15: Inotropes and Vasodilator Drugs

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CHAPTER 15 Inotropes and Vasodilator Drugs

Nathaen Weitzel, MD

Editors note: chapter 1 complements this discussion.

1 What are the benefits of cardiovascular drugs?

All of the components of organ perfusion, including preload (end-diastolic volume), afterload, inotropy, heart rate, and myocardial oxygen supply and demand can be pharmacologically modified. An underlying concept is the Frank-Starling principle, which states that increased myocardial fiber length (i.e., end-diastolic volume) improves contractility up to a point of optimal contractile state, further stretching results in declining performance.

2 Discuss the limitations of drugs that alter vascular tone

Preload can be altered with intravascular volume shifts and with drugs that change vascular tone, most notably the venous capacitance vessels. In addition, arterial vasodilators may shift failing myocardium to a more effective contractile state as a result of afterload reduction and decreased impedance to ventricular ejection. However, the intrinsic contractile state is not improved by vasodilators, in contrast to the effect of positive inotropic agents.

3 What are the general goals of inotropic support and the characteristics of the ideal inotrope?

The goal is increasing cardiac output by improving myocardial contractility to optimize end-organ perfusion. In addition, for enlarged hearts a decrease in ventricular diameter, wall tension, and myocardial oxygen demand is also desirable and should enhance the contractile state and myocardial perfusion. Some inotropic agents also decrease pulmonary vascular resistance, improving right heart output and forward flow.

4 Discuss the hemodynamic profile of the phosphodiesterase III inhibitors amrinone and milrinone

Amrinone and milrinone are approximately equipotent to dopamine and dobutamine in increasing cardiac output through increased inotropy and improved lusitropy (myocardial relaxation). In addition to direct myocardial effects, vasodilation typically occurs, making it difficult to separate the relative contributions of these effects on enhanced cardiac output. Right ventricular function can be favorably impacted as these agents decrease pulmonary vascular resistance (comparable to 20 ppm of nitric oxide in cardiac surgery patients), thus improving forward flow. Coronary vessels and arterial bypass grafts (internal mammary and gastroepiploic arteries and radial artery grafts) become dilated; furthermore, in the presence of these drugs they are less subject to the vasoconstrictive effects of concomitantly administered α-adrenergic agonists.

5 What untoward effects can result from use of phosphodiesterase inhibitors? How are these minimized?

Because the vasodilator effects may be profound, concurrent use of vasoconstrictors (e.g., epinephrine, norepinephrine, and phenylephrine) is often necessary, particularly after cardiopulmonary bypass. Prolonged infusion of amrinone, but not milrinone, may cause significant thrombocytopenia through nonimmune-mediated peripheral platelet destruction.

6 What are other advantages of the phosphodiesterase inhibitors?

In addition to positive inotropy, lusitropy, vasodilation, and a relative lack of significant tachyarrhythmias, these inhibitors may transiently restore β-adrenergic function by decreasing cyclic adenosine monophosphate (cAMP) breakdown and potentiating the action of administered β-adrenergic agonists. These drugs dilate coronary arteries and grafts, improving collateral coronary circulation and attenuating thromboxane activity; in certain clinical situations they may help decrease myocardial oxygen consumption.

7 What intracellular intermediary is involved in the actions of phosphodiesterase III inhibitors and sympathomimetic amines?

Both drug classes increase intracellular cAMP concentrations. Sympathomimetic β-adrenergic stimulation activates sarcolemmal adenyl cyclase, resulting in the generation of increased cAMP from adenosine triphosphate (ATP). Phosphodiesterase (PDE) III inhibitors decrease the breakdown of cAMP. A synergistic effect is noted when β-adrenergic agonists are infused along with PDE III inhibitors.

8 How does increased intracellular cAMP affect the cardiac myocyte? What are the corresponding effects on myocardial function?

