Inotropes, Vasopressors and Vasodilators

Inotropes, Vasopressors and VasodilatorsSuruchi Hasija, Jatin Narula ,Vandana Maravi.ADRENERGIC RECEPTORS AND SIGNALING PATHWAYSThe main control over cardiac contractility is provided by the adrenergic signaling pathways and that over the vascular tone by both - and adrenergic pathways. The and receptors be stimulated by catecholamines circulating in the bloodstream and those released locally from the adrenergic nerve endings.The two main subtypes of adrenergic receptors (ARs) in the cardiovascular system are the 1 and 2 subtypes. Myocardial 1 and 2-AR stimulation leads to increased contractility, whereas vascular 2-AR stimulation induces vascular smooth muscle relaxation. Drug binding to myocardial ARs activates stimulatory G protein. This leads to activation of the enzyme adenylate cyclase that catalyzes the conversion of ATP to cAMP. A cascade of intracellular re live up tos finally leads to the physiological proceeding of increased myocardial contraction or vasodilation.The adrenergic receptors (ARs) are further classified as 1 and 2 subtypes. 1-AR on vascular smooth muscles are the main mediators of vasoconstriction. 2-AR on the neurons function in a negative feedback loop to control -adrenergic vasoconstriction. Stimulation of 1-AR coupled to G protein activates phospholipase C which in turn raises intracellular Ca+2. Stimulation of 2-AR coupled to inhibitory G protein inhibits adenylate cyclase, thereby lowering intracellular Ca+2.INOTROPESInotropy or contractility is the intrinsic property of the cardiac myofibril. It defines the amount of written report that the heart can perform at a given load. Contractility is primarily determined by the availability of intracellular calcium. Depolarization of the cardiac myofibril leads to the ledger entry of a small amount of Ca+2 into the cell which triggers the release of additional Ca+2 from intracellular storage sites (sarcoplasmic reticulum). The binding of Ca+2 to troponin, displacement of tropomyosi n from the binding site on actin and formation of actin-myosin crossbridges eventually leads to contraction of the myofibril. All inotropic agents act by increase intracellular calcium. Catecholamines, phosphodiesterase inhibitors and calcium sensitizers are the roomy classes of available inotropic agents.CatecholaminesCatecholamines comprise the major type of available inotropic agents. Their chemical structure includes a catechol ring, catechol hydroxyl groups and variable side chains. Endogenous(present naturally in the body) catecholamines include epinephrine, norepinephrine and dopamine, and synthetic catecholamines include isoprenaline, dobutamine, dopexamine and fenoldopam. Besides acting directly on adrenergic receptors, some catecholamines whitethorn act indirectly by releasing or inhibiting re-uptake of norepinephrine at the nerve terminal or by metabolism to form norepinephrine.Table 1 Site and mechanism of action of sympathomimeticsTable 2 Haemodynamic make of catech olamines and phosphodiesterase inhibitorsCO=cardiac output, dp/dt=force of myocardial contraction(change in pressure/time), HR=heart rate, SVR=systemic vascular resistance, PVR= pulmonic vascular resistance, PCWP=pulmonary capillary wedge pressure, MVO2=myocardial oxygen consumptionModified from Lehmann A, Boldt J New pharmacological approaches for the perioperative treatment of ischemic cardiogenic shock. J Cardiothorac Vasc Anesth 1997-108, 2005.EpinephrineEpinephrine, a naturally occurring catecholamine, is secreted from the adrenal medulla. The effect on ARs predominate at lower doses and on ARs at higher doses ( 0.1 g/kg/min). It increases heart rate (HR), chance event volume (SV) and coronary blood stream (CBF). The rise in blood pressure (BP) results from increase in HR and cardiac output (CO). Systemic vascular resistance (SVR) decreases at low doses (2-AR effect) but increases at high doses ( effect). It is metabolized in the colored by the enzymes catechol-O-methyl tra nsferase (COMT) and monoamine oxidase (MAO), and the metabolites are excreted in urine. It has arrhythmogenic unwaveringial. In cardiac