An overview of inotropic agents

The use of inotropic agents has been surrounded by many controversies. Recent guidelines for the treatment of patients with chronic and acute heart failure have elucidated some of the issues, but many remain. As a result, a substantial variability in the use of agents between institutions and caregivers remains, which mainly results from the lack of uniform data in the literature. Prospective randomized trials with a long-term follow-up and sufficient power are clearly needed, and a number of trials are currently in progress.     

Use of new inotropic agents in the treatment of acute cardiac failure

The drugs, new and old, useful in the treatment of acute cardiac failure, are reviewed in the light of its pathophysiological mechanisms and of the biochemical aspects of myocardial contraction. Two major classes of drugs are considered, those that stimulate cell membrane adenylcyclase, i.e. beta-agonists (dopamine, dobutamine and dopexamine) and alpha-agonists (glucagon, forskolin, calcium agonists) and those that inhibit the cellular phosphodiesterases, i.e. bipyridine derivatives (amrinone and milrinone) and imidazolone derivatives (fenoximone and piroximone). Virtually, all the inotropic agents act by increasing the entry of calcium into the cell by increasing the intracellular AMPc concentration. Dopamine has a dose-related triphasic activity. At low doses, stimulation of renal dopaminergic receptors increases renal blood flow, glomerular filtration rate and sodium clearance. At moderate doses, dopamine stimulates, for the most part, cardiac beta-adrenergic receptors. Higher doses stimulate alpha-1-adrenergic receptors, with an increase in systemic arterial and venous pressures. Dobutamine exerts a potent positive inotropic action, with little effect on vascular tone and less tachycardia than with other catecholamines, resulting in only a slight increase in myocardial oxygen consumption. The dopamine analogue, dopexamine, increases renal blood flow, myocardial contractility and produces peripheral vasodilation. The haemodynamic effects of phosphodiesterase inhibitors are similar to those of dobutamine, except that these drugs are vasodilators, their positive inotropic properties are weak and their haemodynamic effects persist for at least 8 h after a single dose in heart failure patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Indications for inotropic agents in cardiac surgery

Inotropic drugs are widely used before, during and after cardiac surgery. Besides the old well known inotropic drugs, new sympathomimetic drugs and phosphodiesterase inhibitors are available. They can be used alone or in combination. The choice of drug is difficult to make and depends, for one part, on the side-effects of each drug. Before surgery, they are required for patients who present with cardiogenic shock while waiting for emergency repair of their lesion. During surgery, inotropic drugs are used before, during and after using cardiopulmonary bypass. After surgery, they are used to treat low cardiac output states. A decision algorithm is suggested, but it is modified by personal clinical experience, aetiological patterns and pharmacological data. Therapeutic doses must be adjusted according to haemodynamic data. Physiological controls are required, such as venous return and heart rate. Mechanical assistance devices must not be forgotten, especially after myocardial reperfusion and weaning from extracorporeal circulation.     

Use of inotropic agents in critical illness.

Inotropic agents are useful in increasing oxygen delivery in critically ill patients. The need for inotropic support requires careful assessment of all the available cardiovascular variables. Following the decision to stimulate contractility, the choice of inotrope should take into consideration the adrenergic receptor populations and their effects on the distribution of blood flow. All the inotropes should be administered for a predetermined effect. If this response is not realized, the inotrope should be discontinued. The indiscriminate use of these powerful but dangerous drugs should be discouraged. However, in periods of decreasing oxygen delivery and consumption, these agents improve tissue oxygenation and prevent the development of isolated or multiple organ dysfunction.     

Use of a new inotropic agent, enoximone, in heart surgery]

We report our experience with the use of enoximone in 5 patients with severely depressed preoperative myocardial function who underwent cardiac surgery. In patients 1 and 2, enoximone was administered as the inotropic of choice before cardiopulmonary bypass (CPB) and a substantial improvement of cardiac index was achieved; in these patients, enoximone administration after CPB permitted to overcome low cardiac output which persisted after high dose dobutamine in patient 1, and in patient 2 right ventricular contractility improved. In patient 3 the use of enoximone permitted the discontinuation of CPB, which had not been previously possible with the association of dopamine and dobutamine. In this patient, adrenaline perfusion improved the low cardiac output syndrome but resulted in poorly tolerated side effects. However, in patient 4 the administration of enoximone during pre-CPB did not improve in a reduction in filling pressures without an increase in the cardiac index because the patient was hypovolemic. In patient 5, the administration of enoximone permitted to interrupt the infusion of dobutamine and to reduce the dose of sodium nitroprusside, which had resulted in significant tachycardia, with increased myocardial contractility and a reduction of vascular peripheral and pulmonary resistances. We conclude that enoximone, single or in association with other inotropics, should be considered a drug of choice in patients undergoing cardiac surgery who develop a low cardiac output syndrome.     

