Sympathomimetics

All sympathomimetics are derived from β-phenylethylamine. The presence of hydroxyl groups on the 3- and 4-carbons in the benzene ring designates a compound as a catecholamine, which may be endogenous or synthetic (Fig. 3-1). The noncatecholamine sympathomimetics include a diverse range of drugs, such as the asthma medication albuterol and the central nervous system stimulant amphetamine. Two commonly used vasoactive noncatecholamine sympathomimetics are ephedrine and phenylephrine.

Figure 3.1 Classification of sympathomimetics. All sympathomimetics have a benzene ring and an ethylamine group in position 1. Catecholamines have hydroxyl substitutions in positions 3 and 4 of the benzene ring. Noncatecholamine sympathomimetics may also have substitutions in the benzene ring (e.g., phenylephrine has a single hydroxyl substitution in position 4).

α Receptors.

α₁ Receptors are widely distributed in vascular smooth muscle, particularly in the arterioles of skeletal muscle and the gastrointestinal tract. They are also present on the radial muscle of the eye, the smooth muscle of the uterus, and the sphincters of the bladder and gastrointestinal tract. Stimulation of α₁ receptors causes vasoconstriction, pupillary dilatation (mydriasis), and sphincter contraction.

Peripheral α₂ receptors are located on sympathetic nerve terminals. Stimulation of these receptors inhibits norepinephrine release and therefore causes vasodilation. Stimulation of central α₂ receptors causes sedation, analgesia, and reduced sympathetic outflow. The last effect contributes to vasodilation.

β Receptors.

β1 Receptors are present on the heart; their stimulation results in increased heart rate (chronotropy), increased conduction (dromotropy), reduced refractoriness within the atrioventricular (AV) node, and increased contractility (inotropy). The β1 receptors are also found on the juxtaglomerular cells of the kidney; their stimulation leads to increased renin release.

β₂ Receptors are found on the heart and throughout the vasculature, particularly the arterioles of skeletal muscle, the coronary circulation, and the liver. Their stimulation leads to vasodilation and enhanced diastolic relaxation (lusitropy). Outside of the cardiovascular system, β₂ receptor activation causes bronchodilation, uterine and bladder relaxation, and decreased gastrointestinal motility.

Epinephrine.

Epinephrine is a potent catecholamine with actions at both α and β receptors. At lower doses (0.01 to 0.03 μg/kg/min) β effects predominate, resulting in an increase in contractility and heart rate. Despite β₂ receptor-mediated vasodilation, a fall in blood pressure is uncommon. As the dose increases, α receptor-mediated vasoconstriction predominates, such that at higher doses (>0.05 to 0.1 μg/kg/min) vasoconstriction occurs in most vascular beds. In the acutely failing heart, epinephrine has the advantage of providing increased cardiac output while maintaining coronary perfusion pressure. Epinephrine can cause sinus tachycardia, atrial and ventricular arrhythmias, and marked metabolic disturbance, particularly hypokalemia, hyperglycemia, and lactic acidosis.

Norepinephrine.

Norepinephrine causes potent stimulation at α and β₁ receptors, but unlike epinephrine, it has minimal effect at β₂ receptors. Blood pressure is reliably increased but the effect on cardiac output is variable. Although β₁ receptor stimulation has a direct inotropic effect, in the setting of hypovolemia or impaired ventricular function, increased left ventricular afterload due to α₁ receptor stimulation can cause cardiac output to fall. Similarly, the effect on heart rate is variable: direct β₁ stimulation has a chronotropic effect but increased blood pressure can cause baroreceptor-mediated bradycardia.

Norepinephrine is useful following cardiac surgery to counter the vasodilatory effects of cardiopulmonary bypass and sedation. However, doses above 0.05 to 0.1 μg/kg/min should be avoided in patients with impaired ventricular function unless cardiac output is being measured. Norepinephrine is commonly combined with an inodilator such as dobutamine or milrinone. Norepinephrine is typically commenced at a dose of 0.01 to 0.05 μg/kg/min and titrated to blood pressure. There is no maximum dose, but infusions greater than 0.1 to 0.2 μg/kg/min are rarely needed in cardiac surgery patients except in the presence of vasoplegic syndrome (Chapter 2) or septic shock, in which case doses as high as 0.5 to 1 μg/kg/min may be required. Troublesome metabolic effects, particularly lactic acidosis, are much less common with norepinephrine than with epinephrine.²

Dopamine.

Dopamine is a precursor to norepinephrine and is itself an important neurotransmitter in the peripheral and central nervous systems. Dopamine stimulates α and β receptors and type 1 and 2 dopamine (DA) receptors. DA-1 receptors are found in the renal, mesenteric, and cerebral circulations,³ and their stimulation results in vasodilation. DA-1 receptors are also found in the renal tubule, where they mediate natriuresis. DA-2 receptors are analogous to α₂ receptors in that they are found presynaptically and inhibit the release of norepinephrine. Dopamine also has an indirect mechanism of action.

At low doses (<3 μg/kg/min), dopaminergic effects predominate. At higher doses, initially β receptor effects predominate; then α receptor effects predominate. The widely accepted dose range is 3 to 10 μg/kg/min for β effects and more than 10 μg/kg/min for α effects. However, these dose ranges must be viewed with skepticism. There is huge individual variability in the pharmacokinetics of dopamine such that dramatically different plasma concentrations may occur in different patients who are receiving the same dose.⁴ Furthermore, the clinical effects of a given plasma concentration are dependent on the functional activity of the adrenergic receptors. β Receptors are desensitized in a variety of clinical settings, including after cardiac surgery and with heart failure.^5–7 Because of its indirect action, dopamine has reduced effectiveness in patients with heart failure or shock. Despite these caveats, it is generally true that as the dose of dopamine increases, there is a progressive increase in blood pressure and heart rate.

