Hemodynamic effects of newer antiarrhythmic drugs

David E. Jewitt, The

aim

of a~~ia~rbytbrni~

cardiovascular hawe demonstrated contrast, studies.

and Rile

effects,

in coronary myocardial

shock all

EBz&nd

therapy

Short-term minor falls

only

is to terminate

to depress by therapy

reported. Class II agents Atenoiol resembles

whereas acebutollol has only a mild depressant blood depressant

flow.

The actions

have been precipitated the new antiarrhythmic

or suppress

route

and

with proprawolol

in patients

IV agent werapamil. causes ~eri~bera~

particularly in patients drugs curreaatly studied

~Q~~e~~~atio~, present aprindine, atenolol, or chronically by the ora8 route.

1980,

Vd.

100, No.

6, part

2

with

coronary

resembling with a reduction which vasodilatation.

receiving will cause

From the Cardiac Departmu$ King’s College Hospital, London, England. Reprint requests: David E. Jewitt, B.Sc., MB., F.R.C.P., Director, Cardiac Department, King’s College Hospital, Denmark Hill, London S. E. 5, United Kingdom.

December,

improve tocainide In

function in both animals and patient disopyramide and electromechanical eta-sdrenergic blocking actions all produce a degree

is less of a depressant, effect associated

Class

and

mexilitine, and aortic pressure.

with

The aim of successful antiarrhythmic drug therapy is to terminate or suppress a specific arrhythmia and improve cardiovascular function This action may be achieved by the suppression or termination of arrhythmias that are either directly life threatening or the precipitating cause of cardiovascular failure. An ideal antiarrhythmic drug will a6hieve this objective without general or cardiovascular side effects in therapeutic dosage. It is important, therefore, to document t dynamic effects of newer antiarrhythmic drugs at clinically relevant concentrations and to eonfir that when arrhythmia termination is achiev cardiovascular function is not compromised. These studies need to be performed in patients with heart disease with and witbout evidence of impaired cardiac function. In this report the hemodynamic effects of newer antiarrhythmic drugs will be reviewed in

9

arrhythmias

rny~~ard~a~

depression in an appropriately high needs to be taken when disopyramide,

by the intravenous

specific

studies of the new Class I drugs encainide, in cardiac index with modest rises in mean

has been shown may be precipitated

has been depression.

bemod~~am~~ agent amiodarone

Lon&on, drug

function.

disopyramide Heart failure

dissociation of myocardial

increase potent

MB.

artery

is a calcium channel Hypotension,

beta-blocking some degree

investigations arad werapamil

disease

practolol. The in afterload

Class and

in its Ill an

blocker, has heart failure,

drugs concurrently. of hemodynamic

suggest that are administered

particular either

caution acutely

groups according to their predominant experimental eleetrophysiologic effects, as described in the classification of antiarrhythmic drugs by Vaughan Williams’ and Singh and Vaughan Williams.’

~x~~~~~~e. The influence of mexihtine on left ventricular ejection in patients with abnormal left ventricular function was assessed in six patients with implanted Starr-Edwards aortic valve prostheses. The duration of aortic ball travel time, measured as the QA, interval, is a measure of left ventricular eject&m velocity and was used as an index of myocardial performance. With myo6ardiak depression the $A, interval lengthens. Shaw” showed that mexiiitine, in doses from 50 to 150 mg given intravenousIy over 2 minutes, prolonged the $A, interval in a doserelated manner over the range 58 to ?5O mg and this effect was apparent immediately. It was equal to that produced by equivalent doses of lignocaine, indicating similar effects on left ventricular function. Banim et al.,” in a study of 10 male patients with coronary artery disease, found

0002-8703/80/130984

+ 06$00.60/O

0 1980 The

C. V. Mosby

Co.

