CPP, coronary perfusion pressure; CVR, coronary vascular resistance; DP, diastolic blood pressure; Hgb, hemoglobin; LVEDP, left ventricular end-diastolic pressure; SAT%, percent oxygen saturation.

* Affects both supply and demand.

Modified from Royster RL: Intraoperative administration of inotropes in cardiac surgery patients. J Cardiothorac Anesth 6(suppl 5):17, 1990.

Nitroglycerin

Nitroglycerin (NTG) is clinically indicated as initial therapy in nearly all types of myocardial ischemia.² Chronic exertional angina, de novo angina, unstable angina, Prinzmetal’s angina (vasospasm), and silent ischemia respond to NTG administration.²^–⁶ NTG therapy decreases the incidence of anginal attacks and improves exercise tolerance before angina symptoms.⁷ During therapy with intravenous (IV) NTG, if blood pressure (BP) declines and ischemia is not relieved, the addition of phenylephrine will allow coronary perfusion pressure (CPP) to be maintained while allowing greater doses of NTG to be used for ischemia relief.⁸ If reflex increases in heart rate (HR) and contractility occur, combination therapy with β-adrenergic blockers may be indicated to blunt this undesired increase in HR. Combination therapy with nitrates and calcium channel blockers may be an effective anti-ischemic regimen in selected patients; however, excessive hypotension and reflex tachycardia may be a problem, especially when a dihydropyridine calcium antagonist is used.⁹

Mechanism of Action

NTG enhances myocardial oxygen delivery and reduces myocardial oxygen demand. NTG is a smooth muscle relaxant that causes vasculature dilation. Nitrate-mediated vasodilation occurs with or without intact vascular endothelium.¹⁰ Nitrites, organic nitrites, nitroso compounds, and other nitrogen oxide–containing substances (e.g., nitroprusside) enter the smooth muscle cell and are converted to reactive nitric oxide (NO) or S-nitrosothiols, which stimulate guanylate cyclase metabolism to produce cyclic guanosine monophosphate (cGMP)¹¹^–¹³ (Figure 10-1). A cGMP-dependent protein kinase is stimulated with resultant protein phosphorylation in the smooth muscle. This leads to a dephosphorylation of the myosin light chain and smooth muscle relaxation.^14,¹⁵ Vasodilation is also associated with a reduction of intracellular calcium.¹⁶ Sulfhydryl (SH) groups are required for formation of NO and the stimulation of guanylate cyclase. When excessive numbers of SH groups are metabolized by prolonged exposure to NTG, vascular tolerance occurs.¹⁷ The addition of N-acetylcysteine, an SH donor, reverses NTG tolerance.¹⁸ The mechanism by which NTG compounds are uniquely better venodilators, especially at lower serum concentrations, is unknown but may be related to increased uptake of NTG by veins compared with arteries.¹⁹

Figure 10-1 Mechanisms of the effects of nitrates in the generation of nitric oxide (NO•) and the stimulation of guanylate cyclase (+) and cyclic guanosine monophosphate (cGMP), which mediates vasodilation. Sulfhydryl (SH) groups are required for the formation of NO• and the stimulation of guanylate cyclase. Isosorbide dinitrate is metabolized by the liver, whereas this route of metabolism is bypassed by the mononitrates. GTP, guanosine triphosphate.

(Redrawn from Opie LH: Drugs for the heart, 4th ed. Philadelphia: WB Saunders, 1995, p 33.)

Physiologic Effects

Two important physiologic effects of NTG are systemic and regional venous dilation (Figure 10-2). Venodilation can markedly reduce venous pressure, venous return to the heart, and cardiac filling pressures. Prominent venodilation occurs at lower doses and does not increase further as the NTG dose increases.²⁰ Venodilation results primarily in pooling of blood in the splanchnic capacitance system.²¹ Mesenteric blood volume increases as ventricular size, ventricular pressures, and intrapericardial pressure decrease.²¹

Figure 10-2 Actions of organic nitrates on the major vascular beds and relation of vasodilation to the size of the administered dose. The venous capacitance system dilates maximally with very low doses of organic nitrates. Increasing the amount of drug does not cause appreciable additional venodilation. Arterial dilation and enhanced arterial conductance begin at low doses of nitrates, with further vasodilation as the dosage is increased. With high plasma concentrations of nitrates, the arteriolar resistance vessels dilate, resulting in decreases in systemic and regional vascular resistances.

(Modified from Abrams J: Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 110(part 2):216, 1985; and Abrams J: Nitrates. In Chatterjee K, Cheitlin MD, Karliner J, et al [eds]: Cardiology: An illustrated text/reference, vol 1. Philadelphia: JB Lippincott, 1991, pp 275–290.)

NTG increases the distensibility and conductance of large arteries without changing systemic vascular resistance (SVR) at low doses.²² Improved compliance of the large arteries does not necessarily imply afterload reduction. At greater doses, NTG dilates smaller arterioles and resistance vessels, reducing afterload and BP²³ (see Figure 10-2). Reductions in cardiac dimension and pressure reduce myocardial oxygen consumption (MVO₂) and improve myocardial ischemia²⁴ (Figure 10-3). NTG may preferentially reduce cardiac preload, while maintaining systemic perfusion pressure, an important hemodynamic effect in myocardial ischemia. However, in hypovolemic states, greater doses of NTG may markedly reduce systemic BP to dangerous levels. A reflex increase in HR may occur at arterial vasodilating doses.

Figure 10-3 Effect of sublingual nitroglycerin (NG) on the left ventricular (LV) diastolic pressure-dimension relation in a patient with chronic aortic regurgitation. Dimensions (from an echocardiogram) and pressure data points were obtained in early diastole (minimal pressure) and at end-diastole (peak of QRS). After the administration of nitroglycerin, the pressure-dimension curve is shifted to the left. Triangles represent control; squares represent post-NG.

(From Smith ER, Smiseth OA, Kingma I, et al: Mechanism of action of nitrates. Role of changes in venous capacitance and in the left ventricular diastolic pressure-volume relation. Am J Med 76:14, 1984. copyright 1984 with permission from Excerpta Medical Inc.)

NTG causes vasodilation of pulmonary arteries and veins and predictably decreases right atrial (RAP), pulmonary artery (PAP), and pulmonary capillary wedge pressures (PCWP).²³ Pulmonary artery hypertension may be reduced in various disease states and in congenital heart disease with NTG.^25,²⁶ Renal arteries, cerebral arteries, and cutaneous vessels also dilate with NTG.²⁷ Blood flow to the kidney and brain may decrease if adequate renal and cerebral perfusion pressures are not maintained.

NTG has several important effects on the coronary circulation (Box 10-1). NTG is a potent epicardial coronary artery vasodilator in both normal and diseased vessels. Stenotic lesions dilate with NTG, reducing the resistance to coronary blood flow (CBF) and improving myocardial ischemia.^28,²⁹ Smaller coronary arteries may dilate relatively more than larger coronary vessels; however, the degree of dilation may depend on the baseline tone of the vessel.³⁰ NTG effectively reverses or prevents coronary artery vasospasm.³¹

BOX 10-1 Effects of Nitroglycerin and Organic Nitrates on the Coronary Circulation

(Modified from Abrams J: Hemodynamic effects of nitroglycerin and long-acting nitrates. Am HeartJ 110[pt 2]:216, 1985.)

