4. Inotropes

substance that affects the force of muscular contraction, either positively or negatively. By common usage, however, the term ‘inotrope’ describes one of a range of drugs which increase myocardial contractility.

Most inotropes act via a final common pathway to increase the availability of calcium within the myocyte adenylyl cyclase leads to an increase in the production of cAMP from ATP, which in turn activates protein kinase A. This enzyme phosphorylates sites on the α1-subunits of calcium channels, leading to an increase in open state probability, a rise in calcium flux and an increase in myocardial contractile force.

Earlier steps - lead to the activation of adenylyl cyclase are considerably more complex than this final pathway, there being at least 13 G protein-linked myocardial cell membrane receptors. β-adrenoceptors, 5-HT receptors, and histamine, prostaglandin and vasoactive intestinal peptide receptors interact with Gs(stimulatory) proteins to activate ACh. Adenosine, ACh and somatostatin interact with Gi(inhibitory) proteins to inhibit adenylyl cyclase activation, and α1-adrenoceptors and endothelin receptors interact with Gq proteins to activate phospholipase C and thence protein kinases.

Calcium leads to the final increase in contractility, almost all the inotropes in common use have actions that are cAMP dependent. These include dobutamine, adrenaline, dopexamine, noradrenaline, dopamine, isoprenaline, enoximone, milrinone, ephedrine and glucagon

Inflammatory response: inotropes also appear to modulate the cytokine response. They inhibit secretion of TNF and alter the balance between pro-inflammatory cytokines, particularly IL-6, and anti-inflammatory molecules such as IL-10.

a synthetic catecholamine derivative of isoprenaline which is predominantly a β1-adrenoceptor agonist dose-dependent effects at β2- and α1-receptors. It increases contractility, has minimal effects on heart rate and has little direct effect on vascular tone does not act at renal dopamine receptors, but may increase urine output by improving circulatory performance quoted dose range is 2.5–10.0 μg kg−1 min−1, titrated against response, but much higher rates may be needed in the critically ill.

Exogenous and endogenous catecholamine, which is both an α1-and β-agonist. It causes an α1-mediated increase in the force and rate of myocardial contraction, coupled with an increase in stroke volume secondary to enhanced venous return In low doses, β1-mediated vasodilatation is prominent, but the BP rises because of the increase in cardiac output. As the dose increases so both α- and β-effects are seen, whereas at high doses α1-vasoconstriction predominates. In the context of critical care, adrenaline is given by intravenous infusion at a rate of 0.05–0.20 μg kg

Noradrenaline is another exogenous and endogenous catecholamine. It is a powerful α1-agonist with weaker β-effects which are most pronounced at low doses (<0.05 μg kg−1 min−1). Technically, it is more a vasopressor than a direct inotrope, but it has become the first-line agent in many critical care units. (Rises in SVR are associated with increases in cardiac contractility. This is the Anrep effect.)

inodilator which increases myocardial contractility while decreasing SVR dopamine analogue which also acts both at dopaminergic and β2-adrenergic receptors. It has no effect at α-receptors.

is an endogenous precursor of noradrenaline, which acts on dopaminergic DA1 and DA2 receptors as well as at adrenoceptors effects are dose-dependent: at low doses (up to 5.0 μg kg−1 min−1) it stimulates mainly dopamine receptors, and it was believed that, because this caused renal vasodilatation, it conferred a renal protective effect (There is no evidence for this purported benefit.) At infusion rates of between 5 and 10 μg kg−1 min−1 it causes β1-mediated increases in myocardial contractility and cardiac output

synthetic catecholamine with very potent β-adrenergic effects (both β1 and β2), but with no α-adrenergic activity increase in myocardial contractility and heart rate. It is the drug of choice for pharmacological treatment of complete heart block and for overcoming overdose with β-blockers

increases myocardial contractility by enhancing the sensitivity of cardiac myocytes to calcium (it binds to cardiac troponin C and reduces systemic vascular and coronary vascular resistance (mediated via the opening of ATP sensitive K+ channels in vascular smooth muscle, both venous and arterial does not increase intracellular free calcium and improves cardiac output without increasing oxygen demand. Its elimination half-life is around 60 minutes loading dose of 24 μg kg–1 followed by infusion at a rate of 0.1–0.2 μg kg min

increase in cAMP action of phosphodiesterase-III (PDE-III). enzyme is responsible for the intracellular degradation of cAMP drugs increase contractility while causing peripheral vasodilatation dose of enoximone is 5–20 μg kg−1 min−1 after a loading dose of 90 μg k these drugs can be useful if myocardial β-adrenoceptor downregulation has occurred and the receptors have become desensitized long-standing heart failure and prolonged exposure to circulating catecholamines, but it can also occur acutely

is one of the cardiac glycosides also acts ultimately via an increase in calcium in the sarcoplasmic reticulum other inotropes, however, it inhibits Na+/K+ ATPase increase in sodium concentration reduces the inwardly directed gradient across the cell membrane One calcium ion is extruded from the cell in exchange for three sodium ions. More calcium is therefore available for release from the sarcoplasmic reticulum with each action potential

Glucagon exerts its positive inotropic effect via an increase in the synthesis of cAMP. It is rarely used for this specific purpose, but more commonly in the emergency treatment of hypoglycaemia. (It mobilizes hepatic glycogen.)

not a direct inotrope but has an accepted (and increasing) use as an adjunct vasopressor, particularly in the management of sepsis.