Hemodynamic

an infusion of 1.5 mg/kg mexilitine had minor effects on carldiovascular hemodynamics only. There was a small but significant rise in left ventricular end-diastolic pressure. During handgrip isometric exercise, there were small but significant falls in cardiac output and peak left ventricular dlP/dt associated with a small increase in left ventricular end-diastolic pressure. This lack of major hemodynamic effect was confirmed in studies of 16 patients with valvar heart disease.” In contrast, Saunamgk+ observed further impairment of myocardial function in three of six patients with ischemic heart disease and previous heart failure who were given mexilitine intravenously, achieving a plasma level greater than 1 pg/ml. In many respects mexilitine is comparable to, lignocaine hemodynamically when given intravenously. It is concluded that intravenous administration of mexilitine in clinically effective doses produces little or no adverse hemodynamic effects in the absence of clinical evidence of heart failure. When heart failure is present, caution is necessary during its intravenous administration. In controlled studies of long-term oral mexilitine in the prophylaxis of ventricular arrhythmias, over a 3-month period, there has been no evidence that cardiac failure was precipitated. Disopyramide. A negative inotropic efeect has been demonstrated when disopyramide is administered intravenously to experimental animals and man. Thus in a placebo controlled study in 18 patients with recent myocardial infarction, 100 mg of disopyramide intravenously over 5 minutes significantly prolonged the pre-ejection period and increased the ratio of the pre-ejection period to left ventricu.lar ejection time for more than 15 minutes following drug administration.” However, if the rate of administration of the same dose was prolonged over 10 minutes, a reduced effect was seen. In a study of 10 patients with cardiac disease (six with normal and four with abnormal left ventricular function), 1.5 mg/kg of intravenous disopyramide over 2 minutes, decreased cardiac index, stroke volume, and stroke work index to a greater degree in those patients with abnormal function, both during spontaneous sinus rhythm and when heart rate was maintained stable by atria1 pacing.’ In a recent #study, electromechanical dissociation has been reported following the administra-

American

Heart

Journal

effects of newer

antiarrhythmic

drugs

tion of disopyramide to patients with severe congestive failure and renal insufficiency, in whom the drug was being administered to control recurrent and resistant ventricular tachycardia.8 This indicated the need for dosage reduction in the presence of renal insufficiency and extreme caution. The importance of hemodynamic depression following disopyramide administration was demonstrated when 16 patients with disopyramide-induced cardiac decompensation were reported out of a total of 100 patients consecutively treated with the drug.” Whereas in patients without established left ventricular dysfunction, disopyramide is relatively safe orally, the intravenous route should be used with caution. In the presence of left ventricular dysfunction, disopyramide is potentially a hazardous agent not only intravenously but also during chronic oral therapy and careful clinical observation is mandatory. Tocainide. In a study of 12 patients with established heart disease, 11 of whom had compensated left ventricular dysfunction, small increases in left ventricular end-diastolic pressure have been noted, although no major depression of overall ventricular function was seen Iwith tocainide plasma concentrations within the known therapeutic range.‘O An increase in systemic and pulmonary arterial pressure was observed in this study secondary to increases in vascular resistance in both beds. In patients with valvar heart disease studied echocardiographically in a control study of oral tocainide, no evidence of myocardial depression was observed.” Tocainide, therefore, like lignocaine and mexilitine, appears to cause minimal myocardial depression at therapeutic plasma concentrations. Further information on the hemodynamic effects of tocainide are reported elsewhere in this symposium. Encainide. This new antiarrhythmic agent has been shown electrophysiologically to have important Class 1 actions.” Hemodynamically, it has been studied in patients at the time of catheterization by Harrison.13 In this study, 17 patients were given encainide intravenously, 12 of whom had coronary artery disease and 5 of whom had primary myocardial disease. There was a significant increase in heart rate and systemic vascular resistance following encainide, 0.9 mg/kg body weight intravenously, with a modest decrease in cardiac and stroke index. Left ventricular end-

985

ue, although it remains a useful agent intravenously in intensive arad coronary 6are unbSts. Several new beta-adrenergic blocking drugs, all with comparable antiarrhythmic value, particularly an the management of supraventricular arrbythmiss, have been introduced. ere attention will be hmated to two such ag ts, atenoiol and

Fig. 1. Mean changes in cardiac output in patients receiving graded doses of atenolol during sinus rhythm and during atria1 pacing at constant rate. (From Robinson C, Jackson PG. Fisk C, Jewitt, DE: Haemodynamic effects of atenolol in patients with coronary artery disease. Br Heart J 40:22-8, 1978.

diastolic pressure fell significantly. Changes in cardiac index were most marked in the nine patients with low control cardiac index levels. The mild depression, seen mainly in patients with impaired cardiac function at rest, suggests that this drug’s hemodynamic effects will not detract from its potential value. However, more information is required on the effects of this drug intravenously and orally on systemic and coronary hemodynamies in patients with established heart disease with and without prior left ventricular dysfunction.