Epicardial coronary artery dilation: small arteries dilate proportionately more than larger arteries

Increased coronary collateral vessel diameter and enhanced collateral flow

Improved subendocardial blood flow

Dilation of coronary atherosclerotic stenoses

Initial short-lived increase in coronary blood flow, later reduction in coronary blood flow as MVO₂ decreases

Reversal and prevention of coronary vasospasm and vasoconstriction

Total CBF may initially increase but eventually decreases with NTG despite coronary vasodilation ³² (Figure 10-4). Autoregulatory mechanisms probably result in decreases in total flow as a result of reductions in wall tension and myocardial oxygen consumption.²³ However, regional myocardial blood flow may improve by vasodilation of intercoronary collateral vessels or reduction of subendocardial compressive forces³³ (Figure 10-5). Coronary arteriographic studies in humans demonstrate that coronary collateral vessels increase in size after NTG administration.³⁴ This effect may be especially important when epicardial vessels have subtotal or total occlusive disease.³⁵ Improvement in collateral flow also may be protective in situations in which coronary artery steal may occur with other potent coronary vasodilator agents. The improvement in blood flow to the subendocardium, the most vulnerable area to the development of ischemia, is secondary to both improvement in collateral flow and reductions in left ventricular end-diastolic pressure (LVEDP), which reduce subendocardial resistance to blood flow.³⁶ With the maintenance of an adequate CPP (e.g., with administration of phenylephrine), NTG can maximize subendocardial blood flow⁸ (see Figures 10-4 and 10-5). The ratio of endocardial to epicardial blood in transmural segments is enhanced with NTG.³⁶ Inhibition of platelet aggregation also occurs with NTG; however, the clinical significance of this action is unknown.³⁷

Figure 10-4 Mean blood flow (mL/min/g) ± standard error to four transmural layers of anterior nonischemic myocardium during occlusion of the circumflex coronary artery in animals. Data are reported during control conditions, during infusion of nitroglycerin (0.015 mg/kg/min) (A), during administration of phenylephrine to increase mean arterial pressure to 153 ± 6 mm Hg (B), and during simultaneous administration of nitroglycerin and phenylephrine (C). Nitroglycerin decreases blood flow, and phenylephrine generally increases blood flow in normal myocardium. The combination markedly augments flow. *P < 0.05 in comparison with control measurements. Light circles represent control; dark circles represent nitroglycerin; triangles represent phenylephrine; squares represent nitroglycerin + phenylephrine.

(From Bache RJ: Effect of nitroglycerin and arterial hypertension on myocardial blood flow following acute coronary artery occlusion in the dog. Circulation 57:557, 1978. copyright 1978 American Heart Association.)

Figure 10-5 Mean blood flow (mL/min/g) ± standard error to four transmural layers of the central ischemic zone during occlusion of the circumflex coronary artery in animals. Data are reported during control conditions, during infusion of nitroglycerin (0.015 mg/kg/min) (A), during administration of phenylephrine to increase mean arterial pressure to 153 ± 6 mm Hg (B), and during simultaneous administration of nitroglycerin and phenylephrine (C). Coronary blood flow to all layers of ischemic myocardium is enhanced with the combination. *P < 0.05 in comparison with control measurements. Light circles represent control; dark circles represent nitroglycerin; triangles represent phenylephrine; squares represent nitroglycerin + phenylephrine.

Pharmacology

Organic nitrates are biotransformed by reduction hydrolysis catalyzed by the hepatic enzyme glutathione-organic nitrate reductase.¹⁵ The rate of hepatic denitrification is characteristic of each nitrate and is further dependent on hepatic blood flow or presence of hepatic disease.¹⁵ Common organic nitrates for clinical use are shown in Table 10-2.

TABLE 10-2 Nitroglycerin and Nitrates in Angina

Sublingual Nitroglycerin

Sublingual NTG (0.15- to 0.6-mg tablets) achieves blood levels adequate to cause hemodynamic changes within several minutes; physiologic effects last 30 to 45 minutes.³⁸ Sublingual bioavailability is approximately 80% and bypasses the high first-pass biodegradation in the liver (90%) by nitrate reductase to glycerol dinitrate and nitrite, which are excreted renally. Plasma half-life of sublingual NTG is 4 to 7 minutes. NTG spray has pharmacokinetics and pharmacodynamics equivalent to those of a 0.4-mg sublingual tablet; however, it has a longer shelf half-life compared with the tablets, which decompose in air and warm temperatures.³⁹ A tablet that adheres to the buccal area between the upper lip and teeth has rapid onset and has the advantage of longer half-life than sublingual tablets.⁴⁰ Although NTG is readily absorbed through the gastric mucosa, the high rate of liver metabolism makes oral administration highly unpredictable.

Nitroglycerin Ointment and Patches

NTG ointment (2%) is readily absorbed through the skin, with this method of administration providing longer-lasting effects.⁴¹ Adequate NTG blood levels are reached within 20 to 30 minutes, and duration of action is 4 to 6 hours.⁴¹ Ointment is administered in inches (15 mg/inch), but the surface area of application and not the amount administered determines the blood level achieved. NTG ointment is messy, requires application four times a day, and is most appropriate for nursing administration in special care units.⁴²

NTG patches contain either liquid NTG or NTG bonded to a polymer gel and slowly released to the skin through a semipermeable membrane.⁴³ The pharmacokinetics approach that of a consistent IV infusion.⁴³ Blood levels are reached within 20 to 30 minutes, and a steady state is reached within 2 hours. Blood levels may be maintained up to 24 hours and are largely determined by patch size. Patches or disks contain an NTG concentration per square centimeter, and dosages of 0.2 to 0.8 mg/hr usually are required for relief of myocardial ischemia. Although convenient for patients, tolerance may be a problem with these sustained-release preparations.⁴¹ Intermittent therapy is recommended to avoid tolerance.⁴⁴

Intravenous Nitroglycerin

NTG has been available since the early 1980s as an injectable drug with stable shelf half-life in a 400-μg/mL solution of D₅W (5% dextrose in water). Blood levels are achieved instantaneously, and arterial dilating doses with resulting hypotension may quickly occur. If the volume status of the patient is unknown, initial dosages of 5 to 10 μg/min are recommended. The dosage necessary for relieving myocardial ischemia may vary from patient to patient, but relief is usually achieved with 75 to 150 μg/min. In a clinical study of 20 patients with rest angina, a mean dosage of 72 μg/min reduced or abolished ischemic episodes in 85% of patients.⁴⁵ However, doses as high as 300 to 400 μg/min may be necessary for ischemic relief in some patients. Arterial dilation becomes clinically apparent at doses around 50 μg/min. Drug offset after discontinuation of an infusion is rapid (2 to 5 minutes). The dosage of NTG available is less when administered in plastic bags and polyvinylchloride tubing because of NTG absorption by the bag and tubing, although this is not a significant clinical problem because the drug is titrated to effect.⁴⁶

Adverse Effects

The metabolism of NTG by liver nitrate reductase produces a nitrite that oxidizes the ferrous iron of hemoglobin to the ferric form of methemoglobin. The ferric iron does not bind or release oxygen.⁴⁷ Methemoglobin is formed normally and is reduced by enzyme systems within the red blood cell.⁴⁸ Normally, methemoglobin levels do not exceed 1%, but may increase when direct oxidants are present in the serum (nitrates, sulfonamides, aniline dye derivates). Methemoglobinemia with levels up to 20% is not a clinical problem. Documented increases in methemoglobin blood levels occur with IV NTG, averaging 1.5% in one study of 50 patients receiving NTG for longer than 48 hours.⁴⁹ NTG dosages of 5 mg/kg/day orally should be avoided to prevent significant methemoglobinemia.⁵⁰ However, rare instances of smaller doses causing clinically significant problems have been reported.⁵¹ Nitrates are effective in producing methemoglobin to bind cyanide in sodium nitroprusside toxicity.