surgical patients it is utilise as an extract at 0.01-0.4 g/kg/min to wean patients with poor ventricular function off cardiopulmonary bypass (CPB). (Tables 1 and 2) norepinephrineNorepinephrine is the postganglionic neurotransmitter in the sympathetic rest slight system. It acts on 1AR, 2AR and 1AR, and has negligible action on 2AR. The 1-AR action predominates at lower doses, thereby increasing inotropy, SV and CBF. It increases BP and SVR but decreases HR. The CO remains unchanged. It has arrhythmogenic unbendableial. The clinical dose range is 0.01 to 0.1 g/kg/min. Like epinephrine, it is easily oxidized. It is metabolized by COMT and MAO and taken up by the sympathetic neurons. It decreases renal, hepatic, mesenteric and splanchnic blood flow.DopamineDopamine is a neurotransmitter in the central and peripheral nervous system. It is the i mmediate metabolic precursor of norepinephrine and epinephrine. It acts on ARs, ARs and dopaminergic receptors (DA1-DA5). At 0.5-3 g/kg/min it increases renal and mesenteric blood flow (dopaminergic effects), between 3-8 g/kg/min it increases HR and contractility (-AR effects) and, above 8 g/kg/min it causes vasoconstriction (-AR effects). Intravenous dopamine does not cross the blood brain barrier. It is metabolized in the liver by COMT and MAO.IsoprenalineIsoprenaline has pure AR agonist activity. It causes an increase in HR and contractility (1-AR effect) and decreases SVR (2-AR effect). CO increases due to combined 1 and 2-AR effect. It dilates pulmonary, skeletal, renal and mesenteric vascular beds. It is indicated in the treatment of pulmonary hypertension, bradycardia (especially after orthotopic heart transplantation), heart block and conduction abnormalities. It is utilize in the dose 0.01 to 0.1 g/kg/min. it is metabolized in the liver by COMT. It is arrhythmogenic.Dobuta mineDobutamine is primarily a 1-AR agonist and has positive inotropic effects. It causes modest increase in HR (2-AR effect) and decrease in SVR (2-AR effect). The clinical dose range varies from 2-15 g/kg/min. It is particularly indicated in patients with myocardial pump mischance. Its chemical structure lacks the hydroxyl group of catecholamines. It is metabolized in the liver, although not by COMT and MAO. It increases SV, CO and CBF. The arrhythmogenic potential is less than otherwise catecholamines.DopexamineDopexamine is a synthetic analog of dopamine. It has potent 2-AR and dopamine agonist properties and little 1-AR and -AR activity. It causes vasodilation, increase in HR and inotropy. CO and renal blood flow are increased. It is used in the dose 1-10 g/kg/min. It undergoes methylation and sulfation in the liver and is taken up into the tissues via extraneuronal catecholamine uptake mechanisms. Unlike other catecholamines, it lacks arrhythmogenic potential.FenoldopamFenold opam mesylate is a dopamine DA1 receptor agonist that causes systemic and renal arteriolar vasodilation. It increases renal blood flow at doses of 0.05-0.1 g/kg/min and snips BP at 0.1-0.3 g/kg/min.Phosphodiesterase inhibitorsPhosphodiesterase inhibitors act by preserveing the breakdown of cAMP, thereby prolonging its physiological response. They do not act via -AR stimulation. Their addition to a catecholamine has a synergistic effect in increasing inotropy. They also produce vasodilation and are termed inodilators. They improve myocardial diastolic relaxation (positive lusitropic effect) and augment coronary perfusion. The clinically used phosphodiesterase inhibitors include amrinone, milrinone and enoximone.AmrinoneAmrinone is a bipyridine derivative. It provides positive inotropy and decreases SVR. The decrease in SVR is apparent immediately after administration, whereas positive inotropy is appreciable after 10-15 minutes. They are particularly useful in heart failure by incr easing forward flow. It is administered as a bolus loading dose (0.5-1.5 mg/kg) followed by infusion (5-20 g/kg/min). The potential side effects are thrombocytopenia (2-3%), gastrointestinal upset, myalgia, fever, hepatic dysfunction, ventricular arrhythmias and allergy.MilrinoneMilrinone is a derivative of amrinone