Hemodynamic effects of antiarrhythmic drugs

Hemodynamic Effects of Antiarrhythmic Drugs PAUL J. BLOCK, MD, and ROGER A. WINKLE, MD

In order to use antiarrhythmtc drugs safely, one must understand their hemodynamic effects. Quinldtne and the calcium antagonists have direct cardiac effects and frequently opposing autonomically mediated or indirect cardiac effects. Lidocaine is exceptionally well tolerated, even by patients with severe left ventricular dysfunction. Phenytoin and procainamide have the potential for serious adverse effects, but are generally well tolerated at usual doses. Disopyramide causes serious depression of

left ventricular function in many patients because of its direct myocardial depressant and peripheral vasoconstricting actions. Although bretylium causes an immediate increase in contractility, it can ultimately result in important hypotension. In this review the in vitro and in vivo hemodynamic effects of these and other antiarrhythmic drugs are discussed to provide information that will assist the clinician in using these drugs properly. (Am J Cardiol 1983;52:14C-236)

Patients with coronary artery disease, cardiomyopathy or significant valvular heart disease often have symptomatic or life-threatening arrhythmias that require short- or long-term drug therapy. In these patients, many of whom have a marginally compensated cardiovascular system, one must be concerned about a drug’s cardiac and peripheral vascular effects. A small further decrease in myocardial contractility or a change in peripheral vascular resistance may mean the difference between compensated congestive heart failure and pulmonary edema or the difference between borderline low blood pressure and symptomatic hypotension or shock. It is important to understand all of the cardiovascular effects of any antiarrhythmic medication in order to choose the most appropriate agent for any clinical setting. For these reasons, we review the hemodynamic effects of the frequently used antiarrhythmic agents. Although for many drugs discussed we describe the findings of relevant in vitro and in vivo animal experiments, the major emphasis is on studies that are most applicable to the care of the patients with heart disease. We focus on the drugs that are often prescribed, with less emphasis on medications that are still under investigation and are not yet available for widespread use. A review of the hemodynamic effects of antiarrhythmic drugs shows a variety of contradictory results. A drug that has a negative inotropic effect in one setting will be shown to increase cardiac output in another. Frequently, the methods used for evaluation can explain

these differences. Distinguishing the primary from the secondary effects of an antiarrhythmic drug is important because many of the drugs have a direct effect on the myocardium that is offset by a peripheral or adrenergic effect (Table I). Similarly, direct effects of an agent may be balanced by autonomic reflex actions in response to those or other direct actions. Depending on the balance, overall effects can vary greatly. These interactions can often explain the differing results of studies of isolated myocardial tissue versus those of studies of an intact organism. They can also explain differences between animals with their autonomic reflexes altered, either pharmacologically or surgically, and those that have not been so treated. Other, more obvious factors explaining these differences relate to variation in dose and rate of administration of a drug, nonuniform effects from species to species, and the difficulty in extrapolating these to man, and the differences between anesthetized and unanesthetized subjects. Finally, a distinction must be made between statistically significant and clinically significant results. Some minor hemodynamic effects of an antiarrhythmic drug detected by sensitive methods may reach statistical significance, but have little clinical relevance.

From the Cardiology Division, Stanford University Medical Center, Stanford, California.

Quinidtne Recognizing the primary and secondary cardiovascular effects of quinidine is difficult. Some studies of isolated cardiac muscle have shown quinidine to reduce contractile force;13 others have shown a slight increase in contractility,4 and one showed a positive or negative effect, depending on the quinidine concentration and the rate of electrical stimulation.5 Overall, depression

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TABLIEI

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Summary of Hemodynamic Effects of Antiarrhythmic Drugs

Drug Quinidine IV PO Procaihamide IV PO Lidoarine Bretylium Early Late Disopyramide Phenytoin Diltkem Verapamil Amiodarone Mexiletine Tocainide Encainide Flecainide Lorcainide

Direct Effect on Myocardial Contractility

Effect on Peripheral Vascular Resistance

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of contractility appears to be related to the quinidine concentration. Only minor negative inotropic effects were seen at clinically relevant plasma levels, with significant depression of contractility noted only at considerably higher levels.l-s Most in vivo studies have revealed both direct myocardial and peripheral vascular effects that are important in the overall hemodynamic response to intravenous quinidine. In almost all intact animal models, intravenous quinidine produces significant peripheral vasodilation.e-l5 Schmid et all4 demonstrated that the peripheral vasodilating effect is produced by 2 independent mechanisms. One is by a direct action to relax vascular smooth muscle and the other is by alpha-adrenergic blockade producing inhibition of adrenergic constrictor tone.15 These findings explain the significant decrease in blood pressure and systemic vascular resistance seen after the administr,ation of intravenous quinidine in laboratory animals. ‘j-l5 An animal study of the hemodynamic effects of oral quinidinels did not reveal any effect on blood pressure after 10 days to 2 weeks of therapy. Conclusions from. studies evaluating quinidine’s effects on myocardial contractility are considerably more variable and the mechanisms more complex. Most animal studies evaluating myocardial contractility with the use of a myocarfdial strain gauge, by measurement of peak first derivative of left ventricular (LV) pressure (dP/dt) or by measurement of cardiac output, have found that intravenous quinidine depresses myocardial contractility transiently. 7~~~2~7However, others have shown no significant changesJo or an increasesJ3 and some have yielded variable results from subject to subject.6 Several important studies help to clarify these apparently contradictory results. Folle and Aviado6 re-

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ported a variable effect on myocardial contractility from animal to animal and had 3 dogs in which an increase in contractility was abolished by adrenalectomy. In 2 other studies,8 intravenous quinidine alone produced an increase in myocardial contractility compared with control values. However, after propranolol, intravenous quinidine produced either a decreases or no change13 in contractility. These investigations support the concept that quinidine has no direct positive inotropic effect, but produces reflex sympathetic stimulation secondary to the hypotension it induces. Unfortunately, not all studies have shown these results. A study by Sternll showed a combination of propranolol and quinidine to produce less depression of myocardial contractility than either drug given alone. O’Rourke et all6 found no change in myocardial contractility in dogs treated for 2 weeks with oral quinidine. Few hemodynamic studies of quinidine have been performed in man. One study of 5 heart transplant recipient@ evaluated the effects of intravenous quinidine. The study revealed a significant decrease in blood pressure and cardiac output and, using an assumed right atria1 pressure, no change in systemic vascular resistance. Intravenous quinidine decreased both end-systolic and end-diastolic volumes without any change in ejection fraction. The investigators interpreted their results as demonstrating a possible effect of quinidine to increase venous capacitance, leading to decreased preload with the expected hemodynamic results. The lack of any effect of quinidine on systemic vascular resistance in that study is not well explained. Several studies of the effects of oral quinidine have been performed both in normal volunteers1g-21 and in patients with heart disease. 20-s2Overall, oral quinidine in standard antiarrhythmic doses has few clinically important hemodynamic effects as assessed by noninvasive methods. One early study21 used a single 800-mg