Several mechanisms of nitrate tolerance have been proposed, including a depletion of SH groups, neurohumoral activation, volume expansion, and/or downregulation of nitrate receptors.⁵²^–⁵⁷ Tolerance may occur with all forms of nitrate administration that maintain continuous blood levels of the drug.^17,⁵⁸^–⁶¹ Discontinuation of the drug after prolonged exposure may result in a rebound phenomenon, possibly resulting in coronary vasospasm and myocardial ischemia or infarction.⁶² Tolerance to NTG apparently does not occur in all patients.⁶³ If tolerance develops after prolonged exposure, physiologic responsiveness may be achieved with greater dosages of NTG, an important observation during NTG administration in cardiac surgery.⁶⁴ Intermittent dosing with a nitrate-free interval each day or night can maintain NTG responsiveness.^44,⁶⁵

NTG interferes with platelet aggregation.⁶⁶ The ability of the platelet to adhere to damaged intima is reduced.⁶⁷ Primary and secondary wave aggregation of platelets is also attenuated.⁶⁸ Previously formed platelet plugs are disaggregated.⁶⁹ A clinical study of 10 patients with coronary artery disease (CAD) demonstrated that a mean dosage of NTG (1.19 μg/kg/min) inhibited platelet aggregation by 50%, with a return to baseline platelet aggregation 15 minutes after the infusion was discontinued⁷⁰ (Figure 10-6). NO production increases cGMP, which modulates intracellular platelet calcium and reduces platelet secretion of proaggregatory factors.⁷¹ The clinical significance of these actions remains unclear. As with other potent vasodilators, NTG may increase intrapulmonary shunting of blood and reduce arterial oxygen tension.

Figure 10-6 Typical examples of aggregation responses to (top) adenosine diphosphate (ADP) and to (bottom) thrombin before, during, and after infusion of nitroglycerin (NTG) in patients with coronary artery disease. The amplitude of the curve is calibrated in ohms using a dual-channel impedance aggregometer. Nitroglycerin inhibits platelet aggregation to both reagents, and the effect is rapidly reversible after discontinuation of the drug.

(Modified from Diodati J, Theroux P, Latour JG, et al: Effects of nitroglycerin at therapeutic doses on platelet aggregation in unstable angina pectoris and acute myocardial infarction. Am J Cardiol 66:683, 1990.)

NTG may induce resistance to the anticoagulant effects of heparin.⁷² During simultaneous infusions of NTG and heparin, an increase in the NTG infusion caused the activated partial thromboplastin time to decrease.⁷³ Becker et al⁷⁴ reported NTG-induced heparin resistance at NTG infusion rates greater than 350 μg/min. The authors suggested a qualitative problem with antithrombin III (AT III) because AT III levels did not decrease. Others have suggested that NTG interferes with AT III binding to heparin by N-desulfation of the heparin molecule at the AT III binding sites.⁷⁵ N-desulfation of heparin reduces its anticoagulant activity.⁷⁶

NTG is contraindicated in patients who have used sildenafil, vardenafil, or tadalafil, or in patients who are hypotensive. These drugs for erectile dysfunction inhibit the phosphodiesterase (PDE5) that degrades cGMP, and the cGMP mediates vascular smooth muscle relaxation by NO. NTG-mediated vasodilation is markedly enhanced and prolonged, resulting in cases of profound hypotension, myocardial infarction (MI), and death.⁷⁷ Small doses of NTG have been used, but the amount of time that must elapse after a patient’s last dose of one of these medications before regular doses of nitrates may be safely administered is unclear.⁷⁸^–⁸⁰

Summary

NTG remains a first-line agent for the treatment of myocardial ischemia. Special care must be taken in patients with signs of hypovolemia or hypotension because the vasodilating effects of the drug may worsen the clinical condition. Recent ACC/AHA Guidelines address the prophylactic intraoperative use of NTG and suggest that its usefulness in preventing myocardial ischemia and cardiac morbidity in high-risk patients undergoing noncardiac surgery is unclear.⁸¹

β-Adrenergic Blockers

β-Adrenergic blockers have multiple favorable effects in treating the ischemic heart during anesthesia (Box 10-2). β-Adrenergic blockers reduce oxygen consumption by decreasing HR, BP, and myocardial contractility. HR reduction increases diastolic CBF. Increased collateral blood flow and redistribution of blood to ischemic areas may occur with β-blockers. More free fatty acids may be available for substrate consumption by the myocardium. Microcirculatory oxygen delivery improves, and oxygen dissociates more easily from hemoglobin after β-adrenergic blockade. Platelet aggregation is inhibited. β-Blockers should be started early in patients with ischemia in the absence of contraindications.¹ Many patients at high risk for perioperative cardiac morbidity should be started on β-blockers before surgery and continued for up to 30 days after surgery.⁸²^–⁸⁴ The choice of which β-blocker for any individual patient is based on clinician familiarity and desired pharmacologic profile. There is no evidence that one specific agent is superior to another; however, β-blockers without intrinsic sympathomimetic activity (ISA) are preferable when treating acute myocardial ischemia.

β-Blockers administered during MI reduce myocardial infarct size.⁸⁵ In addition, a reduction in morbidity has been shown to occur with acute IV metoprolol during MI.⁸⁵ Similar findings with reductions in mortality extending up to 3 years after MI have been shown in numerous trials with β-adrenergic blockers^86,⁸⁷ (Figure 10-7). The mechanisms for mortality reduction are unclear. In the absence of contraindications, β-blockers should be a routine part of care in patients with all forms of CAD, including unstable angina and recent MI.

Figure 10-7 Cumulative mortality curves for timolol (top), propranolol (center), and metoprolol (bottom) after myocardial infarction mortality reduction trials.