The new antithrombotic agents

Current antithrombotic agents include anticoagulants (unfractionated and low-molecular-weight heparin, and antivitamin K) and platelet aggregation inhibitors (aspirin, ticlopidine, clopidogrel). Two areas are under particular investigation: specific inhibition, direct or indirect, of factor Xa and factor IIa. Pentasaccharide, an indirect anti-Xa, has proved effective in curing deep-vein thrombosis and more effective than enoxaparin for prophylactic treatment after orthopedic surgery. Administered in a single subcutaneous injection daily, it has no risk of thrombocytopenia; laboratory surveillance is based on anti-Xa activity. Hirudin and melagatran act by direct thrombin inhibition. Unlike hirudin (which requires monitoring of active coagulation time or ecarin clotting time), melagatran requires no laboratory monitoring. It is not associated with an increased risk of hemorrhage. But there is no true antidote at this time. If its efficacy is confirmed, ximelagatran, the orally active prodrug of melagatran, may facilitate the long-term treatment now reserved for antivitamin K. Three antagonists of the tissue factor-factor VIIa complex are also under development: rNAPc2 (Recombinant Nematode Anticoagulant Protein C2), ASIS (Active Site Inhibitor Factor Seven) and recombinant TFPI (Tissue Factor Pathway Inhibitor). Antiplatelet drugs are the reference antithrombotic agents for the prevention and treatment of arterial thrombosis. Aspirin remains in first place (75 to 300 mg/d) but the modest superiority of the thienopyridines (clopidogrel and ticlopidine) is established. Hemogram monitoring is no longer necessary for clopidogrel. Use of aspirin + a thienopyridine after placement of a coronary stent has been validated. Laboratory monitoring of antiplatelet treatments has not been codified.     

Harmful effects of inotropic agents on myocardial protection.

Using an isolated working rat heart model, the pretreatment effects of positive inotropic agents on ischemia-reperfusion injury were investigated. The experiment consisted of (1) working control perfusion; (2) working perfusion with isoproterenol (I), milrinone (M), a combination of these drugs (I + M) and dibutyl-cyclic adenosine monophosphate (DB) followed by ischemic arrest for 33 minutes at 37 degrees C or 150 minutes at 20 degrees C and Langendorff reperfusion; and (3) working perfusion. Under conditions of normothermic ischemia, percent recoveries of postischemic cardiac output (mean +/- standard error of the mean) in the I, M, I + M, and DB groups were 37.8% +/- 12.7%, 61.3% +/- 3.1%, 0%, and 53.1% +/- 5.2%, respectively. Under conditions of hypothermic ischemia, the percent recoveries in I + M and DB groups were 10.9% +/- 7.9% and 29.8% +/- 9.5%; they were all significantly lower than that in the control group. The addition of diltiazem or ryanodine at several concentrations and lowering of the Ca2+ concentration in the St. Thomas' cardioplegic solution did not prevent I + M-induced injury. Our data suggest that pretreatment by I + M aggravated ischemia-reperfusion injury, and adjustments in Ca2+ concentration were not sufficient to prevent that injury.     

新型正性肌力药——左西孟旦

左西孟旦是钙离子增敏剂,并对KATP通道产生作用。它增强心肌收缩力而不增加心肌耗氧量;它还引起冠状动脉和体血管扩张。其药代动力学特点在健康人和在充血性心衰病人中相似。左西孟旦主要用于失代偿性急性心力衰竭和心肌顿抑。现就其药理学和临床应用效果作一综述。     

Anti-ischemic effects of inotropic agents in experimental right ventricular infarction

Background: Right ventricular (RV) function is an important determinant of survival after myocardial infarction. The efficacy of reperfusion therapy might be increased by the cardioprotective action of inotropic agents, which are used for symptomatic therapy in situations with compromised hemodynamics. Therefore, we used a porcine model of RV ischemia and reperfusion (IR) injury to study the influence of milrinone, levosimendan and dobutamine on the extent and degree of myocardial injury.
Methods: IR injury was induced by temporary ligation of the distal right coronary artery for 90 min, followed by 120 min of reperfusion. Treatment was initiated 30 min after coronary artery occlusion. A bolus of milrinone ( n =12; 50 μg/kg) and levosimendan ( n =10; 24 μg/kg) was applied in different groups, followed by continuous infusion of the drugs at 0.5 and 0.2 μg/kg/min, respectively. The effects on myocardial injury and inflammation were compared with a control ( n =12) and a dobutamine group ( n =10), where treatment was started with an infusion of 5 μg/kg/min.
Results: Milrinone and levosimendan reduced the resulting infarct size with respect to the area at risk (41.7±10.2%, 45.7±8.1%) when compared with the control group (58.3±6.1%). In contrast, dobutamine had no effect (55.8±7.7%). All drugs reduced the number of neutrophils infiltrating into the different myocardial regions and the circulating levels of interleukin-6. Increased levels of tumor necrosis factor α during reperfusion were only abated by milrinone and levosimendan.
Conclusions: Cardioprotective properties of milrinone and levosimendan were demonstrated for the first time in a clinically relevant model of RV infarction.     