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oral dose of quinidine and showed a significant decrease in blood pressure with a concomitant decrease in systemic vascular resistance in many patients. Patients with a poor cardiac output at rest had an improved cardiac output, whereas those with normal cardiac output at rest had a decrease. This may again be due to an effect on capacitance and resistance vessels to produce both a decrease in preload and afterload with its consequent hemodynamic effects. Overall, oral quinidine in standard doses appears to be well tolerated, without significant adverse hemodynamic effects, even in patients with LV dysfunction. This conclusion is supported by results of the Boston Collaborative Study,2s in which 652 patients taking quinidine had no exacerbation of congestive heart failure despite a predrug incidence of 35%. The primary hemodynamic effect of intravenous quinidine is peripheral vasodilation of both capacitance and resistance vessels. Its effect on cardiac output will depend on the balance between changes in preload and afterload and the patient’s preexisting hemodynamic state. There is usually a significant decrease in systemic blood pressure, which can often be avoided by rapid volume expansion during the quinidine infusion. Although quinidine does exert a mild negative inotropic effect, this may be offset by a reflex increase in sympathetic tone and is of less clinical importance than the drug’s peripheral effects. Procainamide Studies of the hemodynamic effects of procainamide have also yielded conflicting results. An in vitro study of its effect on an isolated papillary muscle preparation showed no negative inotropic effect at concentrations equivalent to clinically effective plasma levels and an increase in contractility at higher concentrations.’ This has not been observed in studies on intact animals. Most in vivo animal studies demonstrate a negative inotropic effect after large doses of intravenous procainamide.6-8JQs Most also show a significant decrease in systemic blood pressure,s8,24-26 without a significant decrease in systemic vascular resistance.8,25 At similar doses, however, some studies have shown no significant hemodynamic effects of intravenous procainamide27 and others have shown a negative inotropic effect only at high doses, with a positive inotropic effect observed at lower doses.26 Despite the lack of effect on systemic vascular resistance in these studies, the ability of procainamide to produce vasodilation is well known.sJs Why its peripheral effects were not clearly seen in all studies is not known. The hemodynamic effects of intravenous procainamide in man have been studied extensively.2s-s7 The effects seen relate not only to the total dose administered but to the rate of administration.31 Several studies have shown that the drug has a negative inotropic effect One studysg of intravenous at therapeutic doses. 2g~33~a4~37 procainamide in patients undergoing cardiac surgery showed decreases in contractility (measured by the use of a strain gauge sutured to the right ventricle) at doses of 2 and 4 mg/kg. Most other studies have also found that the myocardial depression is dose-related.2s,s4 Only

occasional studies have demonstrated a decrease in cardiac output,33>34 and these changes have generally been small and not of clinical significance. Although this degree of decrease in contractility is of minor importance at the doses generally used, the possibility of more serious clinical effects at higher doses does exist. Most studies in man have shown a significant decrease in systemic blood pressure after the administration of intravenous procainamide,2sJs-36 but others have shown little, if any, effect.3°-32 The difference may again relate to the total dose and the rate of administration. The decrease in blood pressure is thought to be related to peripheral vasodilation, but no consistent change in systemic vascular resistance has been observed.33,34 Overall, at usual antiarrhythmic doses, procainamide has a mild-to-moderate negative inotropic effect and produces a transient decrease in systemic blood pressure. The effects appear related to both total dose and rate of administration. In general, it is well tolerated even in patients with LV dysfunction or acute myocardial infarction.25*31p32 However, the possibility of clinically important effects at high doses in patients with severe LV dysfunction exists, and procainamide should be used with caution under these circumstances. Lidocaine One in vitro study assessing the effect of lidocaine on the isometric contractile force of isolated cardiac muscle had demonstrated a negative inotropic effect’ and another found little or no depressant effect3 The concentration of lidocaine used varied between these 2 studies, and decreased contractility was seen only with concentrations greater than those used clinical1y.l Hemodynamic evaluations in intact animals have shown similar results. Assessment of LV function after administration of intravenous lidocaine by the measurement of changes in peak dP/dt,12*24,25*38 by the use of a myocardial strain gauge,12p26or by the construction of ventricular function curvess4 have all demonstrated similar effects. Lidocaine in doses frequently used in clinical practice has little, if any, hemodynamic effect. The changes observed have consisted of very small transient and clinically insignificant decreases in LV contractile force,26 LV peak dP/dt38 and systemic blood pressure.26>3g These minor changes all returned to control values by 5 to 10 minutes after a bolus was administered. These investigations all show that at very high doses (4 to 40 mg/kg), lidocaine demonstrates dose-related myocardial depression.12J4-26p38 Statistically and clinically important decreases in contractile force,12,26 LV peak dP/dt,12,24p25p38cardiac output25 and systemic blood pressure12,24-26*3gwere consistently seen at doses that would be toxic in man. Many clinical studies have evaluated the hemodynamic effects of lidocaine.2gp31,32,40-44The population used for each investigation was different, but in several studies lidocaine was administered to patients undergoing hemodynamic monitoring during an acute myocardial infarction31s2~40~43or to patients with coronary

