Cardiovascular Pharmacology

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Chapter 3 Cardiovascular Pharmacology

In this chapter the pharmacology of cardiovascular drugs that are used in the intensive care unit (ICU) is reviewed. Specific indications for particular drugs are discussed in other relevant chapters. Guidelines for the reintroduction of medications following routine cardiac surgery are provided in Chapter 17.

INOTROPES AND VASOPRESSORS

Inotropes and vasopressors are some of the most widely used drugs in the ICU, and they can be broadly classified on the basis of their effects on circulation. Inotropic drugs with vasodilatory effects (e.g., isoproterenol, milrinone, levosimendan) are termed inodilators; inotropic drugs with vasoconstrictive effects (e.g., norepinephrine) are termed inoconstrictors. Some drugs are inodilators at lower doses and inoconstrictors at higher doses (e.g., dopamine, epinephrine). Other drugs are pure vasoconstrictors or vasodilators. Vasoactive drugs can also be classified on the basis of their mechanism of action, for example, as sympathomimetics, phosphodiesterase inhibitors, or calcium sensitizers.

The effect of a drug on a vascular bed depends on the activity of the drug at various receptors and the relevant receptor population in that vascular bed. However, the overall effects of a drug on blood pressure, cardiac output, and regional blood flow depend on a complex interplay of factors, of which the direct pharmacologic properties of the drug is but one. Other relevant factors include:

For these reasons it is often difficult to predict the precise effect of a particular agent on an individual patient. These concepts are discussed in greater detail in the following material.

Infusions of vasoactive drugs are prescribed in different ways in different institutions. Three common methods are micrograms per kilogram per minute (μg/kg/min), micrograms per minute (μg/min), and milligrams per hour (mg/hr). In this book μg/kg/min is used. A conversion among the methods is provided in Appendix 1.

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.

Mechanism of Action

Sympathomimetics bind to and stimulate adrenergic receptors that are located on cell membranes. In 1948, Alquist described two adrenergic receptor subtypes, alpha (α) and beta (β), based on their relative responsiveness to norepinephrine, epinephrine, and isoproterenol.1 In the 1970s this classification was refined to include α1, α2, β1, and β2 receptor subtypes. Subsequently, further divisions of each receptor subtype have been discovered, but clinically useful drugs to exploit these expanded classifications have not been developed.

Adrenergic receptors are part of a family of receptors known as G protein coupled receptors. Receptor stimulation by an agonist (see Chapter 4) facilitates the binding of the nucleotide guanosine triphosphate to a G protein, which activates it. The activated G protein then stimulates or inhibits one of a number of second messenger systems. Two second messenger systems mediate the actions of adrenergic receptors:

Vasodilation β1 Heart

β2 Veins Vasodilation    

Individual Sympathomimetics

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.57 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

Phosphodiesterase Type III Inhibitors

The phosphodiesterases (PDEs) are a family of enzymes that catalyze the breakdown of cyclic nucleotides, including cAMP and cGMP. There are multiple subtypes of PDE that have varying tissue distributions and actions.12 Caffeine and theophylline are nonspecific PDE inhibitors that are used as bronchodilators. Papaverine is a vasodilator and nonspecific PDE inhibitor that is used by cardiac surgeons during coronary artery bypass graft (CABG) surgery to prevent spasm of the internal mammary artery.

Drugs that selectively inhibit PDE subtype III function as inodilators. The commercially available PDE-III inhibitors all have a similar pharmacologic profile: they increase contractility and cause pulmonary and systemic (arteriolar and venous) vasodilation. As such, PDE-III inhibitors are useful for treating low cardiac output, particularly in the presence of pulmonary edema or pulmonary hypertension. They are potent vasodilators of coronary grafts13 and cause less tachycardia and atrial fibrillation than dobutamine.10 The inotropic effect is independent of the β1 receptor, which is advantageous in patients with β1 receptor desensitization (see earlier discussion). Also, by combining a PDE-III inhibitor with a β1 receptor agonist, a dual mechanism of action is exploited. Arteriolar and venous dilation can cause modest hypotension. This can be treated with either fluid or low-dose norepinephrine, depending on the status of the patient’s intravascular volume. In patients with cardiogenic shock, the combination of a PDE-III and norepinephrine provides support for both cardiac output and blood pressure, but without the troublesome tachycardia and metabolic disturbance that can occur with epinephrine.