The hemodynamic effects of propranoloi have been extensively investigated in the past and it has become the agent against which all new Class 2 antiarrhythmic drugs with beta-blocking actions are compared. Hemodynamicahy, practolo1 has been shown intravenously to be an effective antiarrhythmic drug producing less hemodynamic depression.‘4 However, development of the ocuHomu6ocutaneous syndrome following its ora! use has restricted its subsequent therapeutic val-

986

enolo8. Atenolol has been shown to possess carcdioselectivity equivalent to that of praetolol and, Bike practolol, atenolol lacks membranestabilizing properties. In contrast, however, aten0101 does not possess mtrinsic sympathomiLmetie activity.‘” Its antiarrhythm~c eficacy has been established in animal studies. its hemodynamic effects have been studied in a group of eight patients with estabhshed obstructive coronary artery disease.” A dose-related decrease in heart rate and cardiac output was shown to be produced without a significant change in systemic arterial pressure when atenolol, 0.03 to 0.E mg/kg body weight intravenously, was given over a total of 5 to 15 minutes (Fig. 1). However, in contrast to the previous findings with practoloi and hke those observed with propranolol, there was a significant fall in cardiac output after atenolol, which was not purely rate dependent (Fig. 1). Left ventricular end-diastolic pressure did not eantly, but there was a dose-relat the maximum rate of rise of le pressure (dP/dtj after atenolol. Systemic vascular resistance increased significantly after atenoBol in the patients at rest and this is comparable to the findings after irntravenous propranolol but contrasts with those after intravenous in similar patients.” The overall hemodynamic effects of atenolol, therefore, more closely resemble those of intravenous propranolol than those of intravenous practolol. It seems likely that the relatively minor hemodynami6 effects that follow intravenous praetolol reflect the combination of cardioselectivity and intrinsic sympathomimetic activity in the same agent, whereas cardioselectivity alone, as in aienolol, results in hemodynamic el#ects similar to those of propranolol. Atenolol is, therefore, of potential value as an antiarrhythmie drug orally but does not have the hemodynamic advantages of practolol for intravenous adminisutslol.

Acebutolol

is a newer

Hemodynamic

effects of newer antiarrhythmic

drugs

CORONARY HAEMODYNAMIC EFFECTS OF INTRAVENOUS AMIODARONE IN DOGS MEAN

LCA

FLOW

CORONARY RESISTANCE mm Hg/ml/min.

MEAN AORTIC PRESSURE mm/m

1.0

0.0jhll C

2-5

5

10

c

2.5

5

IO

I.V. AMIODARONE DOSE mg/kg Fig. 2. Mean coronary open-chest anesthetized

hemodynamic changes dogs. LCA = left coronary

following artery.

ergic blocking drug that has been shown to be approximately o’ne-eighth as potent as proprano101 as a beta antagonist. It exerts membranestabilizing effects similar to those of propranolol. It does have a degree of cardioselectivity and also some intrinsic sympathomimetic activity, although lessmarked than that seen with practolol. Hemodynamically, in doses of 0.5 to 1 mg/kg, it has been shown to cause modest reductions in cardiac output and ejection fraction when administered postoperat.ively to patients who have undergone coronary artery bypass surgery.‘” In a recent study in patients with obstructive cornary artery dliseaseacebutolol, in doses of 0.6 mg/kg body weight intravenously given over 2 minutes, producled only minor systemic hemodynamic effects. The changes in coronary sinus blood flow and coronary vascular resistance were also minor and there was no significant change in myocardial oxygen consumption. It is important to note that the lactate extraction ratio in these patients during control atria1 pacing to angina was -14% -+ 4.5%, indicating lactate production. This was reversled to lactate extraction with a mean value 10% -+ 2% at the same atria1 pa.cing rate after the drug.‘” Acebutolol therefore resembles practolol more closely than propranolol or atenolol hemodynamically. It is likely that this reflects the possession of both weak intrinsic sympathomimetic activity and cardioselective properties. It is a useful alternative to practolol

American

Heart

Journal

graded

doses

of intravenous

amiodarone

in

eight

when an intravenous beta-blocking drug is indicated for the termination of supraventricular arrhythmias. Drugs

with

Class

3 antiarrhythmic

actions

Amiodarone. Amiodarone, originally introduced as an antianginal drug, is the principal agent with Class 3 properties and possesses unique electrophysiologic properties.‘. “” Its antiarrhythmic effects were summarized by Rosenbaum et al.?’ The effects of amiodarone on cardiac and coronary hemodynamics were studied in open-chest anesthetized dogs by Singh et al.“’ Intravenous amiodarone, over the concentration range of 2.5 to 10 mg/kg body weight, produced a dose-related decrease in heart rate and total peripheral resistance with a decrease in cardiac contractile force and left ventricular dP/dt. Despite this, the left ventricular cardiac output increased progressively. No significant fall in left ventricular end-diastolic pressure occurred up to doses of 5 mg/kg body weight intravenously, but at 10 mg/kg intravenously, modest increases in left ventricular filling pressure occurred. These findings, in association with the fall in left ventricular contractile force and left ventricular dP/ dt, suggested a modest negative inotropic effect. The increase in cardiac output with increasing dosage probably reflects the marked reduction in resistance to left ventricular ejection which results from the systemic vasodilatation.