Dopamine at a dose of 1 to 3 μg/kg/min has been termed “renal-dose dopamine” and has traditionally been used to provide selective renal vasodilation in patients at risk for renal dysfunction. However, it is now clear that although low-dose dopamine may increase blood flow to the renal cortex, blood flow to the renal medulla may actually decrease.⁸ Given the relatively hypoxic environment of the renal medulla under normal circumstances (Chapter 1), this effect is potentially harmful. Furthermore, the increase in urine output that occurs with low-dose dopamine is due primarily to a direct tubular natriuretic effect rather than to renal vasodilation. In a well-conducted, large, randomized trial, low-dose dopamine did not reduce the incidence of acute renal failure in patients with early renal dysfunction.⁹ Dopamine has a number of other potentially detrimental effects, including inhibition of hypoxic ventilatory drive, impairment of ventilation-perfusion matching in the lung, and suppression of the secretion of some anterior pituitary hormones, such as prolactin, growth hormone, and thyrotropin.⁸

Isoproterenol.

Isoproterenol is a potent β receptor agonist that has virtually no effect at α receptors. The principal actions of isoproterenol are increased contractility, increased heart rate, and vasodilation. Cardiac output is reliably increased and blood pressure typically falls. In patients with coronary artery disease, isoproterenol can precipitate myocardial ischemia. The main indication for isoproterenol is the treatment of symptomatic bradycardia or heart block, but its use is limited by the development of arrhythmias, hypotension, and metabolic disturbances. The usual dose is 0.01 to 0.05 μg/kg/min.

Dobutamine.

Dobutamine is a synthetic catecholamine with relative specificity for β₁ receptors. Although heart rate is increased, tachycardia is less pronounced than with isoproterenol. Modest β₂ receptor-mediated vasodilation may occur. Cardiac output is reliably increased, but the effect on blood pressure is unpredictable; it may increase, remain stable, or occasionally fall.

Dobutamine is useful for treating low cardiac output following cardiac surgery,¹⁰ and it may be used in combination with norepinephrine for treating septic shock.¹¹ The dose range is 1 to 10 μg/kg/min. At higher doses tachyarrhythmias become common. Metabolic side effects are minimal.

Ephedrine.

Ephedrine is a synthetic noncatecholamine sympathomimetic that has effects at both α and β receptors. It is not metabolized by COMT and therefore has a longer duration of action than the catecholamines. For the most part, ephedrine acts indirectly; thus, its efficacy is reduced in patients with shock or heart failure and after prolonged administration. Ephedrine is not suitable for continuous infusion but may be administered as an intravenous bolus of 5 to 20 mg to treat acute hypotension.

Phenylephrine.

Phenylephrine is a noncatecholamine, direct-acting α receptor agonist that does not possess any significant β receptor activity. Bolus doses of 50 to 100 μg are commonly used during induction of anesthesia in patients with aortic stenosis to counteract the vasodilation produced by anesthetic drugs. In this situation phenylephrine has the advantage of increasing coronary perfusion pressure without increasing heart rate. Cardiac output may fall due to increased afterload and baroreceptor-mediated reflex bradycardia. Phenylephrine has a slightly longer duration of action than norepinephrine. The drug may be administered as a continuous infusion at a dose of 0.1 to 1 μg/kg/min.

Milrinone.

Milrinone is a bipyridine derivative with an elimination half-time of about 2.5 hr. It is administered as a loading dose of 50 μg/kg over 30 min, followed by an infusion of 0.25 to 0.75 μg/kg/min. In patients at risk for hypotension, the loading dose should be reduced or given very slowly. Milrinone is eliminated via the kidneys, and the rate of infusion should be adjusted in patients with severe renal dysfunction so as to avoid excessive vasodilation.

Amrinone.

Amrinone was the first selective PDE-III inhibitor introduced into clinical practice. Like milrinone, it is a bipyridine derivative and is eliminated by the kidneys. Amrinone can cause thrombocytopenia, and for this reason is no longer widely used.

Enoximone.

Enoximone is an imidazolone derivative, and is metabolized primarily by the liver. It is therefore less affected by renal function than the bipyridines. The elimination half-time of enoximone is about 4 hours. Enoximone is administered as a loading dose of 0.5 to 1 mg/kg over 30 minutes, followed by an infusion of 5 to 20 μg/kg/min.

Calcium.

An intravenous bolus dose of calcium chloride of 5 mg/kg (or 0.035 mmol/kg) increases blood pressure but has little effect on myocardial contractility.¹⁵ The duration of effect following a bolus dose is 5 to 10 minutes. The pressor effect is much more pronounced in the presence of hypocalcemia. Calcium chloride does not improve outcome after cardiac arrest¹⁶ and is no longer included in routine resuscitation protocols. However, calcium is useful in the management of hyperkalemia because it reduces potassium-induced arrhythmias, and in the treatment of hypocalcemia.

Vasopressin.

Vasopressin (V; antidiuretic hormone) is a peptide hormone released from the posterior pituitary in response to an increase in serum osmolarity or hypovolemia (Chapters 1 and Chapter 32). Stimulation of V1 receptors within vascular smooth muscle results in vasoconstriction (via the IP₃/DAG second-messenger system), whereas stimulation of V2 receptors in the kidney results in water retention (via the cAMP second-messenger system). An additional action of vasopressin is to increase the release of the von Willebrand factor from the vascular endothelium, which increases platelet aggregation. The elimination half-time of vasopressin is 10 to 30 minutes.

Exogenously administered vasopressin is used to treat catecholamine-resistant vasodilatory shock. In early shock, endogenous stores of vasopressin are released from the posterior pituitary, but as shock progresses, these stores become depleted. In patients with advanced vasodilatory shock, vasopressin infusion at 4 units/hr combined with norepinephrine has been shown to be superior to norepinephrine alone in terms of hemodynamics and markers of splanchnic perfusion.¹⁷ However, higher doses of vasopressin, sufficient to replace rather than augment norepinephrine, can cause a marked reduction in cardiac output and may worsen splanchnic perfusion.¹⁸ In animal models, vasopressin is associated with relatively less vasoconstriction within the coronary, cerebral, and pulmonary circulations than is associated with catecholamines.^19,20 Despite an antidiuretic effect, in patients with vasodilatory shock urine output may actually improve with vasopressin,²¹ presumably due to an improvement in renal blood flow. As with all vasoconstrictors, precipitous reductions in cardiac output can occur with vasopressin, particularly in the settings of hypovolemia and impaired ventricular function. Current recommendations are that vasopressin, in a dose of 0.01 to 0.04 units/min, should be considered in patients with vasodilatory shock who have adequate volume resuscitation and are refractory to high doses of catecholamines.²²

Levosimendan.

