The Clinical Pharmacology Beta-Adrenoceptor-Blocking Matthew

E. Conolly,

Friedrich

T

HE development of agents capable of producing selective blockade of beta-adrenoceptors has proved to be one of the most fruitful, informative, and therapeutically exciting developments in human pharmacology that has emerged since the end of the second world war. These drugs have been invaluable in enlarging our understanding of physiologic mechanisms involved in the regulation of a wide range of bodily functions, both in the laboratory animal and, more particularly, in man. Although initially conceived of as a means of treating angina pectoris, it swiftly became apparent that beta-blocking drugs had much to offer in several other quite different clinical situations. The application of these agents has been accelerated by the development of drugs possessing a degree of selectivity for various subgroups of the betareceptor population. More controversial has been the introduction of agents with varying degrees of intrinsic sympathomimetic activity. A useful range of beta-blocking drugs is now available to the clinician in most (although regrettably not all) Western countries. Experience with them in other parts of the world is growing rapidly. It is not possible in a review of this nature to summarize all that has been written on these drugs. It will be our aim to concentrate on their use in man, making reference to animal data only when they serve to clarify various points. BASIC

PHARMACOLOGIC

ASPECTS

BETA-ADRENOCEPTOR

OF

BLOCKADE

A brief review of the relevant pharmacology is a necessary preliminary to the consideration of their use in man. From the Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, London, England. Reprint requests should be addressed to Matthew E. Conolly, M.D., Department of Clinical Pharmacology, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W.l2.OHS, England. o 1976 by Grune & Stratton, Inc. Progress

in Cardiovascu/ar

Diseases,

Vol.

XIX,

Kersting,

and

of Drugs Colin

T. Dollery

Beta-adrenergicReceptors The releaseof neurotransmitter substancefrom sympathetic postganglionic nerve endings or the administration of exogenous catecholamines results in a biologic responseof the target tissue. This biologic responseis causedby the interaction of the agonist with a chemically distinct part of the cell membrane,the receptor. The concept of drug-receptor interaction was introduced by Langley’ and substantiated by Dale2 who demonstratedthat the pressoreffect of epinephrine could be prevented by ergot alkaloids. Since adrenergic receptors have not yet been isolated, nor defined either chemically or morphologically, characterization is based on indirect (pharmacologic) criteria. Ahlquist3 introduced the concept of two types of adrenergicreceptors, which he termed alphaand beta. He based his classification on the responses evoked by five different sympathomimetic amines on a variety of tissuesin vitro and in vivo. Alphareceptors were defined as those with the highest sensitivity to norepinephrine and the lowest sensitivity to isoproterenol. Those classifiedas betareceptors showed the opposite pattern of sensitivity to the same seriesof sympathomimetic amines.Ahlquist’s classificationwasnot finally accepted until the development of specific betaadrenoceptor-blocking drugs10 yr later established it beyond doubt. The first of this important series of drugs to be described was dichloroisoprotereno1.435 The distribution of the different types of adrenergic receptorsin sympathetically innervated mammalian tissuesis shownin Table 1. At present the evidence indicates that there is only one type of alpha-adrenoceptor.6All respond well to norepinephrine, and all may be blocked not only by ergot, but also by phentolamine, tolazoline, azapetin, and phenoxybenzamine and newer agentslike thymoxamine and indoramine. However, responsesof beta-adrenoceptorsto available agonistsand antagonistsvary quantitatively so much that the existence of subgroupsof betareceptors has been postulated. Lands et al7 proposed that cardiac, intestinal, and adipocyte beta-

No. 3 (November/December),

1976

203

204

CONOLLY,

Table

1.

Heart SA node Atria

Classification Adrenergic

of Responses Stimuli

Increase Increase

to

rate in velocity

conduction AV

node and conducting

system

of

and

contractility Increased conduction, velocity, and shortening of effective refractory period

Ventricle

and

Sphincters Intestine

glycogen-

olysis Constriction Relaxation

and

Sphincters Urinary bladder Detrusor Trigone

Decrease Contraction

Mobility tone

and

Relaxation Contraction

Radial

muscle,

Contraction

iris Ciliary

muscle

(mydriasis) Relaxation vision

sphincters

Eve

Skin Pilomotor muscles Sweat glands Uterus

muscle

*In some tin some SDependent

Specific Antagonism (Blockade)

Competitive Antagonism (Blockade)

Dilatation,

Glycogenolysis

Liver

been developed and a vast literature about the pharmacologic properties and the clinical application of these drugs has been published. For the purposes of this review, some basic terms must be defined, since they provide a conceptual framework for the interpretation of beta-adrenergic drug action.

Contraction

and

GI tract Stomach Mobility tone

DOLLERY

Decrease

rate

Glycogenolysis

Skin and mucosa Bronchial muscle

AND

This requires a unique receptor characterized by a specific response to a given agonist or group of agonists, usually in nanomolar concentrations. Furthermore, the agonist-induced tissue response must be inhibited by specific antagonists that do not affect the response to other agents acting via different receptors.” Thus, stimulation of betaadrenoceptors in the heart, irrespective of the manner in which that stimulation is evoked (sympathetic nerve stimulation, release of catecholamines from the adrenal medulla, or the introduction of exogenous catecholamines) can be blocked by beta-adrenoceptor antagonists. However, response to agents such as calcium, digitalis, or phosphodiesterase inhibitors would be unaffected.

Increased contractility

Blood vessels Skeletal muscle

KERSTING,

for

far

Contraction Secretion Contraction Relaxation

species this is a pure beta-receptor species this is a pure alpha-receptor on functional state (gravidity

effect. effect. and cycle).

receptors should be termed betal-receptors and those of bronchial and vascular smooth muscle beta2-receptors. This classification, although useful, is an oversimplification in that many tissues do not behave as would be predicted by such a scheme,8,9 and it is often possible only to describe the response in terms of the species, the tissue, and the effect observed. Numerous beta-adrenergic-blocking drugs have

An antagonist combining reversibly with the same receptor sites as the agonist is defined as a competitive antagonist. This antagonist occupies the same receptor sites as the agonist, but without evoking the characteristic biologic response of the tissue.” By increasing the concentration of the agonist, the block can be overcome (Fig. 1). In noncompetitive (irreversible) antagonism, increasing agonist concentration will not restore the original response. An example of this is alpha blockade produced by phenoxybenzamine, which alkylates the receptor. However, all the betablocking agents so far described are competitive agents.*

Affinity and Intrinsic Activity Affinity121 l3 is a measure of the ability of a drug (either agonist or antagonist) to form a complex with the receptor. The affinity of an antago-

*An analog of propranolol (N-[ 2-hydroxy-3-(l-naphthoxy)-propyl] -N’-bromoacetylethylene diamine) has recently been described which causes irreversible blockade of the p-adrenoceptor (Alas D, Steer ML, Levitski A: Proc Nat1 Acad Sci USA 73:1921-1925, 1976).

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

205

/

,:’ ,:’

PROPRANOLOL,.f 20 m q qid

...! /

/ ,..'

l ..’

i:

Activity

Drug

2.

Structure-Activity

Cardioselectivity

Prindolol Sotalol Timolol Practolol Tolamolol Metoprolol Atenolol Acebutolol

Relationship (Fig. 2)

Characteristics

of P-blocking

Intrinsic Sympathomimetic Activity

Drugs

in Clinical

Membrane Stability Activity +

Propranolol Alprenolol Oxprenolol

0.;

ipg/kg.min-1)

The chemical structures of beta-adrenergicblocking agents have several features in common with isoproterenol. The 2-C side chain with an alkyl substituted secondary or tertiary amine

(ISA)

Pharmacologic

I.

.’ IA

doxically, some may retain a degree of agonist activity with respect to the same receptor. The extent to which this occurs is very variable (Table 2). The first beta-blocking drug to be synthesizeddichloroisoproterenol-was of no clinical use because of this side effect. The usefulness of pindolol is also limited because of this.i5,16 Other drugs with ISA of no proven clinical significance include alprenolol, oxprenolol, acebutolol, and practolol. Drugs devoid of ISA include propranolol, sotalol, timolol, tolamolol, metoprolol, and atenolol. There is no good evidence that beta-blocking drugs with ISA are inherently safer in patients at risk from beta-blockade (e.g., asthmatics) than those without.‘7

Beta-blockers, by definition, antagonize the action of agonists on the beta-adrenoceptor. ParaTable

I’

0.1

0.05 ISOPROTERENOL

nist can be expressed as the pA2 value. This is defined as the negative logarithm of the molar concentration of antagonist, which requires the agonist concentration to be doubled to restore the original response. Estimation of the pAz value as a standard procedure for measuring the potency of an antagonist is certainly easier in vitro than in vivo. However, even in intact animals and in man, when allowance is made for additional variables such as protein binding, at least an approximation to the in vitro pA2 value can be obtained.i4 Intrinsic activity describes the biologic effectiveness of the drug-receptor complex. Affinity and intrinsic activity are unrelated properties. If, for example, a pure agonist and pure antagonist had the same affinity for the receptor site, the former would cause appreciable and the latter, negligible, activation.”

I’

.’ .' .'PROPRANOLOL ,," 40mq / qid

.!’

../

Fig. 1. Heart rate response to intravenous infusions of isoproterenol before and after treatment with propranolol (0. . . 0, propranolol 20 mg qid: O-.-.0, propranolol 40 mg qid).

Intrinsic Sympathomimetic

/

P

i ..: ,:’ ,:’

I ,

+ +

+ +

+

+

+ + + +

+

+

+

-

+

Use

References 19,22 20 23 61 62 63 64 65 66 67.68 24

--

CONOLLY,

206

Membrane-stabilizing

Fig. 2. Structured blocking drugs.

formulas

of currently

available

beta-

seems to determine the affinity for the betareceptor. The larger the alkyl group, the greater the affinity for the beta-receptor. The nature of the substituents on the aromatic ring determines whether the effect will be predominantly activation or blockade.” The configuration of the asymmetric beta carbon of the side chain is crucial for pharmacologic activity. Beta-blocking potency resides almost entirely in the levorotatory isomer. For propranolollg and alprenolo12’ the (-)levorotatory isomers were up to 100 times more active than the (t)dextrorotatory isomers. Only the racemic mixture is in clinical use. The different stereoisomers of beta-adrenergic-blocking drugs are useful for differentiation between the effects of beta-receptor blockade and nonspecific properties, e.g., local anesthetic activity (v.i.), which are possessed equally by both forms in laboratory studies, but clinically the (t)isomers are of no value.

KERSTING,

AND

DOLLERY

Activity

This term (synonymous with quinidine-like or local anesthetic activity) describes a property of beta-blocking drugs that is completely unrelated to beta-adrenergic blockade. Local anesthetics, quinidine and beta-adrenergic-blocking drugs with membrane-stabilizing activity, all reduce the rate of rise of the cardiac action potential and diminish the overshoot potential without affecting the resting potential or causing any significant prolongation of the duration of the action potential.21 Beta-blocking drugs possessing membrane-stabilizing activity include propranolol,1g’22 oxprenolol,23 alprenolol,20 and acebutolol. 24 In vitro, the membrane-stabilizing effect in human ventricular muscle requires a minimum propranolol concentration of 10 pg/m1,25 which is approximately 100 times the blood level associated with maximum inhibition of exercise tachycardia.26 In every case, if a beta-blocking drug possesses membrane-stabilizing activity, this property resides equally in the two isomers 27328 but it now seems clear that the antiarrhythmic activity of these drugs depends on beta-blockade, and is unrelated to the membranestabilizing effect, which could not occur at the plasma levels associated with the normal clinical doses used.2g Thus, in animals, catecholamineinduced cardiac arrhythmias can be promptly terminated by small doses of the (-)isomer, but much higher doses of the (t)isomer are required for the same effect. Prevention of halothane-plusdopamine-induced arrhythmias in cats could be achieved with 0.5 mg/kg (-)-alprenolol and 7.5 mg/kg (t)-alprenolol.30 Halothane-plus-epinephrine-induced arrhythmia in cats has been prevented by 0.09 mg/kg (-)-propranolol and 4.2 mg/kg (+)-propranolol.ig For reduction of ventricular tachycardia in dogs, caused by large doses of epinephrine, 1 mg/kg of (-)-sotalol and 20 mg/kg of (+)-sotalol were necessary.31 Thus, the importance of beta-adrenoceptor blockade by (-)-isomers in termination of catecholamine-induced arrhythmias is well established. However, the mechanism by which beta-blockers suppress arrhythmias either induced by ouabain or by ligation of coronary arteries is less clear. The suppression of these arrhythmias requires much larger and approximately equivalent doses of the stereoisomers than the suppression of catecholamine-induced arrhythmias.19,30332Y33 The prevention of ouabaininduced arrhythmia is nevertheless unlikely to be

BETA-ADRENOCEPTOR-BLOCKING

207

DRUGS

due to the membrane-stabilizing activity, as Kelliher and Robert? have demonstrated in their experiments that (-)-practolol but not (+)-practolol increased the dose of ouabain necessary to produce arrhythmias and death. In other experiments, the protective effects of (-)-practolol against ouabain toxicity were correlated with the suppression of neuronal activity. 35 Much higher doses of the (t)isomer were required to suppress the spontaneous neural activity to a similar degree. Dohadwalla et a1.36excluded the relevance of a local anesthetic action in protecting against ouabain-induced arrhythmias. In their studies, (+)-propranolol was significantly less active than (+)-propranolol. Beta-blocking Effect and Selectivity Beta-blocking drugs competitively reduce the effect of a beta agonist (e.g., isoproterenol, epinephrine) so that the dose response curve of the agonist is shifted to the right but remains parallel. Since the inhibitory effect of a beta-blocking drug can be completely overcome by a sufficient increase in the concentration of the agonist, the term “complete” beta-blockade, at least in vitro, is meaningless. It is preferable to define the dose of a beta-blocking drug able to block endogenous sympathetic tone. Chamberlain37 compared the effect of cardiac sympathectomy and propranolol on exercise tachycardia in normal subjects. Fifty milligrams of propranolol was not as active as cardiac sympathectomy in blocking the heart rate response to exercise. Coltart and Shand26 suggested that a single oral dose of 80 mg propranolol would abolish exercise-induced tachycardia in normal subjects. However, the demonstration by Shand3’ that plasma levels may vary between subjects on a given dose by as much as 20-fold, coupled with the fact that there may be a fivefold range in the degree of blockade produced by a given plasma concentration of propranolol,39 should engender caution in making such predictions. In a group of patients with angina, for instance, increasing the average daily dose of propranolol from 208 mg to 417 mg caused further reductions in both supine and erect pulse rate.40 A number of beta-blocking drugs have now been described which exhibit selectivity for betaradrenoceptors, so that in low doses a different spectrum of hemodynamic changes is seen.41,42 However, this selectivity is not absolute, and, at higher doses, beta2 antagonism becomes appar-

ent.43 Although the basis for this selectivity is still not understood, several drugs that have this property are now in use. Practolol was the first and, until it was withdrawn because of toxicity (v.i.), was the most widely used. Atenolol and metopro101 are in the early stages of clinical development. Acebutolol, another selective betar -antagonist, appears to be more cardioselective in the: cat than practolol,24 although its selectivity in man is disputed.‘@’ Tolamolol appeared to be as selective as practolol in man* but has now been withdrawn because of carcinogenicity in animals. Cardioselectivity is of undoubted therapeutic value as has been shown in clinical trials in asthmatic subjects, in which practolol caused a lower incidence of respiratory side effects than propranolol. 45946 Nevertheless, any beta-adrenoceptor-blocking drug must be used with considerable caution in asthmatics. This has been pointed out recently by Skinner et a1.,47 who concluded from their results that the use of the cardioselective beta-blockers, practolol and acebutolol, may lead to an increase in airways obstruction. Owing to the differences among the asthmatic patients, the response in the individual is unpredictable. PHARMACODYNAMIC ASPECTS BETA-ADRENOCEPTOR BLOCKADE IN MAN

OF

Heart Rate The heart rate is regulated by the opposing actions of the sympathetic and parasympathetic divisions of the autonomic nervous system.The increasein heart rate causedby adrenergic stimulation is mediated via the cardiacbetal-receptors. A valuable test of the efficacy and duration of betablocking drugs is the isoproterenol dose-response curve (DRC)“’ Y4gin which the degree of betablockade can be quantified by the rightward displacement of the DRC from the control curve, Since the antagonismis competitive, it is possible to generate serial dose-responsecurves exhibiting progressiverightward displacementasthe dose of beta-blocking drug is increasedup to toxic levels, and in this sensethere is no dosethat will produce “complete beta blockade.” However, there is a limit to the intensity of adrenergic stimulation that an intact subject can generate, and beta-blocking drugshave greatly increased our understanding of the contribution that sympathetic activity makesto the regulation

208

of heart rate at rest and on exercise. Furthermore, through the use of selective beta-blocking drugs, it has been recognized that adrenergic effects on the peripheral vasculature also contribute indirectly to the observed change in heart rate. Robin et a1.50found that propranolol, 0.1 mg/kg given intravenously, reduced the resting heart rate by 7 beats/min, while oral propranolol (160 mg/day) reduced the heart rate by about 12 beats/ min.‘l In normal subjects, beta-blocking drugs with ISA produce little or no reduction in resting heart rateszms4 presumably because their ISA is sufficient to balance out the loss of the low level of sympathetic activity that occurs at rest. In patients who have an elevated adrenergic tone because of existing heart disease, however, a reduction in resting heart rate may be seen.” Exercise studies using varying workloads have shown clearly that relatively little of the early increase in heart rate depends on sympathetic activity, but rather it is due to withdrawal of vagal inhibition. However, as the workload increases, so does the importance of the sympathetic component, and thus the reduction in heart rate by beta-blocking drugs becomes more pronounced.56-58 For propranolol, a linear relationship exists between the reduction of exercise-induced tachycardia and the logarithmic values of the dose, or plasma concentration throughout the range covered by clinically used doses within any individual subject,26 although between subjects a fivefold difference in the range of plasma levels of propranolol required to produce a given degree of betablockade has been reported.59 However, for drugs which possess appreciable ISA, such as oxprenolol, practolol, or pindolol, this linear relationship holds only at lower doses. As the dose increases, so that the positive chronotropic effect of the drug becomes more marked, the dose-response curve describing reduction in exercise-induced tachycardia flattens ouL6’ Recent studies with propranolol also suggest a flattening of the concentration-effect curve at low concentrations. Selectivity for beta,-receptors also alters the effect on the response to isoproterenol, which increases the heart rate by two different mechanisms. One is a direct effect on the cardiac betalreceptors. The other is indirect; isoproterenol dilates peripheral blood vessels through its effect

