered acute myocardial infarction. He grouped patients according to whether or not they had new ischemic changes. He found that 70 percent of patients without S-T segment depression had a mortality rate of only 2.1 percent, whereas the 30 percent of patients with S-T segment depression on the exercise electrocardiogram had a mortality rate of 27 percent. It would seem desirable to eliminate the low mortality group from therapy with beta blockers. It would be advantageous if we did not need to administer the drug to all postmyocardial infarction patients in order to obtain the beneficial effect. The overah reduction in mortality of 26 to 39.4 percent by beta-blocker therapy after myocardial infarction is an important enough benefit to warrant therapy in those patients in whom there is no contraindication [15-171. Summary Beta-blocking drugs have provided significant improvement in the medical therapy of many types of heart disease. They are more effective in treating young hypertensive patients than elderly hypertensive patients. These drugs reduce the ventricular rate seen in atrial flutter and fibrillation, and they also volunn 147, Jum 1994

reduce the frequency of ventricular ectopy. Beta blockers are important adjuncts for control of angina pectoris. When these drugs are given for a period of 1 to 3 years after myocardial infarction they reduce the incidence of reinfarction and the frequency of sudden death as well as reduce the overall mortality rate. Factors that may contribute to the overall decreased mortality include the reduction in the reinfarction rate and an increased threshold for ventricular fibrillation as well as those mechanisms that reduce myocardial oxygen utilization. References 1. AhlquistRP.AsRdyoftheadrenotropicr~.AmJPhysiol 1948;153:58&600. 2. PowellCE,SlaterlH.B4ockingofinhMoryactsnagicreoeptors by a dichloro-analog of isoproteronol. J phermacolExpTher 1958;122:480-8. 3. LandsAM, ArnoldA, McAuliffJP, LuduenaFP, BrownTG Jr. Differentlath of receptorsystemsactivatedby sympathc+ mimetic amines. Nature 1967;214:597-8. 4. ArlensEJ, simonisAM. Receptorsand mceptor mechanisms. In: Saxena PR, ForsythRP eds. F blocking agents.New York: Elsevkr, 1976:3-28. 5. Singh BN. Clinical aspects of the ant-c actions of beta-receptorblockingbugs. part 2. ClinicalPharmacology NZ Med J 1973;78:529-35. 6. SinghEN, Jewltt DE. B-adrenergicrecepforbkxklng drugsin cardiac arrhythmias.Drugs 1974;7:42&61. 7. Johnsaon0, RegardhCG. Clinical pharmacokineticsof &adrenoreceptorblockingdrugs. Clln Pharmacoklnet1976; 1:233-63. 8. Meier J. Pharmacokineticcornparlscmof pindololwith other beta&renoceptor-blocking agents. Am Heart J 1982; 104:304-73. 9. WinkleRA, LopesMG,GoodmanDJ, FltzgsraldJW, Schroeder JS, HarrisonDC. Propranololfor pat&eMswith mltral valve prolapse.Am Heart J 1977;93:422-7. 10. KoppesGM, BeckrnannCl-l,JonesFG. PmpmMol therapyfor ventriculararrhythmias2 months after acute myocardial infarction.Am J Cardiol 1980;4&322-8. 11. PrattCM, MatlackJ, CarneyS, et al. Efficacyof metoprololin suppressingventricularectopic beats.Clrculation1980;82 (suppf3):180. 12. DeSoyzaN.KaneJJ,MuphyML,Lad&AR,Doherty&Bissett JK. The long-termsuppressionof ventriculararrhyhnia by oral acebutololin patientswith coronaryarterydisease.Am Heart J 1980;100:631-8. 13. h4organroth J. short-termevaluationof atanobl in hospitalized Drugs1983;25 pathtswithchonkventricularaMythmh. (suppl2):181-5. 14. AndersonJL, Rodier HE, Green LS. Comperstlve effectsof v bkxking drugson expalmmtal ventricular fibrillationthreshoki.Am J Cardlol 1963$1:1196-202. 15. The NorwegianMulticenterStudyhup. Tlmolol-inducedreduction in mortalityand reinfarctlonin patients survlvlng acute myocardlalInfarction.N EnglJ Med 1981;304:8017. 16. HjalmarsonA, Herlitz J, h4alekI, et al. Effect on mortalityof metoprolol in acute myocardlalInfarction:a double-blind randomizedtrial. Lancet 1981;2:823-7. 17. B-BlockerHeart Attack Trial ResearchGroup.A randomized trial of propranololin patients wtth acute myocardielinfarction. 1. MortalityResults.JAMA 1982;247:1707-14. 18. BraunwaklE, Miller JE, KlonerRA, MarokoPR. Role of betaedrenerglc blockade in the tharapy of pathts with myocardlal infarction.Am J Med 1983:7&l 13-23. 19. A MulticentreInternationalStudy.Improvementin prognosis

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