987

Direct intracorsnary injections of amio 0.25 to 4 mg, which were doses too small to exert systemic effects, prcsduced a dose-related increase in coronary blood piiow associated with a fall in coronary vascdar resistance. This conmary vasodilator effect was also seen during intravencm amiodarooe injections in doses of 2.5 to 10 mg/kg body weight. In this instance, the increasing coronary bkmd flow and fall in coronary vascullar resistance was achieved despite a fall in systemic arterial pressure (Fig. 2). Experimentally, therefore, amiodarone creates a favorable balance in oxygen supply and demand by aEecting the major determinants of myocalrdial oxygen consumption. These experimental observations have since been confirmed in 16 patients undergoing coronary artelriography for chest pain, 14 of whom had obstructive coronary artery disease.‘” These clinical studies therefore confirm that amisdarone used intravenously is a powerful systemic and coronary vassdilator, and is relatively safe for use in the acute therapy of patients with cardiac arrhythmias. However, antiarrhythmic therapy with amiodarone is generally indicated and most effective by the oral rcsute. To date, long-term hemodynamie studies using this route of administration have not been pubM~d; however, these are no reports of cardiac failure being precipitated.

pe of this group of ibit membrane transport of calcium is verapamil. It is a synthetic papaverine derivative, initia]lBy introduced as a smsoth muscle relaxant, which has potent peripheral and coronary vassdilator actions. Hn isolated heart muscle it does not exhibit Class P,2, or 3 electrophysiologic actions, and therefore a separate category of action emphasizing the antagonism of the slow inward calcium currents was proposed.’ Its main locus of action appears to be superficially Boeated membrane storage sites for ca1ck4m.‘” In clinical electrophysiology its primary site of action is on the 14-V node where A-V conduction time is increased due to depression of the slow-response fibers. Verapamil has a maskea negative inotropic effect on isolated heart muscle.” In man the most comprehensive study of its hemodynamic effects was reported by Sin& and Roche.z.’ In 20 patients with coronary artery disease or rheumatic valve

lesions,

they bund

the peak effects af im~travenous

verapamil, in a doseof 10mg, occurredbetween

and 5 mhutes

3 after the completion of the injec-

tion and had disappeared by 10 minutes. Mean arterial pffesswreand systemic vascular resistance fell significarntly, with an increase in left ventricular end-diastdie pressure and a reduction in left ventricular dP/dt,,,. Heart rate and cardiac index increased but these changes were not statistically significant. These results therefore hai.. cated that intravenously uerapamil doeshave a negative inotrspic effect, but it is minimized by its peripheral vasodilaitos action in reducing afterload. Caution k clearly necessary, particularly when verapamil is administered to patients with significant myocardial decompensation and in patients with myscar ial infarction, as in these patients there are little data available on the

hemoaynamic~5c~t~0f the drug. The incidence of hehmodynamic side effects is higher in patients previously on betaadrenergic blocking agents w&o are given verapamil either intravenously or orally. The negative instropic actions and depressant effects on impulse generation of the beta-blocking agents and those of verapamil summate. Severe hypotension coupled with bradycardia and asystole may result. The administration of verapamil intravenously is therefore potentially hazardous in the presence of impaired left ventricular function and particularly where prior administration of beta-adrenergic blocking drugs has been employed. In the absence of left ventricular impairment the mild hemodynamic changes observed are unlikely to be clinically important. much

1.

2.

3.

4.

5.

Vaughan Williams EM: Classification of antiarrhythmic drugs. In Sandoes E, Flensted-Jensen E, Eleson KH, editors: Symposium on cardiac arrhythmias. Sweden, 1970, Astra Pharmzceutical Products, Inc. Singh BN, Vaughan Williams EM: A fourth class af anti-dysrhythmic action? Effect of verapamil on ouabain toxicity, on atrial and ventricular intracellular potentials and on other features of cardiac function. Cardiovasc Res 6:109-19, 1972. Shaw TRD: The effect of mexilitine on left ventricular ejection: A comparison with lignocaine and propranoiol. Postgrad &led J 53 (Suppl):69-73, 1977. Campbell NPS, Zaidi SA, Adgey AAJ, Patterson GC, Pantridge, JF: Observations of hemodynamic effects of mexilitine. Br Heart J 41:182-86, 1979. Banim SO, Da Silva A, Stone D, Balcon R: Observations of the haemodynamics of mexiletine. Postgrad Med J 73(SuppP 1):74-77, 1977.