Data confirm the important role of β-blockade in treating patients after acute MI and in reducing mortality in high-risk populations. Immediate β-blockade after thrombolytic therapy in patients with acute MI significantly decreased recurrent early myocardial ischemia and reinfarction.⁸⁸ Early β-blockade is indicated in the treatment of MI⁸⁹,⁹⁰ (Box 10-3). In fact, β-blocker therapy after MI may be greatly underused in patients older than 65 years.⁹¹ Atenolol has been found to reduce ischemia and adverse outcome in patients with mildly symptomatic ischemia.⁹² Multiple studies have shown that perioperative administration of β-adrenergic blockers reduces both mortality and morbidity when given to patients at high risk for CAD who must undergo noncardiac surgery^82–84,^93,⁹⁴ (Figures 10-8 to 10-10). These data suggest that intermediate- and high-risk patients presenting for noncardiac surgery should receive perioperative β-adrenergic blockade to reduce postoperative cardiac mortality and morbidity. However, in the Perioperative Ischemic Evaluation Study (POISE) trial, the use of higher dose metoprolol started in patients on the day of noncardiac surgery was associated with increased risk for severe stroke and greater total mortality.⁹⁵ These findings have led to increased scrutiny of perioperative β-blockade usage. Recent ACC/AHA recommendations on the perioperative use of β-adrenergic blockade for noncardiac surgery are given in Box 10-4.⁸¹

BOX 10-3 ACC/AHA Guidelines for Early Use of β-Adrenoceptor Blocking Agents after Stemi

Reproduced from Antman EM, Hand M, Armstrong PW, et al: 2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction). Circulation 117:296, 2008, by permission.⁹⁰

Early Therapy

Class I *

1. Oral β-blocker therapy should be initiated in the first 24 hours for patients who do not have any of the following: 1) signs of heart failure, 2) evidence of low output state, 3) increased risk * for cardiogenic shock, or 4) other relative contraindications to β-blockade (PR interval > 0.24 sec), second- or third-degree heart block, active asthma, or reactive airway disease. (Level of Evidence: B)

2. Patients with contraindications within the first 24 hours of STEMI should be reevaluated for candidacy for β-blocker therapy as secondary prevention. (Level of Evidence: C)

3. Patients with moderate-to-severe LV failure should receive β-blocker therapy as secondary prevention with a gradual titration scheme. (Level of Evidence: B)

Class IIa:

1. It is reasonable to administer an IV β-blocker at the time of presentation to STEMI patients who are hypertensive and who do not have any of the following: 1) signs of heart failure, 2) evidence of a low output state, 3) increased risk * for cardiogenic shock, or 4) other relative contraindications to β-blockade (PR interval greater than 0.24 seconds, second- or third-degree heart block, active asthma, or reactive airway disease). (Level of Evidence: B)

Class III

1. IV β-blockers should not be administered to STEMI patients who have any of the following: 1) signs of heart failure, 2) evidence of a low output state, 3) increased risk * for cardiogenic shock, or 4) other relative contraindications to β-blockade (PR interval > 0.24 seconds, second- or third-degree heart block, active asthma, or reactive airway disease). (Level of Evidence: A)

STEMI, ST-segment elevation myocardial infarction.

^* Risk factors for cardiogenic shock (the greater the number of risk factors present, the higher the risk of developing cardiogenic shock) are age older than 70 years, systolic blood pressure less than 120 mm Hg, sinus tachycardia greater than 110 bpm or heart rate less than 60 bpm, and increased time since onset of symptoms of STEMI.

Figure 10-8 Overall survival in the 2 years after noncardiac surgery among 192 patients in the atenolol and placebo groups who survived to hospital discharge. The rate of survival at 6 months (180 days) was 100% in the atenolol group and 92% in the placebo group (P < 0.001); at 1 year (360 days), the rates were 97% and 86%, respectively (P = 0.005); and at 2 years (720 days), 90% and 79% (P = 0.019).

(From Mangano DT, Layug EL, Wallace A, Tateo I: Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 335:1713, 1996.)

Figure 10-9 Event-free survival in the 2 years after noncardiac surgery among 192 patients in the atenolol and placebo groups who survived to hospital discharge. The outcome measure combined the following events: myocardial infarction, unstable angina, the need for coronary artery bypass surgery, and congestive heart failure. The rate of event-free survival at 6 months (180 days) was 100% in the atenolol group and 88% in the placebo group (P < 0.001); at 1 year (360 days), the rates were 92% and 78%, respectively (P = 0.003); and at 2 years (720 days), 83% and 68% (P = 0.008).

(From Mangano DT, Layug EL, Wallace A, Tateo I: Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. N Engl J Med 335:1713, 1996.)

Figure 10-10 Kaplan–Meier estimates of the cumulative percentages of patients who died of cardiac causes or had a nonfatal myocardial infarction during the perioperative period and were at high risk for myocardial mortality with and without preoperative treatment of the β-adrenergic blocker bisoprolol. I bars indicate standard errors. The difference between groups was significant (P < 0.001 by the log-rank test).

(From Poldermans D, Boersma E, Bax JJ, et al: The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 341:1789, 1999. copyright ©1999 Massachusetts Medical Society. All rights reserved.)

BOX 10-4 Recommendations for Perioperative β-Blocker Therapy

Adapted from Fleisher LA, Beckman JA, Brown KA, et al: 2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 120:e169, 2009, by permission.

Class I

1. β-Blockers should be continued in patients undergoing surgery who are receiving β-blockers for treatment of conditions with American College of Cardiology (ACC)/American Heart Association Class I guideline indications for the drugs. (Level of Evidence: C)

Class IIa

1. β-Blockers titrated to heart rate and blood pressure are probably recommended for patients undergoing vascular surgery who are at high cardiac risk because of coronary artery disease or the finding of cardiac ischemia on preoperative testing. (Level of Evidence: B)

2. β-Blockers titrated to heart rate and blood pressure are reasonable for patients in whom preoperative assessment for vascular surgery identifies high cardiac risk, as defined by the presence of more than one clinical risk factor.* (Level of Evidence: C)

3. β-Blockers titrated to heart rate and blood pressure are reasonable for patients in whom preoperative assessment identifies coronary artery disease or high cardiac risk, as defined by the presence of more than one clinical risk factor,* who are undergoing intermediate-risk surgery. (Level of Evidence: B)

Class IIb

1. The usefulness of β-blockers is uncertain for patients who are undergoing either intermediate-risk procedures or vascular surgery in whom preoperative assessment identifies a single clinical risk factor in the absence of coronary artery disease.* (Level of Evidence: C)

2. The usefulness of β-blockers is uncertain in patients undergoing vascular surgery with no clinical risk factors * who are not currently taking β-blockers. (Level of Evidence: B)

Class III

1. β-Blockers should not be given to patients undergoing surgery who have absolute contraindications to β-blockade. (Level of Evidence: C)

2. Routine administration of high-dose β-blockers in the absence of dose titration is not useful and may be harmful to patients not currently taking β-blockers who are undergoing noncardiac surgery. (Level of Evidence: B)

^* Clinical risk factors include history of ischemic heart disease, history of compensated or prior heart failure, history of cerebrovascular disease, diabetes mellitus, and renal insufficiency (defined in the Revised Cardiac Risk Index as a preoperative serum creatinine concentration greater than 2 mg/dL).

