Acute positive inotropic intervention: The phosphodiesterase inhibitors

Acute positive inotropic intervention: phosphodiesterase inhibitors Robert DiBianco,

MD Takoma Park, Md., and Washington,

Treatment of myocardial failure in the critical care setting most often implies short-term therapy, which either improves the contractile state of the myocardium or reduces impedance to left ventricular ejection, thereby resulting in increases in the cardiac output and reductions in ventricular filling pressures. These actions can be shown to partially offset some of the unfavorable effects of heart failure including symptoms of dyspnea and fatigue and reduced exercise to1erance.l Before the introduction of the selective phosphodiesterase inhibitor amrinone, cardiac glycosides and catecholamines were the only available positive inotropic agents for the intravenous treatment of heart failure in the United States2 Although cardiac glycosides such as digoxin provide meaningful hemodynamic benefits, the magnitude of the beneficial actions is generally inadequate to normalize derangements of most patients with severe heart failure. In addition, the demonstrable positive inotropic actions are counterbalanced by difficulties with use resulting from the extended plasma elimination half-life and narrow therapeutic/toxic dose ratio. The introduction of the intravenous catecholamines, especially dopamine and dobutamine, has advanced the therapeutic potential for the management of heart failure in the critical care setting. These agents, especially dobutamine, have become the most common form of short-term, intravenous inotropic support for these patients; this undoubtedly reflects the ease of administration, predictability, and dose relationship of favorable hemodynamic changes and the magnitude of beneficial effects such as improved stroke volume and cardiac output, reduced ventricular filling pressures, and associated withdrawal of intrinsic sympathetic tone. Despite the pivotal role of From Washington Medicine.

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and Georgetown

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School of

Reprint requests: Robert DiBianco, MD, Division of Cardiology, Washington Adventist Hospital, 7600 Carroll Ave., Takoma Park, MD 20912.

4lOl28033

The

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catecholamines in the treatment of the acutely ill patient with heart failure, problems, such as excessive tachycardia, hypertension, and vasoconstriction, may occur. In addition, loss of effectiveness with prolonged exposure to ,&agonists, continued symptoms, and clinical heart failure may occur, despite the use of catecholamines. This situation invites continued research for additional therapeutic agents. Phosphodiestrase inhibitors (PDE I) that are selectivefor adenosine3’:5’-cyclic phosphate (CAMP)specific cardiac and vascular phosphodiesterase isozyme III (PDE III) comprise a new group of agents for the treatment of heart failure, which at present are limited to clinical short-term intravenous use and research uses only. Several reviews are available of these compounds.2-5 Of the agents identified to date, only intravenous amrinone and milrinone have been approved by the Food and Drug Administration (FDA) for clinical use. Long-term treatment with each of these agents has been abandoned as a result of prior research. Long-term oral administration of amrinone has produced frequent and serious side effects; long-term oral administration of milrinone has been proved to effect a shortened survival.6, 7 AMRINONE

Since its introduction for clinical use in 1984, intravenous amrinone has represented the only PDE I in the United States. Its use was approved by the FDA for the short-term management of moderately severe heart failure; the following will exclusively address FDA-approved intravenous treatments and will concentrate predominantly on amrinone and to a lesser extent on its congener milrinone, which has not been marketed to date. Amrinone is the prototype bipyridine derivative having inotropic and vasodilator activity shown by in vitro,8-10 in vivo,g, 11-13and clinical studies.r4-s3 It is currently available for intravenous administration for the short-term treatment of heart failure. Milrinone, an analog of the parent compound amrinone, is 30- to 50-fold more potent, but it is essentially sim1871