Increased intracellular cAMP activates protein kinases, which phosphorylate proteins in the sarcolemma, sarcoplasmic reticulum (SR), and tropomyosin complex. This causes elevated calcium (Ca2+) influx via Ca2+ channels, amplifying the effects of Ca2+ on contractile elements. In addition, increased protein phosphorylation in the SR and tropomyosin complex improves lusitropy by stimulating reuptake of Ca2+ into the SR. The end result is a restoration of the myofilaments to their resting state.

9 Describe the hemodynamic profiles of epinephrine, norepinephrine, and dopamine

The effects of a low-dose infusion of epinephrine (<0.04 mcg/kg/min) are primarily limited to stimulation of β1– and α2-adrenergic receptors in the heart and peripheral vasculature, resulting in positive chronotropy, dromotropy (conduction velocity), inotropy, increased automaticity, and vasodilation. Moderate-dose infusion (0.04 to 0.12 mcg/kg/min) generates greater α-adrenergic effects and vasoconstriction, and high-dose infusion results in such prominent vasoconstriction that many of the β-adrenergic effects are blocked.

Hemodynamic dose-response relationship of epinephrine:

image <0.04 mcg/kg/min Primarily β-stimulation
image 0.04 to 0.12 mcg/kg/min Mixed alpha and β-stimulation
image >0.12 mcg/kg/min Primarily α-stimulation

The potency of norepinephrine in stimulating β-adrenergic receptors is similar to that of epinephrine, but it results in significant α-adrenergic stimulation at much lower doses. Typical dosage ranges are 0.02 to 0.25 mcg/kg/min.

Dopamine stimulates specific postjunctional dopaminergic receptors in renal, mesenteric, and coronary arterial beds to produce vasodilation. These dopaminergic effects occur at lower doses (0.5 to 1.0 mcg/kg/min), becoming maximal at 2 to 3 mcg/kg/min. At intermediate doses (2 to 6 mcg/kg/min) β1-adrenergic stimulation is evident. Beginning at doses of about 10 mcg/kg/min (but as low as 5 mcg/kg/min), α-adrenergic stimulation is seen, which at higher doses overcomes dopaminergic effects, producing vasoconstriction.

10 Describe the hemodynamic profiles of isoproterenol and dobutamine

Isoproterenol is an extremely potent β1– and β2– agonist that possesses no α-stimulating properties. Therefore isoproterenol increases heart rate, automaticity, and contractility and dilates both venous capacitance and arterial vessels. It may be a good choice for heart-rate maintenance in a denervated nonpaced transplanted heart. Dobutamine acts principally on β-adrenergic receptors, impacting β1-receptors in a relatively selective fashion. In addition, it has a mild indirect β1-stimulating effect that is secondary to prevention of norepinephrine reuptake but is offset by slightly more potent β2-stimulation. Generally at clinical doses minimal increases in heart rate, positive inotropy, increased cardiac output, and minimal or modest decreases in systemic and pulmonary vascular resistance occur. Because of the indirect β1-stimulating effect, patients concurrently receiving β-blockers can exhibit marked increases in systemic vascular resistance without improvement in cardiac output. In addition, an occasional patient will display dose-related increases in heart rate.

11 Which characteristics of β-adrenergic agonists limit their effectiveness?

image Positive chronotropic and arrhythmogenic effects (dose-dependent effect with epinephrine, isoproterenol, and dobutamine) result in increased myocardial oxygen consumption.
image Vasoconstriction secondary to α1-activation (with norepinephrine, high-dose epinephrine, and high-dose dopamine) results in increased afterload and subsequent increased myocardial wall tension.
image Isoproterenol and dobutamine to a lesser extent produce vasodilation caused by stimulation of vascular β2-receptors. Excessive vasodilation may decrease coronary perfusion.

12 How may the side effects and limitations of β-adrenergic agonists be minimized?

Side effects may be decreased by appropriate dosage adjustments and use of combinations of agents. Currently PDE III inhibitors have a prominent role in this regard. However, both vasopressin and nicardipine at low doses may prove beneficial in these circumstances.