β Receptor

The β receptor was conceptualized by Ahlquist,⁹⁶ who divided various physiologic effects of catecholamine stimulation into α and β responses. The β receptor has been identified biochemically as a polypeptide chain of approximately 50,000 to 60,000 kDa.⁹⁷ The receptor’s structure is common to most receptor proteins that have been identified: seven transmembrane crossings with two extramembranous terminal ends⁹⁸ (Figure 10-11). All receptors that transduce a signal through G proteins share this basic structure.⁹⁹ There are three extracellular and intracellular loops connecting the intramembranous portion of the receptor.⁹⁸ Agonist-antagonist binding occurs at the intramembranous portion, whereas the intracellular loops modulate interaction with the G-protein complex.^100,¹⁰¹ The terminal intracellular end contains amino acid residues that undergo phosphorylation, which relates to desensitization and downregulation of the receptor.¹⁰²

Figure 10-11 Human β₂-adrenergic receptor (darkened area represents the cell membrane). Depicted are two sites of extracellular N-linked glycosylation (Asn5, 16), four cysteine residues that may participate in disulfide bonds (Cys106, 184, 190, 191), an intracellular cysteine residue (Cys341) that may serve as a site of attachment for a palmitate membrane anchor, as well as multiple threonine and serine residues located in C-III and the cytoplasmic carboxyl terminus, which are potential sites of phosphorylation by protein kinase A (PKA), protein kinase C (PKC), or β-adrenergic receptor kinase (βARK).

(Reproduced from Raymond JR, Hnatowich M, Lefkowitz RJ, Caron MG: Adrenergic receptors. Models for regulation of signal transduction processes. Hypertension 15:119, 1990. copyright 1990 American Heart Association.)

Receptor stimulation activates a G protein, which stimulates adenylyl cyclase. The G-protein complex is composed of both stimulatory (G_s) and inhibitory (G_i) intermediary proteins.⁹⁹ Adenylyl cyclase converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which phosphorylates a protein kinase and produces the appropriate cellular response. A typical cascade of this sequence leading to increases in myocardial contractility from β-receptor stimulation is illustrated in Figure 10-12.

Figure 10-12 The β-receptor, G protein, adenylyl cyclase system. With β-receptor stimulation, dynamic changes occur in the G_i and G_s regulatory proteins. Ultimately, G_s stimulates adenylyl cyclase (AC) to convert adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which is metabolized by phosphodiesterase enzyme (PDE). An inactive protein kinase (PK_i) is activated (PK_a) by cAMP, which opens an energy-dependent receptor-operated calcium channel allowing calcium entry into the cell. Calcium cycling occurs with calcium actively pumped out of the cell by Ca²⁺ adenosine triphosphatase (ATPase). This calcium cycling causes a release of calcium from the sarcoplasmic reticulum (SR), allowing calcium to bind to troponin C (T) with subsequent activation of the actin-myosin complex. AMP, adenosine monophosphate.

(Modified from Royster RL: Intraoperative administration of inotropes in cardiac surgery patients. J Cardiothorac Anesth 4:17, 1990.)

β-Receptor numbers in any tissue may decrease with chronic stimulation (downregulation) or increase with chronic blockade (upregulation). The process of desensitization of the adrenergic response in chronic stimulation (i.e., congestive heart failure [CHF]) may involve downregulation of the receptors but may involve either the G-protein complex or adenylyl cyclase. Desensitization may occur quickly, whereas downregulation with actual internalization of the receptor within the cell may take days to weeks.¹⁰³ Myocardial ischemia increases β-receptor density, although it remains controversial whether this upregulation results in greater adrenergic response.¹⁰⁴ Several studies have demonstrated that high-affinity β receptors in nonischemic tissue were shifted to a low-affinity state during ischemia.^105,¹⁰⁶ Also, the levels of G_s and its activity are reduced during myocardial ischemia.¹⁰⁷ However, stimulation of these receptors with isoproterenol during ischemia does result in increases in cAMP production.^104,¹⁰⁸

There are two types of β receptors with a multitude of responses ¹⁰⁹ (Table 10-3). Both β₁– and β₂-receptor stimulation primarily involve cardiac function (Figure 10-13). Responses of isolated human atrial tissue demonstrated greater inotropic response to β₁– than to β₂-receptor stimulation.¹¹⁰ Endogenous norepinephrine produces inotropic responses in human atrial appendages and ventricular papillary muscle by β₁-receptor stimulation, whereas epinephrine produces its maximal inotropic effects on the atria by β₂-receptor stimulation and up to 50% of its maximal inotropic response in the ventricle by β₂-receptor stimulation.^111,¹¹² Sinus node, atrioventricular (AV) node, the left and right bundle branches, and the Purkinje system contain higher densities of β₂ receptors.¹¹³ Clearly, both receptor subtypes have cardiac inotropic, chronotropic, and dromotropic properties.

TABLE 10-3 Physiologic Effects of β₁– and β₂-Receptor Stimulation

Physiologic Effect	β₁ Response	β₂ Response
Cardiac
Increased heart rate	++	++
Increased contractility
Atrium	+	++
Ventricle	++	++
Increased automaticity and conduction velocity
Nodal tissue	++	++
His-Purkinje	++	++
Arterial relaxation
Coronary		++
Skeletal muscle		++
Pulmonary		+
Abdominal		+
Renal	+	+
Venous relaxation		++
Smooth muscle relaxation
Tracheal and bronchial		+
Gastrointestinal		+
Bladder		+
Uterus		+
Splenic capsule		+
Ciliary muscle		+
Metabolic
Renin release	++
Lipolysis	++	+
Insulin secretion		+
Glycogenolysis, gluconeogenesis		++
Cellular K⁺ uptake		+
Antidiuretic hormone secretion (pituitary)	+

Modified from Lefkowitz RJ, Hoffman BB, Taylor P: Neurohumoral transmission: The autonomic and somatic motor nervous systems. In Gilman AG, Rall TW, Niew AS, Taylor P (eds): Goodman and Gilman’s the pharmacological basis of therapeutics. New York: Pergamon Press, 1990, pp 84–121, by permission of McGraw-Hill Companies.

Figure 10-13 Summary of locations of β₁– and β₂-adrenoceptors in rat, guinea pig, dog, and human hearts determined by autoradiography. The β₁– and β₂-adrenoceptors are located on myocardium and specialized conducting tissue. A greater density of β₂-adrenoceptors is located on the atrioventricular node, bundle of His, and left and right bundle branches in comparison with surrounding myocardium in guinea pig. In addition, β₂-adrenoceptors are located on blood vessels, nerve tissue, epicardium, and the aortic valve. In large canine coronary arteries (0.5 to 2 mm in diameter), β₁-adrenoceptors account for 85% of the total population of β-adrenoceptors; in small arterioles (16 to 55 μm), β₂-adrenoceptors comprise 93% of the total population.

(Modified from Summers RJ, Molena-ar P, Stephenson JA: Autoradiographic localization of receptors in the cardiovascular system. Trends Pharmacol Sci 8:272, 1987; and Jones CR: New views of human cardiac β-adrenoceptors. J Mol Cell Cardiol 21:519, 1989.)