Levosimendan is an inotropic drug that acts by stabilizing the interaction between calcium and tropo-nin, so-called calcium sensitization. In addition, levosimendan functions as a vasodilator, partly through PDE-III inhibition and partly by opening adenosine triphosphate gated potassium channels. Because the effect of levosimendan is not mediated by β₁ receptors or increased cAMP, it does not increase myocardial oxygen consumption and is not arrhythmogenic. Levosimendan may be a particularly useful inotropic agent in patients who are receiving β blockers. In the treatment of heart failure, levosimendan is more effective than dobutamine in improving cardiac output and, in one study, was associated with better mortality compared to dobutamine.²³

Levosimendan has an elimination half-time of 1 hour, but it has pharmacologically active metabolites with elimination half-times of up to 80 hours. The drug is usually administered as a continuous infusion of 0.1 to 0.2 μg/kg/min for 24 hours, which may be preceded by a loading dose of 12 to 24 μg/kg. Following a 24-hour infusion, a positive inotropic effect is sustained for several days. Side effects are typically modest and include mild tachycardia and hypotension. So far, levosimendan has been used primarily in patients with decompensated heart failure, but there is some limited experience in its use in patients after cardiac surgery.²⁴

Esmolol.

Esmolol is an intravenously administered, cardioselective β blocker that undergoes very rapid metabolism by plasma esterases. A single bolus dose has a peak effect within 2 to 6 minutes and a duration of effect of less than 20 minutes. The drug may be given as repeated bolus doses of 25 mg or as an intravenous infusion (25 to 300 μg/kg/min). Esmolol is useful for heart rate control of atrial fibrillation or as an adjuvant for suppressing life-threatening ventricular arrhythmias. Esmolol may be used as a “test” β blocker in patients who are at risk for bronchospasm or ventricular decompensation. Esmolol is usually ineffective in treating acute hypertension.

Labetalol.

Labetalol is an α₁ blocker and a nonselective β blocker that is formulated for intravenous and oral use. Labetalol is a useful drug for the treatment of postoperative hypertension. Intravenously, labetalol may be administered as repeated bolus doses of 5 to 10 mg. Labetalol undergoes significant hepatic metabolism and has low oral bioavailability; thus, the oral dose is much higher than the intravenous dose.

Metoprolol.

Metoprolol is a selective β blocker that is available in intravenous and oral formulations. Intravenous metoprolol is useful in the cardiothoracic ICU for treating hypertension and for acute heart rate control in patients with rapid atrial fibrillation (repeat bolus doses of 2.5 mg every few minutes). Orally, metoprolol is used in the dose range of 25 to 200 mg day, typically as a sustained-release formulation. The starting dose for patients with heart failure is 25 mg daily; the dose is gradually increased every 2 weeks.

Carvedilol.

As with labetalol, carvedilol has both α₁ receptor and nonselective β blocking properties. In addition, carvedilol has unique antiproliferative and antioxidant properties.³² Carvedilol is widely used in treating chronic heart failure and patients with impaired left ventricular function following myocardial infarction. The starting dose for patients with heart failure is 3.125 to 6.25 mg twice daily; the dose is increased every 2 weeks. The target maintenance dose is at least 25 mg twice daily.³²

Nitroglycerin.

Nitroglycerin is a very short-acting organic nitrate that is available in several formulations. As a sublingual spray or tablet, nitroglycerin is used in treating acute angina. As a transdermal patch or topical ointment, nitroglycerin is used in the prevention of angina and the treatment of congestive cardiac failure. In the ICU, nitroglycerin is typically administered as a continuous intravenous infusion for the:

The dose range is 0.25 to 5 μg/kg/min, and the clinical effect dissipates within a few minutes after the infusion is stopped. At lower doses (<2 μg/kg/min) the main effect is dilation of veins, coronary arteries, and pulmonary arterioles. Thus, low-dose nitroglycerin is useful in the treatment of myocardial ischemia, pulmonary hypertension, and congestive cardiac failure. By selectively dilating large coronary arteries, nitroglycerin, unlike sodium nitroprusside, does not cause coronary steal. At higher doses, systemic vasodilation becomes more prominent,³³ which can result in hypotension and cause paradoxical worsening of myocardial ischemia. However, in patients with severe hypertension, nitroglycerin is often ineffective in controlling blood pressure.

The production of nitric oxide by the organic nitrates requires the presence of thio- compounds within the vascular endothelium. Infusing nitroglycerin for longer than 8 hours can cause depletion of these compounds, leading to reduced clinical effect.

Other than hypotension, the side effects of nitroglycerin are minimal. Reflex tachycardia can occur but is usually slight. There may be a dose-dependent fall in arterial oxygen saturation due to inhibition of hypoxic pulmonary vasoconstriction. The nitrite metabolites of nitroglycerin can lead to methemoglobinemia but it is not usually clinically significant.

Long-acting Organic Nitrates.

Isosorbide dinitrate and its major active metabolite, isosorbide mononitrate, are orally administered organic nitrates that are available as extended-release preparations for the prevention of angina. As with nitroglycerin, tolerance rapidly develops, and a daily drug-free interval is recommended. With once-daily dosing (in the morning) of isosorbide dinitrate or isosorbide mononitrate, a 12-hour duration of effect is achieved. Nicorandil is a newer long-acting nitrate-like drug that also has potassium-channel-activating properties. It functions as a balanced venous and arteriolar vasodilator, reducing preload and afterload and improving angina. Nicorandil does not appear to be associated with significant tolerance.

Sodium Nitroprusside.

Sodium nitroprusside is a potent dilator of veins and systemic and pulmonary arterioles. It has a rapid onset of action and a very short duration of effect (1 to 2 min). Severe hypotension can occur and the drug must be carefully titrated. The main indication for nitroprusside is the rapid control of hypertension. Nitroprusside can also be used to increase cardiac output in patients with heart failure and for treating pulmonary hypertension; however, there is a substantial risk of systemic hypotension, and other drugs may be more suitable.