13 Is digitalis useful as an inotrope intraoperatively?

Because of its narrow therapeutic ratio and adverse interactions with fluid and electrolyte shifts, digitalis is rarely used intraoperatively as an inotrope.

14 What are the mechanism and sites of action of nitrovasodilators?

Nitrates such as nitroglycerin and sodium nitroprusside are pro-drugs that penetrate the vascular endothelium and become reduced to nitric oxide (NO). Nitroglycerin requires intact endothelial enzymatic activity, which is not present in the smallest or damaged vessels, whereas nitroprusside nonenzymatically degrades into NO and cyanide (a compound highly toxic to the mitochondrial respiratory chain). NO then stimulates production of cyclic guanosine monophosphate (cGMP), resulting in decreased cellular calcium levels and thus vascular smooth muscle relaxation.

Sodium nitroprusside acts primarily on the arterial vasculature whereas nitroglycerin has its most prominent effect on venous capacitance vessels (although this is less true with higher doses). NO can also be delivered directly to the pulmonary circulation by inhalation, thereby reaching the pulmonary vascular smooth muscle by diffusion across the alveolar-capillary membrane. Direct delivery to the pulmonary circulation reduces potentially undesirable systemic hypotension and causes specific pulmonary vasodilation.

15 Describe the antianginal effects of nitrates

Beneficial effects of nitroglycerin and other nitrates in anginal therapy result from improved coronary perfusion, a reduction in myocardial oxygen consumption (MVO2), and antiplatelet effects. Coronary artery spasm is ameliorated, and dilation of epicardial coronary arteries, coronary collaterals, and atherosclerotic stenotic coronary segments occurs. Venodilation reduces venous return, ventricular filling pressures, wall tension, and MVO2 and improves subendocardial and collateral blood flow. Platelet aggregation is inhibited by release of NO and increased formation of cGMP.

KEY POINTS: Inotropes and Vasodilator Drugs image

1. Congestive heart failure with preserved left ventricular systolic function (EF >35%) in the absence of ischemia and valvular pathology suggests diastolic heart failure.
2. Vasopressin has a role in blood pressure maintenance in septic shock, cardiogenic shock, and other shock states.
3. Beneficial effects of nitroglycerin and other nitrates in anginal therapy result from a reduction in MVO2, improved coronary perfusion, and platelet effects.
4. Nicardipine and clevidipine are fast-acting CCB agents with a nearly ideal hemodynamic profile for many cardiac patients with hypertension. They act by reducing afterload, increasing coronary blood flow, and improving myocardial oxygen balance.
5. Low-dose dopamine is ineffective for prevention and treatment of acute renal failure and protection of the gut, and dopamine in general is not an effective treatment for septic shock.
6. Levosimendan is a newer agent that shows promise in the treatment of heart failure and cardiogenic shock following cardiac surgery.

16 Describe the etiology of tachyphylaxis with nitrovasodilators

Therapy with nitroglycerin is often confounded by tachyphylaxis, especially with long-term use, because of changes in the enzymatic machinery responsible for its transformation into NO. Tachyphylaxis may also be caused by adaptive changes in the vascular system itself. Nitrates may also be of limited clinical effect in the presence of a preload insensitive system and fixed pulmonary hypertension.

The presence of tachyphylaxis with administration of sodium nitroprusside suggests a therapeutic ceiling and ensuing cyanide toxicity and is usually associated with prolonged infusions of more than 2 mcg/kg/min or when sulfur donors and methemoglobin stores are exhausted.

17 Discuss the types and mechanisms of action of selective vasodilating agents available for clinical use

Hydralazine directly relaxes smooth muscle, dilating arterioles to a much greater extent than veins and decreasing diastolic more than systolic blood pressure. The response is slow, with onset of 15 to 20 minutes, and somewhat unpredictable, often causing prolonged hypotension. Reflex tachycardia may also be an undesired side effect.