β₂-Adrenoceptors comprise 93% of the total population of β receptors in arterioles and 100% of receptors in epicardium, vena cava, aorta, and pulmonary artery.¹¹² β₂ receptors are found on the intimal surface of human internal mammary artery, but not on the saphenous vein,¹¹⁴ the two vessels most commonly used for coronary artery bypass graft surgery (CABG). β₂-Stimulation results in vascular smooth muscle relaxation and vasodilation.

β₁-Receptor stimulation increases plasma renin production and aqueous humor production. β₂-Receptor stimulation relaxes smooth muscle and produces bronchodilation and uterine relaxation. β₂-Stimulation also increases insulin secretion, glycogenolysis, and lipolysis and shifts extracellular potassium to intracellular sites.

β₃-Adrenoreceptors are found on visceral adipocytes, the gallbladder, and colon. Stimulation of β₃ receptors is thought to mediate lipolytic and thermic responses in brown and white adipose tissue.¹¹⁵

Physiologic Effects

Anti-ischemic Effects

β-Blockade on the ischemic heart may result in a favorable shift in the O₂ demand/supply ratio (see Table 10-1). The reductions in the force of contraction and HR reduce myocardial oxygen consumption and result in autoregulatory decreases in myocardial blood flow. Several studies have shown that blood flow to ischemic regions with propranolol is maintained; however, this is probably secondary to maintenance of α-vasoconstrictor tone of epicardial vessels and of a pressure gradient to the vasodilated endocardial areas of ischemia.^116,¹¹⁷ Reductions in blood flow in some patients with vasospastic angina may worsen with the administration of propranolol.¹¹⁸ Intracoronary infusion of propranolol does not worsen stenotic lesions and actually increases the luminal size of the stenosis at rest and during exercise.¹¹⁹

Antihypertensive Effects

The exact mechanisms involved in BP reduction are not clear. Both β₁– and β₂-receptor blockers inhibit myocardial contractility and reduce HR; both effects should reduce BP. No acute decrease in BP occurs during acute administration of propranolol.¹²⁰ However, chronic BP reduction has been attributed to a chronic reduction in cardiac output (CO).¹²¹ Reductions in high levels of plasma renin have been suggested as effective therapy in controlling essential hypertension.¹²² However, the relation between renin levels and hypertension is not established, and the decrease in BP in patients has no relation to the change in renin levels.^123,¹²⁴ Stimulation of prejunctional β receptors results in norepinephrine release from postganglionic sympathetic fibers and increases in vascular tone to most major organ systems.¹²⁵ Prejunctional β-blockade reduces norepinephrine release, sympathetic nerve traffic, and vascular tone.¹²⁵

Electrophysiologic Effects

Several β-blockers have potent local anesthetic activity at greater serum levels because of sodium-channel–blocking activity and result in depression of phase 0 of the cardiac action potential.¹²⁶ However, this membrane-stabilizing or quinidine-like effect is of questionable clinical relevance because it is observed at concentrations far exceeding therapeutic levels.¹²⁷ Generalized slowing of cardiac depolarization results from reducing the rate of diastolic depolarization (phase 4). Action potential duration (APD) and the QT interval may shorten with β-adrenergic blockers.¹²⁶ The ventricular fibrillation (VF) threshold is increased with β-blockers.¹²⁸ These antiarrhythmic actions of β-blockers are enhanced in settings of catecholamine excess as in pheochromocytoma, acute MI, the perioperative period, and hyperthyroidism.

Metabolic Effects

Although β₂-blockers are reported to reduce insulin release, the clinical significance of this reduction is questionable.¹²⁹ Catecholamines, however, promote glycogenolysis and mobilization of glucose in response to hypoglycemia. In the diabetic patient, nonselective β-blockade may impede this process, thereby worsening recovery from a hypoglycemic episode. Also, the usual hypoglycemic symptoms of tachycardia and anxiety may be suppressed when taking β-blockers, thus delaying detection. In fact, bradycardia and hypertension have been documented as side effects of hypoglycemia in the diabetic patient receiving propranolol because of unopposed β-receptor stimulation with catecholamine release.¹³⁰

Stimulation of β₂-receptors increases the movement of potassium into skeletal muscle cells, reduces aldosterone secretion, and increases renal potassium loss, effects resulting in reduction of serum potassium. β₂-Receptor blockers aid in the maintenance of serum potassium levels by blocking the adrenergic-stimulated movement of potassium intracellularly.¹³¹ β₂-Receptor blockers may cause mild increases in serum potassium concentration, which may be significant in patients with renal insufficiency.¹³²

Inhibition of catecholamine-stimulated lipolysis may occur with β-blockers, which reduces the availability of free fatty acids to activate contracting muscle, such as the heart.¹³³ β-Adrenergic blockers produce increases in serum triglycerides, decreases in high-density lipoprotein cholesterol, and little change in low-density lipoprotein cholesterol. A proposed mechanism is an increase in the relative ratio of α- to β-activity receptors.¹³⁴ Increases in β-receptor activity result in increases in lipoprotein lipase and triglyceride levels.¹³⁵ These effects on blood lipids are concerns for patients receiving chronic therapy. However, animal studies have shown that β-blockers actually have a retarding effect on the development of atherosclerosis.¹³⁶ β-Blockers with ISA produce the smallest changes in the lipid profile.¹³⁷

Intrinsic Sympathomimetic Activity

Several β-blockers (acebutolol, carteolol, penbutolol, pindolol) have agonist and antagonist properties, and are characterized as having ISA.¹³⁸ These agents are actually agonists that elicit a submaximal response and block the effects of endogenous catecholamines in a competitive fashion.¹³⁸ CO and HR are reduced less with ISA drugs.¹³⁹ Peripheral blood flow also is reduced less, making ISA agents attractive in patients with peripheral vascular disease.¹⁴⁰ ISA drugs also cause less bronchoconstriction and are advantageous in chronic obstructive pulmonary disease. Theoretically, differences in changes in β-receptor density should differ with ISA. The effects of ISA drugs reduce β-receptor density (similar to pure agonists), whereas non-ISA agents increase β-receptor density.¹⁴¹ Although controversial, ISA drugs appear to have a role in mortality reduction after MI, similar to non-ISA β-blockers.¹⁴²

General Pharmacology

Lipid-soluble β-blockers (propranolol, labetalol, metoprolol) are well absorbed after oral administration and attain high concentrations in the brain.¹⁴³ Lipid-soluble agents have a high incidence of central nervous system (CNS) side effects, such as depression, sleep disturbances, and impotence. First-pass hepatic metabolism after oral ingestion can be very high but varies from patient to patient and affects daily dosing schedules.¹⁴⁴ Cirrhosis, CHF, and cigarette smoking may reduce hepatic metabolism.¹⁴⁵ Lipophilic agents are highly protein bound. The hepatic metabolism of lipophilic agents is independent of protein binding, which is different from most drugs in which hepatic metabolism occurs only with the unbound drug.¹⁴⁶

Lipid-insoluble or water-soluble agents (atenolol, nadolol, acebutolol, sotalol) are less well absorbed orally but are not hepatically metabolized. These drugs are almost entirely eliminated by renal excretion and must be used with caution in renal insufficiency. The incidence of CNS side effects is low because of lipid insolubility.