The starting dose of nitroprusside is 0.2 to 0.5 μg/kg/min; it can be increased to a maximum of 10 μg/kg/min. The maximum dose should not be used for more than a few minutes. In fact, if doses higher than 2 μg/kg/min are used for any length of time, cyanide toxicity can occur. The metabolism of nitroprusside results in the formation of cyanide, which then reacts with cytochrome C, inhibiting aerobic metabolism and causing lactic acidosis. Cyanide also combines with hemoglobin to form methemoglobin and with sulfur to form thiocyanate. Thiocyanate accumulation can occur following prolonged treatment in patients with renal failure; it manifests as drowsiness, disorientation, delirium, and seizures. Nitroprusside can also cause hypoxemia in patients with acute or chronic lung disease because it inhibits hypoxic pulmonary vasoconstriction. Because nitroprusside causes nonselective dilation of coronary arterioles, it has the potential to cause “coronary steal,” in which vasodilation within nonischemic myocardium diverts blood away from ischemic myocardium. Reflex tachycardia is common.

Hydralazine.

Hydralazine is an arteriolar vasodilator that is available for the acute control of hypertension. The intravenous dose is 2.5 to 10 mg, with an onset of action within 15 minutes and a duration of action of 2 to 4 hours. Reflex tachycardia is common but may be prevented by coadministration of a β blocker. Hydralazine is available for oral use but is rarely given by this route because of problems involving reflex tachycardia, sodium and water retention, metabolic variability, and immunologic reactions.

Fenoldopam.

Fenoldopam is a specific DA-1 receptor agonist that causes natriuresis and vasodilation within mesenteric, renal, coronary, and cerebral circulations. For the treatment of hypertension, doses of 0.1 to 1.6 μg/kg/min have been studied.³⁵ The initial dose should be low (0.1 to 0.2 μg/kg/min) and slowly increased, as this results in less reflex tachycardia than starting at higher doses. The clinical effect dissipates within a few minutes of stopping an infusion. Fenoldopam has an efficacy similar to that of nitroprusside in the treatment of hypertension following cardiac surgery,^36,37 but it is significantly more expensive. Fenoldopam has been investigated as a renal protective agent in cardiac surgery patients. The results of these trials have been conflicting_38,39 and, on balance, current evidence does not support the use of fenoldopam for this purpose.

Nesiritide.

Nesiritide is a synthetic analog of brain (B-type) natriuretic peptide (see Chapter 1). It acts via the cGMP second-messenger system, causing vasodilation of veins, coronary arteries and, to a lesser extent, systemic arterioles.⁴⁰ It also has a mild natriuretic effect. In the treatment of decompensated heart failure, nesiritide is more effective than nitroglycerin in reducing pulmonary capillary wedge pressure and improving dyspnea.⁴¹ Side effects are few and include mild hypotension. Nesiritide is administered as a loading dose of 2 μg/kg followed by an infusion of 0.01 μg/kg/min. Currently, there is only limited experience with nesiritide in cardiac surgery patients.⁴²

Angiotensin-converting Enzyme Inhibitors.

Angiotensinconverting enzyme (ACE) inhibitors block the angiotensin-converting enzyme and therefore inhibit the conversion of angiotensin I into angiotensin II and reduce the synthesis of aldosterone. ACE inhibitors cause arteriolar dilatation and potassium-sparing diuresis, and facilitate ventricular remodeling. ACE inhibitors also inhibit the degradation of other substances including bradykinin, substance P, and the enkephalins. This inhibition contributes to their hypotensive action and is responsible for the side effects of cough and angioedema.

ACE inhibitors are indicated for a range of cardiovascular disorders, including hypertension, coronary artery disease,^43,44 and asymptomatic⁴⁵ and symptomatic left ventricular dysfunction.^46,47 ACE inhibitors also improve survival rates in patients with risk factors for, but without documented evidence of, coronary artery disease.⁴⁴

Side effects of ACE inhibitors include hypotension (particularly with the first dose), renal impairment, and hyperkalemia. These problems are more common in elderly patients with severely impaired ventricular function and those with renal artery stenosis. Serum creatinine may increase by 10% to 15% with commencement of ACE inhibitor therapy, but with continued treatment it usually remains stable or returns to baseline. An abrupt rise in creatinine may indicate the presence of renal artery stenosis in which case the drug should be discontinued. Chronic cough occurs in 5% to 10% of patients.

ACE inhibitors are useful in treating postoperative hypertension, particularly in patients receiving ACE inhibitors preoperatively. However, this class of drug must be used very carefully in the ICU, especially in patients with preexisting renal dysfunction or perioperative hemodynamic instability. The initial dose of ACE inhibitor should be low (e.g., enalapril 1 to 2 mg/day) and only slowly increased. In patients with impaired ventricular function or renal impairment, reintroduction of ACE inhibitor therapy should be delayed for 1 to 2 days after surgery.⁴⁸ The doses of various ACE inhibitors are listed in Table 3-4.

Table 3-4 Dosages of Selected ACE Inhibitors and Angiotensin Receptor Blockers

Angiotensin Receptor Blockers.

The angiotensin receptor blockers (ARBs; see Table 3-4) have an action, therapeutic application, and side-effect profile similar to those of the ACE inhibitors, except that ARBs are not associated with angioedema and cough and are used primarily for treating hypertension. ARBs may be combined with an ACE inhibitor in patients with resistant hypertension or chronic heart failure, and they may have a specific role in the treatment of diastolic heart failure (Chapter 19).

Class I.

Class I agents (known as membrane-stabilizing drugs) block fast sodium channels responsible for phase 0 of the action potential (see Fig. 1.1). Class I agents are further subdivided on the basis of their effect on the duration of the action potential: class IA agents prolong the action potential (class III activity); class IB agents shorten the action potential; class IC agents have no effect on the duration of action potential. Class I drugs act by reducing automaticity, inhibiting retrograde conduction within reentry circuits, and prolonging the refractory period (class IA only). However, the blockade of fast sodium channels reduces the speed of conduction of the action potential, which can precipitate reentry arrhythmias. Class IA agents can also cause torsades de pointes ventricular tachycardia (see subsequent material). Thus, proarrhythmia is a significant problem with class IC agents. The class I drugs encainide and flecainide have been shown to increase mortality rates in patients after myocardial infarction.⁴⁹

Class II.