Nicardipine is a short-acting selective calcium channel blocker (CCB) that acts on the arteriolar beds, providing easier titration and controlled reduction in systemic blood pressure. Nicardipine is becoming the arterial vasodilator of choice for cardiac surgery patients with hypertension since it has more selective coronary vasodilation than systemic vasodilation. The end result is a reduction in afterload; increased stroke volume; and increased coronary blood flow, which results in a favorable effect on myocardial oxygen balance. Onset is 5 to 15 minutes, and duration of action is 4 to 6 hours.

Clevidipine is a new third-generation CCB that is considered an ultrashort-acting arteriolar vasodilator. Metabolized by plasma esterases, the half-life of clevidipine is approximately 2 minutes, with a context-sensitive half-life of 2 to 5 minutes regardless of duration of infusion. It acts much like nicardipine in that it selectively dilates the arteriolar bed, reducing afterload without affecting cardiac filling pressures. It comes in an emulsion much like propofol.

Fenoldopam is a unique parenteral vasodilator that acts via peripheral dopamine-1 receptors. This has a vasodilatory effect that is selective for renal and splanchnic vasculature and causes mild renal diuresis. Onset is 5 minutes, and half-life is roughly 5 minutes with a duration of action of 30 to 60 minutes with infusion. Fenoldopam was thought to provide some degree of renal protection against acute kidney injury (at least in patients having abdominal aortic surgery), but trials in intensive care unit patients and the operative setting have not shown clear benefit. Fenoldopam can cause significant hypotension; thus, if it is used as a renal protective agent, close monitoring of the blood pressure is needed to ensure adequate renal perfusion.

18 Describe the mechanism of action of vasopressin

Arginine vasopressin (AVP) has action at three subtypes of receptors (V1, V2, and V3). The V1 receptor stimulates vascular smooth muscle contraction, resulting in the vasopressor response of AVP. The V2 receptors primarily act in the kidney to produce water retention (antidiuretic hormone), and the V3 receptors act in the central nervous system, and modulate corticotropin secretion. The vasopressin system makes up one of the three vasopressor systems in the body along with the sympathetic system and the renin-angiotensin system. The plasma half-life of AVP is 4 to 20 minutes; thus it must be delivered by infusion for prolonged effects.

19 How may vasopressin aid in the management of cardiogenic or septic shock?

Vasopressin is becoming a mainstay in the treatment of shock states in combination with adrenergic inotropic agents. In the presence of a systemic inflammatory response it has been noted that septic shock patients tend to have low plasma vasopressin concentrations. The use of vasopressin has been shown to improve hemodynamics and reduce requirements of adrenergic agents. The dosage range is still debated, with many studies show doses of 0.01 to 0.04 units/min to be effective. There are published data supporting use of vasopressin following cardiopulmonary bypass, with doses as high as 0.1 unit/min. Bolus doses in situations of cardiac arrest are 20 to 40 units per ACLS guidelines. Higher doses of vasopressin carry higher risk of intense vasoconstriction, bringing up concerns for splanchnic hypoperfusion; however, studies have not clearly defined the extent of this risk.

20 How may β-type natriuretic peptide aid in the management of end-stage congestive heart failure?

Although large, prospective randomized trials have not been conducted to date with nesiritide (β-type natriuretic peptide), some initial data seem to indicate that it may be beneficial for the management of precardiac transplant patients with increased pulmonary vascular resistance and renal failure. Indeed, β-type natriuretic peptide improves the hemodynamic profile, increases renal sodium excretion, and suppresses the renin-angiotensin-aldosterone system, improving clinical symptomatology.