September 22. 1983

artery disease or significant LV dysfunction.Q1*41,42Even in this group of patients, in which one would expect to see the most dramatic results of any adverse hemodynamic effects, no clinically significant changes in myocardial function or systemic blood pressure were observed. These data support the long-standing clinical experience that standard doses of intravenous lidocaine can be used safely without untoward hemodynamic effects, even in patients with acute myocardial infarction and severe LV dysfunction. Although sensitive measurements can detect a mild myocardial depressant effect, this rarely is of clinical significance at the doses generally used. The experimental studies do demonstrate that at very high levels, lidocaine can exert significant negative inotropic effects. Bretylium Bretylium is unique among the antiarrhythmic agents in that short-term studies on isolated cardiac muscle,1,45-48 in intact animals4Q@’ and in mans1 have all shown that it possesses a positive inotropic effect on cardiac muscle. In vitro studies on isolated papillary muscle preparations have shown that bretylium concentrations similar to those used in clinical medicine have a doserelated positive effect on contractile force.1,45-48 Pretreatment of animals with reserpine to produce catecholamine depletion or the addition of propranolol to the bath prevent this positive inotropic effect,45946 suggesting that bretylium’s positive inotropic effect is not a direct effect but rather the result of myocardial catecholamine release. Other studies have shown both a direct and an indirect effect leading to increased contractility.48 There is little question, however, that myocardial catecholamine release plays a major role. It may be that at lower doses, this effect is primary and that at higher doses a direct positive inotropic effect occurs.52 Several in vivo animal investigations support the conclusions from the in vitro studies.49*50A canine study by Gilmore and Siegel” demonstrated an immediate decrease in LV end-diastolic pressure after the administration of bretyl.ium at a time when heart rate and cardiac output were constant, a finding interpreted as consistent with an increase in contractility. During this period, coronary venous blood samples showed a consistent increase in catecholamine content, followed by an increase in arterial catecholamine concentration. After the injection of bretylium, stimulation of cardiac sympathetic efferent nerves produced little cardiac response and little or no increase in myocardial catecholamine release compared with pre-bretylium values. This effect was not simply due to catecholamine depletion, because tvramine caused an adequate catecholamine release. The mechanism of this blocking action is unknown. The early positive inotropic effect of bretylium was demonstrated in man by Jorgensen et a1,51who showed that an intravenous infusion produced an immediate increase in cardiac index, arotic pressure and LV peak dP/dt. However, 301minutes after the infusion, the

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aortic pressure and cardiac index had returned almost to control values and the peak dP/dt was past its maximum and beginning to decrease. The prior administration of propranolol blocked most of these effects, again suggesting the role of catecholamine release. In a subsequent investigation by Chatterjee et a1,45 bretylium was given to patients within 72 hours of an acute myocardial infarction and hemodynamic variables were studied for 2 hours. There was an early increase in blood pressure and heart rate accompanied by an increase in systemic vascular resistance. However, no change in cardiac index or intracardiac pressures was observed. Two hours after the infusion, blood pressure, systemic vascular resistance and heart rate were all below control values, still with no significant change in cardiac index or filling pressures. Bretylium’s most clinically important hemodynamic effect in man is orthostatic hypotension, which can often be profound. A study by Taylor et alp3 in which 62 patients with acute myocardial infarction were treated with bretylium, demonstrated hypotension to be a common finding. In one third of their patients, the drug had to be discontinued as a result of this adverse effect. Other investigators did not find this to be a problem, especially when their patients remained supine.54>55The hypotension probably results from adrenergic neuronal blockade, but its mechanism is not fully understood. In summary, the positive inotropic effect of bretylium, although unique, is transient and probably of little clinical importance in most situations. The subsequent persistent decrease in blood pressure, especially in the upright position, is much more clinically relevant. It is well tolerated by many patients, but can lead to severe consequences, especially in those patients with low or fixed cardiac output on the basis of valvular heart disease or severe LV dysfunction. It must be used with care in these situations. Disopyramide Disopyramide has a negative inotropic effect, both in in vitro experiments using isolated cardiac muscle56 and in studies in intact animals.9 In one recent study in unanesthetized dogs,Q intravenous disopyramide produced dose-related decreases in LV peak dP/dt and stroke volume and significant increases in heart rate, systemic vascular resistance and blood pressure. These changes occurred within 1 minute of injection and persisted for about 30 minutes. No significant change in cardiac output was observed. The investigators believed the changes were to a degree that could produce clinically important adverse effects in man. These concerns have been shown to be well founded in many studies of disopyramide in man44p574Qand are expressed in several recent reviews.70971 Almost all studies show that disopyramide exerts a negative inotropiceffect44,57-63,69,72 in association with a direct effect to increase systemic vascular resistance.44*5sQ1p63,73 The only differences from study to study have been differences in the severity of these changes, and this variation probably reflects differences in the patients being evaluated. The hemodynamic changes observed included increases in systemic blood pressure, decreases

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in cardiac index and stroke volume, and increases in intracardiac filling pressures. Disopyramide causes small but significant increases in LV filling pressures and decreases in cardiac index in normal subjects62 and in patients with poor LV function, the changes are even more remarkable.5se0p63 Occasional dramatic decreases in cardiac output associated with severe hypotension have been noted.60 Studies of oral disopyramide indicate that the cardiac depressant effects of this drug are not unique to the intravenous preparation. 65-6g Reports of cardiogenic shocks7p68 and electromechanical dissociation66 due to disopyramide demonstrate the potential for disastrous results associated with the use of this drug in patients with severe abnormalities of LV function. Podrid et al65 describe the clinical follow-up study of 100 patients who began taking disopyramide for the control of arrhythmias; they emphasize the importance of careful patient selection before the use of this drug. In their group of patients, 62 were taking disopyramide for only several days and the remainder were treated on a long-term basis with 9 months of follow-up evaluations. In 16 of the original 100 patients, clinical congestive heart failure developed during this period, in 3 during the first 48 hours and in 13 during long-term treatment, usually within 3 weeks of beginning the drug. In 55% of the patients with a history of congestive heart failure, congestive heart failure again developed with disopyramide therapy. Only 2 patients without such a history had congestive heart failure while taking this drug. Disopyramide combines a significant negative inotropic effect with a peripheral vasoconstrictive effect that results in some adverse hemodynamic effects in most patients. The changes are of little clinical consequence in patients with well-preserved LV function; however, patients with LV dysfunction and a history of congestive heart failure have a high propensity for clinical deterioration, and disopyramide should be avoided in these patients. Phenytoin Two studies of the effects of phenytoin (formerly diphenylhydantoin) on the isometric force of contraction of isolated cardiac muscle1p74 have shown a significant negative inotropic effect. In one of these,l phenytoin had the most significant depressant effect on contractility of any of the drugs evaluated, including propran0101. Studies in animals have generally shown 2 primary effects: a mild, transient, negative inotropic effect and a transient decrease in blood pressure.17,74*75 The decrease in contractility appeared to be dose-relatedi7174,75 and lasted for 375 to 60 minutes.74 This effect was probably clinically important only at large doses. A transient decrease in systemic arterial pressure was observed in most studies using intravenous phenytoin75y76and appears to be due primarily to peripheral vasodilation.74 This effect is unchanged by denervation75 or beta blockade7* and is considered due to a direct action of phenytoin on the peripheral vasculature. Sanbar et al7s demonstrated that the degree of hypo-