CONOLLY,

KERSTING,

AND

DOLLERY

on beta2-receptors. This causes a fall in blood pressure, leading to reflex reduction in vagal inhibition, and thus an increase in heart rate. Nonselective beta-blocking drugs abolish the vasodilator as well as the cardiac component of isoproterenol’s action, and thus are more effective in reducing an isoproterenol-induced tachycardia than a selective drug such as practolo1.61-68 Myocardial Contractility Accurate measurement of inotropic response can only be achieved by invasive procedures. The most commonly used measure of contractility is the maximum rate of rise of left ventricular pressuredp/dt. Reduction of this index has been demonstrated in patients receiving propranolol,69-71 oxprenolol, 72 alprenolol,B sotalo1,74 practolol,75 and tolamolol. 76 An alternative measure of inotropic effect, duration of the preejection period (PEP), has been used in studies with propranolo1,77-80 oxprenolol,” practolol,79382 and timolol.80 From the standpoint of our understanding of drug actions in man, it is perhaps unfortunate that the myocardial depression attributable to the membrane-stabilizing effect shared by both isomers of propranolol was recognized, for there can be no doubt that the negative inotropic effect seen when these drugs are used clinically is dependent entirely on blockade of the beta-adrenoceptor. In the studies cited above using propranolol, reduced contractility was found after administration of doses that could not possibly have produced plasma levels high enough to cause any membranestabilizing effect. Furthermore, other beta-blocking drugs such as sotalol, practolol, and tolamolol also reduce contractility, even though they are devoid of quinidine-like properties. Intrinsic sympathomimetic activity, on the other hand, may modify the expected effect on contractility. In experimental animals, Goldstein et a1.83 was able to demonstrate an increase in contractility in response to intravenous practolol, and in man intravenous alprenolol, oxprenolol, practolol, and pindolol, contrary to their effects when given by mouth, have been shown to cause either no change or an actual shortening of the PEP.78 Cardiac Output Cardiac output is governed by the activity of the heart and the magnitude of the venous return. Both

BETA-ADRENOCEPTOR-BLOCKING

of these are modulated by adrenergic mechanisms and, therefore, cardiac output will be profoundly modified by beta-adrenergic blockade. The exact pattern of hemodynamic alterations will depend in part on whether or not individual drugs possess cardioselectivity. This is because events in the peripheral vascular bed are of major importance in determining cardiac outputs4 and, as has been pointed out,75 many of the reflex adjustments of the peripheral structures that cardiac beta-blockade provokes may be antagonized by nonselective beta-blockers. Presence or absence of ISA may also influence the effect on cardiac output. Thus, early studies with the nonselective betablocking drug propranolol showed that there was a fall in both heart rate and cardiac output in normal subjects as well as in patients with a variety of cardiovascular disorders.85-92 However, several workers noted that maintaining the heart rate by electrical pacing did not prevent the fall in output caused by propranolo1.55’93-95 In contrast, Gibson and Coltart, who studied 16 patients with mitral and aortic valve disease, found that 5 mg and 15 mg of practolol given into the pulmonary artery during cardiac catheterization produced a 13%-17% fall in heart rate, while stroke volume increased, so that, except at the highest dose in a group of patients with aortic regurgitation, no reduction in cardiac output occurred. Arterial pressure did not change. Plasma Renin Activity

209

DRUGS

(PRA)

The relationship between the hypotensive action of beta-blocking drugs and their ability to reduce PRA is currently one of the more hotly disputed areas of hypertension. There is no doubt that betablocking drugs can antagonize sympathetically mediated renin release.96-‘03 However, adrenergic activity is not the only mechanism whereby renin release is modulated. Other major determinants are sodium balance, posture, and renal perfusion pressure and, unfortunately, there is no consensus with respect to these on the correct way to measure renin. It is, therefore, not surprising that when Biihler et al.“’ reported a relationship between elevated PRA and responsiveness of blood pressure to propranolol, other workers’@’ were not able to confirm their results. A number of other nonselective beta-blocking drugs have been studied. Alprenolol produced a fall in the standing renin,

which correlated significantly with the fall in blood pressure. lo5 Johnston et a1.99 reported a similar correlation between fall in PRA and of blood pressure in acute and chronic studies with prindolol (pindolol) in doses of 20-40 mg/day. Btihler et al.“’ studied a variety of beta-bloclking drugs in eight normal subjects. They found that oxprenolol (100 mg) and pindolol (5 mg) both reduced standing renin significantly and to a greater extent than the supine renin. They interpreted this as being due to a combination of ISA and the different levels of sympathetic tone in the erect and supine positions. They found timolol(l0 mg) to produce a significant fall in PRA in both positions. Selective beta-blocking drugs also influence renin release according to most reports. Aberg’06 found a correlation between fall in blood pressure and in PRA in four hypertensive patients on a no-addedsalt diet, treated with atenolollO0 mg b.i.d. His results conflicted with those of Amery et aLlo who treated 20 hypertensive patients on a 120-meq sodium diet with up to 600 mg atenolol per day. The reason for this conflict is not apparent. hIore recently, Btihler et al. lo1 found 100 mg atenolol effective in reducing both supine and erect PRA in eight normal subjects and observed the same effects with practolol(400 mg). Hollifield et a1310have measured the effect of propranolol in doses ranging from 40 to 960 mg/ day in patients whom they had previously categorized as having low, normal, or high renin. They found that patients with high or normal renin responded favorably to propranolol in doses up to 160 mg/day. In patients with low renins, a comparable fall in blood pressure could be achieved if the dose was increased (up to 960 mgfday in some cases). They argued that in the former patients, propranolol lowered blood pressure by some mechanisms that may or may not be causally related to the fall in plasma renin that was observed, while in the low-renin patients, a different mechanism (possibly mediated via the central nervous system) was involved. Effects of Beta-adrenergic-blocking Agents on Metabolism Both alpha- and beta-adrenergic receptors participate in the sympathetic regulation of carbohydrate, fat, and, to a lesser extent, protein metabolism.“08

210

Epinephrine in man stimulates glycolysis in skeletal muscle predominantly via beta-adrenoceptors and in the liver predominantly via alphaadrenoceptors. log In normal subjects, abolition of glucose mobilization requires simultaneous blockade of alpha-adrenergic receptors in the liver and beta-adrenergic receptors in skeletal muscle with phenoxybenzamine and propranolol, respectively. ‘lo Resting plasma glucose and insulin concentrations in normal individuals are not affected by propranoloi. The fall of plasma glucose levels after administration of insulin is also unaffected, but the rate of recovery of blood glucose levels after insulin-induced hypoglycemia is reduced and the increase of plasma glycerol is prevented, since these effects depend in part on the beta-adrenergic effect of catecholamines reflexly released in response to the hypoglycemia. For this reason, in diabetics treated with insulin, and in some other situations (e.g., fasting), beta-blockade with propranolol may be associated with hypoglycemia. ‘*‘-‘r4 On rare occasions in untreated diabetics, propranolol may cause hyperglycemic, nonketotic coma. 115t116 This has been attributed to the influence of catecholamines on insulin release. Stimulation of pancreatic alpha-receptors inhibits insulin release, whereas stimulation of pancreatic beta-receptors (in this situation blocked by propranolol) enhances release.” 7 In dogs, propranolol, but not practolol, partially and temporarily inhibited isoproterenol-induced insulin secretion, suggesting that the beta-adrenergic receptor involved in insulin secretion is a betaz-receptor.“8 Other factors involved in beta-blockade-induced changes of carbohydrate metabolism are inhibition of hepatic phosphorylase,“’ facilitation of glucose uptake in the periphery,23 increased secretion of growth hormone,120-r22 and inhibition of glucagon secretion.‘23’124 The increase of free fatty acid levels can be prevented by beta-adrenergic blockade,‘211’25 which has been shown to cause inhibition of peripheral lipolysis. 108Y126However, in patients with hyperlipidemia, lipid levels are unaffected by betablockade.‘*’ In alimentary lipemia, no marked decrease has been found after beta-adrenergic blockade.“’ In patients with type IV hyperlipidemia, postprandial hyperlipemia has even been found to be increased following beta-blockade.129 Propranolol has been shown to reduce cholesterolinduced atheromatosis in rabbits,126 thus raising

CONOLLY,

KERSTlNG,

AND

DOLLERY

the question of whether this may add to the beneficial effect of beta-adrenergic blockade, especially coronary artery disease. Careful long-term studies are required to investigate any possible antiatherogenic effect in man. Although the metabolic effects of beta-adrenergic blockade are not nearly as prominent as their hemodynamic effects and the incidence of metabolic side effects is low, beta-adrenergic-blocking agents should be used with caution in patients prone to hypoglycemia, particularly insulin-treated diabetics. PHARMACOKINETICS ADRENOCEPTOR-BLOCKING

OF BETADRUGS

The pharmacokinetics of propranolol has been studied more intensively than almost any other drug in the history of pharmacology. Soon after its introduction, its plasmaconcentration was demonstrated to be much lower and more variable after an oral rather than an intravenous dose, although the drug was quickly and completely absorbed from the gastrointestinaltract.39’13’ Propranolol is a basic, lipid-soluble drug with avolume of distribution of 3-5 liters/kg. Its relatively short half-life of 24-4 hr occurs because the plasma clearance is high, often approaching 1 liter/min. Since the drug is mainly metabolized in the liver and its clearance approaches liver blood flow, it is obvious that hepatic extraction of the drug from the blood must be almost complete. This has proved to be the case,and extraction ratios of up to 90% have been demonstrated in man and dogs.i31Since an oral dose must passthrough the liver, much of the drug is metabolized before it can reach the systemic circulation. Thus, the systemicavailability of an oral dose is often lessthan 30% and at very low dosesit may be almost nil. The result is a high degree of variability in the plasma concentration of propranolol because different individuals extract different proportions of an oral dose.In subjects taking a single dose of 80 mg propranolol, there was a sevenfold range in plasmaconcentration.38 However, a consequenceof the extent of metabolismduring absorption, often referred to as “first-pass” metabolism, is that incrementsin dose may lead to a more than proportional increasein concentration as the extraction mechanismsbegin to be saturated. Increasingthe doseof propranolol from 120-240 to 480 mg daily led to a tenfold

BETA-ADRENOCEPTOR-BLOCKING

211

DRUGS

rise in plasma concentration, although the dose had been increased only fourfold, and at this dose a 20-fold range in plasma levels was seen.38 One important practical consequence of the high first-pass metabolism of propranolol is that an intravenous dose of the drug represents a much larger amount in proportion to an oral dose than would appear from the number of milligrams administered. This may account for a number of catastrophes that occurred in the early phases of propranolol investigation when propranolol was administered by rapid intravenous injection. Several other beta-adrenoceptor-blocking drugs, including oxprenolol and alprenolol, appear to have kinetics very similar to those of propranolol.‘32 Pindolol has somewhat different kinetics. A fourfold variation in plasma concentration has been reported after both oral and intravenous administration. The plasma half-life of this drug is similar to that of propranolol, about 34 hr, but the plasma clearance was lower, between 400 and 500 ml/min. Of the total clearance, 163 ml/min was due to elimination of drug unchanged by the kidney so that the hepatic contribution to clearance is only about a quarter of the hepatic blood flow, and this makes it unlikely that first-pass metabolism is important. 133 Practolol is the least extensively metabolized of the beta-adrenoceptorblocking drugs, 85% being eliminated from the body unchanged. The plasma half-life of practolol varies between 7 and 13 hr.

Metabolism The beta-adrenoceptor-blocking drugs that have high first-pass clearance in the liver are extensively metabolized. Propranolol has been the most completely investigated and a large number of metabolites have been identified. The most important of these is 4-hydroxy-propranolol, which has pharmacologic activity similar to that of propranolol itself and which is present in plasma after a single oral dose in a concentration only slightly less than that of the parent drug.13’ However, 4-hydroxypropranolol appears to have a shorter half-life than that of propranolol and probably does not make a substantial contribution to the pharmacologic effect of propranolol under conditions of steadystate dosing.‘34 Another important product of propranolol is naphthoxy-lactic acid, which is formed as a result of the removal of the iso-

propylamine side chain. It was proposed that isopropylamine itself might be an active metabolite with vasodilator properties but it appears that the amount of this substance formed in vivo is very small and such activity is not important. Many other derivatives are present in plasma; most of these are conjugates of propranolol or 4-hydroxypropranolol and as far as is known these have no pharmacologic activity.

Concentration-Effect

Relationships

Some drugs such as digoxin and phenytoin exert their optimal therapeutic effect over a relatively narrow range of plasma concentrations, and in different patients a wide range of doses may be required to achieve such plasma levels. If the drug is used in a condition where the therapeutic endpoint is not easy to measure, an improvement in efficacy might result from adjusting the dose to achieve the desired plasma concentration, rather than using a dose arrived at empirically. Since the dose requirements of beta-adrenoceptor-blocking drugs vary widely, there has been much interest in the range of concentrations at which significant beta-blockade occurs in man. Two main techniques of measuring betaadrenoceptor blockade have been used. They are dose ratios of isoproterenol required to produce the same response before and after beta-blockade, and inhibition of maximal exercise-induced tachycardia. Since all beta-blocking drugs produce a competitive antagonism to isoproterenol, it is always possible to obtain a dose ratio so long as a high enough dose of isoproterenol is used. Dose ratios of 300 times or greater have been found with single oral doses up to 100 mg of propranolol. However, maximal exercise-induced tachycardia is a response to an endogenous stimulus and it would be anticipated that the concentration-effect relationship might follow the classical S-shaped curve. Pine et a1.135 have produced evidence suggesting that this is so in normal humans and suggests that maximal blockade of the endogenous stimulus occurs at a concentration of about 100 rig/ml. TJsing these data, it has been calculated that the ED-50 for propranolol inhibition of exercise tachycardia in humans ranges from 3 to 8 rig/ml depending on the level of exercise. This conclusion rests on the assumption that the DRC plateau has been reached, but there are other published data suggesting that

212

CONOLLY,

the plateau in some individuals may not be attained with concentrations as high as 500 ng/m1.136 Efforts to apply these concepts to patients with angina and hypertension have been unhelpful. Both Pine et a1.135 and George et a1.r3’j concluded it was not possible to define a concentration in which optimal relief of angina with beta-blockade would occur in every patient. Titration of dose to a maximal therapeutic response remains the preferred method. Likewise in hypertension, studies of beta-adrenoceptor-blocking drugs have shown very little relationship between plasma concentrations of propranolol and oxprenolol and their hypotensive effects. There may be various reasons for this. First, the ED-50 values of betaadrenoceptors may vary in different parts of the body, or at least may require different plasma levels to achieve concentrations approaching the ED-50 value in the environment of the individual receptors. Thus, for example, in hypertension, those mediating ventricular contractile force, renin release, and central blood pressure control might require different plasma concentrations to achieve the maximum effect. Second, the diseases that are being treated are complex and of heterogenous etiology. THERAPEUTIC APPLICATIONS BETA-ADRENOCEPTOR-BLOCKING

OF DRUGS

Originally conceived as a specific agent for the treatment of ischemic heart disease,this diverse group of drugs hasbeen found, often empirically, to be useful in a wide range of conditions, of which hypertension and certain arrhythmias are the most important additions. Beta-Blockade in Hypertension In recent years the controversy over the value of beta-blocking drugs in the treatment of hypertensionlo hasbeen largely resolved. It is now well establishedthat these drugs do have a useful role to play in this situation. It is clear that their usefulness is not confined to hypertensives with a hyperdynamic circulatory state, and attempts to define a subsetof the hypertensive population who might be particularly responsiveto these drugs in terms of plasma renin activity”’ have not been universally accepted.lo4 Indeed, at the present time there is no concensus of opinion on the mechanismor mechanismswhereby thesedrugsdo

KERSTING,

AND

DOLLERY

lower blood pressure.The currently availabledata have been summarizedabove, and this sectionwill be confined to the question of efficacy in hypertension. Propranolol (Inderal@). Several trials have been published but accurate comparisonsbetween them are difficult because of the variability of trial protocols and concomitant use of other drugs, especiallydiuretics. Prichard and Gillam, whose data have previously been reviewed, were able to compare 13 patients who had previously been treated with guanethidine, methyldopa, and bethanidine. About half their patients were on thiazide diuretics. In this group of patients, propranolol achieved the best control of recumbent pressure(135/94 mm Hg) with fewest side effects, and least postural or exercise-induced hypotension. Their dosage regimen was extremely flexible, for although the averagedaily dose of propranolol was 319 mg, the rangewas from 10 to 4000 mg/day. Similar flexibility in dosing was adopted by Zacharias et a1.13*in their study of 109 patients, all of whom alsoreceived thiazides. They observed that 60% of the patients achievedsatisfactory control with lessthan 400 mg/day of propranolol, and that only 20% required more than 600 mg daily. Perhaps because it is now regarded as well established, there have been no recent formal double-blind trials of propranolol by itself. However, Laver et a1.13’ performed a double-blind comparison between propranolol, pindolol (prindolol), and a mixture of reserpine, methyldopa, clonidine, guanethidine, and debrizoquine (therapy previously received by 35 patients with moderately severe hypertension). All patients also received chlorothiazide, and after a 3-mo period on one beta-blocker, the other was gradually substituted. The dose of each was titrated againstthe blood pressure;pindolol (mean dose,57.5 mg/day) resultedin supineand standingpressuresof 138/92 and 132/90 mm Hg, respectively, while for propranolol (meandose,289.3 mg/day) the levelswere 137/90 and 132/88 mm Hg. There were no patients who failed to respond. With both betablockers, side effects were lessthan on the original regimes, and, in particular, reduction of drowsiness,of dizziness, and of impaired sexualfunction in male patients were noted. Patients with advanced renal diseaseon chronic maintenance dialysis may be particularly resistant