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ilar in pharmacologic activity.34T 35 Amrinone and milrinone demonstrate phosphodiesterase-inhibiting activity that is relatively selective for the major phosphodiesterase isozyme in cardiac and vascular tissues, PDE III.35 PDE III differs from the other PDE isozymes in that it is specific for CAMP and does not appear to hydrolyze cyclic guanosine monophosphate. Increased CAMP resulting from reduced hydrolysis probably acts through several mechanisms to release calcium to the contractile elements of the myocardial cell. 23,25 Studies have suggested that the inotropic response is dependent on a well-functioning sarcoplasmic reticulum and that in the immature cell or cells with a damaged or depressed sarcoplasmic reticulum function, the PDE Is are less active.36 Additional observations have suggested that a thyroxine-like activity on membrane Ca2+ adenosine triphosphatase (ATPase) may be a contributing mechanism for milrinone but not amrinone.35 Amrinone therapy is not affected by pretreatment with either digitalis, atropine, reserpine, dibenzyline, or /3-adrenergic blockers.2-4, g, I1 Experimental studies have not routinely shown additive in vitro effects of amrinone and digitalis glycosides.37 Several studies have emphasized the vasodilator activity of amrinone12, 15-20and suggested that the inotropic activity was a minor and secondary effect, although this remains controversial.15, 26 It appears that the inotropic activity of amrinone is correlated to the degree of myocardial cell integrity and perhaps its ability to produce CAMP. 36,38 Inotropic activity may be more easily demonstrated in patients with severe heart failure when high-dose, initial intravenous boluses are used.14 In one study of continuous intravenous administration of amrinone, afterload reduction occurred simultaneously with enhanced cardiac output; however, indexes of inotropic action were not l6 The positive inotropic activity of amrichanged. none may require initial infusion rates of 40 pg/ kg/min (decreased to 10 pg/kg/min after 1 hour) or an intravenous bolus of 0.5 to 3.5 kg/kg (over 1 minute, repeated in 10 minutes if necessary), whereas the vasodilating activity appears with continuous infusion rates of 10 to 40 pglkglmin. Regardless of relative magnitude, the mechanism of action of positive inotropy and peripheral vasodilation is felt to be predominantly the result of increased concentrations of intracellular CAMP and the consequent rise in intracellular calcium concentrations.2-j In addition, a lusitropic action (enhancement of cardiac relaxation) has been observed.2T 3, 5 The relative contributions of the vasodilator, inotropic, and lusitropic activity probably

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depend on the specific clinical circumstances, the patient, and the dose of amrinone or milrinone administered; however, it appears that in most situations the vasodilator action predominates and is of greater magnitude than that of positive inotropy or lusitropy.26 Amrinone does not demonstrate either p-adrenergic agonist activity similar to the catecholamines nor does it act as a digitalis glycoside to inhibit sodiumpotassium ATPase. It therefore allows a different pharmacodynamic profile for the treatment of heart failure secondary to systolic ventricular dysfunction. The hemodynamic actions of amrinone primarily include enhanced ventr,icular systolic function (i.e., positive inotropy), reduced impedance to left ventricular emptying (so-called afterload reduction), and improved ventricular diastolic function (socalled positive lusitropy). The improvement in hemodynamics of patients who have congestive heart failure resulting from parenterally administered amrinone is quantitatively similar to that of dobutamine’8-24 and generally superior to dopamine.2” Several factors have provided enthusiasm for the use of these agents in the management of heart failure; favorable additive activity to the digitalis glycosides, complementary and synergistic actions when combined with catecholamines,3gg 4o and effects that do not produce imbalances of myocardial oxygen supply/demand relationships or coronary hemodynamits. Amrinone has been used successfully to treat heart failure in many different clinical situations. Most often, patients with chronic congestive heart failure have been treated with an initial intravenous bolus (followed by an infusion) and have demonstrated favorable increases in cardiac output, with associated reductions in systemic vascular resistance and pulmonary capillary wedge pressure. Intravenous bolus injections have ranged from 0.75 to 2.0 mg/kg over 3 to 15 minutes with second boluses administered only when initial doses less than 1.5 mg/kg are used. Infusions generally begin at 5 to 30 pug/kg/ min

13, 14,18,20,22

An early study of Le Jemtel et a1.15 treating eight patients with severe heart failure that were concomitantly receiving digitalis and diuretics showed a 49 % increase in cardiac index (1.84 to 2.74, p < O.OOl), associated with reductions in pulmonary capillary wedge pressure of 24% (p < 0.05) and in systemic vascular resistance of 29% (p < 0.01). Similar beneficial results were seen in other studies.14, 16,20,24,26 Treatment has been shown to advance exercise capacity significantly. 25 Improved right ventricular