tension after the administration of phenytoin was not only related to total dose, but more importantly, to the rate of administration of the drug. This may account for many of the differences seen between studies in both animals and man. Findings of hemodynamic studies of phenytoin in man agree with those of animal investigations. In general, the use of intravenous phenytoin has been associated with a transient, mild, negative inotropic effect30*77 and, occasionally, a brief decrease in systemic blood pressure.30778However, some studies found no evidence of decreased contractility7g or change in blood pressure.77179These differences may be related to the population studied or the rate of administration of the drug, as demonstrated by Mierzwiak et al.80 Most of these studies have been done in patients with well-preserved LV function and relatively small doses of phenytoin were used. When hemodynamic effects occurred, they were so mild and so transient as to be clinically inconsequential. High doses of this agent in patients with severely compromised LV function could result in more apparent detrimental clinical effects. A report by Mercer and Osborne78 of 6 years of clinical experience with phenytoin for the treatment of arrhythmias supports the conclusions of the hemodynamic studies. Over this period, intravenous phenytoin was used to treat 774 episodes of arrhythmia. They describe only a rare occurrence of mild, transient hypotension and no precipitation or exacerbation of congestive heart failure. The drug was administered during monitoring of intracardiac pressures in >130 of these episodes and there were no significant effects observed on pulmonary artery pressure. In summary, phenytoin in the dose8 most often used is safe and well tolerated by most patients. It exhibits a mild negative inotropic effect that is generally of little clinical significance even in patients with moderate degrees of LV dysfunction. The hypotension produced by the intravenous infusion of this drug appears to be related not only to total dose, but more importantly, to the rate of administration. It can be almost completely avoided by using slow infusion rates (<25 mg/min) and by avoiding rapid bolus injections. Phenytoin ha8 produced few untoward hemodynamic responses during its long period of clinical use. Calcium Antagonists There are a number of recent reviews of the use of the calcium antagonists.70~71,81-84These drugs demonstrate a great interplay of direct and indirect hemodynamic effects. The overall outcome in any subject is difficult to predict and depends on the relative contribution of these direct effects and reflex responses. This fact makes comparison of one study to the next and the interpretation of their results difficult. Nevertheless, certain responses are consistently observed during the use of these drugs. In vitro studies of perfused hearts and isolated cardiac muscle have shown negative inotropic and chronotropic effects of all the calcium antagonists in general use (nifedipine, verapamil and diltiazem);s only the degree of these effects varied from agent to agent.

September 22, 1983

In animals, calcium antagonists cause a dose-related decrease in systemic vascular resistance and blood pressuress-s1 owing to’ a direct peripheral vasodilating action. The effects on contractility are not quite as consistent. In vivo studies with diltiazem have generally shown no significant change in LV peak dP/dt;@@ nifedipine has produced an improvements9 and verapamil has generally caused some decrease.s5~g0~g1 The chronotropic effects of diltiazem and verapamil in animals have varied from study to study. Most investigators have shown a dose-related decrease in heart rate ss~se~glsome have demonstrated no change,@ss and one ‘showed an increase in heart rate for both of these agents as well as for nifedipine.s5 An interesting study by Bourassa et alss highlights the interplay of the direct and reflex effects of these drugs. Intravenous diltiazem administered to anesthetized dogs produced no change in heart rate despite a 30% decrease in mean aortic pressure. When aortic pressure was returned to control levels by mechanical constriction, the resulting heart rate decreased to 85% of the control value. Their conclusion was that the dlirect negative chronotropic effect of diltiazem was masked by the reflex increase in heart rate resulting from the drug-induced decrease in systemic arterial blood pressure. Almost all studies in man show a substantial decrease in blood pressure and systemic vascular resistance immediately after intravenous administration~~gz-i’Jz and demonstrate that this effect is not abolished by betaadrenergic blockade. 1e1~102Similar results have been observed with a different time course after oral administration.lo3-lo5 Most investigators have found a decrease in LV peak dP/dt after the administration of a calcium antagonist!~3~s7~gsJo1 and many have reported an increase in LV end-diastolic pressure.g3y96-gs In spite of these findings, cardiac index increased in most studies in which it was evaluatedg2~sPgs~gsJ03 and was found to decrease or :remain unchanged primarily when beta-blocking drugs were given in conjunction with the calcium antagonists.101J02J05 The extent of these hemodynamic changes at the standard doses used have generally been small and well tolerated. However, the potential for clinical deterioration in some patients with severe LV dysfunction who are treated with calcium antagonists does exist.gs The effects of the calcium antagonists on heart rate in man have been studied in several investigations, with variable results.ss~e2-geJ01-10s In most, diltiazem and verapamil produced no consistent change in heart rate.s2~g4,g6~g7~ggJ04 Olthers have shown a slight increase in heart rateg3~g5~gsJ03and some have shown a decrease,ss especially iin conjunction with beta-blocking drugs.101J05 Most of these changes have been small and of little clinical significance. In general, in man verapamil appears to have a greater overall negative chronotropic effect than diltiazem, and nifedipin’e usually produces a small increase in heart rate due to its potent peripheral vasodilating effect. In any given patient, however, the effect on heart rate for any of these agents is difficult to predict. In summary, the hemodynamic effects of the calcium antagonists result from a complicated interaction of

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direct and reflex effects. All of the agents produce peripheral vasodilation by direct action on the vasculature. This produces a reflex increase in sympathetic tone, leading to an increase in myocardial contractility and heart rate. These positive inotropic and chronotropic effects may be offset by direct negative inotropic and chronotropic effects. The net result depends on the particular agent used, the particular patient involved and the interplay of the various factors. In most patients, the calcium antagonists do not exert serious adverse hemodynamic effects. However, some patients with severe LV dysfunction may have clinical deterioration. In this group of patients calcium antagonists must be used with caution. Amiodarone Several reviews70*71JosJc7 and a number of clinical studies10a114 suggest that the hemodynamic effects of amiodarone are related to its total dose as well as to the baseline cardiovascular state of the patient in whom it is used. The use of intravenous amiodarone has been assessed in patients with various degrees of LV dysfunction. In most of these, a dose of 5 mg/kg of amiodarone was given as a bolus,10*,10s,113,114 and in some this was followed by a constant infusion.lseJ13 A decrease in arterial pressure was noted in most patients,10sJ13J14 but an occasional investigation revealed no significant change in this measurement.log The rate of drug administration correlated with the decrease in systemic blood pressure in some patients.108 Although most data have shown that the decrease in arterial pressure is due to peripheral vasodilation with an associated decrease in systemic vascular resistanCe,70,71,10S-108some studies have demonstrated little or no change.logJ14 Most studies have also revealed a moderate decrease in heart rate associated with intravenous administration of amiodarone.icsJi* Few studies have made careful measurements of changes in myocardial contractility after administration of intravenous amiodarone. A study in intact dogs demonstrated that a dose of 10 mg/kg had a negative inotropic effect as measured by a decrease in LV peak dP/dt115 Studies in patients using smaller doses of amiodarone have shown variable results. Some have shown increases in cardiac index and decreases in LV end-diastolic pressure,lOs and others have shown slight decreases in cardiac index and small increases in pulmonary capillary wedge pressure.1csJ14 The differences may well be a result of differences in the baseline LV function of those patients being evaluated. In these intravenous studies, no exacerbation or precipitation of clinical congestive heart failure was seen, even in patients with severe LV dysfunction.108~1~~113However, an occasional patient did have severe hypotension that required temporary pressor support.ll* Investigations of oral amiodarone have demonstrated similar results.l1°-l12 Doses of amiodarone of 200 to 1,200 mglday did not produce the deterioration or appearance of congestive heart failure, even in patients with severe LV dysfunction followed for as long as 22 months.‘ll No detailed hemodynamic data are supplied in these studies, but in general, the drug appeared well