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

to antihypertensive therapy unless nephrectomy is carried out. It has recently been reported that propranolol in doses up to 480 mg/day may greatly reduce the need for so drastic a step.i4’ Medical Research Council trial. The British Medical Research Council has set up a pilot study to determine the feasibility of a long-term evaluation of treating mild hypertensives with either bendrofluazide 5 mg twice daily or propranolol up to 120 mg twice daily, with the further addition of methyldopa or guanethidine if required. This regimen has reduced pretreatment systolic pressures by 13 and 17 mm Hg, and diastolic pressures by 6 and 7 mm Hg for men and women, respectively. No serious toxic reactions have so far been encountered, the only surprising observation being the high incidence of impotence in men on thiazides. It is estimated that 90,000 patient-years of observation (5 yr in 18,000 patients) will be required for a full evaluation of this regime in mild hypertension. The cost (in 1975 prices) is estimated at $S,OOO,OOO,a small fraction of the cost of treating cerebrovascular and ischemic heart disease in Britain today. More importantly, it is to be hoped that this and similar trials being set up in other countries, notably Sweden and the United States, will answer the vexed question of the value of treating mild hypertension.14i Alprenolol (Aptin@). Alprenolol has been less widely used than propranolol, but the available evidence indicates that it also lowers blood pressure effectively. Tibblin and Ablad14’ performed a double-blind cross-over comparison between alprenolol (up to 400 mg/day) and a placebo in 11 patients. The supine pressure of 175/ 111 mm Hg (control) and 176/l 10 mm Hg (placebo) fell significantly to 153/101 on alprenolol. Standing pressures were 173/121, 171/121, and 152/108 mm Hg, respectively. This too was a significant reduction. Four of the 11 patients showed a continuing fall in pressure throughout the period of study. In a more prolonged study, Bengtsson’43 followed 26 female patients for 2 yr. They were given alprenolol in an open fashion after completing a double-blind comparison with propranolol in which the two drugs had been shown to be equivalent.144 Over this 2-yr period, the supine pressure had maintained its original reduction from 184/ 106 to 145/91 mm Hg, corresponding values for the standing pressures being 179/l 13 and 145/96

213

mm Hg. Some patients also took chlorthalidone, and nine patients required an increase in alprenolol in the early phase of the trial, but all remained stable thereafter. One patient had symptoms of mild asthma, but no other untoward effects were noted. Comparable results have been reported by Comerford and Pringle145 who used alprenolol in doses of 200-800 mg/day. Some patients also took concomitant diuretics or hydralazine. Elderly patients tolerate alprenolol well in doses up to 400 mg/day at least,lM although cardiac failure may be precipitated as well by alprenolol as by any other beta-blocker. In a double-blind cross-over comparison of alprenolol (400 mg/day) and propranolol (160 mg/day), no significant difference could be demonstrated between the two drugs.14’ A compa.rison between chlorthalidone plus alprenolol (400-800 mg/day) and chlorthalidone plus methyldopa (750-1500 mg/day) produced similar falls in blood pressure, but more severe side effects were encountered by the patients on methyldopa.‘48 Oxprenolol (Trasicor@). Leishman et al. 14’ examined the effect of oxprenolol (daily dosage up to 420 mg) in 19 patients. The trial design used an “open” run-in period during which pressure control was attempted. Five patients were removed because of inadequate response. In the remaining 14 patients (necessarily a very selected population), a double-blind comparison between placebo and oxprenolol (average daily dose, 320 mg/day) showed a significant reduction in recumbent (173/ 102 to 160/99 mm Hg) and standing (165/106 to 15 l/99 mm Hg) blood pressure in response to oxprenolol. No side effects were experienced. Tuckman et a1.i5’ reported the use of oxprenolol in an average daily dose of 374 mg (range, 60-600 mg) given in an open fashion to 17 patients. They give results as mean pressures, and confirm an absence of postural hypotension. Lying and standing pressures of 140 and 139 mm Hg were both reduced to 127 mm Hg. Pindolol (prindolol, Visken@, LB46). Only recently introduced, pindolol has not as yet been the subject of extensive evaluation. It differs from propranolol most markedly in its prominent ISA; although there are also other differences (see above), they are clinically less important. However, it is probably the ISA that is responsible for the paradoxical loss of pressure control seen in a

214

small proportion of patients when the dose is increased much above 40 mg/day.r5 ,I6 A recent double-blind comparison between propranolol and pindolol by Laver et al.13’ has already been discussed. Waal-Manning and Simpson’s1 reported 48 patients, many of whom were receiving concomitant diuretics, who were changed from reserpine, methyldopa or adrenergic neurone blocking drugs to pindolol or placebo in a double-blind fashion. Pindolol in an average dose of 15 mg/day was found to be significantly better than placebo. Almost all patients preferred pindolol to their previous therapy because of reduced side effects. Practolol (Eraldin@). To date, this is the only selective beta,-antagonist which has had widespread clinical use. It differs from propranolol in several important respects, other than selectivity. It possesses ISA, but is devoid of MSA. It is far less lipid-soluble than propranolol, and therefore penetrates the central nervous system to a much smaller extent.“’ Nevertheless, it does exert a significant hypotensive effect. Thus Leishman et al. 1r4’ Prichard et al.,‘53 Esler and Nestel,‘54 and Sundquist et al.“’ have all shown significant and clinically useful reductions in blood pressure without orthostatic symptoms. However, the recent recognition of serious toxic effects of practolol (see below) had led to the disuse of this drug in all but a few acute situations, so the reports cited above will not be considered further here. Within the last 2 yr numerous other betablocking drugs have appeared, although as yet none have been fully evaluated. Timolol (Blocadren@, MK 950). This is a nonselective beta-blocking drug, which is dose for dose about six times more potent than propranolol and which has very little intrinsic sympathomimetic activity. It appears to be as effective a hypotensive agent as propranolol.‘56-‘58 Sotalol (Betacardone@, Sotacor@, MJ 1999). Sotalol is another nonselective beta-blocker, also devoid of ISA. On a weight basis, it is appreciably less potent than propranolol, with a dose-related fall in pressure occurring with doses of 200-600 mg/day.‘55 Acebutolol (Sectral,@ M & B I7803A). This drug behaves as a selective beta-blocking drug in animal studies, although this has not been the general finding in man.44 In doses up to 1000 mg/day, it appears to be an effective hypotensive agent,“’ but full double-blind evaluation is still awaited.

CONOLLY,

KERSTING,

AND

DOLLERY

Several beta-blocking drugs with proven betalselectivity are now available in place of practolol. Atenolol (Tenormin@, ICI 66082). In doses of 200-400 mg/day, atenolol has been shown to be effective in lowering pressure in moderately severe hyper-tensives.i60-‘62 Metoprolol (Betaloe@, Lopresor@, H93/26). This drug has produced broadly similar results,‘63 although most of the available data have not yet been published. Use of Beta-Blockade in Patients With Renal Failure Although deterioration has been reported in patients with impaired renal function after the introduction of propranolol,‘64T165 in general it has been found that any initial deterioration is followed by improvement and stabilization in renal function.r6’j Impaired renal function should not, therefore, be regarded as a contraindication to the introduction of these valuable hypotensive agents. Use of Beta-blocking Drugs With Vasodilators Peripheral vasodilatation produces a fall in blood pressure that evokes a reflex tachycardia and an increase in cardiac output. This may not only be unpleasant and even dangerous, but it will reduce the hypotensive effect of the vasodilator. Increasing use has been made of the combination of vasodilators such as hydralazine with diuretics plus a beta-blocker to prevent the tachycardia. The advent of newer, more effective vasodilators such as minoxidilr6’ has led to a growing interest in this form of treatment, which can achieve a reduction in pressure when all other drug combinations fail. Zacest et al.‘@ studied the combination of hydralazine and propranolol in 23 patients also taking diuretics. They found that 80-160 mg propranolol per day lowered both supine and standing pressures, and that the addition of hydralazine achieved diastolic pressures below 90 mm Hg without an increase in heart rate. Gottlieb et al.16’ compared hydralazine with another vasodilator, minoxidil, in 11 patients who received concomitant propranolol and hydrochlorothiazide. Supine blood pressure fell from 191/128 mm Hg while on propranolol and the diuretic, to 169/108 with the addition of hydralazine, and to 142/92 while on minoxidil. Hydralazine was used in doses of 200800 mg/day and minoxidil 2.0-30 mg/day. The propranolol dose needed to be increased from the control levels in most patients, but none required

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

more than 160 mg/day. Other workers167~‘70 have also reported that, in combination with minoxidil, effective doses of propranolol have not exceeded 240 mg/day. Beta-Blockade

in lschemic

Heart

Disease

Angina Pectoris Angina occurs when the oxygen requirements of the myocardium exceed the supply available, which may be limited because of obstructive lesions (coronary occlusion, aortic stenosis), inadequate diastolic perfusion pressure (aortic incompetence, major arteriovenous fistula), or inadequate oxygen carrying capacity of the blood (severe anemia). If the oxygen supply cannot be improved, the only way to relieve pain is to reduce myocardial work. Trinitrin achieves this both by reducing peripheral resistance (and hence blood pressure) and by reducing venous return to the heart. Betaadrenergic blockade may achieve the same effect by reducing the adrenergically mediated effects on left ventricular work, which determines myocardial oxygen requirements. It was the recognition of this relationship and the potential therapeutic importance of it that provided the impetus for the development of beta-blocking drugs.“i The value of beta-adrenergic blockade in angina is established beyond question, and much of the important literature on which this conclusion is based has been reviewed earlier by Dollery et al.” At that time, the only widely used drug was propranolol and its ability to attenuate angina in a dose-related manner has since been clearly demonstrated by Prichard and Gillam, but other equally nonselective beta-blockers appeared soon after, namely alprenolol and oxprenolol. Both are comparable to propranolol in relieving angina 172-176 although both possess ISA. Sdtalol (Betacardone@, Sotacor@, MJ 1999). This is a nonselective beta-blocker with neither ISA nor any quinidine-like activity. It has been compared with propranolol in the treatment of angina by Prichard and colleagues. In an acute study using intravenous sotalol, Prichard et al.52 found sotalol (50 mg) and propranolol (38 mg) to be equivalent and marginally superior to oxprenolol (60 mg) and practolol(l53 mg) in delaying the onset of pain. However, in a more prolonged titrated oral dose study, Horn and Prichard”’ found propranolol to be more effective than sotalol. Comparable results were reported from a titrated

215

dose single-blind oral study by Atkins et a1.i” and a double-blind study by Toubes et al.,l’” the former study being marginally in favor of propranolol and the latter of sotalol. Timolol (Blocadren@, MK 950). This is also nonselective and without ISA and appears to be effective in reducing the frequency of angina1 attacks,‘*’ although no detailed reports of its use have been published as yet. Nonselective beta-blocking agents should not be given to patients with obstructive airways disease. For this reason, the development of selective betal-receptor antagonists has been an important advance, although the selectivity is not absolute and diminishes as the dose increases. Practolol was the first and, so far, still the most widely used of these agents. While in use, it was found to be effective, albeit less so than propranolol when both drugs were used in optimal doses.52,‘81 However, as noted above, it has recently been withdrawn because of the small but increasingly recognized incidence of serious toxic effects. For this reason, reports dealing with practolol will not be discussed further. More recently, other selective betalblockers have been developed. Atenol (Tenormin@, ICI 66082). Atenol is a selective antagonist that differs from practolol by being devoid of ISA. In an acute study, 5 mg atenolol and propranolol were compared in ten patients with severe angina by Astrom and Vallin.182 Both drugs produced an equal reduction in the tachycardia of exercise but maximal working capacity was higher after atenolol than propranolol, possibly because of its lack of effect on the peripheral vascular adaptation to exercise. An important observation was that atenolol was associated with a slight increase in airways conductance, in contrast to the reduction caused by propranolol. Roy et a1.1s3 recently described its use in 11 patients with severe angina. They performed a double-blind comparison between atenolol, practolol, and a placebo and found that atenolol produced significantly greater reduction in angina1 attacks and trinitrin requirements than practolol did, although exercise tolerance was not further improved. Meroprolol (Betaloc@, Lopressor@, H93/26). This is another selective betal-antagonist without ISA. No trial results have yet been published, but preliminary data indicate that it is an effective i antianginal agent. Tolamolol (UK-6448-01). Another recently developed selective betal-blocker devoid of ISA,

216

tolamolol has been the subject of several clinical trialsiE4-la6 and has been shown to be superior to practolol and comparable to propranolol in relieving pain and reducing ECG changes. However, having recently failed to pass chronic carcinogenicity tests in animals, it has been withdrawn and will not, therefore, be discussed further. Adequacy of dosage. It should be self-evident that if beta-blocking drugs are to be effective in relieving angina, the dose used must be large enough to produce substantial beta-blockade. Prichard and Gillam4’ demonstrated that the range of doses required in 16 patients ranged from 80 to 1280 mg propranolol per day, and that relief of angina in all these patients was linearly related to dose. It has recently been pointed outls7 that the common practice of using reduction in resting heart rate as an index of beta-blockade is unreliable, and will lead to many patients being wrongly classified as therapeutic failures. Reduction of peak exerciseinduced tachycardia is a better index of the degree of beta-blockade. Effects of sudden withdrawal of beta-blockade. The medical literature has contained anecdotal reports 188-191 since 1966 of patients with ischemic heart disease who deteriorated and in some cases died after the abrupt cessation of beta-blocking drugs. These reports were confirmed by observations in six patients reported by Alderman et al.‘92 and have been extended by a double-blind study in 20 patients performed by Miller et al.lg3 They found that in patients who had been on propranolol for as short a period as 6-12 wk. sudden withdrawal led to serious complications in ten patients, some of whom died. Although it is plausible to argue that, in patients who have been on betablocking drugs for a long time, withdrawal may merely be unmasking the effects of progression of the underlying disease, other mechanisms must be operative in this more acute study. These might include continued increased physical activity in the patient once symptomatic relief has been experienced, or the unmasking of increased sympathetic activity. These suggestions are speculative, however. Whatever the mechanism, at the present time it must be recommended that withdrawal of betablocking drugs in patients with ischemic heart disease should be done gradually and that, during that phase, physical activity should be restricted. Verapamil in myocardial &hernia. Several studies have indicated the usefulness of this agent in

CONOLLY,

KERSTING,

AND

DOLLERY

angina, and these have recently been reviewed.‘” Absence of any bronchoconstrictor effect may in some situations make it a preferable agent. It is mentioned here in order to stress that combinations of this drug and beta-blocking agents should be avoided.‘95,215,216

Myocardial Infarction The role of beta-blockade in the treatment of myocardial infarction continues to be controversial and has still not been adequately studied. Prevention. Beta-blockade per se has no effect on the progress of coronary atheroma. However, it does reduce myocardial oxygen requirements and may enable the cardiac muscle to tolerate, for a while, what would otherwise be an inadequate supply of oxygen. This may explain why abrupt withdrawal of such drugs has been associated with worsening of angina or the development of frank infarction in some patients. The relevant reports were discussed in the preceding section. Beta-blockade in acute myocardial infarction. It is now well established that myocardial infarction is not an all-or-none phenomenon. It has been shown that around the initially infarcted area there is an ischemic area that may not finally die until several days have elapsed.1963197It has been demonstrated that reduction of myocardial oxygen requirements will decrease the final size of the infarct and vice versa.198-200 In dogs with experimental occlusion of a coronary artery, propranolol will reverse the epicardial ST-segment elevation, and these ECG changes are associated with reduction in the size of the infarct as mentioned above. Predictably, exogenous catecholamines have been found to have the reverse effect.“’ In man, Pelides et al.‘” have shown that practolol given within 72 hr of an infarct reduced the precordial STsegment elevation. Mueller et al.203 have extended these findings by demonstrating a reduction of myocardial hypoxia (as estimated by lactate uptake) in patients given propranolol within the first 12 hr of an infarction. Apart from a direct metabolic effect, additional benefit may also be anticipated in patients in whom there is a tachycardia 204,205 The prevention of sudden death after myocardial infarction. Potentially one of the most exciting developments in the management of ischemit heart disease in recent times has been the

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

report from SwedenzM that patients who had already had a myocardial infarct were less prone to sudden death if treated with a beta-blocking drug. They observed 230 patients who survived a myocardial infarction. After discharge from the hospital, the patients were grouped into four separate risk strata, determined by the degree of myocardial damage, and within each stratum randomly allocated patients received a placebo or alprenulol, 400 mg daily. Within all the separate strata, the incidence of nonfatal reinfarction appeared much the same, but the incidence of sudden death was significantly reduced for patients taking alprenolol. The mechanism of this beneficial effect is not yet known. Ahlmark et a1.207reported a similar study using 400 mg/day alprenolol in patients who survived an initial myocardial infarct. Like Wilhelmsson et al., they noted a significant reduction in sudden deaths in alprenolol-treated patients compared with matched controls. However, they also reported a reduction in the actual reinfarction rate in patients receiving alprenolol. Recently, there was reported2’* a multicenter double-blind trial in which 3038 patients, taken l-4 wk after an acute myocardial infarction, were given either practolol, 200 mg twice daily, or a placebo. The trial was prematurely terminated after the reports on practolol toxicity emerged; nonetheless, it was found that there had been a significant reduction in overall mortality, in sudden deaths, in all cardiac events, and in the subsequent development of angina or arrhythmias. The improvement in mortality was predominantly in those with an anterior myocardial infarction, although other workers ‘Og have not found the site of the infarct to be of prognostic significance. The evidence in favor of a prophylactic effect of beta-blocking drugs in the management of patients following infarction are persuasive. These observations urgently need to be confirmed and extended. Beta-blocking Cardiac

