What Is a Positive Inotrope?

Positive inotropic drugs are drugs that have a positive inotropic action on the heart. Its main mechanism of action is to increase myocardial contractility and increase cardiac output.

Brief introduction of positive inotropic drugs

Positive inotropic drugs are drugs that have a positive inotropic action on the heart. Its main mechanism of action is to increase myocardial contractility and increase cardiac output. On the one hand, there is a lot of evidence that long-term or excessive application of positive inotropic drugs may expand the contradiction between energy supply and demand, and even lead to increased mortality. On the other hand, these drugs have the effect of alleviating symptoms, improving the hemodynamics of patients, and improving the quality of life of patients. In the treatment of some severe heart failure patients, especially in the rescue of heart failure patients, these positive inotropic drugs are indeed needed.

Clinical classification of positive inotropic drugs

The commonly used positive inotropic drugs in clinic are divided into cyclophosphine adenosine (cAMP) dependent and cAMP independent. The cAMP-dependent types include -receptor agonists, phosphodiesterase (PDE) III inhibitors and adenylate cyclase agonists; cAMP-independent types include Na / K-ATPase inhibitors and calcium sensitizers .

1. cAMP Positive inotropic drugs 1. cAMP dependent

1.1 receptor agonists This class of drugs stimulates myocardial adrenergic beta receptors, which increases myocardial adenylate cyclase activity. cAMP), cAMP increases the release of calcium ions from the sarcoplasmic reticulum and increases the amount of calcium ions in the cell, thereby exerting a positive inotropic effect. Representative drugs are dopamine and dobutamine.

1.1.1 Dopamine: At low concentrations (<2 g / (kg · min)), dopamine only acts on peripheral dopamine receptors, directly and indirectly reduces peripheral resistance, improves renal blood flow and glomerular filtration rate, and increases urine Volume and sodium excretion rate, and enhance the response to diuretics. At high concentrations [> 2 g / (kg · min)], -adrenergic receptors are activated, directly and indirectly increasing myocardial contractility and cardiac output. When dopamine dose is> 5g / (kg · min), it acts on -adrenergic receptors and increases peripheral vascular resistance.This effect may be beneficial for patients with hypotension, but it may be harmful for patients with acute heart failure, because May increase left ventricular load, pulmonary arterial pressure, and pulmonary circulation resistance. Dopamine small-dose intravenous infusion [ 2 to 3 g / (kg · min)] is used for decompensated heart failure with low blood pressure and low urine output, which can improve renal blood flow and urine output. Because patients' individual responses to dopamine vary widely, the use should be gradually increased from a small dose, so as not to cause an increase in heart rate and blood pressure.

1.1.2 Dobutamine: Dobutamine is a derivative of dopamine, which mainly produces dose-dependent positive muscle strength and time-varying effects by exciting 1 and 2 receptors, and reflexively reduces sympathy Tension reduces vascular resistance. At low doses, dobutamine causes mild vasodilation, resulting in a decrease in afterload and an increase in stroke output. Large doses of dobutamine cause vasoconstriction. In patients with heart failure, dobutamine increases cardiac output and increases renal blood flow, and an improvement in diuretic effects can be observed. Dobutamine is used to increase cardiac output. Infusion is usually started from 2 to 3 g / (kg · min), and it is not necessary to give a load. Then gradually adjust the infusion rate based on symptoms, diuretic response or hemodynamics. The hemodynamic effect is dose-dependent and can be increased to 20 g / (kg · min). Prolonged dobutamine infusion (24-48 h) can cause drug resistance and partially lose hemodynamic effects. Dobutamine can increase the incidence of atrial or ventricular arrhythmias. This effect is dose-dependent. Therefore, the application time of dobutamine should not be too long, and the dosage should not be too large.

1.2 Phosphodiesterase inhibitors (PDEI) The mechanism of action is to reduce the phosphodiesterase activity and hinder the degradation of cAMP in the cell, and increase the cAMP concentration, further increase the protein kinase activity on the cell membrane, and promote the Ca channel membrane protein phosphate. The activation of Ca channels increases Ca influx and increases myocardial contractility. Representative drugs for clinical application are amrinone and milrinone. These drugs have significant force-varying, relaxing, and peripheral vasodilation effects, which increase cardiac output and stroke volume, and are accompanied by a decrease in pulmonary artery pressure, pulmonary wedge pressure, and systemic and pulmonary vascular resistance. Its hemodynamic effect is between a simple vasodilator effect (such as sodium nitroprusside) and a significant positive inotropic effect (such as dobutamine). The site of action is at the distal end of the beta-adrenergic receptor, so its effect is maintained even when treated with a beta-blocker. PDEI is used when there is evidence of insufficient peripheral blood perfusion, congestion and pulmonary edema with or without response to conventional doses of diuretics and vasodilators, and maintenance of systemic blood pressure (Class IIb recommendation, level of evidence C). These drugs are superior to dobutamine in patients receiving beta blockers and / or dobutamine deficient response (Class IIa recommendation, Level of Evidence C). The dosage of amrinone is 0.75 mg / kg after the dilution, and it is injected intravenously, and then intravenously infused at 5-10 g / (kg min). The daily dosage is 100 mg. Milinone, the first dose of 25 g / kg, after 10 to 20 minutes after injection, and then maintain the infusion at a dose of 0.375 to 0.75 g / (kg · min). The side effect is the excessive expansion of peripheral veins leading to hypotension, which is mainly seen in patients with low filling pressure.