PDE-III inhibitors are available as intravenous formulations for short-term use. Unlike the sympathomimetics, they have durations of action measured in hours, so their effects cannot be readily judged. Oral formulations of PDE-III inhibitors for the treatment of chronic heart failure have been studied but have resulted in higher mortality rates.14

Miscellaneous Vasoactive Drugs

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

β Blockers

β Blockers antagonize the effect of endogenous and exogenous sympathomimetics at β adrenergic receptors, thereby reducing heart rate and myocardial contractility. β Blockers can be broadly classified as nonselective (blockade of both β1 and β2 receptors) or as β1-receptor-selective. Some β blockers also have peripheral vasodilatory activity mediated by either α1 receptor blockade (e.g., carvedilol, labetalol) or β2 receptor stimulation (e.g., celiprolol).

β Blockers tend to be either lipid-soluble (e.g., metoprolol) or water-soluble (e.g., atenolol). Lipid-soluble agents typically undergo extensive hepatic metabolism and have a low oral bioavailability. Some lipid-soluble β blockers are metabolized by the cytochrome P-450 (CYP) 2D6 enzyme system, so their metabolism is susceptible to inhibition by other drugs (see Table 4-3). In contrast, water-soluble agents have high oral bioavailability and tend to be eliminated unchanged by the kidney. In patients with hepatic impairment, a water-soluble β blocker is appropriate, whereas in patients with renal impairment, a lipid-soluble β blocker may be more appropriate.

β Blockers have antihypertensive, antiarrhythmic, and antiischemic actions, and they inhibit ventricular remodeling. Treatment with β blockers is associated with reduced mortality rates in patients with coronary artery disease2528 and chronic heart failure (see Chapter 19) and in high-risk patients undergoing noncardiac surgery.29 In patients undergoing CABG surgery, preoperative treatment with β blockers is associated with reduced perioperative mortality rates.30 Acute cessation of chronic β blocker treatment can precipitate myocardial ischemia.31

In the cardiothoracic ICU, β blockers are used in the following circumstances:

The adverse effects of β blockers include bradycardia and AV block (particularly when used with digoxin, verapamil, or diltiazem); hypotension; acute ventricular decompensation; bronchospasm; and central nervous system effects such as headache and sleep disturbance. Central effects are potentially worse with lipid-soluble β blockers. Peripheral vascular effects are potentially worse with nonselective agents.

In patients with ventricular dysfunction, introduction of a β blocker may initially worsen the symptoms of heart failure. Ventricular remodeling and improved ejection fraction develop slowly over several months. Thus, β blockers should be avoided in patients who have only recently discontinued inotropic support or who are fluidoverloaded. Introduction of β blockers for the treatment of heart failure is generally not appropriate in the ICU. Characteristics of commonly used β blockers are listed in Table 3-2.

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

Nitrates

The organic nitrates (nitroglycerin, isosorbide dinitrate, isosorbide mononitrate) cause vasodilation in veins and pulmonary and systemic arterioles. Nitrates reduce preload and afterload, decrease myocardial work, and cause coronary vasodilation within large conductive arteries. The organic nitrates and sodium nitroprusside function as nitric oxide donors, which cause vasodilation via the cGMP second-messenger system.

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.

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.

Calcium Channel Blockers

Calcium channel blockers reduce the intracellular calcium concentration within vascular smooth muscle and myocytes, causing, to a variable degree, inhibition of cardiac conduction, reduced myocardial contractility, and arteriolar vasodilation. All agents are available orally. In addition, diltiazem, verapamil, nifedipine, and nicardipine are available as intravenous formulations. Some calcium antagonists undergo hepatic metabolism by the CYP3A enzyme system, and therefore their metabolism may be enhanced or inhibited by other drugs (see Table 4-3). Calcium channel blockers are widely used in treating angina, hypertension, and cardiac arrhythmias. In the ICU, calcium channel blockers are indicated for treatment of postoperative hypertension, for preventing spasm within coronary artery bypass grafts, and for treating cardiac arrhythmias.

The dihydropyridine calcium channel blockers (nifedipine, amlodipine, isradipine, felodipine) are specific arteriolar vasodilators (including potent coronary vasodilation) and have minimal effects on myocardial contractility and cardiac conduction. Intravenous nicardipine is useful in the ICU for the rapid control of hypertension. Its main disadvantage is its relatively long half-time (about 40 min), making the drug less readily able to be titrated than nitroglycerin or nitroprusside. Long-acting dihydropyridine calcium channel blockers are used primarily for treating hypertension and angina but are also used after CABG surgery to prevent spasm within arterial bypass grafts.

The main side effects of chronically administered dihydropyridine calcium channel blockers are headache and dependent (ankle) edema; reflex tachycardia can occur but is usually modest with the long-acting agents. Short-acting formulations such as the original capsule form of nifedipine cause rapid reflex adrenergic activation and are associated with increased mortality rates in patients with myocardial infarction.34 For this reason, short-acting formulations are no longer used.