Class II agents are the β blockers. β Blockers function as antiarrhythmic drugs by blunting sympathetic tone and reducing the excitability of myocardial cells. Within pacemaker cells, β blockers reduce the slope of phase 4 of the action potential, thus decreasing the rate of firing of the sinoatrial node and increasing the conduction time (↑PR interval) and refractoriness of the AV node.

Class III.

Class III drugs block potassium channels responsible for phase 3 (repolarization) of the action potential. Thus, class III drugs prolong the action potential and increase the QT interval. Prolongation of the action potential increases myocyte refractoriness, which can interrupt reentry circuits. However, it also predisposes to early after-depolarizations (Chapter 21), which can precipitate torsades de pointes ventricular tachycardia. All class III (and class IA) drugs have the potential to cause torsades de pointes and should be avoided in patients with QT prolongation.

Class IV.

The class IV agents are the calcium channel blockers. Diltiazem and verapamil reduce the slope of phase 4 of the action potential within pacemaker tissue, causing a decrease in heart rate and an increase in the PR interval.

Amiodarone (Class III).

is a class III antiarrhythmic drug that also has class I, II, and IV activity. Acutely, amiodarone functions mainly as a b blocker. It is available in both oral and intravenous preparations. Amiodarone has proven efficacy for prophylaxis and pharmacologic cardioversion of a wide range of arrhythmias, including atrial fibrillation and life-threatening ventricular arrhythmias (see Chapter 21). Compared to other class III agents, amiodarone has a low incidence of proarrhythmia, with a rate of torsades de pointes ventricular tachycardia of less than 1%. Furthermore, amiodarone causes less hypotension than many other intravenously administered agents and can therefore be used with relative safety in patients who are inotrope-dependent or who have impaired ventricular function. Rapid intravenous administration can cause transient (but marked) hypotension; this effect is due primarily to the Tween 80 solvent. When given as a slow intravenous bolus (e.g., 300 mg over 15 to 30 min) or as a continuous infusion, amiodarone is remarkably well tolerated.

Amiodarone is highly lipid soluble with a very large steady-state volume of distribution. It is rapidly concentrated within myocardial tissue but only slowly distributed to fat. The use of the term “loading dose” with respect to amiodarone is confusing. To fully load the steady-state volume of distribution requires more than 10 g of amiodarone; an amount of drug that must be given over days to weeks to avoid plasma levels that are toxic. In the acute setting, the term “loading dose” refers to the initial volume of distribution (see Chapter 4, Pharmacokinetic Considerations, and Fig. 4-1). Once the initial volume of distribution has been loaded, a reduced dose of drug is administered, either orally or by continuous infusion, to maintain plasma levels as the drug is redistributed to peripheral compartments. Once a steady state has been achieved, a much lower maintenance dose is required. Dose regimes for intravenous and oral amiodarone are provided in Table 3-6.

Table 3-6 Dosing Schedules for Amiodarone

Acutely, amiodarone is associated with relatively few side effects. One concern is a possible relationship between amiodarone and acute respiratory distress syndrome (ARDS). This association has been observed in critically unwell patients⁵⁰ and following cardiac⁵¹ and thoracic⁵² surgery. However, these studies are retrospective and observational, and the association has not been confirmed by all investigators.⁵³ Given the clear benefits of amiodarone in cardiac surgery patients and the lack of a definitive association between it and ARDS, it is reasonable to continue to use the drug for the treatment and prevention of perioperative arrhythmias.

In contrast to acute treatment, chronic treatment with amiodarone is associated with a number of side effects (Table 3-7). Pulmonary fibrosis is a rare but potentially fatal complication that usually, but not always, resolves after discontinuation of the drug. The high iodine content of amiodarone causes thyroid dysfunction (hypo- and hyperthyroidism) in up to 10% of patients in long-term treatment. Mild hypothyroidism may be managed with thyroxine without the need to discontinue treatment.

Table 3-7 Side Effects of Chronic Amiodarone Therapy

Amiodarone interacts with many hepatically metabolized drugs and also displaces some protein-bound drugs, notably warfarin and digoxin. Amiodarone inhibits a number of subtypes of the CYP enzyme system, including 2C9 (responsible for warfarin metabolism), 2D6, and 3A. Substrate drugs for CYP2D6 and CYP3A are listed in Table 4-3. The maintenance dose of warfarin may need to be greatly reduced in patients receiving amiodarone. Amiodarone should be avoided in patients with documented hypersensitivity to iodine and in patients with prolonged QT intervals or histories of torsades de pointes ventricular tachycardia.

Sotalol (Class III).

This is a nonselective β blocker with important class III activity.⁵⁴ Higher doses are required for the class III effect than for b blockade. Sotalol is effective against a wide range of arrhythmias, including atrial fibrillation and recurrent ventricular tachycardia (Chapter 21). However, in patients with impaired ventricular function, sotalol can cause considerable hypotension, particularly when given intravenously. Proarrhythmia is a greater concern with sotalol than with amiodarone, with an incidence of torsades de pointes of about 2%. Sotalol should be avoided in a patient who has a corrected QT (QTc) interval greater than 0.45 seconds and should be discontinued if the QTc exceeds 0.55 seconds during treatment.

The intravenous dose is 1 mg/kg (not exceeding 100 mg) over 10 to 20 min. The oral dose is 80 mg twice daily, increasing to 160 mg twice daily as tolerated. Sotalol is eliminated mostly unchanged by the kidneys, and the dose should be reduced in cases of renal failure. Sotalol should be avoided in patients with asthma, severe renal impairment, marked bradycardia and heart block, and uncorrected hypokalemia or hypomagnesemia. Only the oral formulation is available in the United States.

Ibutilide (Class III).