Levosimendan, a new inotropic and vasodilator agent

Several clinical studies suggest substantial limitations of currently available positive inotropic substances, including beta1-adrenoceptor agonists and phosphodiesterase III inhibitors in the short- and long-term treatment of heart failure. The reasons for these detrimental effects are related to the mechanism of action of these drugs, including increases in intracellular Ca2+ with subsequent increases in myocardial oxygen demand and arrhythmogenesis. Levosimendan, a myofilament Ca2+ sensitizer with inotropic effects, increases myocardial performance without substantial changes in oxygen consumption and with neutral effects on heart rhythm. In addition, levosimendan has vasodilatory effects that are achieved by stimulation of adenosine triphosphate-dependent potassium channels. This action may be of specific interest in the setting of myocardial ischemia. To date, levosimendan is approved in 31 countries worldwide, and more patients with heart failure have participated in randomized controlled trials with levosimendan than with any other intravenous inotropic agent.     

Oral antihyperglycemic agents and renal disease: new agents, new concepts

The results of the Diabetes Control and Complications Trial (DCCT) and UK Prospective Diabetes Study trials in type 1 and type 2 diabetes, respectively, have proved the importance of intensive glucose management in the prevention of microvascular complications (retinopathy, nephropathy, and neuropathy). Both trials showed encouraging trends for a decrease in macrovascular complications, and this is being pursued in new studies. These findings have led to more strict goals for glucose control. As glucose levels are aimed to be closer to the normal range, the risk for hypoglycemia also increases dramatically. The choice of the agent therefore is more influenced currently by the risk for hypoglycemia. There are presently four classes of oral antihyperglycemic agents. These agents differ greatly in terms of mechanisms of action, efficacy, side effect profiles, and cost. Except for Acarbose, all classes decrease the glycosylated hemoglobin by a similar magnitude: 1.0 to 1.5%. In chronic renal failure, the oral agents that can be used therefore include the insulin secretagogues repaglinide and nateglinide and the thiazolidinediones (rosiglitazone and pioglitazone) with caution. Insulin also can be used safely in renal failure.     

The response of blood flow between the internal thoracic and ileocecal arteries to inotropic agents in a canine model

(Received for publication on May 15, 1996; accepted on Mar. 4, 1997)     

Amrinone (Wincoram)--a new positive inotropic and vasodilator agent

The bipyridine derivative amrinone is a specific phosphodiesterase III blocking agent. In vitro and in vivo studies show a dose-dependent increase in myocardial contractility induced by amrinone. In patients with congestive heart failure, the inotropic and vasodilator effects of amrinone contribute to cardiac improvement. When amrinone is used, the increase in myocardial oxygen consumption due to increased contractility is offset by the reductions in preload and afterload. In hearts with very high wall tension, myocardial oxygen consumption may even decrease with amrinone. Amrinone therapy is not accompanied by significant increases in heart rate. Tachyphylaxis has not been observed. The elimination half-life ranges between 2.5 and 3.5 h. A large quantity of amrinone is excreted unchanged, and therefore in cases of renal impairment the possibility of cumulation exists. The main adverse reaction of amrinone is a reversible thrombocytopenia induced by a dose-dependent decrease in platelet survival time. Therefore, frequent platelet counts are necessary when amrinone is administered. Numerous studies in patients with chronic congestive heart failure confirmed the beneficial hemodynamic effects of amrinone. Experience in the treatment of acute perioperative heart failure with amrinone are still limited, but the present results are encouraging; an additive effect of amrinone to catecholamines seems especially promising in the therapy of severe postoperative low-cardia-output syndrome.     

新型正性肌力药左西孟旦的作用机制及临床应用

左西孟旦是一种新型正性肌力药--钙增敏剂,可通过钙敏作用增强心肌收缩力,激活K+通道使血管扩张,且并不增加心肌氧耗和心率,因而具有改善心功能和心肌保护等作用.可应用于治疗急性失代偿心力衰竭、心肌缺血后心脏收缩力异常、心肌顿抑以及用于心脏手术期间循环的调控等方面.     

吸入麻醉药对心肌收缩力的抑制作用

常用的吸入麻醉药,如氟烷、安氟醚、异氟醚与七氟醚等,在产生全麻作用的同时,也降低了心肌的收缩力。导致这种负性肌力作用的因素有很多。近年来,对其作用机制的研究越来越深入,提出了一些新的观点,现就此予以综述。