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performance has also been demonstrated, a result stemming from right ventricular afterload reduction.“” Dose-related reductions in systemic arterial pressure are seen in most situations, probably reflecting the dose dependency of plasma levels.41 The reduction in systemic vascular resistance is associated with a rise in cardiac output, and resultant reductions in blood pressure and increments in heart rate are minimized; often these parameters are not importantly altered.l”, Ifi, ZJO The elimination half-life of amrinone is in excess of 2 hours and may vary depending on the degree of heart failure present.41 This compromises the ability to terminate excessive hypotension or other adverse drug reactions should they arise. Excessive hypotension has most often been associated with low ventricular filling pressures and is most directly countered by volume expansion when this occurs. Myocardial oxygen consumption measured during treatment of heart failure in animals13 or patients has declined in association with improved cardiac outputs.l?, 27 This has been postulated to reflect the predominant vasodilatory actions of amrinone.‘” In studies of patients with severe ischemic cardiomyopathy, amrinone has produced significant beneficial hemodynamic effects (cardiac index increased 69% ; systemic vascular resistance decreased 41% , and pulmonary capillary wedge pressure was reduced 16%) simultaneously with a 30% reduction in measured myocardial oxygen consumption.“l The frequent association of coronary artery disease with heart failure suggests that the reduction in myocardial oxygen consumption would be of benefit to patients with ischemic heart disease. There has been no comparison of the relative efficacy and safety of the phosphodiesterases, catecholamines, and digitalis glycosides with respect to this theoretic consideration. However, we have found that the catecholamine dobutamine can be used safely in patients with underlying coronary artery disease.42 Inotropic agents of all classes, including digitalis, catecholamines, and phosphodiesterase inhibitors, have been shown to be potentially arrhythmogenic. Amrinone and milrinone have been found to produce an increase in both supraventricular and ventricular arrhythmias, suggested to be a direct result of their ability to increase CAMP levels8, 43,44 Under the carefully observed and controlled critical care setting, however, arrhythmogenicity should not pose a major limitation of use. The introduction of inotropic agents to patients must be observed and monitored carefully with anticipated immediate action

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for the treatment of spontaneous or provoked arrhythmias. There has been ample documentation of arrhythmic safety during infusion of amrinone.‘“, I8 Treatment with amrinone produces minor increases in heart rate that are comparable with dobutamine and generally less than the increases in sinus rate seen with dopamine. l8 Specific study of the electrophysiologic activity of amrinone has shown that treatment produces reductions in the atria1 and atrioventricular nodal effective refractory periods and atrioventricular functional refractory period.30, 31 Amrinone may increase the ventricular response to supraventricular arrhythmias such as atria1 fibrillation or flutter. Adverse drug reactions of greater than 1% incidence with the intravenous phosphodiesterase inhibitor amrinone experienced by 462 patients from clinical studies include arrhythmia (3.0% 1; thrombocytopenia (2.4 % ); gastrointestinal symptoms, especially nausea (1.7%); and hypotension (1.3%). The arrhythmia profile did not identify a characteristic type of arrhythmia. Thrombocytopenia was not associated with bone marrow suppression or antiplatelet antibodies.3” SUMMARY

AND

CONCLUSIONS

Phosphodiesterase inhibitors that are selective for CAMP-specific cardiac and vascular PDE III comprise a new group of agents for the treatment of heart failure, which at present are limited to clinical shortterm intravenous use and research uses only. Although both intravenous amrinone and milrinone are FDA approved, only amrinone is available for general clinical use. Selective phosphodiesterase inhibition produces beneficial actions of positive inotropy and peripheral vasodilation that result from increased cardiac and vascular muscle concentrations of intracellular CAMP and ionic calcium. In addition, a positive lusitropic action (enhancement of cardiac relaxation) has been observed. Neither /3-adrenergic agonist activity nor inhibition of the sodium-potassium ATPase is produced by these agents. The magnitude of hemodynamic improvement generally exceeds that of the cardiac glycosides and is comparable with that of intravenous catecholamines such as dobutamine. The different pharmacodynamic profile of the PDE inhibitors is additive to the effects of cardiac glycosides, complementary and synergistic to the actions of catecholamines, and has been shown to have favorable effects on coronary hemodynamics. As a result there is continued enthusiasm for the short-term intravenous use of amrinone and potentially milrinone in the

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setting of acute heart failure resulting from systolic dysfunction (after myocardial infarction, open heart surgery, or infectious or toxic myocarditis), heart failure resulting from right ventricular systolic dysfunction, and when patients with severe heart failure await cardiac transplantation. Initiation of treatment with an intravenous bolus followed by a maintenance infusion provides prompt increases in stroke volume and cardiac output and simultaneous reductions in right and left ventricular filling pressures and systemic vascular resistance. Amrinone is especially valuable in patients with heart failure associated with increased systemic vascular resistance (or systemic arterial hypertension) and in those having an inadequate response to intravenous dobutamine or those receiving fl- or calcium channel-blocking agents. These favorable aspects are countered by a small percentage of adverse reactions that include arrhythmia provocation, nausea and hypotension, and an increased elimination half-life that reduces the ability to control drug action on a minute-to-minute basis after administration. The salutary hemodynamic effects of short-term, intravenous selective phosphodiesterase inhibition with amrinone (and possibly milrinone in the future) are an important adjunct or alternative to catecholamines and digitalis glycosides in the management of the patient with severe heart failure.