Drugs

in the

Treatment

of

Arrhythmias

Beta-blocking drugs have been used in the treatment of cardiac arrhythmias for more than a decade, but considerable confusion continues to exist about their mode of action. This has largely come about because of the practice of extrapolating from results obtained with isolated tissues (often

217

studied in very nonphysiologic solutions) to the clinical situation, in an uncritical fashion. The fact that both isomers of propranolol possess quiniminelike activity when examined at high concentrations in vitro210-213 has led many workers to assume that this property was responsible for its antiarrhythmic activity. However, the concentrations of propranolol required to produce this effect are in the millimolar range, which may be achieved in animals214 whereas, except possibly for a very brief interval after an intravenous injection, conventional clinical doses produce micromolar concentrations, at which level only effects due to beta-blockade will occur. The most important of these in the context of arrhythmia controt are reduction of automaticity and slowing of conduction. This is not to say, however, that beta-blocking drugs will only be effective in arrhythmias that can be directly attributed to catecholamines (halogenated hydrocarbon anesthesia; pheochromocytoma). Clinical experience has shown that they are useful in managing many other types of arrhythmias as well. It is probably because their usefulness derives from removal of normal adrenergic effects where (e.g., on automaticity and conductivity) these might be unfavorably additive with respect to the prevailing arrhythmia-producing stimulus, such as digitalis intoxication. As with any potent drug, there are contraindications to the use of beta-blocking drugs, and with the advent of other potent antiarrhythmic agents such as lidocaine, diphenylhydantoin and verapamil, whose properties differ in several important respects, it has become more important than ever to determine accurately the nature of the arrhythmia. Furthermore, a sound grasp of the pharmacology of the various antiarrhythmic agents will indicate which drugs may profitably be combined with beta-blocking agents (e.g., quinidine) and which might under some circumstances produce an undesirable summation of effects (e.g., Verapamil@ 215,216). As noted previously, lo it is difficult to evaluate reports of the drug treatment of unstable arrhythmias because of the difficulty of knowing whether change in rhythm was due to medical intervention or whether it would have happened anyway. The clinical situation is often further complicated by the almost inevitable polypharmacy to which patients with arrhythmias are exposed.

218

The Treatment of Individual Arrhythmias Beta-receptor-blocking drugs are valuable in a large number of arrhythmias. With the exception of those related to catecholamines and digitalis, they are generally more useful in treating superventricular arrhythmias than those of ventricular origin. Supraventricular arrhythmias. These respond in a variable manner to beta-blockade. Exact interpretation of the cardiogram may, at rapid rates, be impossible; at the outset, beta-blockade may be used in an attempt to slow the heart rate sufficiently to establish an accurate ECG diagnosis,*17 although this maneuver may not be successful. Sinus tachycardia. Usually having an obvious cause (e.g., thyrotoxicosis-discussed elsewhere), sinus tachycardia may occasionally be sufficiently distressing to require direct intervention, and, provided this is not due to adrenergic activity required to prevent cardiac failure, beta-blockade is an effective form of therapy.218 Supraventricular ectopics. These may herald the onset of atria1 fibrillation in a variety of situations, and it is doubtful if beta-blockade would prevent this development. 21QWhen attributable to digitalis, however, a favorable response is to be expected (see below). Paroxysmal supraven tricular tachycardia. In broad terms two separate types are recognized: 1) Those caused by abnormal conduction, either within the AV node, giving rise to a reciprocating AV nodal tachycardia, or through a lateral AV node bypass (e.g., bundle of Kent), giving rise to reentry arrhythmias such as the Wolff-ParkinsonWhite (WPW) syndrome. 2) Those caused by ectopic activity in atria1 tissue. These, although often caused by digitalis, may also be associated with car pulmonale and can occur in hearts that are otherwise apparently normal.220 The place of beta-blocking drugs in this group of arrhythmias is not yet finally determined. There is no doubt that, by slowing conduction in the AV node, the arrhythmia may be successfully terminated. If they are not immediately effective themselves, they may increase the effectiveness of maneuvers increasing vagal tone that before betablockade had been unsuccessful.221 Furthermore, it has been pointed out21Q that if sinus rhythm is still not restored, the use of beta-blocking drugs leaves open the option of direct current countershock, which is not the case with digitalis. Never-

CONOLLY,

KERSTING,

AND

DOLLERY

theless, definitive evaluation of their worth in managing supraventricular tachycardia cannot yet be made, since Schamroth et a1.222and Krikler and Spurrell 223 have reported very promising results with Verapamil and, in certain situations, further evaluation may show this to be the preferred drug. Atria1 flutter. Atrial flutter is nowadays generally managed by rapid right atrial pacing, which has superceded direct current countershock, but beta-blockade can be used to slow the heart and may restore sinus rhythm.224 Atria1 fibrillation. This is an arrhythmia that must be approached with caution when considering the use of beta-blocking drugs, since this arrhythmia occurs so often in hearts which are severely diseased and therefore dependent on high levels of adrenergic tone to avert failure (see above), and there is no evidence that beta-blocking drugs possessing ISA are any safer in this situation.225 However, there are certain specific instances in which the additive effect of betablockade on slowing AV conduction may produce a clinically useful reduction in ventricular rate, such as in thyrotoxicosis, or when patients are unable to tolerate the requisite dose of digoxin.220,226 They may also be of value in treating atria1 fibrillation in hypertrophic cardiomyopathy (see below) where the inotropic effect of cardiac glycosides may be harmful. Combination with other drugs. There have been several reports of the beneficial effects of combining low doses of beta-blocking drugs with agents possessing membrane-stabilizing activity. Stern227 reported the use of a combination of low doses of each, thus minimizing side effects in patients with a variety of rhythm disorders. Sixtyfour patients with chronic atria1 fibrillation (13 after open-heart surgery) were treated with propranolol (up to 40 mg/day) and quinidine (up to 800 mg/day); in 45 of these patients sinus rhythm was restored. Nineteen patients with paroxysmal atrial arrhythmias were treated with up to 50 mg propranolol plus up to 1 .O g quinidine with success in 17 cases. Maintenance of sinus rhythm was observed in 53 out of 72 patients who had been restored to sinus rhythm from chronic atria1 fibrillation by a variety of techniques. The daily doses of propranolol and quinidine ranged up to 40 and 800 mg, respectively. Levi and Proto228,22Q describe similar studies in which 233 patients with long-standing atria1 fibril-

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

lation were treated with a combination of propranolol, practolol, alprenolol, and pindolol. With each beta-blocker, given every 6 hr, the dose was titrated against the ventricular rate until it fell to 60-80 beats/min, at which point 150 mg quinidine was added to each dose. With propranolol, 64.8% reverted to sinus rhythm, as opposed to 56.2% with alprenolol, 65.9% with pindolol, and 45.7% with practolol. The overall success rate was 60.9%. A key factor in determining success in this study was the duration of fibrillation before therapy. Those patients who responded best had had fibrillation for less than 6 mo (110 cases), whereas only 32 of those who responded had had atria1 fibrillation for longer. It is impossible to evaluate fully studies of this nature that do not contain controls treated in a more conventional manner. Nonetheless, it is noteworthy in that, in both reports, low doses of both classes of drugs were used with apparent success in patients with stable arrhythmias. Pharmacokinetic considerations governing doses, routes, and rates of administration have been discussed above and have also recently been reviewed elsewhere.230 Ventricular arrhythmias. If those arrhythmias that are caused by catecholamines (pheochromocytoma, halothane anesthesia, exercise, exogenous administration) and digitalis are excluded, betablocking drugs are not of great value, although in a series of patients with chronic multiple ventricular extrasystoles not related to drug therapy2’ the ectopic foci were suppressed by racemic propranolol in doses that produced plasma levels of 40-80 rig/ml. In contrast, d-propranolol was without effect even at plasma levels up to 310 rig/ml. However, their value in the long run is not established, nor have they been adequately compared with other antiarrhythmic agents like quinidine. In most cases of ventricular tachycardia the arrhythmia is associated with severe organic heart disease and beta-blocking drugs are liable to precipitate cardiac failure. Stern227 studied a number of patients with ventricular ectopics and a smaller number with recurrent ventricular tachycardia. Twenty-eight patients with ventricular ectopic beats were treated with propranolol and quinidine in doses up to 30 mg and 800 mg/day, respectively, achieving abolition of the arrhythmia in 19 patients. Two out of four patients with recurrent ventricular tachycardia lost their arrhythmias when

219

treated with 30-40 mg/day propranolol plus 0.81.2 g/day quinidine. As noted earlier, these results lack adequate controls but are of interest in that low doses of the two types of antiarrhythmic agents were used with apparent success in previously persistent arrhythmias. Beta-blockade in the treatment of digitalis toxicity. Digitalis is one of the most common causes of cardiac arrhythmias. The most common associations are with bigeminy and paroxysmal atria1 tachycardia with some degree of AV block, although almost every type of arrhythmia has been attributed to digitalis intoxication. As already discussed, it is virtually certain that the beneficial effects of these drugs depend on beta-blockade rather than any nonspecific property, and in this respect, slowing of spontaneous depolarization (reduced automaticity), slowing of conduction, and increasing the effective refractory period are likely to be the key factors. However, it must be recognized that, since digitalis may also interfere with conductivity, the two classes of drugs may summate to produce an unwanted worsening of conductivity even leading to a complete block. For this reason, even though beta-blocking drugs are often valuable in treating digitalis toxicity, they are not likely to be the final solution, and this explains why there is continued interest in diphenylhydantoin, which may actually increase conductivity, or the use of digitalis antibodies, or true pharmacologic antagonists like potassium canrenoate. Finally, it should be added that no pharmacologic approach is an adequate substitute for sound clinical practice, which will include anticipation of situations likely to lead to digitalis toxicity, nor for meticulous attention to such ancillary factors as hypoxia or hypokalemia, which are likely to aggravate the effects of the glycoside. Arrhythmias associated with myocardial infarction and cardiomyopathies are discussed in the appropriate sections. Beta-blocking

Drugs

in the

Treatment

of Cardiomyopathies

The cardiomyopathies are a group of poorly understood diseases of heart muscle, whose etiologies are for the most part obscure and whose classification is therefore necessarily descriptive. Four broad types are recognized, namely hypertrophic, congestive, restrictive, and obliterative. The latter two, on pathologic grounds, would not appear to

220

CONOLLY,

be primarily due to a disorder of myocardial function, and since they appear to offer no scope at present for treatment with beta-blocking drugs, they will not be discussed. Hypertrophic

Cardiomyopathy

(HCM)

This disease is also known as hypertrophic obstructive cardiomyopathy (HOCM) or idiopathic hypertrophic subaortic stenosis (IHSS), notwithstanding the facts that 10%20% of patients with this disorder may have no demonstrable outflow tract obstructionz3r and that the clinical course bears no relationship to the left ventricular systolic gradient.232 Patients may present with palpitations, dyspnea, syncope, or angina. Complications include atria1 fibrillation, cardiac failure, and systemic emboli. The annual mortality is between 3% and 4% and, in a number of these, death is sudden and unexpected. It may be related to tachycardia or to the onset of atria1 fibrillation, which, by reducing the already severely reduced left ventricular filling, may cause a dramatic fall in cardiac output and coronary perfusion, perhaps leading to ventricular fibrillation. The clinical features of this disease have been well described.232-235 The disease may be transmitted as an autosomal dominant233 and up to 30% of new cases have a positive family history. Pathologically, HCM is characterized by massive but irregular hypertrophy predominantly of the septum but often of other parts of the ventricles as well. The muscle fibers are arranged in whorls. They are short, thick, and fragmented, and fibrous tissue arising within the myocardium replaces variable, amounts of muscle tissue.236 The original suggestion 237 that there may be an increase in adrenergic nerve fibers in the affected myocardium has not been confirmed. Hemodynamically, the dominant abnormality appears to be a failure of the left ventricle to fill. The rate of filling is reduced238 and isovolumnic relaxation time is prolonged.231 To this must be added the effect of muscle hypertrophy per se in reducing the size of the ventricular cavity.231 Impairment of ventricular compliance (distensibility) is reflected in an elevation of left ventricular end diastolic pressure (LVEDP). When outflow tract obstruction does occur, it can be worsened by further reduction in ventricular volume (standing, Valsalva’s maneuver) or by a decrease in transmural pressure in the outflow

KERSTING,

AND

DOLLERY

tract (lowered blood pressure). Inotropic agents will effectively create the same situation. Adrenergic agents seem to have a particularly unfavorable combination of effects. By their inotropic action they may worsen outflow tract obstruction, and they also cause an increase in LVEDP. In contrast, atria1 pacing to produce an equivalent or greater tachycardia leads to a fall in LVEDP.239 A great deal of controversy still exists over the use of beta-blocking drugs in this condition. Even now there still have been no long-term studies that would indicate whether or not they can alter the natural history of the disease, and short-term studies are difficult to evaluate because of the inherent var-iability of the disease in any given patient. In using these drugs a physician might hope for five effects. First, a reduction of the pressure gradient across the outflow tract, and hence an arrest or reversal of the hypertrophic process; second, a reduction or abolition of arrhythmias; third, relief of angina and other symptoms; fourth, improvement of left ventricular compliance and filling; and fifth, the prevention of sudden death. It has been repeatedly shown that beta-blocking drugs have little or no effect on the resting pressure gradient ~4’ but that the increase that occurs in response to inotropic stimuli may well be reduced. Thus, Braunwald et a1.233showed that intravenous pronethanol reduced the effects of exercise. The inotropic response was lessened so that the peak left ventricular systolic pressure fell from 205 to 170 mm Hg, and the maximum pressure gradient across the outflow tract was reduced from 79 to 3.5 mm Hg. Other workers have noted similar changes with propranolol. Using the cardioselective betar-blocker practolol, Webb-Peploe et a1.239 and Matlof and Harrison241 have noted relatively little effect on the increase in pressure gradient caused by isoproterenol. This difference has been attributed to the fact that practolol does not prevent the peripheral vasodilator effect of isoproterenol. The unmodified fall in arterial pressure will prevent any lessening of the pressure gradient across the outflow tract. As indicated above, the outflow tract pressure gradient is not the major abnormality in HCM; more important is the loss of ventricular compliance (made worse by inotropic agents) which so impedes left ventricular function. It has been shown by invasive239T241and noninvasive methods that both propranolol and practoiol improve

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

ventricular function. In the study by Hubner et aI.242 propranolol (320 mg/day), practolol (800 mg/day), and placebo were compared in a doubleblind trial. Both drugs produced favorable changes in ventricular compliance and reduction of angina and palpitations. Dyspnea was improved only in patients already severely disabled (grade III). The beneficial effects achieved statistical significance only for propranolol, but in a fixed-dose study it is not possible to say whether this difference is due soIely to dose, or whether it is a reflection of pharmacologic differences, e.g., with respect to ISA. One important point to emerge from this study was that improvement in ventricular function could be demonstrated even in patients free of symptoms. From the point of view of modifying the natural history of the disease, this may be an important consideration. Long-term studies are very few in number and do not provide enough information to permit definition of the value of beta-blocking drugs in HCM. Many of the early studies used relatively low doses of propranolo1243 (the only beta-blocker used to any extent) and this coupled with the variable course which HCM is inclined to run makes assessment difficult. From the earliest studies,244,245 it was clear that beta-blockers could, not surprisingly, relieve angina in patients with HCM. The benefit was often striking, although not all patients maintained their initial improvement.244’246 Arrhythmias are a serious complication of HCM and one of the possible benefits of beta-blockade might be reduction or abolition of arrhythmias. 2401247Cherian et a1.244 reported a reduction in syncopal attacks in five out of the six patients with this symptom, but Hardarson et a1.,243 reporting a 4$-yr follow-up of 119 patients, 83 of whom received propranolol (albeit no more than 240 mg/day), 29 practolol, and 2 pronethalol, were unable to show any reduction in the incidence of sudden death. Clearly, more detailed studies using higher doses are required. Dyspnea is a common symptom in HCM, and early reports suggested that beta-blocking drugs would relieve this. However, more extensive experience 240 has shown that this will only be so in patients who are severely incapacitated to begin with (grades II to IV of the New York Heart Association Scale). The long-term hemodynamic effects of betablockers has not been established. These drugs

221

were initially introduced because it was thought that excessive adrenergic activity was instrumental in causing outflow tract obstruction. However, as noted above, obstruction is not an invariable feature of the disease, and in any case, although betablockers will reduce the increase in obstruction caused by inotropic stimuli, they have no effect on the resting values. A more important defect is the impaired ventricular compliance. Beta-blocking drugs may improve this abnormality, even in patients who are still asymptomatic. For this reason it has been suggested241 that administration of beta-blocking drugs may favorably influence the natural history of the disease. Conclusive information on this key issue is still lacking and will take years of careful study to obtain. However, it is a point that must be clarified because many patients are picked up before symptoms develop, and it is clear that surgery (which is indicated in cases with severe hypertrophy) makes no difference to the long-term outcome.243

