44 Inotropes, pressors, and vasodilators

There has been a perceptible change in the approach to the management of chronic heart failure (CHF) from focusing on inotropy, to a predominantly neurohormonal approach to therapeutic intervention. By contrast, in acute heart failure (AHF) the critical inability of the myocardium to maintain a cardiac output sufficient to meet the demands of the peripheral circulation demands urgent intervention to restore adequate perfusion.¹ Thus, haemodynamic considerations are pivotal, and the use of inotropes, pressors, and vasodilators remains widespread.^2,3 This is despite concerns about the potential of inotropic agents to increase mortality in some patient populations.^4,5 Current recommendations are therefore that inotropes should be used only in selected patients, and withdrawn as soon as adequate organ perfusion is restored. The present chapter reviews the pharmacology of positive inotropic drugs, the principles underlying the choice of vasoactive drugs in AHF, and potential future developments in the field.

Classically, direct inotropic effects are mediated via release of calcium ions from the myocyte sarcoplasmic reticulum and other subsarcolemmal sites, and subsequent interaction between calcium and contractile proteins. The release of calcium is effected via cyclic AMP (cAMP)-dependent or -independent mechanisms (Fig. 44.1). cAMP increases phosphokinase A (PKA) activity which promotes opening of the cell membrane L-type calcium channels, in turn promoting intracellular calcium entry, and then increasing calcium release via the ryanodine receptor in the sarcoplasmic reticulum. PKA also phosphorylates phospholamban and calmodulin, promoting uptake of calcium into the sarcoplasmic reticulum, and may potentially additionally promote sarcoplasmic reticulum calcium release independently via a voltage sensitive release mechanism. There are numerous cell membrane receptors on the human myocardium, many of which are linked to G proteins (Gs, Gi, Gq). The different G proteins have a number of specific effects, including the modulation of cAMP formation (Gs, Gi), and production of diacylglycerol and inositol triphosphate (Gq), with resultant changes in intracellular calcium ion concentration. More novel inotropic agents act by increasing the sensitivity of the contractile process.⁶

The β₁- and β₂-adrenergic receptors found on the surface of cardiomyocytes (Fig. 44.1, Table 44.1) mediate cardiac responses to endogenous and exogenous catecholamines via coupling to the G_s proteins resulting in production of cAMP.⁷ Stimulation of β₁-receptors (but not β₂-receptors) results in PKA-mediated phosphorylation of phospholamban and cardiac contractile proteins⁸ and promotes cardiomyocyte apoptosis.^9,10 In heart failure, there is a redistribution in the proportions of β₁- and β₂-receptors on the cardiomyocyte surface modulating the responses of the myocyte to adrenergic stimulation.¹¹ The redistribution, together with the relative desensitization of β-receptor pathways found in heart failure, and down-regulation of receptor numbers with prolonged administration of β-agonists, may additionally alter the clinical effects of inotropic agents, although the precise implications are not yet fully understood. β-Receptor agonists include the catecholamines (adrenaline, noradrenaline, dopamine, dobutamine, isoprenaline, and dopexamine) which contain a benzene ring with different ethylamine side chains. They all activate different adrenoreceptors to varying degrees depending on the dosage used (Table 44.1).

Phosphodiesterase (PDE) is a ubiquitous enzyme that catalyses the hydrolysis of both cAMP and cGMP. A number of drugs inhibit the different subtypes of the enzyme with varying degrees of specificity (Table 44.2): however, those most relevant to positive inotropic effects relate to PDE III or IV (the biguanides amrinone and milrinone, and the imidazolone derivative enoximone).

A number of drugs increase intracellular calcium levels via cAMP-independent mechanisms, or exert their positive inotropic effect by increasing sensitivity to calcium. Inhibition of the ATPase-dependent Na⁺/K⁺ pump leads to a gradual increase in intracellular sodium. This in turn leads to a reduction in the exchange of intracellular calcium with extracellular sodium, thus increasing calcium stores in the sarcoplasmic reticulum (Fig. 44.1). The only currently used inotrope with such an action is the cardiac glycoside digoxin.¹² α₁-Receptor agonists (phenylephrine, methoxamine) act on myocardial α₁ receptors resulting in an increase in contractility via Gq protein-mediated increases in inositol phosphatase 3 and calcium release from the sarcoplasmic reticulum, additionally acting to sensitize the contractile proteins (Fig. 44.1). Finally, the myofilament calcium sensitizers (pimobendan, levosimendan) augment calcium binding to the calcium-specific regulatory site of cardiac troponin C, stabilizing calcium-induced conformational changes and thus inducing positive inotropy with no related change in intracellular calcium (Fig. 44.1).