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tolerated. In one study 3 deaths from progressive congestive heart failure were reported during 13 months of follow-up, but the association with amiodarone therapy in those patients was not described.llz Some investigators have also found a modest negative chronotropic effect of oral amiodarone.l10 Overall, both oral and intravenous amiodarone is well tolerated in most patients. It does exhibit mild negative inotropic and chronotropic effects and its intravenous administration produces peripheral vasodilation with a decrease in arterial blood pressure. In most situations, these effects are not of clinical importance. However, with high doses or rapid infusion rates and in patients with severe LV dysfunction, the potential for significant hypotension does exist. Mexiletine and Tocainide Investigations on the hemodynamic effects of mexiletine11e-122 and tocainide l~-~~* have generally shown similar results. The use of intravenous mexiletine in animals118 and in man116JL7J2c-122 has produced few significant hemodynamic effects. Small decreases in arterial pressure and LV peak dP/dt and small increases in LV end-diastolic pressure have been observed in some studies,llsJ20 but in almost all cases these have been so mild and transient as to be of no clinical significance. Cardiac output has generally remained unchanged. One study by Saunamlki117 did include 2 patients who had a significant decrease in arterial blood pressure associated with a decrease in systemic vascular resistance and 2 other patients who had significant increases in pulmonary capillary wedge pressure. Even in these patients, no clinical deterioration was seen. The significant changes in these hemodynamic measurements after intravenous mexiletine administration in this investigation are unusual and may be related to the severe degree of LV dysfunction of those 4 patients before drug administration. Kuhn et all’s examined the hemodynamic effects of a single large dose of mexiletine administered orally to a group of patients with coronary artery disease. They found no clinically or statistically significant changes in systemic or pulmonary artery pressure or in cardiac output for up to 6 hours after the dose was given. Tocainide also causes mild and usually clinically unimportant hemodynamic effects. The use of the drug intravenously produces small decreases in LV peak dP/dt125J27 or small increases in LV end-diastolic123 or pulmonary capillary wedge pressure.‘27 Some investigators have also reported slight increases in systemic vascular resistance.123J26 Measurements of cardiac output have generally shown no change before and after administration of the drug.1z3Jz5Jz7 Large doses of tocainide administered orally to anesthetized dogs produced decreases in LV peak dP/dt and aortic flow and increases in LV end-diastolic pressure.124 Even these large doses produced only small to moderate effects and small doses produced no measurable hemodynamic changes. Oral tocainide in man has produced no significant hemodynamic effects even in patients with acute myocardial infarction,‘% and has not caused any change in echocardiographic dimensions

when administered to patients with valvular heart disease.128 Overall, mexiletine and tocainide in both oral and intravenous form have been well-tolerated hemodynamically, even in patients with moderately severe LV dysfunction. They both have mild negative inotropic effects, but these have not been shown to be of clinical importance. Encainide, Flecainide, Lorcainide Hemodynamic evaluations of encainide, flecainide and lorcainide have been few, but their results are similar. Intravenous encainide given to patients with varying degrees of LV dysfunction produced little or no negative inotropic effect and had little or no effect on systemic vascular resistance.12g Oral encainide similarly produced no significant change in radionuclide ejection fraction at rest or during treadmill exercise in a group of patients with fairly well preserved LV function.130 Flecainide has been less systematically evaluated. When administered intravenously to anesthetized pigs, decreases in LV peak dP/dt and cardiac output were observed and appeared to be dose-related.131 In man, only oral flecainide has been studied and only its effects on echocardiographic parameters have been evaluated.lsz-134 No detailed hemodynamic studies have been done. Nevertheless, these investigations showed oral flecainide to be well tolerated, without significant effects on blood pressure or echocardiographic measurements in patients with fairly well preserved LV function.132-134 No clinical deterioration or change in exercise tolerance was observed.ls4 Intravenous lorcainide has been evaluated in more detail. It produces decreased contractility of isolated papillary muscles studied in vitro.135 In vivo studies in dogs have shown that it causes transient decreases in LV peak dP/dt, systemic arterial blood pressure and systemic vascular resistance and, at high doses, occasionally produces significant increases in LV end-diastolic pressure.135 Studies of intravenous lorcainide administered to man have demonstrated small decreases in LV peak dP/dtlss and cardiac output.136J37 In the study by Meinertz et a1,136 angiographically determined LV ejection fraction decreased by a small amount in almost all patients after intravenous lorcainide was administered. In all of these investigations, the changes were small and of little clinical significance in the groups of patients studied. In summary, encainide, flecainide and lorcainide appear to be well tolerated hemodynamically when administered to patients with fairly well preserved LV function. However, all exert a mild negative inotropic effect and must be used with care in patients with severely compromised LV contractility or poorly compensated congestive heart failure. The dearth of systematic hemodynamic studies in these groups of patients makes it impossible to realistically assess the risk of using these agents in such patients. Certainly, the theoretical risk of clinical deterioration exists and appropriate caution must be exercised.

September 22, 1993

Conclusion Ant&rhythmic drugs are often used in patients with organic heart disease who have varying degrees of LV dysfunction and who have overt or compensated congestive heart failure. Most antiarrhythmic agents, with the exception of bretylium, have mild or moderate negative inotropic efflects when examined by sensitive methods. In practice, however, most of these drugs, with the possible exception of disopyramide, when used at standard doses rarely produce clinically important hemodynamic effects. However, in patients with severe LV dysfunction or when high doses are required, the hemodynamic effects mlay become clinically important. In these circumstances, the basic characteristics of each agent must be examinled to choose the most appropriate drug.