Pindolol and timolol have intermediate lipid solubility properties and are metabolized partially by the liver (50%) and excreted through the kidneys (50%). Acebutolol, which is water soluble, has an active metabolite, diacetolol, which is water soluble and excreted renally.¹⁴⁷ The plasma elimination of acebutolol is more rapid than that of diacetolol. For further information on the available oral and IV β-adrenergic blockers for treatment of myocardial ischemia, see Table 10-4. Additional β-blockers with other indications, such as carvedilol (for CHF) and sotalol (for arrhythmias), are covered later in this chapter.

TABLE 10-4 Properties of β-Blockers in Clinical Use

Pharmacology of Intravenous β-Adrenergic Blockers

Propranolol

Propranolol has an equal affinity for β₁ and β₂ receptors, lacks ISA, and has no β-adrenergic receptor activity. It is the most lipid-soluble β-blocker and generally has the most CNS adverse effects. First-pass liver metabolism (90%) is very high, requiring much greater oral doses than IV doses for pharmacodynamic effect.¹⁴⁸ Although propranolol has an active metabolite (4-hydroxypropranolol), the metabolite’s half-life is much shorter and does not add to the clinical effect.¹⁴⁹ Serum half-life of the drug after IV dosing is 3 to 4 hours.¹⁵⁰

Because of the high hepatic extraction of propranolol, factors that affect hepatic blood flow markedly affect propranolol plasma levels. Because propranolol reduces hepatic blood flow, it can reduce its own metabolism, as well as the metabolism of other drugs.¹⁵¹ This must be taken into consideration during anesthetic procedures in patients with liver disease, reduced CO states, and right ventricular (RV) heart failure (HF).

Propranolol serum levels of 100 ng/mL produce a maximum β-blocking effect in relation to reducing exercise-induced tachycardia.¹⁴⁴ Propranolol still produces a 50% reduction of exercise-induced tachycardia at serum levels of 12 ng/mL.¹⁵² Reductions in HR with propranolol occur at lower serum levels than depression of myocardial contractility.¹⁵³ Accordingly, as drug levels decrease after discontinuation of therapy, reductions in the chronotropic response last much longer than reductions in inotropy.¹⁵³ This is an important concept in treating tachycardias in patients with significant ventricular dysfunction and CHF.

The usual IV dose of propranolol initially is 0.5 to 1.0 mg titrated to effect. A titrated dose resulting in maximum pharmacologic serum levels is 0.1 mg/kg. The use of continuous infusions of propranolol has been reported after noncardiac surgery in patients with cardiac disease.¹⁵⁴ A continuous infusion of 1 to 3 mg/hr can prevent tachycardia and hypertension but must be used with caution because of the potential of cumulative effects.

Metoprolol

Metoprolol was the first clinically used cardioselective β-blocker. Its affinity for β₁ receptors is 30 times greater than its affinity for β₂ receptors, as demonstrated by radioligand binding.¹⁵⁵ Metoprolol is lipid soluble, with 50% of the drug metabolized during first-pass hepatic metabolism and with only 3% excreted renally.¹⁵⁶ Protein binding is less than 10%. Metoprolol’s serum half-life is 3 to 4 hours. Because of its lipophilic properties, metoprolol has been shown in animal studies to diffuse into ischemic tissue better than atenolol, a hydrophilic β-receptor blocker.¹⁵⁵

As with any cardioselective β-blocker, greater serum levels may result in greater incidence of β₂-blocking effects. Metoprolol is administered intravenously in 1- to 2-mg doses, titrated to effect. The potency of metoprolol is approximately half that of propranolol. Maximum β-blocker effect is achieved with 0.2 mg/kg intravenously.

Esmolol

Esmolol’s chemical structure is similar to that of metoprolol and propranolol, except it has a methylester group in the para position of the phenyl ring, making it susceptible to rapid hydrolysis by red blood cell esterases (9-minute half-life).¹⁵⁷ Esmolol is not metabolized by plasma cholinesterase. Hydrolysis results in an acid metabolite and methanol with clinically insignificant levels.¹⁵⁸ Ninety percent of the drug is eliminated in the form of the acid metabolite, normally within 24 hours.¹⁵⁸ A loading dose of 500 μg/kg given intravenously followed by a 50-to 300-μg/kg/min infusion will reach steady-state concentrations within 5 minutes. Without the loading dose, steady-state concentrations are reached in 30 minutes.¹⁵⁸

Esmolol is cardioselective, blocking primarily β₁ receptors. It lacks ISA and membrane-stabilizing effects and is mildly lipid soluble. Esmolol produced significant reductions in BP, HR, and cardiac index after a loading dose of 500 μg/kg and an infusion of 300 μg/kg/min in patients with CAD, and the effects were completely reversed 30 minutes after discontinuation of the infusion.¹⁵⁹ Initial therapy during anesthesia may require significant reductions in both the loading and infusion doses.

Hypotension is a common side effect of IV esmolol. The incidence of hypotension was greater with esmolol (36%) than with propranolol (6%) at equal therapeutic end points.¹⁶⁰ The cardioselective drugs may cause more hypotension because of β₁-induced myocardial depression and the failure to block β₂ peripheral vasodilation. Esmolol appears safe in patients with bronchospastic disease. In another comparative study with propranolol, esmolol and placebo did not change airway resistance, whereas 50% of patients treated with propranolol experienced development of clinically significant bronchospasm.¹⁶¹ Phlebitis may occur at the site of IV administration after prolonged infusion.¹⁶²

Esmolol inhibits human plasma cholinesterase during in vitro studies, in which clinically insignificant prolongation of duration of succinylcholine action by esmolol was reported.¹⁶³ Digoxin levels may increase slightly with concomitant esmolol administration.¹⁶⁴ In addition, both esmolol and landiolol, a new short-acting β₁-receptor blocker, also suppress the bispectral index during general anesthesia.¹⁶⁵

Labetalol

Labetalol is an equal mixture of four stereoisomers with varying α- and β-blocking properties. Labetalol provides selective α₁-receptor blockade and nonselective β₁– and β₂-blockade. The potency of β-adrenergic blockade is 5- to 10-fold greater than α₁-adrenergic blockade.^15,¹⁶⁵ Labetalol has partial β₂-agonist effects that promote vasodilation.¹⁶⁶ Labetalol is moderately lipid soluble and is completely absorbed after oral administration.¹⁶⁷ First-pass hepatic metabolism is significant with production of inactive metabolites.¹⁶⁷ Renal excretion of the unchanged drug is minimal. Elimination half-life is approximately 6 hours.¹⁶⁷

In contrast with other β-blockers, clinically, labetalol should be considered a peripheral vasodilator that does not cause a reflex tachycardia. BP and systolic vascular resistance decrease after an IV dose.¹⁶⁸ Stroke volume (SV) and CO remain unchanged, with HR decreasing slightly.¹⁶⁹ The reduction in BP is dose related, and acutely hypertensive patients usually respond within 3 to 5 minutes after a bolus dose of 100 to 250 μg/kg.¹⁷⁰ However, the more critically ill or anesthetized patients should have their BP titrated beginning with 5- to 10-mg IV increments. Reduction in BP may last as long as 6 hours after IV dosing.