and is 20 times more potent. It does not cause fever or thrombocytopenia. It is administered as a bolus loading dose (50 g/kg over 10 minutes) followed by infusion (0.375-0.75 g/kg/min).EnoximoneEnoximone is an imidazole derivative that has more pronounced vasodilatory effect than inotropic effect. It is administered as a bolus loading dose (0.5-1 mg/kg) followed by infusion (5-10 g/kg/min).LevosimendanLevosimendan is a new inotropic agent belong to the class of calcium-sensitizing agents, i.e., it sensitizes the myocardium to the actions of calcium. It has vasodilating and anti-ischemic properties mediated by opening of K+-ATP channels. The haemodynamic effects include increase in SV and CO and reduction in filling pressures, mean arterial pressure (MAP), mean pulmonary artery pressure (MPAP) and SVR. It also promotes lusitropy. It is useful in patients with compromised left ventricular function, difficulty in weaning from CPB and right ventricular failure. It is used in a loading dose of 12 g/kg over 10 minutes followed by an infusion of 0.1 g/kg/min.Calcium chlorideCalcium ions play an important role in excitation-contraction coupling in the cardiac myofibrils. It has positive inotropic effect that is effective after CPB and in the short treatment of myocardial pump failure. The rise in BP occurs secondary to increased inotropy and vasoconstriction. However, it can attenuate the -AR effects of epinephrine in the postoperative cardiac surgical patients. It is administered in the dose of 2-4 mg/kg every 10 minutes. Calcium Gluconate the clinically available compound of calcium ,contains less than half of ionized calcium and has to be metabolized in the liver before action.VASODILATORSVasodilators cause relaxation of arterial smooth muscle thereby reducing SVR and MAP. In addition, they also have venodilating property. They back up discontinuation of CPB by decreasing preload, right and left ventricular afterload, improving lusitropy and CBF. They are useful in the perioperative treatment of systemic and pulmonary hypertension, myocardial ischemia and ventricular dysfunction complicated by excessive pressure or volume overload.Sodium nitroprussideSodium nitroprusside (SNP) acts by acting as a substrate for the formation of nitric oxide (NO) in the vascular endothelium. Binding of NO to its receptor induces a conformational change in the enzyme guanylate cyclase and production of cGMP from GTP. cGMP is the second messenger that eventually leads to vascular smooth muscle relaxation via numerous intermediate steps. SNP predominantly causes arterial and arteriolar vasodilation, but at high doses venodilation also occurs. Ref lex tachycardia is apparent with its administration. SV and CO are increased only if the preload is maintained with intravenous silvers. SNP has a potential to cause coronary steal phenomenon in patients with coronary artery disorder as the epicardial coronary arteries also dilate diverting blood away from the stenosed endocardial coronary arteries. It decreases pulmonary vascular resistance (PVR) and MPAP. It abolishes hypoxic pulmonary vasoconstriction and may contribute to hypoxia. The infusion rate is 0.5 g/kg/min, and titrated to effect. It is reconstituted in a dextrose-containing solution. SNP is sensitive to light, therefore the infusion syringe and tubing are wrapped with opaque material to prevent light induced structural breakdown of the drug. Cyanide toxicity may occur with the use of SNP above 1.5 mg/kg acute dose or 8 g/kg/min chronic infusion. SNP is used during hypothermic CPB to promote uniform cooling by preventing cold induced vasoconstriction, to reduce the per fusion pressure, to reduce afterload by decreasing SVR and to increase pulmonary blood flow by decreasing PVR.NitroglycerinNitroglycerin (NTG) acts by the same mechanism as other nitrates. NTG is primarily a venodilator and reduces ventricular preload and myocardial oxygen consumption. NTG is of particular importance in patients with congestive heart failure as it unloads the left ventricle. It has modest effects on SVR and BP. It reduces PVR. The starting dose of intravenous nitroglycerin