21 What is diastolic heart failure and what management options are available?

Congestive heart failure in the presence of preserved left ventricular systolic function (ejection fraction [EF] >35%) and the absence of ischemia and valvular pathology suggests diastolic heart failure. Chronic management with angiotensin-converting enzyme inhibitors is being evaluated in several large clinical trials, with the premise that decreased aldosterone and angiotensin levels ameliorate deleterious collagen remodeling of the cardiac structure. Acute management is directed at alleviating diastolic dysfunction by the following:

image Reduction in heart rate with β-blockade may benefit preload-sensitive diastolic dysfunction.
image Low-dose PDE inhibitors and L-type CCBs (dihydropyridines) may improve cellular myocardial relaxation.
image Nitrates may improve symptomatology in certain volume-overloaded cases of diastolic dysfunction.

22 What are the clinical indications and current evidence for using dopamine?

There is now scientific evidence that low-dose dopamine is ineffective for prevention and treatment of acute renal failure and protection of the gut. It may be apparent that low-dose dopamine, in addition to not achieving the preset goal of organ protection, may also be deleterious because it can induce renal failure in normovolemic and hypovolemic patients. Dopamine also suppresses the secretion and function of anterior pituitary hormones, thereby aggravating catabolism and cellular immune dysfunction and inducing central hypothyroidism. In addition, it blunts the ventilatory drive, increasing the risk of respiratory failure in patients who are being weaned from mechanical ventilation. There have also been recent observational trials that seem to indicate an increased mortality in septic patients treated with dopamine, whereas similar patients treated with norepinephrine did not demonstrate this mortality risk. Based on current metaanalysis (which is lacking good, prospective randomized data), dopamine is now considered a fourth-line agent for cardiogenic, septic, or vasodilatory shock.

23 Describe the new inotropic agent levosimendan, including mechanism of action and place in clinical therapy

Levosimendan is a pyridazinone-dinitrite and a member of a new class of pharmacologic agents, the “calcium sensitizers.” This drug acts to increase contractility without elevating intramyocardial calcium levels. This is achieved by stabilizing troponin C in an active form, thus providing inotropic support in similar fashion to other agents but with much lower intracellular calcium requirements. It increases systolic force while maintaining coronary perfusion via coronary artery vasodilation, along with mild systemic and pulmonary vasodilation. It can be used synergistically with β-adrenergic agents and seems to have a low arrhythmogenic potential.

Levosimendan performs as well if not better in congestive heart failure when compared to dobutamine. In cardiac surgery patients the combination of dobutamine and levosimendan resulted in better maintenance of stroke volume following bypass than dobutamine and milrinone combined. Based on current evidence, recommended dosing is to start with a <36 mcg/kg bolus followed by a 0.4 mcg/kg/min infusion. There are numerous trials demonstrating success with this agent, but more randomized trials are needed. Infusion durations in current studies only reach 24 hours, limiting long-term use recommendations.

24 What mechanism of action accounts for the inotropic effect of thyroid hormone?

Thyroid hormone affects chronic changes in protein synthesis such as alterations of nuclear synthetic machinery, structural changes of the myosin isozyme, and increased expression of β-adrenergic receptors. In addition, more immediate augmentation of contractility results secondary to an increase in mitochondrial respiration and ATP production, enhanced function of sarcolemmal Ca-ATPase, and augmented sodium entry into myocytes. Elevated intracellular sodium levels increase intracellular calcium concentration and activity.

SUGGESTED READINGS

1. Leone M., Martin C. Vasopressor use in septic shock: an update. Curr Opin Anesthesiology. 2008;21:141-147.

2. Ouzounian M., Lee D.S., Liu P.P. Diastolic heart failure: mechanisms and controversies. Nat Clin Pract Cardiovasc Med. 2008;5:375-386.

3. Raja S.G., Rayen B.S. Levosimendan in cardiac surgery: best available evidence. Ann Thorac Surg. 2006;81:1536-1546.

4 Treschan T.A., Peters J. The vasopressin system. Anesthesiology. 2006;105:599-612.

5 Venkataraman R. Can we prevent acute kidney injury? Crit Care Med. 2008;36:S166-S171.

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