Two other types of calcium channel blockers are in clinical use: verapamil, a phenylalkylamine; and diltiazem, a benzothiapine. Besides causing vasodilation, these drugs have effects on myocardial contractility and cardiac conduction. Diltiazem is discussed later under the heading Antiarrhythmic Drugs. The characteristics of selected calcium channel blockers are provided in Table 3-3.

Miscellaneous Vasodilators

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 conflicting38,39 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 and Angiotensin Receptor Blockers

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

Drug Initial Dose (mg) Maintenance Dose
ACE Inhibitors
Captopril 6.25 mg three times daily 25-50 mg three times daily
Enalapril 2.5 mg daily 10-20 mg daily or twice daily
Lisinopril 2.5 or 5 mg daily 10-40 mg daily
Quinapril 2.5 or 5 mg daily 10-40 mg daily
Perindopril 2 mg daily 4-8 mg daily
Ramipril 1.25 or 2.5 mg daily 2.5-10 mg daily
Cilazapril 0.5 mg daily 1-5 mg daily
Fosinopril 10 mg daily 20-40 mg daily
Angiotensin Receptor-Blocking Drugs
Losartan 25 or 50 mg once daily 50-100 mg daily
Candesartan 8 or 16 mg once daily 8-32 mg daily
Telmisartan 20 or 40 mg daily 80-120 mg daily

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).

Antiarrhythmic Drugs

The ideal antiarrhythmic drug for use in the ICU would have minimal myocardial depression, have a rapid onset of action when given intravenously, have a low incidence of proarrhythmia, and be effective against common postoperative arrhythmias—particularly atrial fibrillation and life-threatening ventricular tachycardia/fibrillation. The agent that most closely suits these ideals is amiodarone, and this agent is discussed in detail subsequently. Other drugs commonly used in the cardiothoracic ICU include diltiazem, digoxin, β blockers, adenosine, and the electrolytes potassium and magnesium.

Antiarrhythmic drugs may be classified on the basis of their electrophysiologic properties using the system proposed by Vaughan Williams and Brahma Singh (Table 3-5). Digoxin, adenosine, and magnesium do not fit into this classification system. The electrophysiologic basis of cardiac action potentials is described in Chapter 1, and the treatment of specific arrhythmias, in Chapter 21.

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

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

Indication Dosing Regime
Acute suppression of life-threatening arrhythmias in the ICU Option 1
  5 mg/kg IV over 30 min, followed by infusion of 1 mg/min
  Option 2
  150-300 mg over 10-30 min, followed by infusion of 2 mg/min for 4 hr, followed by infusion of 1 mg/min
Intravenous prophylaxis of atrial and ventricular arrhythmias in critically unwell patients 2 mg/min for 4 hours followed by 1 mg/min
Oral postoperative prophylaxis of atrial fibrillation 400 mg three times daily for 2 days, followed by 200 mg three times daily for 1 week, then stop
Oral loading dose with amiodarone 400 mg twice daily for 7 days, followed by
  400 mg daily for 6 weeks
Maintenance oral dose 200 mg daily

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

Atropine-resistant bradycardia or heart block
Pulmonary fibrosis
Hypo- and hyperthyroidism
Elevated hepatic transaminases
Corneal deposits causing peripheral visual halos
Photodermatitis and photosensitivity
Gray-blue skin discoloration
Tremor and ataxia
Parasthesia
Proximal myopathy

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

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).

Diuretics

Diuretic drugs cause sodium loss (natriuresis) and water loss (diuresis) by the kidney and, as such, are important in the management of hypertension and edematous states. Diuretic drugs are classified by their mechanism of action within the kidney as loop diuretics, thiazide diuretics, or potassium-sparing diuretics. Doses of commonly encountered diuretics are listed in Table 3-8.

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.

Antiplatelet Drugs

A number of antiplatelet drugs are encountered in the cardiothoracic ICU, all of which, to varying degrees, can increase bleeding. All antiplatelet drugs cause prolongation of the bleeding time but do not cause any abnormalities in routine tests of coagulation. Antiplatelet drugs vary with respect to their duration of effect (5 to 7 days for aspirin and clopidogrel; 4 to 12 hours for glycoprotein IIb/IIIa receptor antagonists), and their impact on postsurgical bleeding (minor for aspirin; intermediate for clopidogrel; high for glycoprotein IIb/IIIa receptor blockers). Recommendations for antiplatelet drugs in acute coronary syndromes are summarized in Table 18.12. Other drugs relating to bleeding and coagulation are discussed in Chapter 30.

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

Lipid-lowering Drugs

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.7072

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.

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