is 0.5 g/kg/min which may be titrated to effect. Attention must be paid to the fluid status as CO may drastically reduce. At higher doses systemic vascular dilation occurs. NTG is helpful in coronary artery disease because it causes epicardial coronary artery dilation. It is metabolized in the liver. Methemoglobinemia occurs at high infusion rates. Intravenous nitroglycerin has a half-life of 1-3 minutes. Tolerance develops when administered for more than 8 hours.azotic oxideNitric oxide (NO) is t he endothelium derived relaxing factor. Its mechanism of action has been described above. It has a very short half-life of 5 seconds. Inhaled NO promotes pulmonary vascular dilation. It can be used upto 80 parts per million (ppm) in patients with severe right ventricular failure and pulmonary arterial hypertension. As inhaled NO is rapidly taken up by the heme group of guanylate cyclase, it only acts locally in the pulmonary vascular bed causing pulmonary vasodilation. It has no systemic effects.PhenoxybenzaminePhenoxybenzamine is a non-competitive 1 and 2-AR blocker. It decreases PVR and SVR, thereby increasing CO. It is used to promote vasodilation during deep hypothermic circulatory arrest for uniform cooling and for the treatment of pulmonary hypertension. Phenoxybenzamine is a very potent and long acting vasodilator. It was traditionally used for afterload reduction, pulmonary vasodilatation, and in adrenal tumors such as pheochromocytoma. Phentolamine, a shorter acting agent i s now more unremarkably used.VASOPRESSORSVasopressors act on arteries and arterioles to increase SVR (-AR effect). They have some AR effect also. Catecholamines such as norepinephrine, and epinephrine and dopamine at high concentrations are potent vasoconstrictors. In addition, sympathomimetics such as phenylephrine, methoxamine, ephedrine, metaraminol and mephentermine are also vasoconstrictors. They are metabolized by COMT and MAO.PhenylephrinePhenylephrine is a pure 1-AR agonist and its primary action is to increase SVR. Reflex bradycardia may be seen. Vasoconstriction of renal, splanchnic and other vascular beds occurs. Coronary perfusion pressure is increased due to increase in diastolic pressure. The intravenous bolus dose is 50-100 g and infusion rate is 0.5-1.0 g/kg/min. Its effect is apparent in 1 minute and lasts upto 20 minutes. It is commonly used to increase SVR and therefore the perfusion pressure on CPB.MephentermineMephentermine has direct action on -AR and -AR, an d indirect action by releasing norepinephrine at the nerve terminal. It increases CO and SVR. Its acts immediately on intravenous gibe and its action lasts 30 minutes. It is used in 15-45 mg bolus doses and as 0.1% infusion titrated to effect.VasopressinVasopressin,a hormone of the anterior pituitary is a potent vasoconstrictor. It mediates vasoconstriction by inhibiting K+ ATP channels on vascular smooth muscles and blunting the rise in cGMP (due to NO and ANP) and cAMP (due to 2-AR stimulation). It is one of the modalities of treating vasodilatory shock after CPB. It is used in the infusion dose of 0.01-0.1 U/min for this purpose. At higher doses it has the potential to cause renal and splanchnic vasoconstriction. It is also administered as a bolus dose of 40 U i.v. during cardiopulmonary resuscitation.Suggested readingHoffman TM. Newerinotropesin pediatric heart failure. J Cardiovasc Pharmacol. 2011 Aug58(2)121-5Rognoni A, Lupi A, Lazzero M, Bongo AS, Rognoni G. Levosimendan fro m basic science to clinical trials. Recent Pat Cardiovasc Drug Discov. 2011 Jan6(1)9-15.Tavares M, Rezlan E, Vostroknoutova I, Khouadja H, Mebazaa A. New pharmacologic therapies for acute heart failure. Crit Care Med. 2008 Jan36(1 Suppl)S112-20.Petersen JW, Felker GM. Inotropesin the management of acute heart failure. Crit Care Med. 2008 Jan36(1 Suppl)S106-11Ward RM, Lugo RA Cardiovascular drugs for the newborn.Clin Perinatol. 2005 Dec32(4)979-97Hug CC Jr. make a choice ofinotropesandvasodilatorsin clinical situations.J Card Surg. 1990 Sep5(3 Suppl)272-7Stanford GG. Use of inotropicagentsin critical illness. Surg Clin North Am. 1991 Aug 71(4)683-98.