Inotropes, Vasopressors and Vasodilators

I nonropes, 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 catechola minutees circulating in the furrowstream 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 change magnitude contractility, whereas vascular 2-AR stimulation induces vascular smooth massiveness relaxation. Drug binding to myocardial ARs activates stimulatory G protein. This leads to activation of the enzyme adenylate cyclase that catalyzes the conversion of adenosine triphosphate to cAMP. A cascade of intracellular reactions finally leads to the physiological effect of augmentd myocardial c ontraction or vasodilation.The adrenergic receptors (ARs) are further classified advertisement 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 grummet to control -adrenergic vasoconstriction. Stimulation of 1-AR coupled to G protein activates phospholipase C which in unfreeze 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 work that the marrow squash can perform at a given load. Contractility is primarily determined by the availability of intracellular calcium. depolarization of the cardiac myofibril leads to the entry of a small amount of Ca+2 into the cell which triggers the release of add-onal Ca+2 from intracellular storage sets (sarcoplasmic reticulum). The binding of Ca +2 to troponin, displacement of tropomyosin from the binding site on actin and formation of actin-myosin crossbridges eventually leads to contraction of the myofibril. All inotropic performers act by increasing intracellular calcium. Catecholamines, phosphodiesterase inhibitors and calcium sensitizers are the broad classes of available inotropic agents.CatecholaminesCatecholamines counterbalance the major type of available inotropic agents. Their chemical substance structure includes a catechol ring, catechol hydroxyl radical groups and variable side chains. Endogenous(present naturally in the body) catecholamines include epinephrine, norepinephrine and dopamine, and synthetic substance catecholamines include isoprenaline, dobutamine, dopexamine and fenoldopam. Besides acting directly on adrenergic receptors, some(prenominal) catecholamines whitethorn act indirectly by let go or inhibiting re- inhalation of norepinephrine at the nerve terminal or by metamorphosis to form no repinephrine. send back 1 Site and implement of action of sympathomimeticsTable 2 Haemodynamic effects of catecholamines and phosphodiesterase inhibitorsCO=cardiac output, dp/dt=force of myocardial contraction(change in twitch/time), HR= marrow post, SVR= general vascular resistivity, PVR= pulmonic vascular resistance, PCWP= pneumonic capillary wedge pressure, MVO2=myocardial oxygen aspirationModified from Lehmann A, Boldt J New pharmacologic approaches for the perioperative treatment of ischemic cardiogenic traumatise. J Cardiothorac Vasc Anesth 1997-108, 2005.EpinephrineEpinephrine, a naturally occurring catecholamine, is secreted from the adrenal medulla. The effects on ARs predominate at lower panellings and on ARs at higher back breakers ( 0.1 g/kg/min). It increases heart rate (HR), stroke loudness (SV) and coronary thrombosis blood flow (CBF). The rise in blood pressure (BP) results from increase in HR and cardiac output (CO). Systemic vascular resistance (SVR) decr eases at low doses (2-AR effect) but increases at high doses ( effect). It is metabolized in the colored by the enzymes catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO), and the metabolites are excreted in urine. It has arrhythmogenic secureial. In cardiac surgical patients it is implementd as an infusion at 0.01-0.4 g/kg/min to wean patients with unfortunate ventricular function off cardio pneumonic bypass (CPB). (Tables 1 and 2) norepinephrineNorepinephrine is the postganglionic neurotransmitter in the clement nervous 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 potential. The clinical dose field is 0.01 to 0.1 g/kg/min. bid epinephrine, it is easily oxidized. It is metabolized by COMT and MAO and taken up by the sympathetic neurons. It decreases renal, hepat ic, mesenteric and intuitive blood flow.DopamineDopamine is a neurotransmitter in the central and peripheral nervous system. It is the immediate 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 colored 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 c onductivity abnormalities. It is used in the dose 0.01 to 0.1 g/kg/min. it is metabolized in the liver by COMT. It is arrhythmogenic.DobutamineDobutamine is primarily a 1-AR agonist and has authoritative 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 limitedly indicated in patients with myocardial pump ill. 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 other 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 tissue s via extraneuronal catecholamine uptake mechanisms. Unlike other catecholamines, it lacks arrhythmogenic potential.FenoldopamFenoldopam 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 stifles BP at 0.1-0.3 g/kg/min.Phosphodiesterase inhibitorsPhosphodiesterase inhibitors act by preventing 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 as well as produce vasodilation and are termed inodilators. They improve myocardial diastolic relaxation (positive lusitropic effect) and increase 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 immediat ely after administration, whereas positive inotropy is appreciable after 10-15 bites. They are particularly utile in heart failure by increasing forward flow. It is administered as a bolus encumbrance 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 belonging to the class of calcium-sensitizing agents, i.e., it sensitizes the myocardium t o the actions of calcium. It has vasodilating and anti-ischemic properties mediate 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 as well as set aheads lusitropy. It is useful in patients with compromised leave 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-term 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 hold back venodilating property. They aid 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 smoot h muscle relaxation via numerous intermediate steps. SNP predominantly causes arterial and arteriolar vasodilation, but at high doses venodilation also occurs. inborn reflex tachycardia is apparent with its administration. SV and CO are increased only if the preload is maintained with intravenous fluids. SNP has a potential to cause coronary steal phenomenon in patients with coronary artery disease as the epicardial coronary arteries also dilate deviate 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 subway are wrapped with opaque material to prevent light induce structural breakdown of the drug. Cyanide toxicity may occur with the use of SNP above 1.5 mg/k g 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 perfusion 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 glyceryl trinitrate is 0.5 g/kg/min which may be titrated to effect. Attention mustiness be paid to the fluid status as CO may drastically reduce. At higher doses systemic vascular dilation occurs. NTG is reformative in coronary artery disease because it causes epicardial coronary artery dilation. It is metabolized in the liver. Methemoglobin emia occurs at high infusion rates. Intravenous nitroglycerin has a half life of 1-3 minutes. Tolerance develops when administered for more than 8 hours.Nitric oxideNitric oxide (NO) is the 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 l ong acting vasodilator. It was traditionally used for afterload reduction, pulmonary vasodilatation, and in adrenal tumors such as pheochromocytoma. Phentolamine, a shorter acting agent is now more commonly 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, and indirect action by releasing norepinephrine at the nerve terminal. It increases CO and SVR. Its acts immediately on intravenous injection 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. 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