Inotropes, Vasopressors and Vasodilators

Suruchi Hasija, Jatin Narula ,Vandana Maravi.

ADRENERGIC RECEPTORS AND SIGNALING PATHWAYS

The main control over cardiac contractility is provided by the β–adrenergic signaling pathways and that over the vascular tone by both α- and β–adrenergic pathways. The α and β receptors are stimulated by catecholamines circulating in the bloodstream and those released locally from the adrenergic nerve endings.

The two main subtypes of β–adrenergic receptors (β–ARs) in the cardiovascular system are the β₁ and β₂ subtypes. Myocardial β₁– and β₂-AR stimulation leads to increased contractility, whereas vascular β₂-AR stimulation induces vascular smooth muscle relaxation. Drug binding to myocardial β–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 reactions finally leads to the physiological effect of increased myocardial contraction or vasodilation.

The α–adrenergic receptors (α–ARs) are further classified as α₁ and α₂ subtypes. α₁-AR on vascular smooth muscles are the main mediators of vasoconstriction. α₂-AR on the neurons function in a negative feedback loop to control α-adrenergic vasoconstriction. Stimulation of α₁-AR coupled to G protein activates phospholipase C which in turn raises intracellular Ca⁺². Stimulation of α₂-AR coupled to inhibitory G protein inhibits adenylate cyclase, thereby lowering intracellular Ca⁺².

INOTROPES

Inotropy or contractility is the intrinsic property of the cardiac myofibril. It defines the amount of work 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 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 tropomyosin from the binding site on actin and formation of actin-myosin crossbridges eventually leads to contraction of the myofibril. All inotropic agents act by increasing intracellular calcium. Catecholamines, phosphodiesterase inhibitors and calcium sensitizers are the broad classes of available inotropic agents.

Catecholamines

Catecholamines 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 may act indirectly by releasing or inhibiting reuptake of norepinephrine at the nerve terminal or by metabolism to form norepinephrine.

Table 1: Site and mechanism of action of sympathomimetics

Table 2: Haemodynamic effects of catecholamines and phosphodiesterase inhibitors

CO=cardiac output, dp/dt=force of myocardial contraction(change in pressure/time), HR=heart rate, SVR=systemic vascular resistance, PVR=pulmonary vascular resistance, PCWP=pulmonary capillary wedge pressure, MVO₂=myocardial oxygen consumption

Modified from Lehmann A, Boldt J: New pharmacologic approaches for the perioperative treatment of ischemic cardiogenic shock. J Cardiothorac Vasc Anesth 19:97-108, 2005.

Epinephrine

Epinephrine, a naturally occurring catecholamine, is secreted from the adrenal medulla. The effects on β–ARs predominate at lower doses and on α–ARs at higher doses (> 0.1 µg/kg/min). It increases heart rate (HR), stroke volume (SV) and coronary blood flow (CBF). The rise in blood pressure (BP) results from increase in HR and cardiac output (CO). Systemic vascular resistance (SVR) decreases at low doses (β₂-AR effect) but increases at high doses (α effect). It is metabolized in the liver by the enzymes catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO), and the metabolites are excreted in urine. It has arrhythmogenic potential. In cardiac surgical patients it is used as an infusion at 0.01-0.4 µg/kg/min to wean patients with poor ventricular function off cardiopulmonary bypass (CPB). (Tables 1 and 2)

Norepinephrine

Norepinephrine is the postganglionic neurotransmitter in the sympathetic nervous system. It acts on α₁–AR, α₂–AR and β₁–AR, and has negligible action on β₂–AR. The β₁-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 range is 0.01 to 0.1 µg/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.

Dopamine

Dopamine is a neurotransmitter in the central and peripheral nervous system. It is the immediate metabolic precursor of norepinephrine and epinephrine. It acts on α–ARs, β–ARs and dopaminergic receptors (DA1-DA5). At 0.5-3 µg/kg/min it increases renal and mesenteric blood flow (dopaminergic effects), between 3-8 µg/kg/min it increases HR and contractility (β-AR effects) and, above 8 µg/kg/min it causes vasoconstriction (α-AR effects). Intravenous dopamine does not cross the blood brain barrier. It is metabolized in the liver by COMT and MAO.

Isoprenaline

Isoprenaline has pure β–AR agonist activity. It causes an increase in HR and contractility (β₁-AR effect) and decreases SVR (β₂-AR effect). CO increases due to combined β₁– and β₂-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 used in the dose 0.01 to 0.1 µg/kg/min. it is metabolized in the liver by COMT. It is arrhythmogenic.

Dobutamine

Dobutamine is primarily a β₁-AR agonist and has positive inotropic effects. It causes modest increase in HR (β₂-AR effect) and decrease in SVR (β₂-AR effect). The clinical dose range varies from 2-15 µg/kg/min. It is particularly indicated in patients with myocardial pump failure. 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.

Dopexamine

Dopexamine is a synthetic analog of dopamine. It has potent β₂-AR and dopamine agonist properties and little β₁-AR and α-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 µg/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.

Fenoldopam

Fenoldopam 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 µg/kg/min and reduces BP at 0.1-0.3 µg/kg/min.

Phosphodiesterase inhibitors

Phosphodiesterase inhibitors act by preventing the breakdown of cAMP, thereby prolonging its physiological response. They do not act via β-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.

Amrinone

Amrinone 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 increasing forward flow. It is administered as a bolus loading dose (0.5-1.5 mg/kg) followed by infusion (5-20 µg/kg/min). The potential side effects are thrombocytopenia (2-3%), gastrointestinal upset, myalgia, fever, hepatic dysfunction, ventricular arrhythmias and allergy.

Milrinone

Milrinone 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 µg/kg over 10 minutes) followed by infusion (0.375-0.75 µg/kg/min).

Enoximone

Enoximone 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 µg/kg/min).

Levosimendan

Levosimendan is a new inotropic agent belonging 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 µg/kg over 10 minutes followed by an infusion of 0.1 µg/kg/min.

Calcium chloride

Calcium 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 β-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.

VASODILATORS

Vasodilators cause relaxation of arterial smooth muscle thereby reducing SVR and MAP. In addition, they also have 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 nitroprusside

Sodium 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. 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 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 µg/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 µg/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.

Nitroglycerin

Nitroglycerin (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 µg/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.

Nitric oxide

Nitric 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.

Phenoxybenzamine

Phenoxybenzamine is a non-competitive α₁– and α₂-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 is now more commonly used.

VASOPRESSORS

Vasopressors act on arteries and arterioles to increase SVR (α-AR effect). They have some β –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.

Phenylephrine

Phenylephrine is a pure α₁-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 µg and infusion rate is 0.5-1.0 µg/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.

Mephentermine

Mephentermine has direct action on α-AR and β-AR, and indirect action by releasing norepinephrine at the nerve terminal. It increases CO and SVR. Its acts immediately on intravenous injection and it’s action lasts 30 minutes. It is used in 15-45 mg bolus doses and as 0.1% infusion titrated to effect.

Vasopressin

Vasopressin,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 β₂-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.

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