24. 25. 26. 27. 26. 29. 30. 31. 32.

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patients: findings based on data from the Boston Collaborative Drug Surveillance Program. Prog Cardkwasc Dis 1977;20:151-163. Taybr BE, Nash CB. A comparison of the effects of qulnatholate, lldocaine and procainamtds on ouabakr-induced ventricular tachycardia and cardiac function. Arch Int Pharmacodyn 1979;232:279-290. Cote P, Harrleon DC, Baslle J. Schroeder JS. Hemodynamic interaction of procainamide and ltdocaine after experimental myocardial Infarction. Am J Cardiol 1973;32:937-942. Auaten WG. Moran JM. Cardiac and oerioheral vascular effects of tiiine and procainamida. Am J Cardiol 1965,16:701-707. O’Rourke RA, Bfshop VS, Stone HL, Rapaport E. Lack of effect of procainamide on ventricular function of conscious dogs. Am J Cardiol 1969:23:238-243. Schmld PG, Nelson LD, Hefafad DD, Mark AL, Abboud FM. Vascular effects of procaine amide in the dog: predcmlnance of the inhlbltoryeffect on ganglionic transmission. Circ Res 1974;35:949-960. Hanleon DC, Sprouee JH, Morrow AG. The antiarrhythmic properties of lidocaine and procaine amide: clinical and physiologic studies of their cardiovascular effects in man. Circulation 1963;28:4S6-491. Karlsaon E, Bermbag C. Haemodynamic effects of procainamkfe and phenytoin at apparent therapeutic plasma levels. Eur J Clin Pharmacol 1976;10:305-310. Burton JR, MaMew MT, Armstrong PW. Comparative effects of lldocaine and procainamide on acutely impaired hemodynamics. Am J Med 1976; 61:215-220. Miller RR, Hllllard 0, Lies JE, Maasuml RA, Zells R, Mason DT, Amsfardam EA. Hamodynamic effects of procainamtde in patlents with acute myocardll infarction and comparison with lklocaine. Am J Med 1973; 55:161-169. McClandort RL, Hansen WR, Klnaman JM. Hemodynamic changes lollowing procaine amide administered intravenously. Am J Med Sci 1951; 222:375-391. Jawad-Kanber C, Sherrod TR. Effect of loading dose of procaine amide on left ventricular performance in man. Chest 1974;66:269-272. Mark LC, Kayden HJ. Steele JM, Cooper JR, Berlin I, Rovenstlne EA. Brodle BB. The physiological disposition and cardiac effects of procaine amide. J Pharmacol Exp Ther 1951;102:5-15. Stearns NS, Callahan EJ, Ellis LB. Value and haxards of intravenous procaine amide (“Pronestyf”) therapy. JAMA 1952;148:360-364. Galerls P, Boudoufas H, Bchaal SF, Lewis RP, Llma JJ. Effect of procainamide on left ventricular performance in patients with primary myocardial disease. Eur J Clin Pharmacol 1990;18:311-314. Lfebannan NA, Harrfs RS, Katz RI, Llpsschutz HM, Do&fin M, Fisher VJ. The effects of liMocaine on the electrical and mechanical activity of the heart. Am J Cardiol 1969;22:375-380. Kaenan TH, Freeman JJ, Bowefl JW. Kosh JW. Selected cardiovascular and central properties of three lidocaine analogs. Pharmacology 1979;

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40. Rahkntoola SH,, Slnno MZ, Loeb HS, Chuqulmla R, Rosen KM, Gunnar RM. Lidocaine Infusion in acute myocardlal infarction. Arch Intern Med 1971;129:416-419. 41. B RR,.LMbmson AD; CMkkess RH, WfBams JF. Hemodynamt effects of lidocarne in patients with haart disease. Circulation 1969;37: 965-972. 42. Grossman JI, Cooper JA, Frfeden J. Cardiovascular effects of Infusion of lkfocaine on patients with heart disease. Am J Cardiol 1969;24:191197. 43. Boudoulas H, Bchaal BF, Lewis RP, Welch TO, DeGreen P, Kates RE. Negative inotropic effect of lidocalne in patients wlth coronary arterial disease and normal subjects. Chest 1977;71:170-175. 44. Kotter V, Llnderer T, Bchroder R. Effects of disopyramtde on systemic and ccronary hemodynamics and mvocardbl metabolism in oatients with coronary artery dis&ase: comparison with lidocaine. Am J Cardlol 1990:46:469-475. 46. Chatterlee K, Mandel WJ. Vvden JK. Parmlev WW. Forrester JS. Cardiovascular effects of brei-yliitmtosyiate in a&tie myocardffl infarction. JAMA 1973:223:757-760. 46. Markls JE,~Koch-Weser J. Characteristics and mechanism of inotropic and chronotropic actions of bretylium tosylate. J Pharmacol Exp Ther 1971;179:94-102. 47. Amsterdam EA, Spann JF, Mason DT, Zelts RF. Characterization of the positive inotropic effects of bretylium tosylate: a unique property of an antiarrhythmic agent (abstr). Am J Cardiol 1970;25:91. 46. Lals T, Amsterdam EA, Zells R, Mason DT. Mechanism of the oositive inotropic action of bretylium tosylate: combined norepinephrlne’release and direct effect (abstr). Circulation 1971:43:Suoal ll:ll-169. 49. Bacaner MB. Quaritltatll comparison of bretyliti Wtthother antifitxillatory drugs. Am J Cardiol 1968;21:504-512. 50. Gllmore JP, Sbgel JH. Mechanism of tha myocardtal effects of bretylium. Circ Res 1992;10:347-353. 51. Jorgeneen CR, Bathe RJ, Wang Y, Van Tassel !A, Duval DL. The inotrrgf” effect of bretylium in man (abstr). Circulatron 1971;43:suppl lbll52. Helsaenbuttel RH. Blgger.JT. Bretylium tosylate: a newly available antiz_ic drug for ventricular arrhythmias. Ann Intern Med 1979;Ql: 53. Taylor Bi, Saxton C, Davies PS, Stoker JB. Bretylium tosylate in prevention of cardiac arrhythmias after myocardial infarction. Br Heart J 1970;32:326. JA, Frleden J. Bretylium tosylate. Am Heart J 1971;92:70354. Cp 55. Becaner MB. Treatment of ventricular fibrillation and other acute arrhythmlls with bretylium tosylate. Am J Cardiol 1969;21:530-543. 56. Na{;f WG. Ths pharmacology of dwopyramide. J Int Med Res 1976;4: 57. Jensen 0, Slgurd B, Uhrenhott A. Haemodynamic effects of intravenous disopyramkie in heart failure. Eur J Clin Pharmacol 1975:8:167-173.