Congestive Cardiomyopathy This is more properly thought of as the outcome of a number of disease processes r-ather than a single disease entity. It may follow viral infections, but often the cause is quite obscure. A striking aspect of the disordered physiology is the prominence of dilatation over hypertrophy, the dilatation being diffuse, symmetric, and akinetic. Conventional antifailure therapy is of little avail, and the prognosis in severe cases is bleak.231 In view of this, the astonishing report of the beneficial use of beta-blocking drugs in treating congestive cardiomyopathy by Waagstein et al.%’ deserves close scrutiny. Seven patients with severe congestive cardiomyopathy were treated for periods of 2-12 mo with practolol (six patients) or alprenolol (one patient) in doses of 50-400 mg/ day and 100 mg/day, respectively. in four the improvement was rapid and more gradual in the rest. Prior to beta-blockade, all patients had a resting tachycardia that subsided on treatment, and exercise tolerance improved in all of them. Two patients with resistant edema and ascites had a diuresis after beta-blockade and were able to reduce or discontinue diuretic drugs. Some patients showed a reduction in heart size on chest x-ray, and in some the digoxin requirement was reduced. No patient requiredincreased antifailure therapy because of beta-blockade. Apex cardiography and phono-

CONOLLY,

cardiography showed changes suggesting improved left ventricular compliance. Clearly, these results are of great interest and, if confirmed, of considerable importance. Not only do they offer new hope in the treatment of these patients, but they also may shed new light on the pathogenesis of the congestive cardiomyopathies. Beta-Blockade

in the

Treatment

of Thyrotoxicosis

The role of the adrenergic nervous system in producing the features of thyrotoxicosis remains uncertain. Many of the features of the disease do resemble the effects of sympathetic stimulation and can be ameliorated although not totally abolished by a variety of maneuvers such as spinal anesthesia, ganglion blockade, and blockade of postganglionic adrenergic neurones. In recent years, these observations have been extended to include the effect of beta-adrenoceptor antag0nists.i’ The results obtained have been rather conflicting. It is still not established if there is increased adrenergic activity (owing either to increased levels of catecholamines or altered receptor sensitivity24g-251) or whether, at least in the heart, the changes should be attributed to a direct effect of thyroxine, via its own specific receptors, on an adenylate cyclase system,2s2 which may be entirely separate from that which (probably) mediates the cardiac betaadrenergic effects. 253 The contradictions in the literature may partly be explained by the fact that some data have been derived from clinical observations in thyrotoxic patients, while others have been based on experimentally induced thyrotoxicosis in man or laboratory animals. Despite these uncertainties, beta-blocking drugs have frequently been used as an adjunct to the conventional treatment of thyrotoxicosis. Particular benefit has been obtained in the management of thyrotoxic crises (thyroid storm), a potentially lethal complication of this disease. The original observations of Buckle254 using pronethalol and Parsons and Jewitt255 using propranolol have been reviewed previously. Their findings have recently been confirmed by Das and Krieger256 and by Mackin et al. 257 Beta-blockade produces a rapid reduction in fever, tachycardia, and central effects such as restlessness and disorientation. There are no reports yet available relating to the use of other beta-blockers, selective or nonselective, in the management of this medical emergency.

KERSTING,

AND

DOLLERY

Lee et al.258 describe the use of propranolol in doses of 40-720 mg/day as the sole preoperative medication in 20 thyrotoxic patients undergoing partial thyroidectomy. No complications were encountered before or during surgery, and indeed the thyroid gland in most patients was reported as being less friable than in patients prepared in more conventional ways. Postoperatively, it was necessary to continue propranolol for 4-7 days to prevent the onset of symptoms or signs of hyperthyroidism, but no other problems were encountered. Previously, the use of propranolol in combination with Lugol’s iodine or other conventional medication has been described.25g’260 Reasons for considering the preoperative use of beta-blocking drugs include: a dramatic shortening of the necessary period of preoperative preparation; an additional means of controlling patients who respond poorly to conventional drugs; and an alternative form of therapy for patients who have hypersensitivity reactions to other antithyroid drugs. As part of the routine medical management of thyrotoxicosis, beta-blocking drugs are of less certain value. All are capable of reducing heart rate, although pronethalol, oxprenolol, alprenolol, and practolol, all of which possess ISA, are less effective than those without it, such as propranolol, Other manifessotalol, and pindolol. X2,261,262,263 tations of the disease such as tremor, hyperreflexia, agitation, hemodynamic changes, hyperkinesia, and those eye signs attributable to sympathetically innervated smooth muscle all may be reduced by propranolo1,264,265 practolol,266 and sotalo1.2523267Pindolol has less effect on hemodynamic changes but is otherwise similar.263 It has been observed that the responsiveness of thyrotoxic heart failure to conventional therapy may be improved by beta-blocking drugs.“j8 Recently, it has been reported that propranolol is effective in reversing the elevation in serum calcium, which is occasionally seen in thyrotoxicosis.26g However, despite all these observations, biochemical evidence of elevated thyroxin levels remains.263’270 Patients fail to gain weight satisfactorily”’ despite an improved nitrogen balance,271 and evidence of increased metabolism persists.2521260~263 Indeed, doubt has been expressed about the desirability of reducing cardiac output by beta-blockade in the face of this increased metabolism.2511267 It appears, therefore, that beta-blocking drugs in

BETA-ADRENOCEPTOR-BLOCKING

general are useful in the treatment of thyrotoxic crisis. They may also be useful in preoperative preparation for thyroid surgery. In the long-term managementof thyrotoxicosis, however, although they may help to reduce symptoms and signsbefore other remedies,such as radioiodine, have had time to act,270 by themselvesthey cannot be recommendedsince they do not influence the underlying diseaseprocess. Beta-Blockade

223

DRUGS

in Psychiatry

Ignorance of the pathogenesisof virtually every psychiatric state makes it inevitable that deployment of beta-blocking drugs has been on an entirely empirical basis.The data currently available do not permit conclusive decisionsto be made about any therapeutic value they may have in psychiatry.

Anxiety Granville-Grossmanand Turner2” first suggested that beta-blocking drugsmight be of value in treating anxiety. Since that time several studies have appeared, and most of these have been reviewed by Whitlock and Price.273The studies overall are rather inconclusive, even when the investigators utilized a satisfactory double-blind protocol. However, the dosesusedthroughout were all at the low end of the therapeutic range.More recently, Tyrer and Lader281have reported a double-blind study in which propranolol (up to 360 mg/day) was compared with diazepam (up to 1X mglday) or placebo. It wasfound that patients derived benefit from propranolol only if they presented initially with dominant somatic (as opposed to psychic) symptoms. It is probable that relief of unpleasant symptoms such as palpitations may interrupt a self-perpetuating situation2s2 in which somatic symptoms increasethe anxiety felt by the patient.

Schizophrenia The use of propranolol in this areais highly controversia1.272,273Several studies have appeared that describe the use of huge doses(up to 5800 mg/day) in schizophrenic patients.274-276 In general,favorable resultshave beenclaimedin patients with acute psychotic states,while chronically affected patients do not seemto respond. Furthermore, an associationbetween high initial urinary levels of catecholaminesand 3-methoxy, 4-hydroxy, phenylglycol and a beneficial effect of propranolol has been reported.275 It hasalsobeen stated that responseto beta-blockadebecomesapparent in the first few days of treatment,276sometimesin a matter of hours.277 Before credence can be given to these claims, further studies are urgently needed. None of the above were basedon a double-blind design.The number of patients studied is still small, and patient selection is open to criticism in that someof the situations treated might be expected to remit spontaneously, and some patients received other drugs concomitantly. 278It is important to resolve this matter, because as some of these studies showed,high dosesof propranolol may give rise to harmful side effects, including ataxia, confusion, visual hallucinations, toxic psychosis,asthma, and congestive cardiac failure in susceptiblepatients, and hypertension, which, in some patients, is of considerableseverity.275,276,27g

Beta-Blockadeand Tremor Tremor may occur in several situations. It is common in senilestatesand Parkinson’sdisease.It may occur without obvious neurologic disease(essential tremor), or it may only be evoked in situations involving emotional stress(nervous tremor). There is good evidence that the latter resultsfrom adrenergicactivity. It can be mimicked by intraarterial infusions of isoproterenol or epinephrine and can be blocked by acute administration of proIn the study by Young et al.,285it pranolol.283-285 was reported that essentialtremor did not respond to acute injections of small dosesof propranolol, although oral medication at higher doses(120-240 mg/day) was effective if the drug was given long enough for a higher steady-state level to be achieved. Two long-term studies286,287 have given conflicting results, but in both these studies involving patients with essentialtremor, only a small dose of propranolol (120 mg/day) wasused. The tremor of Parkinson’s diseaseis probably unaffected by beta-blockade.2867288 Beta-blocking drugs have been usedin a variety of other psychiatric conditions, including drug dependence, alcohol withdrawal, and mania. However, the data are scanty and permit no evaluation of the usefulnessof theseagentsin suchconditions at this time.

224

CONOLLY,

Beta-Blockade and Migraine Although the clinical features of migraine are well known”’ the underlying mechanisms remain obscure. Beta-blockers were empirically used in an attempt to reduce the vasodilation that gives rise to the headache. A number of properly conducted double-blind studies using propranolol have shown this drug to have a worthwhile prophylactic effect in migraine.290-2g3 Not surprisingly, beta-blocking drugs with significant ISA are of no benefit 289,294,295 SIDE

EFFECTS

The adverse effects of beta-adrenoceptor-blocking drugs can be divided into two categories: 1) those that result from known pharmacologic consequenceof beta-adrenoceptor blockade, and 2) other reactions that do not appear to result from beta-adrenoceptorblockade. Side effects of the first category are widespread because of the ubiquitous nature of the sympathetic nerve supply in the control of body function. Seriousreactions of this type include asthma, heart failure, hypoglycemia, severe bradycardia, worsening of claudication, and Raynaud’s phenomenon. Bronchoconstriction The innervation of the airways is complex and involves alpha- and beta-adrenoceptorsand cholinergic receptors. Beta-receptor stimulation can dilate the airways by relaxing bronchial smooth muscle and by reducing the releaseof smooth muscle contracting substances such as histamine and SRS-A.2g6,2g7 Beta-adrenoceptor agonists are widely used to treat asthma, and beta-adrenoceptor-blocking drugs can provoke attacks of asthma in patients who have not experienced wheezing previously. It is standard practice to question patients about wheezing before prescribing propranolol and other beta-blocking drugs and to avoid their useif the history is positive. Some beta-receptor-blocking drugshave a degree of selectivity for cardiac (betai) as opposed to smooth muscle(beta2) receptors, and these drugs are lesslikely to provoke asthma,although the relative risk is hard to quantify and is almost certainly dependent on the dose used. Thus, a low dose of cardioselective beta-blockade might produce appreciable cardiac beta-receptor blockade with only a minor degreeof blockade of smooth

KERSTING,

AND

DOLLERY

muscle receptors. However, in high dosesselectivity is lost.43 Conversely, propranolol has a minor degree of selectivity for smooth muscle beta2receptors as opposed to cardiac ones, so that at low dosesit will have proportionately more effect on the airways than on the heart.2g8This selectivity too will be lost at high doses. Other betareceptor-blocking drugs have a degree of sympathomimetic activity and this has been claimed to lessen the risk of bronchospasm.There is, however, no reasonto supposethat ISA would be any more valuable in avoiding asthma than it is in preventing congestive cardiac failure, and in a recent study on oxprenolol, sevenout of 12 patients with airways obstruction showeda significant reduction in forced expiratory volume. ’ 7 The safest course is to avoid beta-receptorblocking drugs in patients with airways obstruction. In marginal cases, serial measurementsof ventilatory function may be helpful. Heart Failure There are severalcircumstancesin which blockade of beta-receptors may causecongestivefailure in the heart that was on the borderline of failure before treatment: 1) in an enlarged heart dependent on sympathetic drive to maintain it on a compensatedStarling curve; 2) if the stroke volume is restricted and tachycardia is needed to maintain output; and 3) in the presenceof aortic incompetence where prolonged diastolewill increaseregurgitant flow. Heart failure appearsto be a relatively uncommon complication of treatment with beta-blocking drugs. Stephen reported 13 instancesout of 1500 casestreated orally with propranolol.2ggHeart failure is most likely to ariseearly in treatment and it is unlikely that the patient who remains out of failure in the early weeks of treatment will subsequently go into heart failure. Furthermore, cardiac failure is not an absolute contraindication to the useof beta-blocking drugs,sinceif the clinical situation demands them, digitalis and diuretics may be given concomitantly. Hypoglycemia In man, mobilization of muscle glycogen is a beta-receptor-mediated function, while mobilization of liver glycogen dependson alpha-receptor stimulation. As a result, beta-receptor-blocking drugs may retard recovery from hypoglycemia.

BETA-ADRENOCEPTOR-BLOCKING

225

DRUGS

Likewise, if liver glycogen is reduced by fasting or illness, administration of beta-blocking drugs may prolong recovery from hypoglycemia, since alternative stores cannot be mobilized. This has been previously discussed (see above and Dollery et al.“). Bradycardia Slowing of the heart rate is a normal response to treatment with a beta-receptor-blocking drug devoid of intrinsic sympathomimetic activity. Since healthy individuals can sustain heart rates of 50 or less without any disability, there appears to be no reason for concern when propranolol induces heart rates of this level so long as there is no evidence of heart failure. If it is essential to correct the bradycardia, atropine may be given. If there is a partial or complete atrioventricular conduction defect, use of a beta-blocking drug may lead to a serious bradyarrhythmia. It is usual to exclude such patients from treatment with beta-blocking drugs on the basis of the electrocardiographic findings. Conduction defects below the AV node are not affected by beta-blockade. Intermittent Claudication and Raynaud’s Phenomenon Patients with peripheral vascular disease who suffer intermittent claudication often report worsening of their claudication when treated with betablocking drugs. This is due to the reduction of peripheral blood flow consequent on the fall in cardiac output and possibly also loss of a peripheral vasodilator effect. Intermittent claudication is therefore a relative contraindication to treatment with beta-blocking drugs. Worsening of provocation of Raynaud’s phenomenon is one of the more common side effects of treatment with propranolol. It may in part reflect the selectivity of propranolol for vascular smooth muscle as opposed to cardiac smooth muscle. Provocation of Raynaud’s phenomenon is more common in women than men.300 Other Effects Many other side effects have been ascribed to beta-receptor-blocking drugs, e.g., skin rashes and changes in bowel function, but it is not certain that these are causally related. Vivid dreams and visual hallucinations do appear to be causally related to treatment with beta-blocking drugs espe-

cially propranolol but may also occur with others like practolol, notwithstanding a lesser penetration into the central nervous system. Oculocutaneous Syndrome Practolol, although less potent as a beta-adrenoceptor-blocking drug than propranolol, had come into very wide use in England and some other countries. In 1975, Wright reported that skin and eye changes, including blindness, could result from practolol,301 and other reports quickly added deafness, oral and nasal dryness, and sclerosing peritonitis to this list. In consequence, the drug has been withdrawn or its use drastically restricted. Close attention has been focused on this syndrome both because of its inherent interest and because of fears that it may occur with other beta-adrenoceptor-blocking drugs. The main features of this syndrome in 439 patients reviewed by Nichols302 were as follows. Eye. The first symptom is usually a gritty feeling in the eye which can progress into a panconjunctivitis, keratitis, and pannus formation. In Nichols’ series, 18 patients had severe eye changes, 112 had corneal damage without loss of sight, and 146 had eye changes without cornea1 involvernent. The average time to develop this syndrome w,as 23 mo after initiating treatment. Skin. The skin changes usually begin with an itchy rash that may involve the palms and the soles of the feet. Thickened plaques appear in the skin and may resemble the skin lesions of psoriasis. Immunofluorescent studies have revealed granular deposits at the dermal-ectodermal junction in some cases303 Ear. Deafness with serous otitis media has been reported in some patients receiving practolol. Sclerosing Peritonitis Thirty-three patients with this syndrome were included in Nichols’ report. They may present with colicky abdominal pain or an abdominal mass, and some cases have presented months after stopping treatment with practolol. The peritoneum becomes covered with a film of white fibrous tissue with thicker plaques. 304 The natural history of the condition is unknown and the diagnosis has usually been made at laparotomy or autopsy. Patients appear to improve with time after cessation of treatment. The mean time to diagnosis of sclerosing peritonitis after starting practolol was 37

226

CONOLLY,

mo. Because of the difficulty of diagnosing the condition, practolol has been withdrawn from clinical use apart from a restricted range of indications in the hospital.

Other Beta-blocking Drugs and the Oculocutaneous Syndrome Since both skin rashes and complaints of a dry and gritty eye are common among patients who have never received beta-blocking drugs, it is to be expected that there will be reports of these symptoms in patients who are taking other betablocking drugs. To date, the most numerous of these reports have concerned oxprenolol. However, it is by no means certain that any beta-blocking drug other than practolol can cause this syndrome.305 Unfortunately, there appears to be no way of finding out short of observing large numbers of patients for several years.