This is a class III antiarrhythmic drug available for intravenous use.⁵⁵ It is structurally similar to sotalol but, unlike sotalol, does not usually cause hypotension in patients with impaired ventricular function. Ibutilide may be used for the pharmacologic cardioversion of atrial fibrillation, atrial flutter, and ventricular tachycardia. The use of ibutilide is limited by its relatively high incidence of torsades de pointes ventricular tachycardia. The dose (for patients >60 kg) is 1 mg over 10 minutes; if unsuccessful, the dose may be repeated 10 minutes later.^55,56

Ibutilide should be avoided in a patient with a QTc greater than 0.45 seconds and in a patient with hypokalemia or hypomagnesemia.⁵⁵ The drug should be administered under continuous ECG monitoring, and the infusion should be stopped when the patient reverts to sinus rhythm or if the QTc exceeds 0.55 seconds. ECG monitoring should continue for 4 hours following treatment.

Dofetilide (Class III).

This is an orally administered class III antiarrhythmic agent that is indicated for the pharmacologic cardioversion of atrial fibrillation and flutter. Dofetilide can be safely used in a patient with impaired ventricular function⁵⁷ but is associated with a high incidence of torsades de pointes ventricular tachycardia. The drug should be avoided in a patient with a QTc greater than 0.45 seconds. The dose is 250 to 500 μg twice daily, but this must be decreased in a patient with renal failure. Dofetilide is contraindicated in a patient with a creatinine clearance less than 20 ml/min.⁵⁶

Diltiazem (Class IV).

This is indicated for rate control of atrial fibrillation and for the pharmacologic cardioversion of AV nodal reentry tachycardia. Intravenously, diltiazem may be administered as repeated bolus doses of 10 to 20 mg or as a continuous infusion of 5 to 15 mg/hr. Orally, diltiazem may be commenced at 30 to 60 mg every 6 hours, increasing up to a maximum of 360 mg per day. Alternatively, a slow-release formulation may be used at a dose of 180 to 360 mg daily. Diltiazem has a very low rate of proarrhythmia but can cause marked bradycardia and heart block, particularly when administered with a β blocker or digoxin. Diltiazem has less effect on cardiac contractility than verapamil but must be used cautiously in patients with impaired ventricular function. Diltiazem is both a substrate and an inhibitor of the CYP3A enzyme system (see Table 4-3) and is therefore involved in important drug interactions.

Lidocaine (Class IB).

This is an intravenously administered local anesthetic drug that has been used for many years for the treatment of ventricular tachycardia. In patients with myocardial infarction, lidocaine suppresses ventricular extrasystoles but does not reduce the likelihood of developing ventricular fibrillation; therefore, lidocaine is not indicated for suppression of ectopy. For the treatment of intractable ventricular tachycardia, lidocaine is usually less effective than amiodarone (see Chapter 21).

Because of high first-pass metabolism, lidocaine must be administered intravenously. (Mexiletine is an orally administered drug with pharmacologic properties virtually identical to those of lidocaine.) The elimination half-time of lidocaine is about 4 hours, but the duration of effect following an intravenous bolus dose is only a few minutes because of redistribution. Lidocaine is usually given as a bolus dose of 1 mg/kg over 1 to 2 minutes, which may be supplemented with one or two further doses of 0.5 mg/kg separated by 15 minutes. Following this, lidocaine may be administered as an intravenous infusion at 1 to 4 mg/min, ensuring that the total dose does not exceed 300 mg in the first hour. Serum levels should be obtained after 12 to 24 hours, aiming for a concentration of 6 to 21 μmol/l, (1.5 to 5 μg/ml). High serum levels produce neurologic symptoms, which include paresthesia, dysphoria, and agitation. The infusion rate should be reduced in patients with low cardiac output (because of a reduced rate of redistribution) and in patients who develop neurologic symptoms. Although lidocaine has no sedative properties itself, it augments the sedative effect of other hypnotic drugs.

Digoxin.

This is a cardiac glycoside that is useful for rate control in patients with atrial fibrillation and as a supplementary treatment for heart failure. At therapeutic doses, digoxin has a parasympathomimetic effect, which causes increased refractoriness of the AV node and a slowing of the ventricular response rate in atrial fibrillation. However, at toxic doses digoxin has a sympathomimetic effect and causes delayed after-depolarizations; both of these effects cause arrhythmias. Many different arrhythmias are seen with digoxin toxicity. Common types include junctional tachycardia, bigeminy, and second-degree AV block. Cardiac toxicity is exacerbated by hypokalemia, hypercalcemia, and hypomagnesemia. Noncardiac signs of toxicity include nausea, vomiting, diarrhea, delirium, agitation, and visual disturbances. Serum levels of digoxin are increased in patients taking amiodarone and, to a lesser extent, diltiazem. The maintenance dose of digoxin should be halved in patients receiving amiodarone.

Digoxin may be given as a loading dose of 10 to 15 μg/kg in three divided doses 4 hours apart. A typical adult loading-dose regime involves 500 μg, then two doses of 250 μg 4 and 8 hours later. The maintenance dose is 0.125 to 0.25 mg daily. Digoxin has an oral bioavailability of 75%, so the intravenous dose should be slightly less than the oral dose. If rapid heart-rate control is required the loading dose should be given intravenously. Digoxin is excreted largely unchanged by the kidneys, and the maintenance dose should be reduced in patients with renal impairment. A digoxin level should be obtained 24 to 48 hours following a loading dose (taken 6 hours after the daily maintenance dose). The therapeutic range is 0.6 to 2 nmol/l (or 0.5 to 1.5 ng/ml), and toxicity occurs with levels above 2.6 nmol/l (2 ng/ml).

Adenosine.

This is an endogenous nucleoside that causes brief but profound inhibition of the sinoatrial and AV nodes. Adenosine is effective for the acute conversion of supraventricular AV nodal reentry tachycardia and can be used to slow down atrial flutter to confirm the diagnosis. The drug is most effective if given as a rapid intravenous bolus into a central vein. The initial dose is 6 mg which, if ineffective, may be increased to 12 then 18 mg. Adenosine can cause transient heart block (or even asystole), vasodilation, hypotension, chest pain, dyspnea, and bronchospasm. Following an intravenous bolus dose, adenosine is very rapidly cleared from plasma, resulting in a duration of effect of only a few seconds.