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58. HuMng J, Rosenhanwr G. Hemodynamic and electrocardiographic effects of disopyramide in patients with ventricular arrhythmia. Acta Med Stand 1976;199:41-51. 59. Huftlng J, Rosenhamer 0. Kinetics of hemcdynamic and electrocardiographic changes following intravenous disopyramide. Acta fvted Stand 1979;205:417-423. Leach AJ, Brown JE, Armstrong PW. Cardiac depression by intravenous disopyramide in patients with left ventricular dysfunction. Am J Med 1980;68:839-844. 81. Naqvi N, Thompson DS, Morgan WE, W55atns BT, Coltart DJ. l-laemodynamic effects of disopyramide in patients after open-heart surgery. Br Heart J 1979;42:587-594. 62. Thadanl U, Manyari D, Gregor P, Dtowoyeye J, Leach A, West RO, Parker Jo. liemodynamic effects of disopyramide at rest and during exercise in normal subjects. Cathet Cardiovasc Diagn 1981;7:27-34. 83. Befeler B. The hemodynamic effects of norpace (part I). Angiology 1975:28:99-101. 64. Landmark K, Simonsen S, Thaulow E. Electrophysiological and hemodvnamic disturbances in a patient overdosed with disopyramide. J Card&a% Pharmacol 1979;1:585-589. 65. Podrid PJ, Schoeneberger A, Lown B. Congestive heart failure caused by oral disopyramide. N Engl J Med 1980;302:614-817. 88. Desal J, Hlrschfeld D, Peters R, Sohelnman M, Gonzalez R. Electromechanical dissociation associated with disopyramide (abstr). Circulation 197857. 58:Suppl ll:ll-178. 67. Story JR, Abdulla AM, Frank MJ. Cardiogenic shock and disopyramide phosphate. JAMA 1979;242:654-855. 88. Bauman DJ. Myocardial depression with disopyramide. Ann Intern Med 1981;94:411-412. 69. Cathcart-Rake WF, Coker JE, Atkins FL, Huffman DH, Hassanein KM, Shen DD. Azarnoff DL. The effect of concurrent oral administration of propranoiol and disopyramide on cardiac function in healthy men. Circulation 1980:61:938-945. 70. Zlper DP, Troup PJ. New antiarrhythmic agents: amiodarone, aprindine, disopyramide. ethmozin. mexiletlne. tocainide, verapamil. Am J Cardiol 1978;41:1005-1024. 71. Jewttt DE. Hemodynamic effects of newer antttythmic drugs. Am Heart J 1980;100:984-989. 72. Wlllls PW. The hemodynamic effects of norpace (part II). Angiology 1975;28:102-110. 73. Davies GJ, Marrott PK, Mutr JR. Haemodynamic and electrocardiographic effects of intravenous disopyramide (Rythmodan) following acute myocardial infarctfon. Br J Clin Pharmacol 1979;7:183-187. 74. Nayler WG, Mclnnes I, Swarm JB, Race D, Carson V? Lowe TE. Some effects of diphenylhydantoinand propranolol on the cardrovascufar system. Am Heart J 1988;75:83-95. 75. Mbtter CO, Moran JM, Austen WG. Cardiac and peripheral vascutar effects of diphenylhydantoin sodium. Am J Cardiol 1966;17:332-338. 76. Sanbar SS. Metabolic and hemodynamic effects of diphenylhydantoin. Oklahoma State Med Assoc J 1975;68:329-335. 77. Lleberson AD, Schumacher RR, Chlldress RH, Boyd DL, Wllllams JF, Effect of diphenylhydantoincn left ventricular function in @ients wtth heart disease. Circulation 1967;36:892-899. 76. Mercer EN, C&borne JA. The current status of diphenylhydantoinin heart disease. Ann Intern Med 1967;87:1084-1107. 79. Conn RD, Kennedy JW, Blackman JR. The hemodynamic effects of diphenylhydantoin. Am Heart J 1967;73;500-505. 80. Mlerzwlak DS, Mltchell JH, Shapiro W. Effect of diphenylhydantoin (Dilantin) on lefl ventricular function in dogs (abstr). Clin Res 1966:14:42. 81. Stone PH, Antrnan EM, Mulfer JE, Braunwaid E. Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II: Hemodynamlc effects and clinical applications. Ann Intern Med 1980;93:886-904. 62. Low RI, Takeda P, Mason DT, DeMarfa AN. The effects of calcium channel Mo;j$nt agents on cardiovascular function. Am J Cardiol 198249: “_.

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63. Slngh BN, Chew CC, Josephson MA, Packer M. Pharmacologic and hemodynamic mechanisms underlying the antianginal actions of verapamil. Am J Cardiol 1982;50:686-893. 84. Packer M, Leon MB, Borrow RO, Kleval J, Roslng DR, Sukamanlan VB. Hemodvnamic and clinical effects of combined veraoamil and orooranolol therapy in angina pectoris. Am J Cardiol 1982;50:903-912. . 65. Millard RW, Lathrop DA, Grupp 0, Ashraf Y, Grupp IL, Schwartz A. Differential cardiovascular effects of calcium channel blocking agents: potential mechanisms. Am J Cardiol 1982;49:499-506. 66. Bourassa MO, Cote P, Theroux P, Tubau JF, Genaln C, Waters DD. Hemodynamics and coronary flow following dilttzem administration in anesthetized dogs and in humans. Chest 1980;78:224-230. 67. lshlkawa H, Matsushima A, Matsul H, Shindo T, Morlfujl T, Okabayashl M. Effects of diltiazem hydrochloride (CRD-401) on hepatic. superior mesenteric and femoral- hemodynamics. Arzneim-ForschlDrug Res 1978:28:400-402. 66. Fujlmoto T, Peter T, Mandel WJ. Electrophysiologic and hemodynamic actions of diltiazem: disparate temporal effects shown by experimental dose-response studies. Am Heart J 1981;101:403-407. 89. Rlbeiro LOT, Brandon TA, DeBauohe TL, Maroko PR, Miller RR. Antiarrhythmic and hemodynamic effects of calcium channel blocking agents during coronary arterial reperfusion: comparative effects of verapamil and nifedipine. Am J Cardiol 1981;48:69-74. 90. Mangiardf LM, Harlman RJ, McAllister RG, Bhargava V, Surawkz B, Shabetei R. Electrophysiologic and hemodynamic effects of verapamil: correlation with plasma drug concentrations. Circulation 1978;57: 366-372. 91. Harlman RJ, Mangiardl LM, McAllister RG, Surawlcz B, Shabetal R, Kishfda H. Reversal of the cardiovascular effects of verapamil by calcium and sodium: differences between electrophysiologic and hemodynamic responses. Circulation 1979:59:797-804. 92. Kolwaya Y, Takeshlta A, Nakamura M. Hemodynamic effects of intra-