Carcinogenicity Pronethanol, the first beta-adrenoceptor-blocking drug to achieve wide use, was withdrawn by its manufacturers because it caused thymic tumors and lymphosarcomata in mice, although it did not do so in rats or dogs. 3ffi The doses used to produce the tumors were up to 200 mg/kg, while clinical doses did not exceed 2.5 mg/kg. Recently, tolamolol, a cardioselective beta-adrenoceptor-blocking drug, has been withdrawn from clinical trials because it caused mammary tumors in mice and rats in high doses. The relevance of these findings to causation of tumors in man is difficult to evaluate; the doses

KERSTING,

AND

DOLLERY

used were high and the relationship between malignant tumors in animals and man is unclear. The most disturbing aspect has been the suggestion that this might be a pharmacologic property of beta-adrenoceptor antagonism rather than carcinogenicity by some other mechanism. The basis of this argument is that cyclic AMP levels in cells are reduced by beta-adrenoceptor antagonists and that treatment of cultured sarcoma cells with cyclic AMP enables them to acquire several morphologic characteristics of normal fibroblasts.307 However, several beta-receptor-blocking drugs including propranolol have successfully passed carcinogenecity testing in animals. Furthermore, it cannot be concluded that, because increased levels of cyclic AMP cause cultured tumor cells to acquire a more normal morphology, blockade of beta-receptors in normal cells in vivo will predispose to malignant change. In the initial studies of pronethalol, which led to its abandonment, the possibility existed of there being an essential viral cofactor involved in the malignant transformation.308 In more recent studies of another beta-blocking drug, in which pronethalol was used as a carcinogenic “yardstick,” no tumors developed in the pronethaloltreated animals. At present, the arguments concerning the effects on cyclic AMP levels in relation to carcinogenesis are purely theoretical. The whole area has recently been thoughtfully reviewed by Chlapowski et a1.30g ACKNOWLEDGMENT The authors borough for through many

are deeply indebted to Bernadette Edinher patience in typing this manuscript alterations into its final form.

REFERENCES 1. Langley JN: On the reaction of cells and of nerve endings to certain poisons: Chiefly as regards the reaction of striated muscles to nicotine and to curare. J Physiol (Lond) 33:374-413, 1905 2. Dale HH: On some physiological actions of ergot.,J Physiol (Land) 34:163-206,1906 3. Ahlquist RP: A study of the adrenotropic receptors. Am J Physiol 153:586-599, 1948 4. Slater IH, Powell CE: Blockade of adrenergic inhibitory receptor sites by 1-(3’,4’-dichIorophenyl)-2-isopropylaminoethanol hydrochloride. Fed Proc 16:336, 1957 5. Powell CE, Slater IH: Blocking of inhibitory adrenergic receptors by a dichloro-analog of isoproterenol. J Pharmacol Exp Ther 122:480-488,1958 6. Furchgott RF: The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory, in Blaschko H, Muscholl E (eds):

Handbook of Experimental Pharmacology, vol 33. New York, Springer-Verlag, 1972, pp 283-335 7. Lands AM, Arnold A, McAuliff JP, et al: Differentiation of receptor systems activated by sympathomimetic amines. Nature 214:597-598, 1967 8. Bristow M, Sherrod TR, Green RD: Analysis of beta receptor drug interactions in isolated rabbit atrium, aorta, stomach and trachea. J Pharmacol Exp Ther 171:52-61, 1970 9. Lefcowitz RJ: Heterogeneity of adenylate cyclasecoupled beta adrenergic receptors. Biochem Pharmacol 24:583-590, 1975 10. Dollery CT, Paterson JW, Conolly ME: Clinical pharmacology of beta receptor blocking drugs. Clin Pharmacol Ther 10:765-799,1969 11. Consequences of drug receptor interaction: Analysis of the graded dose-response relationship, in Goldstein

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

A, Ptronow L, Kalman SM (eds): Principles of Drug Action. New York, John Wiley & Sons, 1974, pp 82-111 12. Ariens EJ: The structure-activity relationships of beta-adrenergic drugs and beta-adrenergic blocking drugs. Ann NY Acad Sci 139:606-631,1967 13. Ariens EJ, van Rossum JM, Simonis AM: Affinity, intrinsic activity and drug interactions. Pharmacol Rev 9: 218-236,1957 14. Nickerson M: The pharmacology of adrenergic blockade. Pharmacol Rev 1:27-l 0 1, 1949 15. Thome P: Letter. Med J Aust 1:1242, 1971 16. Weal-Manning H, Simpson FO: Paradoxical effect of pindolol. Br Med J 3:155-156, 1975 17. Addis GJ, Thorp JM: Effects of oxprenolol on the airways of normal and bronchitic subjects. Eur J Clin Pharmacol9:259-263, 1976 18. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics. London, Collier, Macmillan Ltd., 1970, pp 484-487; 566 19. Barrett AM, Cullum VA: The biological properties of the optical isomers of propranolol and their effects on cardiac arrhythmias. Br J Pharmacol34:43-55, 1968 20. iblad B, Brogzrd M, Ek L: Pharmacological properties of H 56/28, a beta adrenergic receptor antagonist. Acta Pharmacol Toxicol 25 (Suppl 2):9-40, 1967 21. Vaughan Williams EM, Papp J Gy: The effect of oxprenolol on cardiac intracellular potentials in relation to its antiarrhythmic local anaesthetic and other properties. Postgrad Med J 46 (Nov Suppl): 22-32, 1970 22. Black JW, Duncan WAM, Shanks RG: Comparison of some properties of pronethalol and propranolol. Br J Pharmacol Chemother 25:577-591, 1965 23. Brunner H, Hedwall PR, Maier R, et al: Pharmacological aspects of oxprenolol. Postgrad Med J 46 (Nov Suppl): 5-14,197o 24. Basil B, Jordan R, Loveless AH, et al: p-adrenoceptor blocking properties and cardioselectivity of M & B 17,803 A. Br J Pharmaco148:198-211,1973 25. Coltart DJ, Meldrum SJ: The effect of propranolol on the human and canine transmembrane action potential. Br J Pharmacol40:148P, 1970 (abstract) 26. Coltart DJ, Shand DG: Plasma propranolol levels in the quantitative assessment of p-adrenergic blockade in man. Br Med J 3:731-734, 1970 27. Ariens EJ: Wirkung and Wirkungsmechanismus von Katecholamines und ihren Derivaten. Naunyn Schmiedebergs Arch. Pharmakol Exp Path01 257:118-141, 1967 28. Levy JV, Richards V: Inotropic and chronotropic effects of a series of p-adrenergic blocking drugs: Some structure-activity relationships. Proc Sot Exp Biol Med 122:373-379,1966 29. Coltart DJ, Gibson DG, Shand DG: Plasma propranolol levels associated with suppression of ventricular ectopic levels. Br Med J 1:490-491, 1971 30. Katz RL, Lord CO, et al: Anesthetic-dopamine cardiac arrhythmias and their prevention by beta adrenergic blockade. J Pharmacol Exp Ther 158:40-45,1967 31. Somani P, Watson DS: Antiarrhythmic activity of the dextroand levorotatory isomers of 4-(2-isopropylamino-1-hydroxy ethyl) methane-sulfonanihde (MJ 1999). J PharmacolExp Ther 164:317-325,1968 32. Duce BR, Garberg L, Smith ER: Effects of (I)-

227 propranolol, (*)- and (+)- and (-)-alprenolol on unanaesthetized dogs with ventricular arrhythmias resulting from coronary artery ligation. Br J Pharmacol 39:809-816, 1970 33. Sannamaki KJ: Studies on the anti-arrhythmic effect of dextroalprenolol. Pharmacol Clin 3:23-31, 1970 34. Kelliher GJ, Roberts J: The effects of d(+)- and I(-)-practolol on ouabain-induced arrhythmia. Eur J Pharmacol20:243-247, 1972 35. Kelliher GJ, Roberts J: A comparison of the effects of sotalol and the isomers of practolol on adrenergic nervous activity. Life Sci 13:1231-1243, 1973 36. Dohadwalla AN, Freedberg AS, Vaughan-Williams EM: The relevance of p-receptor blockade to ouabaininduced cardiac arrhythmias. Br J Pharmacol 36:257-267, 1969 37. Chamberlain DA: The haemodynamic effects of beta-adrenergic blockade in man. Cardiologia 49 (Suppl 21~27-42, 1966 38. Shand DG: Individualization of propranolol therapy. Med Clin North Am 58:1063-1069, 1975 39. Shand DG, Nuckolls E, Oates JA: Plasma propranolol levels in adults with observations in four children. Clin Pharmacol Ther 11:112-120, 1970 40. Prichard BNC, Gillam PMS: Assessment of propranolol in angina pectoris. Clinical dose response curve and effect on electrocardiogram at rest and on exercise. Br Heart J 33:473-480, 1971 41. Dunlop D, Shanks RG: Selective blockade of adrenoceptive beta-receptors in the heart. Br J Pharmacol 32:201-218,1968 42. Hainsworth R, Karim F, Stoker JB: Blockade of peripheral vascular responses to isoprenaline by three beta-adrenoceptor antagonists in the anaesthetized dog. Br J Pharmacol51:161-168,1974 43. Lertora JL, Mark AL, Johannsen UJ, et al: Selective beta1 receptor blockade with oral practolol in man. J Clin Invest 56:7I9-724, 1975 44. Briant RH, Dollery CT, Fenyvesi T, et al: Assessment of selective beta-adrenoceptor blockade in man. Br J Pharmacol49:106-114, 1973 45. MacDonald AG, McNeil1 RS: A comparison of the effect on airway resistance of a new beta blocking drug, ICI 50,172 and propranolol. Br J Anaesth 40:508-510, 1968 46. Bernecker C, Roetscher I: The beta blocking effect of practolol in asthmatics. Lancet 2:662, 1970 47. Skinner C, Palmer KNV, Kerridge DF: Comparison of the effects of acebutolol (Sectral) and practolol on airways obstruction in asthmatics. Br J Clin Pharmacol 2: 417-422,1975 48. Cleaveland CR, Rangno RE, Shand DG: A standardized isoproterenol sensitivity test. The effects of sinus arrhythmia, atropine and propranolol. Arch Intern Med 130:47-52, 1972 49. George CF, Conolly ME, Fenyvesi F, et al: Intravenously administered isoproterenol sulfate dose response curves in man. Arch Intern Med 130:361-364, 1972 50. Robin E, Cowan C, Puri P, et al: A comparative study of nitroglycerin and propranolol. Circulation 36: 175-186, 1967 51. Le Winter MM, Crawford MH, Karliner JS, et al:

228 Effects of oral propranolol in normal subjects. Clin Pharmacol Ther 17:709-712,197s 52. Prichard BNC, Aellig WH, Richardson GA: The action of intravenous oxprenolol, practolol, propranolol and sotalol on acute exercise tolerance in angina pectoris: The effect on heart rate and the electrocardiogram. Postgrad Med J 46 (Nov Suppl): 77-85,197O 53. Johnsson G, Sjogren J, Solve11 L: Beta blocking effect and serum levels of alprenolol in man after administration of ordinary and sustained release tablets. Eur .I Clin Pharmacol3:74-81, 1971 54. Gugler R, Hobel W, Bodem G, et al: The effect of pindolol on exercise-induced cardiac acceleration in relation to plasma levels in man. Clin Pharmacol Ther 17: 127-133, 1975 55. Sowton E, Hamer J: Hemodynamic changes after beta-adrenergic blockade. Am J Cardiol 18:317-320, 1966 56. Epstein SE, Robinson BF, Kahler RL, et al: Effects of beta-adrenergic blockade on the cardiac response to maximal and submaximal exercise in man. J Ciin Invest 44:1745-1753,196s 57. Robinson BF, Epstein SE, Beiser GD, et al: Control of heart rate by the autonomic nervous system. Circ Res 19:400-411, 1966 58. Ekblom B, Goldberg AN, Kilbom A, et al: Effects of atropine and propranolol on the oxygen transport system during exercise in man. Stand J Clin Lab Invest 30: 35-42,1972 59. Dollery CT, George CF: Propranolol-ten years from introduction, in Melmon K (ed): Cardiovascular Drug Therapy. Philadelphia, F.A. Davis, 1974, pp 255268 60. Kelly JG, Carruthers SG, Brown HC: Comparison of the effects of some beta adrenoceptor blocking agents in man. Br J Clin Pharmacol3: 345P-346P, 1976 61. Levy JV: Cardiovascular effects of prinodolol (LB46) a potent beta-receptor antagonist. J Clin Pharmacol 11:249-260,197l 62. Lish PM, Weikel JH, Dungan KW: Pharmacological and toxicological properties of two new beta-adrenergic recepror antagonists. J Pharmacol Exp Ther 149:161-173, 1965 63. Franciosa JA, Freis ED: Normal cardiac output during beta blockade with timolol in hypertensive patients. Clin Pharmacol Ther 18:158-164, 1975 64. Barrett AM: The pharmacology of practolol. Postgrad Med J 47 (Suppl):7-12, 1971 65. Adam KR, Boyles SM: Haemodynamic and coronary vascular responses after p-adrenoceptor blockade in the anaesthetized dog: A comparison of tolamolol with practolol and propranolol. Eur J Pharmacol 26:96-107, 1974 66. iblad B, Carlsson E, Ek L: Pharmacological studies of two new cardioselective adrenergic beta-receptor antagonists. Life Sci 12:Part 1, 107-119, 1973 67. Barrett AM, Carter J, Fitzgerald SD, et al: A new type of cardioselective adrenoceptive blocking drug. Br J Pharmacol48:3401, 1973 68. Harry JD, Knapp MF, Linden RJ: The actions of a new p-adrenoceptor blocking drug, ICI 66082, on the

CONOLLY,

KERSTING,

AND

DOLLERY

rabbit papillary muscle and on the dog heart. Br JPharmacol51:169-177, 1974 69. Lewis CM, Brink AJ, Theron MJ, et al: Beta adrenergic blockade, hemodynamics and myocardial energy metabolism in patients with ischemic heart disease. Am J Cardiol21:846-859, 1968 70. Wiener L, Dwyer EM Jr, Cox JW: Hemodynamic effects of nitroglycerin, propranolol, and their combination in coronary heart disease. Circulation 39:623-632, 1969 7 1. Choquet Y, Capone RJ, Mason DT, et al: Comparison of the beta adrenergic blocking properties and negative inotopic effects of oxprenolol and propranolol in patients. Am J Cardiol 29:257, 1972 (abstract) 72. Bensaid J, Siebat L, Lenegre J: Haemodynamic effects of intravenous oxprenolol. Postgrad Med J 46 (Nov Suppl): 49-56, 1970 73. Kerber RE, Goldman RH, Alderman EL, et al: Circulatory responses to beta-adrenergic blockade with alprenolol. Am J Cardiol 29:26-32, 1972 74. Hutton J, Lorimer AR, Hillis WS, et al: Haemodynamics and myocardial function after sotalol. Br Heart J 34:787-790, 1972 75. Gibson DG, Coltart DJ: Haemodynamic effects of practolol. Br Heart J 34:95-99, 1972 76. Hiliis WS, Hutton J, Lawrie TD, et al: The effects of a new beta-adrenoceptor blocking compound, tolamolol, on haemodynamics and myocardial function in man. Br J Pharmacol51:15-19,1974 77. Harris WS, Schoenfeld CD, Weissler AM: Effects of adrenergic receptor activation and blockade on the systolic pre-ejection period, heart rate and arterial pressure in man. J Clin Invest 46:1704-1714, 1967 78. Hunt D, Shaman G, Clark RM, et al: Effects of beta-adrenergic blockade on the systolic time intervals. Am J Med Sci 259:97-113, 1970 79. Leon DF, Thompson ME, Shaver JA, et al: Hemodynamic effects of practolol at rest and during exercise. Circulation 45:46-54, 1972 80. Achong MR, Piafsky KM, Ogilvie RJ: Comparison of cardiac effects of timolol and propranolol. Clin Pharmacol Ther 18:278-286, 1975 81. Frei F, Imhof P, Dubach UC: Effects of cy- and preceptor blockade on systolic time intervals. Eur J Clin Pharmacol7: l-10, 1974 82. Schneck DW, Aoki VS, Kroetz FW, et al: Correlation of beta blockade with serum practolol levels after oral administration. Clin Pharmacol Ther 13:685-693, 1972 83. Goldstein RE, Hall CA, Epstein SE: Comparison of relative inotropic and chronotropic effects of propranolol, practolol and sotalol. Chest 64:619-627, 1973 84. Guyton A: Regulation of cardiac output. Anesthesiology 29:314-326, 1968 85. Shinebourne E, Fleming J, Hamer J: Effects of beta adrenergic blockade during exercise in hypertensive and ischaemic heart disease. Lancet 2: 1217-1220, 1967 86. Ulrych M, Frohlich ED, Dustan HP, et al: Immediate hemodynamic effects of beta-adrenergic blockade with propranolol in normotensive and hypertensive man. Circulation 37:411-416, 1968

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

87. Johnsson G, de Guzman M, Bergman H, et al: The hemodynamic effects of alprenolol and propranolol at rest and during exercise in hypertensive patients. Pharmacol Ciin 2:34-39, 1969 88. Frohlich ED, Tarazi RC, Dustan HP, et al: The paradox of beta adrenergic blockade in hypertension. Circulation 37:417-423, 1968 89. Prichard BNC, Shinebourne E, Fleming J, et al: Haemodynamic studies in hypertensive patients treated by oral propranolol. Br Heart J 32:236-240, 1970 90. Ulrych M, Franciosa J, Conway J: Comparison of a new beta adrenergic blocker (MK 950) and propranolol in man. Clin Pharmacol Ther 13:232-238, 1972 91. Tarazi RC, Sevard Y, Dustan HP, et al: Cardioselective beta adrenergic blockade in hypertension. Clin Pharmacol Ther 13:154, 1972 (abstract) 92. Stenberg J, Wasir H, Amery A, et al: Comparative hemodynamic studies in man of adrenergic betar receptor agents without (H93/26, metoprolol) or with (H87/07) intrinsic sympathomimetic activity. Acta Pharmacol Toxico1 36 (Suppl5):76-84, 1975 93. Bloomfield DA, Sowton E: Rate-independent effects of propranolol. The differentiation between chronotropic, inotropic and peripheral vascular responses. Circ Res 21 (Suppl3):243-247, 1967 94. Donoso E, Cohn LJ, Newman BJ, et al: Effects of propranolol on patients with complete heart block and implanted pacemakers. Circulation 36:534-538, 1967 95. Lund-Larsen PG, Sivertssen E, Lorentsen E, et al: Hemodynamic effects of beta adrenergic blockade in patients with complete heart block and implanted pacemaker. ActaMed Stand 183:511-513,1968 96. Winer N, Chokshi DS, Walkenhorst WG: Effects of cyclic AMP, sympathomimetic amines and adrenergic receptor antagonists on renin secretion. Circ Res 29:239248, 1971 97. Michelakis AM, McAllister RG: Effect of chronic adrenergic receptor blockade on plasma renin activity in man. J Clin Endocrinol 34:386-397, 1972 98. Maurer KA, Rosskamp E, Krause DK, et al: Stimulatory action of various drugs on plasma renin activity and angiotensin II concentration in normals, patients with arterial hypertension and congestive heart failure, in Genest J, Koiw E (eds): Hypertension ‘72. New York, Springer-Verlag, 1972 pp 140-148 99. Johnston CJ, Anavekar N, Chua KG, et al: Plasma renin and angiotensin levels in human hypertension following treatment. Clin Sci Mol Med 45:287-290, 1973 100. Biihler FR, Laragh JH, Baer L, et al: Propranolol inhibition of renin secretion. New Engl J Med 287:12091214,1972 101. Biihler FR, Marbet G, Pate1 U, et al: Reninsuppressive potency of various beta adrenergic blocking agents at supine rest and during upright exercise. Clin Sci Mol Med 48 (Suppl2):61s-64s 1975 102. George CF, Lewis PJ, Steiner JA, et al: A comparison of propranolol and compound R03-4787 in the treatment of arterial hypertension in man. Clin Sci Mol Med 48:65s-67s, 1975 103. Weber MA, Oates HF, Stokes GS: Beta adrenergic receptors and renin release: Studies with beta adrenocep-