The vascular endothelium is highly complex, with synthetic and metabolic capabilities. It reacts to a variety of substances to produce vasodilatation or constriction (Fig. 44.2). The drugs used in the management of heart failure may have simultaneous dilator and constrictor effects depending upon the pathological process and the vascular bed studied, and differential effects on the arterial/venous and pulmonary/systemic circulations depending upon the distribution of receptors and the downstream signalling pathways. A number of mechanisms have been implicated in the mechanism of action of drugs used to modify vascular reactivity in heart failure including cAMP-dependent, cGMP-dependent and hyperpolarization-mediated dilatation/constriction. These mechanisms depend upon changes in intracellular calcium concentrations and/or myosin light chain phosphorylation, with an increase in intracellular calcium resulting in myosin light chain phosphorylation and thus sustained constriction.⁶

β₂-Adrenergic receptors mediate their dilatory effects on vascular tone by coupling to the Gs proteins resulting in an increase in adenylyl cyclase activity, and an increase in cAMP. The resultant PKA-mediated phosphorylation of myosin light chain kinase reduces the phosphorylation of myosin light chains themselves. α₁-Receptor agonists and vasopressin (via vascular V₁ receptors) mediate their effects by coupling with the G proteins. An increase in smooth muscle contractility results from Gq and Gi protein-mediated increase in inositol phosphatase 3, and calcium release from the sarcoplasmic reticulum. Nitric oxide donors (inducible NO, nitrates, and nitroprusside) reduce vascular tone via an increase in intracellular cGMP and protein kinase G activity, resulting in the dephosphorylation of myosin light chains. Neseritide acts by binding to the particulate guanylyl cyclase receptor of vascular smooth muscle and endothelial cells leading to increased intracellular cGMP and thus smooth muscle cell relaxation. Of note, the differential effects on the venous and arterial circulation reflect the relative concentration of guanylyl cyclase in the different vascular beds.

Inotropic agents are those which act predominantly by increasing cardiac contractility, although many have combined vasodilator or constrictor effects, depending upon the dosage used (Table 44.1). Numerous studies have failed to show reduced mortality with their use in AHF with some showing actual harm.^4,5 Routine administration of the drugs in AHF is thus not recommended, in particular where there is ongoing myocardial ischaemia. However, on occasion their transient use may be life-saving for individual, selected patients. Current guidelines recommend that their use be considered in patients with a low cardiac output state, in the presence of signs of hypoperfusion or congestion despite the use of diuretics and/or dilators.^1,13,14 Additional recommendations are that inotropic drugs should be administered as early as possible and reduced or stopped as soon as adequate organ perfusion is restored. Such guidance demands a rapid diagnosis of inadequate cardiac output and of the presence of potentially reversible cause for deterioration.^1,3 Treatment algorithms based on the systolic blood pressure and estimated left-sided filling pressures are shown in Fig. 44.3.

A structural analogue of isoprenaline, dobutamine acts as an agonist at β₁- and β₂-receptors. It thus acts as an inotrope increasing cardiac output while also decreasing vascular resistance. Dobutamine can exacerbate tachycardia and tachyarrhythmias, and in the presence of hypovolaemia can result in profound hypotension. Dosage should be titrated up to 15 µg/kg/min according to clinical effect. When used in patients receiving concomitant β-blocker therapy, the dose may need to be increased to 20 µg/kg/min. Therapy should be weaned gradually while simultaneously optimizing oral therapy.¹