Propafenone.

This is a class IC agent with weak β-blocking properties that is used in the treatment of supraventricular and ventricular arrhythmias. Propafenone is associated with proarrhythmia, causing ventricular tachycardia (not torsades de pointes) in up to 5% of patients. Propafenone can also cause marked hypotension in patients with impaired ventricular function. For these reasons, propafenone is not commonly used in the ICU. Intravenously, propafenone is administered as a bolus dose of 1 to 2 mg/kg for pharmacologic cardioversion of atrial fibrillation or AV nodal reentry tachycardia. Orally, propafenone is used as second-line therapy for the maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation. The dose is 150 to 300 mg three times daily, up to 900 mg daily.

Magnesium sulfate.

This is a safe and efficacious antiarrhythmic agent that has a broad application in the cardiothoracic ICU (Chapter 21). It is useful in preventing and treating postoperative atrial and ventricular arrhythmias and is specifically indicated for torsades de pointes ventricular tachycardia (including that which is drug induced) and multifocal atrial tachycardia.

The dose of magnesium sulfate is 0.05 to 0.1 mmol/kg (or 15 to 30 mg/kg) intravenously over 10 minutes, which may be repeated after 30 minutes. Magnesium is reasonably well tolerated, even in patients with impaired ventricular function. However, rapid intravenous administration can cause hypotension and bradycardia. Magnesium is a useful pulmonary vasodilator. Extracardiac side effects include muscle weakness and prolongation of the effect of neuromuscular blocking drugs. Elimination is reduced in renal failure.

Loop Diuretics.

Loop diuretics (furosemide and bumetanide) are the most potent of the diuretics and are widely used in the treatment of pulmonary and systemic edema. Loop diuretics bind reversibly to a chloride channel receptor site in the ascending limb of the loop of Henle, inhibiting the reabsorption of filtered sodium and chloride. This reduces the hypertonicity of the renal medulla, inhibiting water reabsorption by the collecting ducts. In addition, loop diuretics increase the excretion of potassium, hydrogen ions, magnesium, and calcium.

Both furosemide and bumetanide are available in oral and intravenous preparations. Following an intravenous dose of either agent, diuresis is very rapid, beginning 15 minutes after administration and lasting up to 2 hours. Following an oral dose, diuresis begins in 30 to 60 minutes and lasts 2 to 4 hours. The oral bioavailability of furosemide is 60% and is 100% for bumetanide. Loop diuretics are effective in renal failure, but higher doses are required. However, the elimination of furosemide and, to a lesser extent, bumetanide is impaired in renal failure, increasing the risk of side effects.

The main adverse effect of loop diuretics is an excessive clinical effect: hypovolemia, hypokalemia, hypochloremic metabolic alkalosis, and hypomagnesemia. Other side effects include deafness, hyperuricemia (and gout), and allergic skin rashes. The effect of loop diuretics on serum sodium concentration is difficult to predict. The urinary sodium concentration in a patient on a furosemide infusion is typically less than 100 mmol/l; thus, acutely, hypernatremia can occur. However, if urinary losses are replaced with a low-sodium solution (e.g., intravenous 5% dextrose or oral water), hyponatremia will develop. Chronic furosemide use typically results in hyponatremia. Furosemide and, to a lesser extent, bumetanide can cause deafness. This risk is greatest in patients with renal impairment who are receiving high doses of furosemide, by either infusion or rapidly administered intravenous bolus doses. The role of loop diuretics in the treatment of systemic edema and renal failure is debatable and is discussed in Chapters 32 and Chapter 33, respectively.

Thiazide Diuretics.

Thiazides diuretics (e.g., chlorothiazide, hydrochlorothiazide, metolazone) inhibit sodium and chloride reabsorption in the distal nephron. Thiazide diuretics promote potassium and magnesium excretion but, unlike loop diuretics, inhibit calcium excretion. Thiazide diuretics are less potent than loop diuretics and are ineffective when the glomerular filtration rate falls below about 30 ml/min.⁵⁸ Thiazide diuretics are used in the treatment of hypertension and mild heart failure. All thiazide diuretics are administered orally except chlorothiazide, which is also available for intravenous use. Thiazide diuretics are formulated with other agents such as ACE inhibitors for the treatment of hypertension. In the cardiothoracic ICU, thiazides, particularly metolazone, are occasionally useful as cotreatment in patients who are refractory to loop diuretics. Metolazone has a long duration of action (12 to 24 hours) and is slightly more efficacious than other thiazide diuretics because it has an additional diuretic effect in the proximal nephron. Adverse effects of thiazides include excessive clinical effects (hypovolemia, hyponatremia, hypokalemia, hypochloremic metabolic alkalosis), hyperuricemia, hyperlipidemia, hyperglycemia, photosensitivity, and allergic skin rashes.

Potassium-sparing Diuretics.

Aldosterone antagonists (spironolactone, eplerenone) inhibit the action of aldosterone in the collecting duct; as such, these agents cause modest diuresis and natriuresis but inhibit potassium and hydrogen ion secretion. Aldosterone antagonists are most useful in conditions associated with increased aldosterone secretion, notably congestive cardiac failure and hepatic cirrhosis. Spironolactone and eplerenone have been shown to reduce mortality rates in patients with severe heart failure.^59,60 Both agents are administered orally and are suitable for once-daily dosing.

The side effects of aldosterone antagonists include hyperkalemia, hyperchloremic metabolic acidosis, gynecomastia, acute renal failure, and kidney stones. Hyperkalemia, with the potential for cardiac arrest, is the most feared complication of aldosterone antagonists. Toxicity is greatest in patients with renal impairment and those receiving ACE inhibitors or nonsteroidal antiinflammatory drugs. Following the initiation of treatment with an aldosterone antagonist, potassium supplements should be stopped and serum potassium and creatinine carefully monitored.

Amiloride is a potassium-sparing diuretic that blocks sodium reabsorption in the collecting duct. It is useful as an adjuvant to furosemide in patients with hypokalemia. It too should be avoided in cases of renal failure.