229 tor blocking agents in the conscious rabbit. Clin Sci Mol Med 48 (Suppl2):89s-91s, 1975 104. Bravo EL, Tarazi RC, Dustan HP: Beta adrenergic blockade in diuretic-treated patients with essential hypertension. New Engl J Med 292:66-70, 1975 105. Castenfors J, Johnsson H, Or6 L: Effect of alprenolol on blood pressure and plasma renin activity in hypertensive patients. Acta Med Stand 193:189-195, 1973 106. iberg H: Beta receptors and renin release. New Engl J Med 290: 1026,1974 107. Amery A, Billiet L, Fagard R: Beta receptors and renin release. New Engl J Med 290:284, 1974 108. Himms-Hagen J: Sympathetic regulation of metabolism. Pharmacol Rev 19:367-461,1967 109. Porte D: Sympathetic regulation of insulin secretion. Its relation to diabetes mellitus. Arch Intern Med 1231252-260, 1969 110. Antonis A, Clark ML, Hodge RL, et al: Receptor mechanisms in the hyperglycaemic response to adrenaline in man. Lancet 1: 1135-1137, 1967 111. Abramson EA, Arky RA, Woeber KA: Effects of propranolol on the hormonal and metabolic responses to insulin-induced hypoglycaemia. Lancet 2: 1386-1388, 1966 112. Hesse B, Pedersen JT: Hypoglycaemia after propranolol in children. Acta Med Stand 193:551-552, 1973 113. Hesse B, Bollerup AC, Olesen KH: The influence of beta-blocking agents on plasma volume and extracellular volume in ischaemic heart disease. Stand .I Clin Lab Invest 34:215-217, 1974 114. Wray R, Sutcliffe SBJ: Propranolol-induced hypoglycaemia and myocardial infarction. Br Med J 2:592, 1972 115. Podolsky S: A possible role of propranolol in recurrent nonketotic hyperosmolar diabetic coma. Diabetes 19 (Suppi 1):398, 1970 116. Podolsky S, Pattavina CG: Hyperosmolar nonketotic diabetic coma: A complication of propranolol therapy. Metabolism 22:685-693, 1973 117. Porte D, Robertson RP: Control of insulin secretion by catecholamines, stress, and the sympathetic nervous system. Fed Proc 32:1792-1796, 1973 118. Loubatieres A, Mariani MM, Sore1 G, et al: The action of beta adrenergic blocking and stimulating agents on insulin secretion. Characterization of the type of beta receptor. Diabetologia 7:127-132, 1971 119. Sherline P, Lynch A, Glinsmann WH: Cyclic AMP and adrenergic receptor control of rat liver glycogen metabolism. Endocrinology 91:680-690, 1972 120. Hansen AP: The effect of adrenergic receptor blockade on the exercise-induced serum growth hormone rise in normals and juvenile diabetics. J Clin Endocrinol 33:807-812, 1971 121. Imura H, Kato Y, Ikeda M, et al: Effect of adrenergic blocking or stimulating agents on plasma growth hormone, immuno-reactive insulin, and blood free fatty acid levels in man. J Clin Invest 50:1069-B079, 1971 122. Werrbach JH, Gale CC, Goodner CJ, et al: Effect of autonomic blocking agents on growth hormone, insulin,

230 free fatty acids and glucose in baboons. Clin Res 17: 111, 1969 123. Harvey W, Fabona G, Unger R: Effect of adrenergic blockade on exercise-induced hyperglucagonemia. J Clin Invest .52:38a, 1973 124. Lawrence AM, Hagen TC, Kirsteins L: Propranolol hypoglycemia and impaired glucagon secretion. Clin Res 20:770,1972 125. Pinker EJ, Pattee CJ: Effect of beta adrenergic blockade on resting and stimulated fat mobilization. J Clin Endocrinol27: 1441-1450, 1967 126. WhittingtonCoIeman PJ, Carrier D Jr, Douglas BH: The effects of propranolol on cholesterol-induced atheromatous lesions. Atherosclerosis 18:337-345, 1973 127. Lloyd-Mostyn RH, Krikler DM: Raised serum lipids unaffected by beta blockade. Lancet 2: 1040,197O 128. Barboriak JJ, Friedberg HD: Propranolol and alimentary lipemia in man. J Lab Clin Med 78:986, 1971 129. Barboriak JJ, Friedberg HD: Propranolol and hypertriglyceridemia. Atherosclerosis 17:31-35, 1973 130. Paterson JW, Conolly ME, Dollery CT, et al: The pharmacodynamics and metabolism of propranolol in man. Pharmacol Clin 2:127-133, 1970 131. Shand DG, Evans GH, Nies AS: The almost complete hepatic extraction of propranolol during intravenous administiation in the dog. Life Sci 10:1417-1421, 1971 132. Ablad B, Borg KP, Johnsson G, et al: Combined pharmacokinetic and pharmacodynamic studies of alprenolo1 and 4-hydroxy alprenolol in man. Life Sci 14:693704,1974 133. Gugler R, Herold W, Dengler HJ: Pharmacokinetics of pindolol in man. Eur J Clin Pharmacol 7:1724,1974 134. Cleaveland CR, Shand DG: Effect of route of administration on the relationship between beta adrenergic blockade and plasma propranolol level. Clin Pharmacol Ther 13:181-195, 1972 135. Pine M, Favrot L, Smith S, et al: Correlation of plasma propranolol concentrations with therapeutic response in patients with angina pectoris. Circulation 52: 886-893,1975 136. George CF, Fenyvesi T, Dollery CT: Pharmacological effects of propranolol in relation to plasma levels, in Davies DS, Prichard BNC (eds): Biological Effects of Drugs in Relation to their Plasma Concentration. London, Macmillan, 1973, pp 123-133 137. Prichard BNC, Gillam PMS: Treatment of hypertension with propranolol. Br Med J 1:7-16, 1969 138. Zacharias FJ, Cohen JK, Presst J, et al: Propranolol in hypertension: A study of long term therapy 1964-1970. Am Heart J 83:755-761, 1972 139. Laver MC, Fang P, Kincaid-Smith P: Double-blind comparison of two beta blocking drugs with previous therapy in the treatment of hypertension. Med J Aust 1:174-176,1974 140. Smith EC, Dahr SK, Freedman P: Propranolol in the management of hypertension in a long term dialysis program. JAMA 229:1777-1778, 1974 141. Miall WE, Brennan PJ, Mann AH: Medical Research Council’s treatment trial for mild hypertensionan interim report. Clin Sci Mol Med (in press)

CONOLLY,

KERSTING,

AND

DOLLERY

142. Tibblin G, iblad B: Antihypertensive therapy with alprenolol, a beta adrenergic receptor antagonist. Acta Med Stand 186:45 1-457, 1969 143. Bengtsson C: Long term effect of alprenolol as antihypertensive agent. Acta Med Stand (Suppl 554) g-14,1974 144. Bengtsson C: Comparison between alprenolol and propranolol as antihypertensive agents. A double blind crossover study. Acta Med Stand 192:415-418, 1972 145. Comerford MB, Pringle A: A long term study of the antihypertensive effect of alprenolol. Acta Med Stand (Suppl554) 15-22, 1974 146. Eisalo A, Heino A, Munter J: The effect of alprenolol in elderly patients with raised blood pressure. Acta Med Stand (Suppl554) 23-31, 1974 147. Somer T, Luomanmaki K, Frick MH: Alprenolol and propranolol in the treatment of hypertension: A comparative study. Acta Med Stand (Suppl 554) 33-37, 1974 148. Tuomilehto J, Puska P, Mustaniemi H: A comparative study of alprenolol and alpha methyldopa respectively in combination with chlorthalidone in hypertension. Acta Med Stand (Suppl554), 47-54, 1974 149. Leishman AWD, Thirkettle JL, Allen BR, et al: Controlled trial of oxprenolol and practolol in hypertension. Br Med J 4:342-344,197O 150. Tuckman J, Martin R, Hodler J: Hypertoniebehandlung mit hohen Dosen von Oxprenolol, allein oder in Kombination mit dem Vasodilatator Dihydralazin. Helv Med Acta 36:243-244, 1972 15 1. Waal-Manning HJ, Simpson FO: Pindolol: A comparison with other antihypertensive drugs and a double blind placebo trial. NZ Med J 80: 15 1-1.57, 1974 152. Scales B, Cosgrove MB: The metabolism and distribution of the selective adrenergic beta receptor blocking agent, Pratt J Pharmacol Exp Ther 175:338-347, 1970 153. Prichard BNC, Boakes AJ, Day G: Practolol in the treatment of hypertension. Postgrad Med J 47 (Suppl): 84-92,197l 154. Esler MD, Nestel PJ: Evaluation of practolol in hypertension. Effects on sympathetic nervous system and renin responsiveness. Br Heart J 35:469-474, 1973 155. Sundquist H, Anttila M, Arstila M: Antihypertensive effects of practolol and sotalol. Clin Pharmacol Ther 16:465472,1974 156. Franciosa JA, Fries ED, Conway J: Antihypertensive and hemodynamic properties of the new beta adrenergic blocking agent timolol. Circulation 48: 118124,1973 157. Louis WT, Morgan 0, Anavekar SN, et al: Evaluation of MK950 as an antihypertensive agent, in Magnani B (ed): Beta Adrenergic Blocking Agents in the Management of Hypertension and Angina Pectoris. New York, Raven Press, 1974 158. Lohmoller G, Frohlich ED: A comparison of timolol and propranolol in essential hypertension. Am Heart J 89:437-442, 1975 159. Letac B, Fillastre JP, Wolf LM: The treatment of essential hypertension with acebutolol (Sectral). Clin Trials J 3:92-95,1974

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

160. Hansson L, Henningsen NC, Karlberg BE, et al: Hypotensive action of ICI 66082, a new beta adrenergic blocking agent. Int J Clin Pharmacol 10:206-211,1974 161. Hansson LH, Aberg H, Karlberg BE, et al: Controlled study of atenolol in treatment of hypertension. Br Med J 2:361-310, 1975 162. Petrie JC, Galloway DB, Webster J, et al: Atenolol and bendrotluazide in hypertension. Br Med J 4: 133-135, 1975 163. Taylor SH, Davidson C, Singleton W, et al: Comparison of the blood pressure lowering effects of beta adrenoceptor antagonists with different pharmacological properties: Dose-response studies during chronic treatment. Clin Sci Mol Med 50:2OP, 1976 164. Warren DJ, Swainson CP, Wright N: Deterioration in renal function after beta blockade in patients with chronic renal failure and hypertension. Br Med J 2:193194,1974 165. Warren DJ: Beta adrenergic receptor blockade and renal function. Am Heart J 91:265-266, 1976 166. Kincaid-Smith P, Fang P, Laver MC: A new look at the treatment of severe hypertension. Clin Sci Mol Med 45 (Suppll):75s-87s 1973 167. Pettinger WA, Mitchell HC: Minoxidil-an alternative to nephrectomy for refractory hypertension. N Engl J Med 289:167-171, 1973 168. Zacest R, Gilmore E, Koch Weser J: Treatment of essential hypertension with combined vasodilation and beta adrenergic blockade. New Engl J Med 286:617-622, 1972 169. Gottlieb TB, Katz FH, Chidsey CA: Combined therapy with vasodilator drugs and beta adrenergic blockade in hypertension: A comparative study of minoxidil and hydralazine. Circulation 45:571-582, 1972 170. Gilmore E, Weil J, Chidsey C: Treatment of essential hypertension with a new vasodilator in combination with beta adrenergic blockade. New Engl J Med 282521-521, 1970 171. Black JW, Stephenson JS: Pharmacology of a new adrenergic beta-receptor blocking compound (nethalide). Lancet 2:311-314, 1962 172. Sharma B, Meeran MK, Galvin MC, et al: Comparison of adrenergic beta blocking drugs in angina pectoris. Br Med J 3:152-155, 1971 173. Sowton E, Smithen C: Double blind three-dose trial of oral alprenolol in angina pectoris. Br Heart J 33: 601-606,1971

174. Lewis BS, Bakst A, Gotsman MS: Oxprenolol in angina pectoris. S Afr Med J 46:1209-1214, 1972 175. Hethrington DJ, Comerford MB, Nyberg G, et al: Comparison of two adrenergic beta receptor blocking agents alprenolol and propranolol in treatment of angina pectoris. Br Heart J 35:320-333, 1973 176. Thadani U, Sharma B, Meeran MK, et al: Comparison of adrenergic beta receptor antagonists in angina pectoris. Br Med J 1: 138-142, 1973 177. Horn ME, Prichard BNC: Variable dose comparative trial of propranolol and sotalol in angina pectoris. Br Heart J 35:555,1973 178. Atkins JM, Blomqvist G, Cohen LS: Sotalol (MJ

231

1999) and propranolol in the treatment of angina pectoris. Clin Res 18:21, 1970 179. Toubes DB, Ferguson RK, Rice AJ, et al: Beta adrenergic blockade vs placebo in angina pectoris. Clin Res 18:345, 1970 180. Brailovsky D: Timolol maleate (MK-950): A new beta blocking agent for the prophylactic management of angina pectoris. A multicenter multinational cooperative study, in Magnani B (ed): Beta Adrenergic Blocking Agents in the Management of Hypertension and Angina Pectoris. New York, Raven Press, 1974, pp 117-l 37 181. Sandler G, Clayton GA: Clinical evaluation of practolol, a new cardioselective beta blocking agent in angina poectoris. Br Med J 2:399-402, 1970 182. Astrom H, Vallin H: Effect of a new beta adrenergic blocking agent, ICI 66082, on exercise haemodynamics and airway resistance in angina pectoris. Br Heart J 36:1194-1200, 1974 183. Roy P, Day L, Sowton E: Effect of new beta adrenergic blocking agent, atenolol (Tenormin) on pain frequency, trinitrin consumption and exercise ability. Br Med J 3:195-197, 1975 184. Aronow WS, March H, Vangrow JS, et al: Effect of tolamolol versus propranolol on cardiovascular haemodynamics in patients with angina. Br Heart J 36 : 10781081,1974 185. Nordonfelt I, Olsson L, Persson S: Clinical trial of a new beta receptor blocking agent, tolamolol, in angina pectoris. Eur J Clin Pharmacol7 1.57-162, 1974 186. Jackson G, Atkinson L, Oram S: Double blind comparison of tolamolol, propranolol, practolol and placebo in the treatment of angina pectoris. Br Med J 1:708-712, 1975 187. Jackson G, Atkinson L, Oram S: Reassessment of failed beta blocker treatment in angina pectoris by peak exercise heart rate measurements. Br Med J 3:616-618, 1975 188. Bruce RA: In discussion. Am J Cardiol 18:353, 1966 189. Slome R: Withdrawal of propranolol and myocardial infarction. Lancet 1: 156, 1973 190. Nellen M: Withdrawal of propranolol and myocardial infarction. Lancet 1:558, 1973 191. Diaz RG, Somberg JC, Freeman E, et al: Withdrawal of propranolol and myocardial infarction. Lancet 1:1068,1973 192. Alderman EL, Coltart J, Wettach GE, et al: Coronary artery syndromes after sudden propranolol withdrawal. Ann Intern Med 81:625-627, 1974 193. Miller RR, Olson HG, Amsterdam EA, et al: Propranolol-withdrawal rebound phenomenon. N Engl J Med 293:416-418,1975 194. Krikler D: Verapamil in cardiology. Eur J Cardiol 2:3-10, 1974 195. Jerie P: Letter. Br Med J 1:711, 1976 196. Manning JP, Pensinger RR, Fehn PA: Cardiac alkaline phosphatase activity and potassium concentration in dogs with acute myocardial infarction. Cardiovasc Res 2:308-313, 1968 197. Cox JL, McLaughlin VW, Flowers NC, et al: The ischemic zone surrounding acute myocardial infarction.