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REFERENCES

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35. Mylotte KM, Cody V, Davis PJ, Davis FB, Blas SD, Scchoenl M. Milrinone and thyroid hormone stimulate myocardial membrane Ca2+-ATPase activity and share structural homologies. Proc Nat1 Acad Sci 1985;82:7974-8. 36. Wilhurst PT, Walker ,JM, Fry CH, et al. Inotropic and vasodilator effects of amrinone on isolated human tissue. Cardiovasc Res 1984;18:302. 37. Brown L, Erdmann E. Non-additive positive inotropic effects of amrinone and oubain on cat papillary muscles. Klin Wochenschr 1984;62:390-3. 38. Leier CV. Acute inotropic support. Cardiotonic drugs-a clinical survey. New York: Marcel Dekker, 1986:72-5.

Vasodilators

in the intensive

Gary S. Francis, MD Minneapolis,

Cardiology Division, Medical School.

Reprint requests: Gary S. Francis, HC. 420 Delaware SE, Minneapolis, 410128034

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39. Gage J, Rutman H, Lucid0 D, Le Jemtel TH. Additive effects of dobutamine and amrinone on myocardial contractility and ventricular performance in patients with severe heart failure. Circulation 1986;74:367-73. 40. Guimond JG, Matuschak GH, Meyers F, Keating D. Augmentation of cardiac function in end-stage heart failure by combined use of dobutamine and amrinone. Chest 1986;90:302-4. 41. Edelson J, Stroshane R, Benziger DP, et al. Pharmacokinetics of the bipyridines amrinone and milrinone. Circulation 1986;73(suppl 111):145-52. 42. Pozen RG, DiBianco R, Katz RJ, Borta R, Myerburg RJ, Fletcher RD. Myocardial metabolic and hemodynamic effects of dobutamine in heart failure complicating coronary _ arterv I disease. Circulation 1981;63:1279-85. 43. Onuaeuluchi G. Tanz RD. McCawlev E. Electrocardioeranhic changes induced by amrinone in the-isolated perfused guineapig langendorff heart preparation. Arch Int Pharmacodyn Ther 1983;264:263-73. 44. Onuaguluchi G, Tam. RD. Electromechanical dissociation and possible uncoupling of phosphorylation following tachydysrhymogenic dose of amrinone in the guinea-pig Langendorf heart preparation. Arch Int Pharmacodyn Ther 1984;271:8197.

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Intravenous vasodilator drugs are widely used to treat patients with severe congestive heart failure who are hospitalized in intensive care units. This strategy is based on the long-standing principle that “unloading” the failing left ventricle results in a substantial reduction of left ventricular filling pressure and a consistent increase in cardiac output with little or no change in arterial pressure. Although the concept of unloading the left ventricle to improve left ventricular performance was well known to physiologists at the turn of the century, the introduction of bedside catheterization with balloon-tipped pulmonary artery catheters in the 1970s and the subsequent demonstration that nitroprusside markedly improves cardiac output and reduces left ventricular filling From the Minnesota

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pressure in patients with severe left ventricular dysfunction has led to the widespread use of vasodilators in patients in intensive care units. More recently, intravenous nitroglycerin has gained wide acceptance both as an effective agent in the syndrome of unstable angina pectoris and as a vasodilator to treat congestive heart failure. Reducing systemic vascular resistance by directacting vasodilators lessens myocardial oxygen demand in proportion to the reduction of the stresstime interval.’ This is in contradistinction to positive inotropic agents such as dobutamine and the phosphodiesterase inhibitors, which can increase myocardial energy demand.l An increase in myocardial oxygen consumption may be particularly hazardous in patients with severe underlying coronary artery disease. Because of the increased metabolic cost of positive inotropic agents, it may be preferable to begin with a direct-acting vasodilator agent such as nitroprusside or nitroglycerin when considering the treatment of patients with severe congestive heart failure. 1875