A naturally occurring precursor of noradrenaline, at low doses (0.5–3 µg/kg/min) dopamine has its predominant activity on the doperminergic DA₁ and DA₂ receptors. At higher doses (3–10 µg/kg/min), its β₁ effects predominate, with some β₂-mediated peripheral vasodilatation, thus maintaining mean arterial pressure, venous capacitance and preload. Higher doses of dopamine should be used with caution as they are associated with an increasing risk of tachycardia, tachyarrhythmias, and α stimulation resulting in increased systemic vascular resistance.¹

Milrinone and enoximone are predominantly phosphodiesterase III inhibitors (PDEIs), acting as inodilators: that is, their use results in an increase in cardiac output and stroke volume with a concomitant reduction in pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP), and systemic/pulmonary vascular resistance. As their site of action is downstream from the β receptors, they may be used in patients treated with concomitant use of β-blocker therapy. Milrinone and other PDEIs should be used with caution in patients with coronary artery disease (CAD) as there may be an increase in medium-term mortality.^4,15 Although milrinone has similar haemodynamic effects to dobutamine, there are some important differences. Milrinone has more significant vasodilatory effects, and appears to cause less tachycardia and increase in myocardial oxygen demand. Further, milrinone is renally cleared and has a longer half-life. It should, therefore, be used with caution in renal impairment. In certain circumstances, a loading dose can be used, although this is rarely done in practice because of the potential for provoking profound haemodynamic instability.¹

Levosimendan is a calcium sensitizer that exerts its inotropic effect by binding to troponin C in cardiomyocytes. It additionally causes significant vasodilatation through its action on ATP-sensitive potassium channels and has mild PDE inhibitory action at higher doses. Its haemodynamic effects are to increase cardiac output and stroke volume, and reduce PCWP and systemic/pulmonary vascular resistance. Because of metabolism to active metabolites, its haemodynamic effects persist for several days after discontinuation of treatment. Levosimendan should be used with caution in those with a relatively low systemic vascular resistance. As with milrinone, the drug may be loaded (although in the presence of haemodynamic instability the bolus should be omitted), and is effective even in the presence of β-blockade.

An endogenous catecholamine formed by the methylation of noradrenaline, adrenaline acts on cardiac β₁- and peripheral α₁-receptors resulting in inotropic and vasoconstrictor effects. Adrenaline additionally acts as a constrictor of venous beds causing an increase in preload; however, peripheral β₂-receptor activation results in vasodilator activity. The net effect of adrenaline on systemic vascular resistance is thus less predictable than with noradrenaline. Adrenaline is also dromotropic (speeds conduction in the AV node), and bathmotropic (makes myocytes more electrically excitable). The potential adverse effects of adrenaline are thus (1) to increase myocardial work and oxygen consumption significantly, (2) to have proarrhythmogenic effects, and (3) to induce/exacerbate myocardial ischaemia. Further, stimulation of the Embden–Meyerhof pathway resulting in pyruvate production increases lactic acid, especially in the presence of an impaired citric acid cycle. Although adrenaline is not recommended for the routine treatment of AHF in current guidelines, it is frequently used at low doses in patients with severe refractory haemodynamic instability as a potentially life-saving measure, and as part of current advanced life support (ALS) guidelines in the management of cardiac arrest.¹⁶

Isoprenaline is a synthetic derivative of dopamine, with potent β₁ and β₂ effects. Its chronotropic effects predominate and it is therefore infrequently used as an inotrope, being more frequently used to provide a temporary increase in heart rate pending institution of definitive pacing, or whilst awaiting resolution of the bradycardia. One exception is in the presence of significant pulmonary hypertension where isoprenaline acts both as an inotrope and a pulmonary vasodilator.

Vasodilators are recommended early in the treatment of AHF in the absence of hypotension (systolic blood pressure 〈90 mmHg) or severe obstructive valvular disease. However, there is a high incidence of side effects (Table 44.1). The effects of vasodilators are to reduce both right- and left-sided filling pressures and systemic vascular resistance, resulting in improved haemodynamics and symptoms. Coronary artery flow is usually not compromised unless either a steal phenomenon occurs, or the left ventricular end-diastolic pressure remains high despite a fall in diastolic blood pressure. Dosage and administration of the principal vasodilators used in AHF are shown in Table 44.1.