December,

1980,

Vol.

lOQ, No.

6, part

2

Hemodyaamic

5a

6.

I. 8.

9.

Saunamaki KI: Hemodynamic effects of a new antiarrhythmic agent mexilitine in iscbemic heart disease. Cardiovasc Res S:788-92, 1975. Hillis WS, Twedldel A, Lorimer AR, Lawrie TDV: Some aspects of the clinical pharmacology of intravenous disopyramide afjter myocardial infarction. J Int Med Res 4(Suppl):74, 1976. Sutton R: Hemodynamics of intravenous disopyramide. J Int Med Res 4(Suppl):46-8, 1966. Desai J, Hirschfeld D, Peters R, Scheinman M, Gonzalez R: Electromechanical dissociation associated with disopyramide. Circullation 58(Suppl II):178 1978. Podrid PJ, Schoenberger A, Lown B: Congestive cardiac failure caused bv oral disoavramide. N Enal J Med 3CJ2:614-7, 1980. ” Winkle RA, Anderson F, Peters F, Meffin PG, Fowles RE, Hainson D’C: The hemodynamic effects of ineravenous tocainide in patients with heart disease. Circulation 57:787-92, 1978. Ryan WF, Karliner JS: Effects of tocainide on left ventricular performance at rest and during acute alterations in heart rate and systemic arterial pressure. Br Heart J 41:175-81, 1979. Gibson JK, Somani P, Bassett AL: Electrophysiological effects of encainide on canine Purkinje fibers. Eur J. Pharmacol 52:161-69, 1978. Harrison DC, Winkle R, Sami M, Mason J: Encainide: A new and potent antiarrhythmic agent. AM HEART J. 100:1046-1054, 1980. Jewitt DE: Hemodynamic side effects of antiarrhythmic drugs. In Sandoe E, Flensted-Jensen E, Olesen KH, editors: Symposium of cardiac arrhythmias. Sweden, 1970, Astra Pharmaceutical Products, Inc. Barrett AM, Carter J, Fitzgerald JD, Hull R, Le Count

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19.

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11.

12.

13.

14.

15.

American Heart J~umal

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21.

22.

23. 24.

efects of newer antiarrhythmic

drzgs

D: A new type of cardioselective adrenoceptive blocking drug. Br J Pharmacol48:340, 1973. Robinson C, Jackson PG, Fisk C, Jewitt DE: Haemodynamic effects of atenolol in patients with coronary artery disease. Br Heart J. 4?:22-8, 1978. Jewitt DE, Mercer CJ, Shillingford JP: The circulatory effects of practolol in patients with acute myocardial infarction. Cardiovasc Res 4:188-93, 1970. Mason JW, Specter JM, Ingels MB, Daughters GT, Ferris AC, Alderman EL: Haemodynamic effects of acebutolol. Br Heart J 40:29-34, 1978. Daly K, Bergman G, Atkinson L, Jackson G, Jewitt DE: Systemic and coronary hemodynamic effects and changes in myocardial metabolism produced by acebuto101. Br Heart J. (In press.) Singh BN, Jewitt DE, Downey JM, Kirk ESR, Sonnenblick EH: Effects of amiodarone and L8040, novel antiangina1 and antiarrhythmic drugs on cardiac and coronary haemodynamics and on cardiac intracellular potentials. Clin Exn Pharmacol Phvsiol 3:427-42. 1976. Rosenbaum MB, Chiale PA: Halpern MS, Nau GJ, Brzybylski J, Levi RJ, Lazzari JO, Elizari :MV: Clinical efficacy of amiodarone as an antiarrhythmic agent. Am J Cardiol 38:934, 1976. C6t.e P, Bourassa MG, Delaye J, Janm A, Froment R, David P: Effects of amiodarone on cardiac and coronary haemodynamics and on myocardial metabolism in patients with coronary artery disease. Circulation 59:1165-72, 1979. Naylor W,‘Krikler D: Verapamil and the myocardium. Postgrad Med J 50:441-46, 1974. Singh BN, Rocbe AHG: Effects of intravenous verapamil on haemodynamics in patients with heart disease AM HEART J 94:593-99, 1977.

989