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113. Morady F, Schelnman M, Shen E, Shapiro W, Sung R, DlCarto L. Intravenous amiodarone in the acute treatment of recurrent ventricular tachycardia (abstr). Circulation 1982;66:Suppl II:&222. 114. Schwartz A, Shen E. Schelnman M, Morady F, Chatlerjee K. Hemodynamic effects of intravenous amiodarone in-patients with recurrent veittricular tachvcardia and deoressed lefl ventricular function (abstr). Clin Res 1983;3i:81A. 115. DeBoer LWV! Nosta JJ, Kfoner RA, Braunwald E. Stud&s of amiodarone during experrmental myocardial infarction: beneficial effects on hemodynamics and infarct size. Circulation 1982;85:508-512. 116. Campbell NPS, Zaidl SA, A$fey AAJ, Palresort GC, Pantrtdge JF. Ob;;tv!$ on haemodynamrc effects of rnexrlebne. Br Heart J 1979;41: 117. Saunamakl KI. Haemodynamic effects of a new anti-arrhythmic agent, mexiletine (Ko 1173) in ischaemic heart disease. Cardiovasc Res 1975; 9:788-792. 118. Marshall RJ, Muir AW, Winslow E. Comparative antidysrhythmic and haemodynamic. effects of orally or intravenously administered mexltetine y8;,org 8001 In the anaesthehzed rat. Br J Fharmacol 1981;74:381119. Kuhn P, Klkpera M, Kroiss A, Zllcher H, Kaindl F. Antiarrhythmic and haemodynamic effects of mexiletine. Postgrad Med J 1977;53:81-83. 120. Banim SO, Da Sllva A, Stone D, Balcon R. Observations of the haemodynamics of mexiletine. Postgrad Med J 1977;53:74-76. 121. Porenel H. iiaemodynamic studies on mexiletine. a new ant&rhythmic a nt. Postgrad Med J 1977;53:78-80. 122. s8eaw TRD, Royds R. Effect of KO 1173, a new antiarrhythmic drug, on contractile state of diseased left ventricle and on frequency of ‘stable’ premature beats (abstr). Br Heart J 1973;35:558. 123. Winkle RA, Anderson JL, Peters F, Meffln PJ, Fowles RE, Harrfsen DC. The hemodynamic effects of intravenous tocainide in patients with heart disease. Circulation 1978;57:787-792. 124. Coltart DJ, Berndt TB, Kermit R, Harrison DC. Antiarrhythmic and circulatory effects of Astra W36095. Am J Cardiol 1974;34:35-41. 125. Schwartz M, Covlno B, Duce B, Narang R, Flore J, Mark&s M, Rid S, Smith E. Acute hemodynamic effects of tocainide in patients undergoing

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cardiac catheterization. J Clin Pharmacol 1979;19:lssue 2. 3:100-107. 126. Nyquisf 0, Forssell 0,Nordlander R, Schenck-Gustalsson K. Hemodynamic and antiarrhythmic effects of tocainide in patients with acute myocardial infarction. Am Heart J 1980;100:1000-1005. 127. lkram H. Hemodynamic and electrophysiologic interactions between ant&rhythmic drugs and beta blockers, with spe&al reference to tccainide. Am Heart J 1980;100:107~6-1080. 126. Ryan WF, Karffner JS. Effects of tocaintde on left ventricular performance at rest and during acute allterations in heart rate and systemic arterial pressure. Br Heart J 1979:,41:175-181. 126. Tucker CR, Winkle RA, Peters FA, Harrison DC. Acute hemodynamic effects of intravenous encainkia in oatients with heart disease. Am Haart J 1982;104:209-215. 130. MBlanco R, Fletcher RD, Cohen Al, Goftdlener JS, Slngh SN, Katz RJ, Bates HR. Sauerbrunn 6. Treatment of freauent ventricular arrhvthmia with encafnide: assessment using serial ambutatory electrocarcti&ams, intracardiac electrophysiologic studies, treadmill exercise tests, and radionuclide cineangiographic studies. Circulation 1982:85:1134-l 147. 131. Verdouw PD, Deckers JW, Canard GJ. Antiarrhythmic and hemodynamic actions of flecainide acei!ate (R-818) in the ischemic porcine heart. J

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Cardiovasc Pharmacol 1979;1:473-486. 132. Hodges M, Haugland JM, Granrud 0, Canard GJ, Asfnger RW, Mfkell FL, Krejci J. Suppression of ventricutar ectopic depolarizations by flecainkfe acetate, a new antiarrhythmic agent. Circulation 1982;65:879-885. 133. Anderson JL, Stewart JR, Perry BA, Van Hamersveld DD, Johnson TA, Canard GJ, Chang SF, Kvam DC, Pfff 6. Oral flecainkie acetate for the treatment of ventricular arrhythmias. N Engl J Med 1981;305:473-477. 134. Duff HJ, Roden DM, Maffuccl RJ, Vesper BS, Canard 01, Hfggkw SE, Oates JA, Smith RF, Woesfey RL. Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide. Am J Cardiol 1981; 48:1133-1140. 136. Carmellet E, Janssen PAJ, Marshoom R, Van Nuefen JM, Xhonneux R. Antianhythmic, etectrophysiofogicand hemo@namic effects of lorcainkfe. Arch Int Pharmaccdyn 1978;231:104-130. 136. Melnerfz T, Kerstlng F, Kasper W. Jusf H, Bechtofd H, Jahnchen E. Haem&ynamic effects of a single intravenousdcse of lorcainide in patii with heart disease. Eur J Clin Pharmacol 1980;18:481-465. 137. Shfta A, Bernard R, Mcafinckx R, Dehacker M. Haemodynamic reactions after intravenous injection of lorcainfde hydrochlorkfe in acute myocardial infarction. Eur J Cardiol 1981;12:237-242.