Aspirin.

Aspirin is a nonsteroidal antiinflammatory drug that irreversibly inhibits the enzyme cyclooxygenase, an essential component in the synthesis of prostaglandins and thromboxanes. Aspirin has antiinflammatory, analgesic, antipyretic, and antiplatelet effects. The antiplatelet action of aspirin occurs as a consequence of the inhibition of the synthesis of platelet thromboxane A2, which is essential for platelet aggregation. A single dose of aspirin inhibits aggregation for the lifespan of the platelet (5 to 7 days).

Low-dose aspirin (83 mg/day) is indicated in a wide range of thromboembolic conditions, including acute coronary syndromes, stable or unstable angina, ischemic neurologic events, and the implantation of bioprosthetic valves and following coronary artery bypass graft surgery. However, aspirin is a relatively weak antiplatelet agent, inhibiting only thromboxane-induced aggregation. Platelet aggregation can still be induced by other stimuli, notably thrombin. Low-dose aspirin is relatively safe and does not appear to increase postoperative bleeding, even in patients undergoing repeat sternotomy.⁶¹ Thus, in most cardiac surgical units, aspirin is continued throughout the perioperative period.

Thienopyridines: Ticlopidine and Clopidogrel.

Ticlopidine and clopidogrel are structurally related thienopyridine compounds that irreversibly inhibit adenosine-diphosphate-induced platelet aggregation. Clopidogrel has a more rapid action and a better safety profile than ticlopidine. Maximal inhibition of platelet aggregation occurs 3 to 5 days after taking a standard dose of clopridogrel (75 mg) but within 6 hours of taking a 300 mg loading dose.⁶² Platelet function takes 5 to 7 days to return to normal after the drug is withheld.

Clopidogrel improves survival in patients with unstable angina and non-ST segment myocardial infarction⁶³ and reduces myocardial infarction and other adverse outcomes in patients undergoing percutaneous coronary intervention (PCI).⁶⁴ The optimal duration of treatment has not been determined, but the major benefit occurs in the first 30 days.⁶³ Clopidogrel is also used by some surgeons following off-pump CABG surgery to improve graft patency. Patients receiving both clopidogrel and aspirin prior to CABG surgery are more likely than those treated with aspirin alone to have major bleeding that requires transfusion or reoperation.⁶² Thus, if possible, clopidogrel should be stopped at least 5 days prior to surgery.⁶⁵

Glycoprotein IIB/IIIA Receptor Blockers.

Glycoprotein IIb/IIIa receptor blockers (tirofiban, lamifiban, epifibatide, abciximab) inhibit platelet aggregation by preventing the binding of fibrinogen and the von Willebrand factor (and other adhesive molecules) to glycoprotein IIb/IIIa receptors on the surface of activated platelets. Glycoprotein IIb/IIIa receptor blockers are used in the treatment of acute coronary syndromes, particularly if PCI is undertaken (Chapter 18). All currently available agents are administered as an intravenous bolus followed by an infusion for 1 to 3 days. Inhibition of platelet aggregation occurs within 30 minutes of a bolus dose and persists for up to 12 hours following discontinuation of the infusion.

The main adverse effect of glycoprotein IIa/IIIb receptor blockers is bleeding, particularly in patients undergoing surgery. There is no reversal for these agents, and any transfused platelets are inactivated. The best strategy is to delay surgery for 8 to 12 hours following discontinuation of the infusion. Contraindications to glycoprotein IIb/IIIa receptor blockers are similar to those for fibrinolytic agents and include coagulopathy, platelet disorders, cerebrovascular disease, major surgery, and severe hypertension. Platelet count and hemoglobin should be checked prior to treatment every 6 hours after commencement of therapy, then daily.

Statins.

Hydroxy-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (commonly referred to as statins) form the mainstay of lipid-lowering treatment. Available compounds include simvastatin, atorvastatin, pravastatin, and fluvastatin. These compounds are structural analogs of HMG CoA reductase, the enzyme that controls the rate-limiting step in cholesterol synthesis. All statins have high first-pass extraction by the liver with most of the absorbed dose being excreted in the bile.

Statins are indicated primarily in the treatment of dyslipidemia, particularly in patients with coronary artery disease and after CABG surgery.⁶⁶ There is also evidence that statins have antiinflammatory effects that provide an additional benefit over and above their lipid-lowering effect.^67,68 Statins inhibit the development of inflammatory coronary artery disease following heart transplantation⁶⁹ and appear to have a protective effect in patients who develop septic shock.^70–72

The main adverse effects of statins are hepatotoxicity and myopathy. Intermittent elevations in aminotransferases occur in some patients taking statins, but severe hepatotoxicity is rare. If aminotransferase levels increase to more than three times the upper limit of normal, the drug should be stopped. Increases in serum creatine kinase without muscle pain occur in up to 10% of patients. If muscle pain does occur, creatine kinase should be measured; if levels are elevated, the drug should be stopped immediately because rhabdomyolysis can develop.

Other Lipid-lowering Drugs.

Nicotinic acid is a water-soluble vitamin (B₃) that decreases serum cholesterol and triglycerides by decreasing the synthesis of very-low-density lipoproteins. Nicotinic acid is indicated in the treatment of elevated plasma triglyceride levels. Many patients experience unpleasant flushing with nicotinic acid, which can be ameliorated by aspirin or ibuprofen. Deranged liver function tests may occur, but hepatic toxicity is rare. Acipimox is a nicotinic-acid-like lipid-lowering drug but has fewer side effects.

The fibric acid derivatives (gemfibrozil, fenofibrate, bezafibrate) are lipid-lowering agents that act by a number of mechanisms, including reduced secretion of very-low-density lipoproteins by the liver. Side effects include skin rash, gastrointestinal symptoms, myopathy, arrhythmias, hypokalemia, and deranged liver-function tests. There is an increased risk for myopathy when administered with statins; with this combination, creatine kinase and liver function should be monitored every 3 to 6 months.

Etzetimibe inhibits the gastrointestinal absorption of cholesterol from dietary and biliary sources. It has a rapid onset of action, a long duration of effect, and very few side effects.