232 Its morphology as detected by dehydrogenase straining. Am Heart J 76:650-659,1968 198. Raab W: The nonvascular metabolic myocardial vulnerability factor in “coronary heart disease.” Am Heart J 66:685-706, 1963 199. Maroko PR, Kjekshus JK, Sobel BE, et al: Factors influencing infarct size following experimental coronary artery occlusion. Circulation 43:67-82, 1971 200. Maroko PR, Braunwald E: Modification of myocardial infarction size after coronary occlusion. Ann Intern Med 79:720-733, 1973 201. Herbaczynska-Cedro K: The influence of adrenaline secretion on the enzymes in heart muscle after acute coronary occlusion in dogs. Cardiovasc Res 4:168-175, 1970 202. Pelides LJ, Reid DS, Thomas M, et al: Inhibition by beta blockade of the ST segment elevation after acute myocardial infarction in man. Cardiovasc Res 6:295-301, 1972 203. Mueller HS, Ayres SM, Religa A, et al: Propranolol in the treatment of acute myocardial infarction. Effect on myocardial oxygenation and hemodynamics. Circulation 49: 1078-1087,1974 204. Redwood DR, Smith ER, Epstein SE: Coronary artery occlusion in the conscious dog. Effects of alteration in heart rate and arterial pressure on the degree of myocardial ischemia. Circulation 46: 323-332, 1972 205. Shell WE, Sobel BE: Deleterious effects of increased heart rate on infarct size in the conscious dog. Am J Cardiol 31:474-479, 1973 206. Wilhelmsson C, Vedin JA, Wilhelmsen L, et al: Reduction of sudden deaths after myocardial infarction by treatment with alprenolol. Lancet 2:1157-1160, 1974 207. Ahlmark G, Saetre H, Korsgren M: Reduction of sudden deaths after myocardial infarction. Lancet 2: 1563, 1974 208. Green KG: Improvement in prognosis of myocardial infarction by long term beta adrenoceptor blockade using practolol. Br Med J 3:735-740, 1975 209. Ahlmark G, Saetre H: Position of myocardial infarct and result of alprenolol treatment. Br Med J 1:837, 1976 210. Lucchesi BR, Whitsitt LS, Brown NL: Propranolol (Inderal) in experimentally induced cardiac arrhythmias. Can J Physiol Pharmacol44:543-547, 1966 211. Morales-Aguilera A, Vaughan Williams EM: The effects on cardiac muscle of beta-receptor antagonists in relation to their activity as local anaesthetics. Br J Pharmacol24:332-338, 1965 212. Vaughan Williams EM: Mode of action of beta receptor antagonists on cardiac muscle. Am J Cardiol 18: 399-405, 1966 213. Shinebourne E, White R, Hamer J: A qualitative distinction between the beta receptor blocking and local anesthetic actions of anti arrhythmic agents. Circ Res 24: 835-841,1969 214. Allen JD, Shanks RG: Effects of tiprenolol, practolol and propranolol on experimental ventricular tachyarrhythmias. Br J Pharmacol5 1:179-185, 1974 215. Benaim ME: Asystole after verapamil-a letter. Br Med J 2:169-170,1972 216. Boothby CB, Garrard CS, Pickering D: Intra-

CONOLLY,

KERSTING,

AND

DOLLERY

venous verapamil in cardiac arrhythmias-a letter. Br Med J 2:349,1972 217. Irons GV, Ginn WN, Orgain ES: Use of betaadrenergic receptor blocking agent (propranolol) in the treatment of cardiac arrhythmias. Am .I Med 43: 16 l-l 70, 1967 218. Schamroth L: Immediate effects of intravenous propranolol on various cardiac arrhythmias. Am J Cardiol 18:438-443, 1966 219. Singh BN: Clinical aspects of the antiarrhythmic actions of beta receptor blocking drugs: Part 1. Pattern of response of common arrhythmias. NZ Med J 79:482486,1973 220. Krikler DM: A fresh look at cardiac arrhythmias. Lancet 1:851-854, 913-918, 974-976,1034-1037,1974 221. Frieden J, Rosenblum R, Enselberg CD, et al: Propranolol treatment of chronic intractable supraventricular arrhythmias. Am J Cardiol22:711-717, 1968 222. Schamroth L, Krikler DM, Garrett C: Immediate effects of intravenous verapamil in cardiac arrhythmias. Br Med J 1:660-662,1972 223. Krikler DM, Spurrell RAJ: Verapamil in the treatment of paroxysmal supraventricular tachycardia. Postgrad Med J 50:447-453, 1974 224. Gibson D, Sowton E: The use of beta adrenergic blocking drugs in dysrhythmias. Progr Cardiovasc Dis 12: 16-32, 1970 225. Lund-Larsen PG, Sivertssen E: Haemodynamic effects of propranolol (Inderal) and H56/28 (Aptin) in patients with acute myocardial infarction. A comparative study. Acta Med Stand 186:187-196, 1969 226. Stock JPP: Beta adrenergic blocking drugs in the clinical management of cardiac arrhythmias. Am J Cardiol 18:438-444,1966 227. Stern S: Treatment and prevention of cardiac arrhythmias with propranolol and quinidine. Br Heart J 331522-525, 1971 228. Levi GF, Proto C: Combined treatment of atria1 fibrillation with propranolol and quinidine. Cardiology 55X249-254, 1970 229. Levi GF, Proto C: Combined treatment of atria1 fibrillation with quinidine and beta blockers. Br Heart J 34:911-914,1972 230. Wit AL, Hoffman BF, Rosen MR: Electrophysiology and pharmacology of cardiac arrhythmias. IX. Cardiac electrophysiologic effects of beta adrenergic receptor blockade. Part B. Am Heart J 90:665-675, 1975 231. Goodwin JF: Prospects and predictions for the cardiomyopathies. Circulation 50:210-219, 1974 232. Swan DA, Bell B, Oakley CM, et al: Analysis of the symptomatic course and treatment of hypertrophic obstructive cardiomyopathy. Br Heart J 33:671-685, 1971 233. Braunwald E, Lambrew CT, Rockoff SD, et al: Idiopathic hypertrophic subaortic stenosis-a description of the disease based upon an analysis of 64 patients. Circulation (Suppl4) 30:3-119, 1964 234. Frank S, Braunwald E: Idiopathic hypertrophic subaortic stenosis-clinical analysis of 126 patients with emphasis on the natural history. Circulation 37:759-788, 1968 235. Perloff JK: Clinical recognition of aortic Stenosis:

BETA-ADRENOCEPTOR-BLOCKING

DRUGS

The physical signs and differential diagnosis of the various forms of obstruction to left ventricular outflow. Progr Cardiavasc Dis 10:323-352, 1968 236. Van Noorden S, Olsen EGJ, Pearse AGE: Hypertrophic obstructive cardiomyopathy. A histological histochemical and ultrastructural study of biopsy material. Cardiovasc Res5:118-131, 1971 237. Pearse AGE: The histochemistry and electron microscopy of obstructive cardiomyopathy, in Wolstenholme GEW, O’Connor M (eds): Cardiomyopathies: A Ciba Foundation Symposium. London, Churchill, 1964, pp 132-165 238. Stewart S, Mason DT, Braunwald E: Impaired rate of left ventricular filling in idiopathic hypertrophic subaortic stenosis and valvular aortic stenosis. Circulation 37:8-14, 1973 239. Webb-Peploe MM: Management of hypertrophic obstructive cardiomyopathy by beta blockade, in Wolstenholme GEW, O’Connor M (eds): Hypertrophic Obstructive Cardiomyopathy. Ciba Foundation Study Group No. 37. London, Churchill, 1971, p 103 240. Goodwin JF: The congestive and hypertrophic cardiomyopathies-a decade of study. Lancet 1:733-739, 1970 241. Matlof HJ, Harrison DC: Acute haemodynamic effects of practolol in patients with idiopathic hypertrophic subaortic stenosis. Br Heart J 35:152-158, 1973 242. Hubner PJB, Ziady GM, Lane GK, et al: Double blind trial of propranolol and practolol in hypertrophic cardiomyopathy. Br Heart J 35:1116-1123, 1973 243. Hardarson T, De La Calzada CS, Curie1 R, et al: Prognosis and mortality of hypertrophic obstructive cardiomyopathy. Lancet 2: 1462-1467, 1973 244. Cherian G, Brockington IM, Shah PM, et al: Beta adrenergic blockade in patients with hypertrophic obstructive cardiomyopathy. Am Heart J 73:140-141, 1967 245. Cohen LS, Braunwald E: Amelioration of angina pectoris in idiopathic hypertrophic subaortic stenosis with beta adrenergic blockade. Circulation 35 :847-85 1, 1967 246. Sloman G: Propranolol in management of muscular subaortic stenosis. Br Heart J 29:783-787, 1967 247. Goodwin JF, Oakley CM: The cardiomyopathies. Br Heart J 34:545-552, 1972 248. Waagstein F, Hjalmarson R, Varnauskas E, et al: Effect of chronic beta adrenergic blockade in congestive cardiomyopathy. Br Heart J 37:1022-1036,1975 249. Levey GS: Catecholamine hypersensitivity, thyroid hormone and the heart-a reevaluation. Am J Med 50: 413-420, 1971 250. Brewster WR, Isaacs JP, Osgood PF, et al: The hemodynamic and metabolic interrelationships in the activity of epinephrine, norepinephrine and the thyroid hormones. Circulation 13: l-20, 1956 251. Ramsay I: Adrenergic beta blockade in hyperthyroidism. Br J Clin Pharmacol2:385-388, 1975 252. Grossman W, Robin NI, Johnson LW, et al: The enhanced myocardial contractility of thyrotoxicosis-role of the beta adrenergic receptor. Ann Intern Med 74:869874,197l 253. Levey GS, Epstein SE: Myocardial adenyl cyclase:

233 Activation by thyroid hormone and evidence for two adenyl cyclase systems. J Clin invest 48:1663-1669, 1969 254. Buckle RM: Treatment of thyroid crisis by beta adrenergic blockade. Acta Endocrinol57: 168-176, 1968 255. Parsons V, Jewitt D: Beta adrenergic blockade in the management of acute thyrotoxic crisis, tachycardia and arrhythmias. Postgrad Med J 43:756-762, 1967 256. Das G, Krieger M: Treatment of thyrotoxic storm with intravenous administration of propranolol. Ann Intern Med 70:985-988, 1969 257. Mackin JF, Canary JJ, Pittman CS: Thyroid storm and its management. New Engl J Med 291:13961398,1974 258. Lee TC, Coffey RJ, Mackin J, et al: The use of propranolol in the surgical treatment of thyr’otoxic patients. Ann Surg 177~643-647, 1973 259. Vinik AI, Pimstone B, Hoffenberg R: Sympathetic nervous system blocking in hyperthyroidism. J Clin Endocrinol Metab 28~725-727, 1968 260. Pimstone B, Joffe B: The use and abuse of beta adrenergic blockade in the surgery of hyperthyroidism. S Afr Med J 44:1059-1061, 1970 261. Pimstone BL: Beta adrenergic blockade in thyrotoxicosis. S Afr Med J 43 (Suppl Dee 6): 27-29, 1969 262. Turner P: Alprenolol and propranolol in hyperthyroid tachycardia. Br J Pharmacol40: 146P, 1970 263. Schelling JL, Scazziga B, Dufour RJ, et al: Effect of pindolol, a beta receptor antagonist, in hyperthyroidism. Clin Pharmacol Ther 14:158-164,1973 264. Howitt G, Rowlands DJ: Beta sympathetic blockade in hyperthyroidism. Lancet 1:628-631, 1966 265. Shanks RG, Hadden DR, Lowe DC, et al: Controlled trial of propranolol in thyrotoxicosis. Lancet 1:993-994, 1969 266. Nelson JK, McDevitt DG: Comparative trial of propranolol and practolol in hyperthyroidism. Br J Clin Pharmacol2:411-416, 1975 267. Grossman W, Robin NI, Johnson LW, et al: The effect of beta blockade on the peripheral manifestation of thyrotoxicosis. Ann Intern Med 74:875-879, 1971 268. Mackin JF, Canary JJ, PittmanCS: Beta adrenergic blockade in hyperthyroidism-a letter. N Engl J Med 2921645-646, 1974 269. Rude RK, Oldham SB, Singer FR, et al: Treatment of thyrotoxic hypercalcemia with propranolol. N Engl J Med 294:431-433,1976 270. Hadden DR, Bell TK, McDevitt DG, et al: Propranolol and the utilization of radioiodine by the human thyroid gland. Acta Endocrinol (Kbh) 61:393399, 1969 271. Georges LP, Santangelo RP, Mackin JF, et al: Metabolic effects of propranolol in thyrotoxicosis. I: Nitrogen, calcium and hydroxyproline. Metabolism 24: 1 l-23, 1975 272. Jefferson JW: Beta adrenergic blockade in psychiatry. Arch Gen Psychiatr 31:681-691, 1974 273. Whitlock FA, Price J: Use of beta adrenergic receptor blocking drugs in psychiatry. Drugs 8:109-124, 1974 274. Atsmon A, Blum I, Wijsenbeek H, et al: The short term effects of adrenergic blocking agents in a small

234 group of psychotic patients. Psychiatr Nemo1 Neurochir 74:251-258, 1971 275. Atsmon A, Blum I, Steiner M, et al: Further studies with propranolol in psychotic patients. Relation to initial psychiatric state, urinary catecholamines and 3-methoxy 4 hydroxy phenyl glycol. Psychopharmacol 27:249-254,1972 276. Yorkston NJ, Zaki SA, Malik MKU, et al: Propranolol in the control of schizophrenic symptoms. Br Med J 4:633-635, 1974 277. Atsmon A: Propranolol therapy helps some patients with mentaldisorders. JAMA 224: 173-174, 1973 278. Editorial: New drugs for schizophrenia. Br Med J 4:614-615, 1975 279. Blum I, Atsmon A, Steiner M, et al: Paradoxical rise in blood pressure during propranolol treatment. Br Med J 4:623, 1975 280. Granville-Grossman KL, Turner P: The effect of propranolol on anxiety. Lancet 1:788-790, 1966 281. Tyrer PJ, Lader MH: Response to propranolol and diazepam in somatic and psychic anxiety. Br Med J 2: 1416, 1974 282. Editorial: Beta blockers in anxiety and stress. Br Med J 1:415,1976 283. Owen DAL, Marsden CD: Effect of adrenergic blockade on Parkinsonian tremor. Lancet 2:1259-1262, 1965 284. Marsden CD, Foley TH, Owen DAL, et al: Peripheral beta adrenergic receptors concerned with tremor. Clin Sci 33:53-65, 1967 285. Young RR, Growdon JH. Shahani BT: Beta adrenergic mechanisms in action tremor. N Engl J Med 293:950-953,197s 286. Pakkenberg H: Propranolol in essential tremor. Lancet 1:633, 1972 287. Balla JI: Treatment of essential tremor with propranolol. Lancet 1:205, 1973 288. Editorial: Miracle cures in Parkinson’s disease. Br Med J 3:1-2, 1975 289. Lance JW: The pathophysiology and treatment of migraine. NZ Med J 79:954-960, 1974 290. Ludvigsson J: Propranolol in treatment of migraine in children. Lancet 2:799, 1973 291. Wideroe T-E, Vigander T: Propranolol in the treatment of migraine. Br Med J 2:699-701,1974 292. Diamond S, Medina JL: Controlled study of the prophylaxis of migraine with propranolol. Clin Pharmacol Ther 17:232, 1975 293. Borgesen SE, Nielsen JL, Moller CE: Propranolol in migraine. Lancet 2:58,1974

CONOLLY,

KERSTING,

AND

DOLLERY

294. Sjaastad 0, Stensrud P: Clinical trial of a beta receptor blocking agent (LB 46) in migraine prophylaxis. Acta Neurol Stand 48:124-128, 1972 295. Ekbom K: Alprenolol for migraine prophylaxis. Headache 15 : 129-132, 1975 296. Schild HO: Histamine release and anaphylactic shock in isolated lungs of guinea pigs. Q J Exp Physiol 26:165-179, 1937 297. Orange RP, Kaliner MA, Laraia P, et al: Immunological release of histamine and slow reacting substance from human lung. II. Influence of cellular levels of cyclic AMP. Fed Proc 30:1725-1729,197l 298. Vaughan Williams EM, Bagwell EE, Singh BN: Cardiospecificity of beta receptor blockade. Cardiovasc Res 7~226-240, 1973 299. Stephen SA: Propranolol in acute myocardial infarction. A multicentre trial. Lancet 2: 1435-1438, 1966 300. Fitzgerald DG: Personal communication, 1976 301. Wright P: Untoward effect associated with practolol administration. Oculomucocutaneous syndrome. Br Med J 1:595-598, 1975 302. Nichols JT: Personal communication, 1976 303. Felix RH, Ive FA, Dahl MGC: Cutaneous and ocular reactions to practolol. Br Med J 4:321-324, 1974 304. Windsor WP, Durrein F, Dyer NH: Fibrinous peritonitis: A complication of practolol therapy. Br Med J 2:68, 1975 305. Furhoff A-K, Nordlander M, Peterson C: Cross sensitivity between practolol and other beta blockers?a letter. Br Med J 1:831, 1976 306. Paget GE: Carcinogenic action of pronethalol. Br Med J 2:1266-1267, 1963 307. Johnson GS, Friedman RM, Pastan I: Restoration of several morphological characteristics of normal fibroblasts in sarcoma cells treated with adenosine 3’,5’ cyclic monophosphate and its derivatives. Proc Nat1 Acad Sci (USA) 68:425-429, 1971 308. Alcock SJ, Bond PA: Observations on the toxicity of Alderlin (pronethalol) in laboratory animals. Excerpta Medica International Congress Series No. 81. “Some Factors Affecting Drug Toxicity.” See Roe FJC. In discussion, pp 38-39, 1964 309. Chlapowski FJ, Kelly LA, Butcher RW: Cyclic nucleotides in cultured cells, in Greengard P, Robinson GA (eds): Advances in Cyclic Nucleotide Research, ~016. New York, Raven Press, 1975, pp 245-338 310. Holliiield JW, Sherman K, Zwagg RV, et al: Proposed mechanism of propranolol’s antihypertensive effect in essential hypertension. N Engl J Med 295:68-73, 1976