These are prodrugs that undergo complex biotransformation, predominantly in smooth muscle,¹⁷ to form nitric oxide (NO) or S-nitrosothiol, which, via cGMP, result in venous and arterial vasodilatation. Clearance is by extraction, blood hydrolysis, or glutathione–nitrate reductase in the liver. Nitrates are administered as detailed in Table 44.1 and should be titrated up to maximum tolerated dosage. Potential haemodynamic effects include: reduction in right- and left-sided filling pressures; a fall in systemic and pulmonary vascular resistance; and a fall in systolic blood pressure. Therapy is usually associated with little or no change in heart rate, but results in an increase in cardiac output due to reduction in afterload, reversal in ischaemia and reduction in severity of any mitral regurgitation. Other effects are shown in Table 44.3. The limitations of nitrates include the development of resistance, with a marked attenuation of initial effects within hours of starting therapy in up to 50% of patients.^18,–20

Sodium nitroprusside is a potent vasodilator and is generally considered the standard against which other vasodilators are assessed. Comprising the sodium (or potassium) salt of a complex molecule containing a ferrous iron atom bound to five cyanide molecules and nitric acid, nitroprusside mediates its effects by decomposition to produce nitrosothiol on contact with red blood cells. This in turn generates cGMP in the vascular smooth muscle, resulting in NO-mediated vasodilatation. Clearance is via hepatic metabolism to thiocyanate, which is then renally excreted with a half-life of 3–4 days. The administration and dosage of nitroprusside is shown in Table 44.1. The haemodynamic effects of nitroprusside are to reduce systemic and pulmonary vascular venous tone, increase vascular compliance, and reduce afterload and any atrioventricular valvular regurgitation, with the net effect of increasing cardiac output. The main limitation of the drug relates to the toxicity of its metabolites (cyanide and thiocyanate), the presence of which are related to the dose and duration of therapy. Where toxicity is suspected (lactic acidosis, confusion, fits) thiocyanate toxicity should be suspected, and treated using haemofiltration.

This recombinant DNA preparation of human ventricular brain natriuretic peptide (BNP) has an elimination half-life of 18 min.²¹ Clearance is via binding to cell surface receptors, uptake and intracellular proteolysis, proteolytic cleavage via neutral endopeptidases within renal tubular and vascular cells, and renal filtration. The administration and dosage of nesiritide is shown in Table 44.1. The haemodynamic effects are to reduce venous tone, increase vascular compliance, and reduce systemic and pulmonary vascular resistance, with an increase in cardiac output. Other effects of nesiritide are shown in Table 44.3. The main limitations of its usage are hypotension and availability.

Although nesiritide has been widely used in the United States, it has not been licensed for use by the European regulatory authorities, at least partly because some preliminary studies suggest that it may worsen outcome.^22,23

The vasoconstrictor effects of arginine vasopressin have led to development of antagonists proposed for the use in AHF. A dual V_1a/2 vasopressin receptor antagonist (conivaptan) reduces PCWP and right atrial pressure, with no significant change in blood pressure, heart rate, cardiac output and pulmonary/systemic vascular resistance.²⁴ The use of vasopressin antagonists is not currently recommended routinely in the treatment of AHF.

Vasopressor agents are not generally recommended in the management of AHF, but the use of vasodilator/inodilators drugs and/or the concomitant presence of sepsis in the critically ill patient with AHF may demand their use. Care must always be exercised to avoid an excessive increase in systemic vascular resistance resulting in a critical deterioration in cardiac output. Further, regional vasoconstriction in key vascular beds may result in life-threatening hypoperfusion which must be rapidly recognized.

Noradrenaline is a potent β₁- and α₁-agonist, causing peripheral vasoconstriction especially in the pulmonary and splanchnic beds. The α-mediated increase in systemic vascular resistance opposes its β-mediated inotropic effects, manifesting clinically with an increase in mean arterial pressure and a minor increase in heart rate, but little change in cardiac output. The effects of noradrenaline are dose related; in low doses the β effects are apparent, whereas in higher doses vasoconstrictive α effects predominate. The dose of noradrenaline should therefore be titrated to achieve a mean arterial pressure consistent with adequate end-organ perfusion, as excessive doses result in tissue ischaemia, progressive metabolic acidosis, and excessive systemic vascular resistance, resulting in a fall in cardiac output.