1.3 Adenylate cyclase agonist Adenylate cyclase agonist mainly includes forskolin. Forskolin is a diterpenoid that is extracted from the root of Coleopharyngeum cotyledon of the Indian Labiata plant. It can bypass the receptor and GTP binding protein to directly activate adenylate cyclase, thereby increasing cAMP concentration.

2 . cAMP Positive inotropics 2. cAMP-independent

2.1 Na ⁺ / K ⁺ -ATPase inhibitors are cardiac glycosides. These drugs are derived from plants and are mainly digitalis, including digitalis, digoxin, and hair. Anthocyanin C, poisonous glycoside K. Mainly by inhibiting the Na ⁺ -K ⁺ -ATP enzyme on the myocardial cell membrane, the intracellular Na ⁺ concentration is increased, the K ⁺ concentration is decreased, and the exchange of Na ⁺ and Ca ⁺² makes the intracellular Ca ⁺² concentration increased. Increased myocardial contractility. At general therapeutic doses, it can inhibit the cardiac conduction system. Digitalis also has a direct excitatory effect on the vagus nervous system. In acute heart failure, cardiac glycosides increase cardiac output slightly and reduce filling pressure. Cardiac glycoside can effectively prevent the recurrence of acute decompensation in patients with acute decompensation of severe heart failure. For acute myocardial infarction, the use of digitalis within 24 hours of the acute phase can cause fatal arrhythmias, so digitalis should not be used. Digitalis of pulmonary edema caused by mitral stenosis is not effective. But the latter two, such as rapid ventricular rate with atrial fibrillation, can use digitalis to slow down the ventricular rate, which is conducive to the relief of edema. Cardiac glycosides are most suitable for patients with atrial fibrillation with rapid ventricular rate and known ventricular enlargement with left ventricular dysfunction. For acute heart failure, fast-acting preparations are usually selected and lanolin C is administered intravenously. The first dose can be 0.4 to 0.8 mg, diluted with 20 ml of a 25% to 50% glucose solution and slowly injected intravenously. Later, according to the situation, 1-2 hours will be injected again. The safety range of such drugs is small, and the therapeutic dose is close to 60% of the toxic dose, so the symptoms and blood concentration should be monitored during the medication. The main symptoms of poisoning include gastrointestinal reactions, central nervous system reactions, and contraindications for the use of cardiac glycosides of various arrhythmias including: bradycardia, second and third degree atrioventricular block, sick sinus node syndrome, neck Sinus syndrome, preexcitation syndrome, hypertrophic obstructive cardiomyopathy, hypokalemia and hypercalcemia.

2.2 Calcium sensitizers Calcium sensitizers include pimobendan and levosimendan. Pimobendan is a calcium sensitizer that has been studied more clinically. In addition to enhancing the affinity of troponin C for Ca ⁺² , it also has the effect of inhibiting phosphodiesterase type III. Levosimendan: is a new generation of calcium sensitizer, mainly to increase the sensitivity of myocardial contractile protein to Ca ⁺² , promote myocardial contraction; dilate blood vessels, reduce the load of the heart before and after, increase coronary blood flow. Its half-life is about 80 hours, so a 24-hour infusion can prolong its hemodynamic effect. For patients with symptoms of low cardiac output and heart failure with severe hypotensive myocardial systolic dysfunction (Class a recommendation, level of evidence B) Levosimendan is usually administered in the first dose of 12-24 g / kg. (More than 10 min), and then given a continuous intravenous drip, the dose is 0.05 to 0.1 g / (kg · min). Its hemodynamic effect is dose-dependent and can be titrated gradually to a maximum dose of 0.4 to 0.6 g / (kg · min). Most clinical data indicate that the intravenous infusion lasts for 6 to 24 hours, but the hemodynamic effect lasts for> 48 hours after the end of the infusion. Levosimendan infusion is used for severe decompensated heart failure caused by left ventricular dysfunction, with increased dose-dependent cardiac output and stroke output, pulmonary wedge pressure, systemic vascular resistance, and pulmonary vascular resistance Decreased, heart rate increased slightly and blood pressure decreased.

Summary of Positive Inotropics

In summary, each type of drug has its own advantages, but also has its adverse effects. Most of them will increase the patient's mortality rate while improving symptoms and improving the quality of life of patients, so find and study new positive inotropic drugs. Is the future direction of drug development.

Positive Inotropic References

[1] Wang Xiancai, Feng Shiliang, chief translator. Xi's Internal Medicine, 21st Edition, Cardiovascular Disease Volume. Beijing: World Book Publishing Company, 2005.89-102.

[2] Wang Debing, Zhang Shuji, editor. Diagnosis and treatment of critical illness. Beijing: China Science and Technology Press, 1995. 145-162.
[3] Liu Meilin, Chen Yahong. Application of positive inotropic drugs in acute heart failure [J]. Chinese Journal of Multiple Organ Diseases in the Elderly, 2007, 6 (2): 91-93.