These α-agonists cause a rise in systolic and diastolic pressures, a marked increase in systemic and pulmonary vascular resistance, and a concomitant decrease in cardiac output. Because of the profound constrictor effects and the fall in cardiac output associated with their administration, the only use of these drugs in AHF is in the emergency and short-term support of blood pressure in the periarrest situation or in cardiogenic shock, while definitive life-saving treatment is initiated.

Arginine vasopressin is released from the posterior pituitary in response to increased serum osmolality or reduced plasma volume. Vasopressin becomes a constrictor in shock states, where its actions are to produce constriction in some vascular beds, and dilatation in others (renal, pulmonary, mesenteric, and vascular). The precise mechanisms are not well understood, but may include blockade of activated ATP-sensitive K⁺ channels in vascular smooth muscle, a decrease in the NO second messenger cGMP, and stimulation of endothelin-1 synthesis. As with other constrictors, the use of vasopressin in AHF is generally limited to the short-term support of the circulation of the critically ill patient in whom there is profound and life-threatening vasodilatation, resistant to other agents.

Intravenous vasoactive agents may be indicated in patients with a low cardiac output state determined either clinically and/or by cardiac output monitoring. Their use should also be considered in the presence of significant pulmonary or peripheral congestion despite the appropriate use of diuretics and/or vasodilators. Algorithms to guide the institution of therapy and the potential choice of inotropic drug have been published,¹ but the choice and dose of inotropic drug must be tailored to the individual patient’s circumstances (Fig. 44.3, Table 44.3). When considering the choice of vasoactive agent, several important principles apply. First, the heart should be considered as two pumps in series, with the effects of reducing and increasing the filling pressures of each considered independently. This is particularly relevant when a wide discrepancy exists between the stroke work equations of the right and left hearts. Second, the underlying pathophysiology of AHF must be considered and the precipitant or cause reversed where possible. Where ischaemia is present, positive inotropic agents which increase myocardial oxygen consumption should be avoided if the haemodynamics allow, and mechanical support maybe more beneficial. Finally, repeated re-evaluation of global and regional perfusion is required in order to optimize organ perfusion.

There are marked limitations in the management of AHF using currently available vasoactive agents due to their many adverse effects. Novel agents with potential for short-term alternative pharmacological support are at varying stages of investigation. Istaroxime is a prototype of a new class of drug with two actions: it increases sarcoplasmic reticular calcium ATPase isoform 2a (SERCA 2a) activity and inhibits the Na⁺,K⁺-ATP pump. It thereby has inotropic and lusitropic activity with no increase in myocardial oxygen demand, and no adverse haemodynamic consequences.²⁵ Cardiovascular effects are to increase systolic blood pressure and reduce heart rate and PCWP, while increasing cardiac output.

Cinaciguat is a haem-independent activator of soluble guanylate cyclase, with a potentially more predictable vasodilator response than established nitrate-based vasodilator therapies.²⁶ Chimeric natriuretic peptides are being developed, proposed to combine the beneficial effects of the different natriuretic peptides while avoiding their potentially detrimental effects, and reducing the risk of hypotension. Cardiac myosin activators are cardiac-specific myosin ATPase activators that may increase myocardial contractility by accelerating the phosphate-release step of the crossbridge cycle, thereby improving efficiency of the contractile apparatus.²⁷ Finally, peptide hormones, the urocortins, have been shown to exert inotropic and lusitropic effects by their binding to the CRH-R2 receptor on the myocardium and vascular endothelium.^28,–31

Although these drugs may offer alternative methods of positive inotropic support, they are all limited to short-term use in order to support the failing circulation while more definitive therapy is instigated. Further, their adverse side-effect profile, and requirement for close patient monitoring, demand that therapy be reduced as soon as the haemodynamic status of the patient allows, whilst instituting more standard oral therapy. Although some of the newer agents in development seem promising, modern demands for a high level of evidence showing outcome benefit will undoubtedly prove a significant hurdle in their widespread usage.