Significant Adverse Effects

CHF can be precipitated by β-adrenergic blockers, especially when other cardiac drugs with myocardial depressant properties are used, such as calcium blockers and disopyramide. β-Blockers blunt the usual reflex in sympathetic activity with these other depressant agents.¹⁷¹ Similarly, these effects are additive on the conduction system, and heart block can occur. Propranolol reduces the clearance of many drugs that depend on hepatic metabolism by reducing hepatic blood flow (e.g., lidocaine).¹⁷²

β₂-Blocker effects cause bronchospasm and peripheral vasoconstriction, which can exacerbate symptoms in patients with chronic pulmonary disease and peripheral vascular disease. Impotence is a problem in some patients. The lipophilic agents cause many CNS side effects such as depression, sleep disturbances, and fatigue. Hypoglycemia is a significant problem for patients with diabetes.

Sudden withdrawal of β-adrenergic blockers can precipitate a state of enhanced adrenergic activity, resulting in tachycardia, hypertension, arrhythmias, myocardial ischemia, and infarction.¹⁷³ Most studies indicated that this period of hypersensitivity occurs from 2 to 6 days after withdrawal of β -blockade. This corresponds to an increase in human lymphocyte β receptors during this period. Continuing β-receptor blockers before cardiac surgery results in a more stable anesthetic induction, intubation, and sternotomy sequence than performing anesthesia and surgery during a period of withdrawal hypersensitivity.^83,¹⁷⁴ Furthermore, reinstitution of small doses of β-adrenergic blockade after cardiac surgery smooths the postoperative course and reduces the incidence of tachyarrhythmias.¹⁷⁵

Summary

β-Adrenergic blockers are first-line agents in the treatment of myocardial ischemia. These agents effectively reduce myocardial work and oxygen demand. There is growing evidence that β-adrenergic–blocking agents may play a significant role in reducing perioperative cardiac morbidity and mortality in noncardiac surgery.¹⁷⁶

Calcium Channel Blockers

Calcium channel blockers reduce myocardial oxygen demands by depression of contractility, HR, and/or decreased arterial BP.¹⁷⁷ Myocardial oxygen supply may be improved by dilation of coronary and collateral vessels. Calcium channel blockers are used primarily for symptom control in patients with stable angina pectoris. In an acute ischemic situation, calcium channel blockers (verapamil and diltiazem) may be used for rate control in situations when β-blockers cannot be used. The most important effects of calcium channel blockers, however, may be the treatment of variant angina. These drugs can attenuate ergonovine-induced coronary vasoconstriction in patients with variant angina, suggesting protection via coronary dilation.¹⁷⁸ Most episodes of silent myocardial ischemia, which may account for 70% of all transient ischemic episodes, are not related to increases in myocardial oxygen demands (HR and BP) but, rather, intermittent obstruction of coronary flow likely caused by coronary vasoconstriction or spasm.¹⁷⁹ All calcium channel blockers are effective at reversing coronary spasm, reducing ischemic episodes, and reducing NTG consumption in patients with variant or Prinzmetal’s angina.¹⁸⁰ Combinations of NTG and calcium channel blockers, which also effectively relieve and possibly prevent coronary spasm, are currently rational therapy for variant angina. β-Blockers may aggravate anginal episodes in some patients with vasospastic angina and should be used with caution.¹⁸¹ Preservation of CBF with calcium channel blockers is a significant difference from the predominant β-blocker anti-ischemic effects of reducing myocardial oxygen consumption.

Calcium channel blockers have proved effective in controlled trials of stable angina.¹⁸²^–¹⁸⁵ However, rapid-acting dihydropyridines such as nifedipine may cause a reflex tachycardia, especially during initial therapy, and exacerbate anginal symptoms. Such proischemic effects probably explain why the short-acting dihydropyridine nifedipine in high doses produced adverse effects in patients with unstable angina. The introduction of long-acting dihydropyridines such as extended-release nifedipine, amlodipine, felodipine, isradipine, nicardipine, and nisoldipine has led to fewer adverse events. These agents should be used in combination with β-blockers. Some patients may have symptomatic relief improved more with calcium channel blockers than with β-blocker therapy, although currently it is difficult to predict which patients respond better by other than empiric observation.

The causes of unstable angina may involve coronary vasospasm, accelerated atherosclerotic process, or enhanced platelet aggregation with fibrin clot formation. Calcium channel blockers have favorable effects in all three of the processes and are effective in the relief of symptoms of unstable angina.¹⁸⁶ There are no significant clinical differences in the response of patients with unstable angina to β-adrenergic blockers and calcium channel blockers.¹⁸⁷

Calcium Channel

Calcium channels are functional pores in membranes through which calcium flows down an electrochemical gradient when the channels are open. Calcium channels exist in cardiac muscle, smooth muscle, and probably many other cellular membranes. These channels also are present in cellular organelle membranes such as the sarcoplasmic reticulum (SR) and mitochondria. Calcium functions as a primary generator of the cardiac action potential and an intracellular second messenger to regulate various intracellular events.¹⁸⁸

Calcium enters cellular membranes through voltage-dependent channels or receptor-operated channels. The voltage-dependent channels depend on a transmembrane potential for activation (opening). Receptor-operated channels either are linked to a voltage-dependent channel after receptor stimulation or directly allow calcium passage through cell or organelle membranes independent of transmembrane potentials.

There are three types of voltage-dependent channels: the T (transient), L (long-lasting), and N (neuronal) channels.¹⁸⁹ The T and L channels are located in cardiac and smooth muscle tissue, whereas the N channels are located only in neural tissue. The T channel is activated at low voltages (−50 mV) in cardiac tissue, plays a major role in cardiac depolarization (phase 0), and is not blocked by calcium antagonists.^190,¹⁹¹ The L channels are the classic “slow” channels, are activated at greater voltages (−30 mV), and are responsible for phase 2 of the cardiac action potential. These channels are blocked by calcium antagonists.^190,¹⁹¹

As mentioned previously, receptor-operated channels regulate calcium entry through voltage-regulated channels or through channels regulated by the receptor system per se. The β-adrenergic receptor operates an L-type voltage-dependent channel, which is activated by phosphorylation of a protein kinase by cAMP generated by the β-adrenergic receptor.¹⁹¹ β₁-Receptor stimulation activates a G protein, which causes phospholipase C to hydrolyze phosphatidylinositol diphosphate to diacylglycerol (DAG) and inositol triphosphate (IP₃).¹⁹² DAG activates protein kinase C that likely phosphorylates an L-type channel allowing calcium entry, whereas IP₃ is a second messenger that interacts with the SR and directly promotes calcium release from the SR through an intracellular calcium channel.¹⁹³ A receptor- operated channel also may increase calcium entry stimulated directly by a G protein. Both α₂-receptor and β-receptor stimulation may activate G-protein–regulated channels, which are not voltage dependent^194,¹⁹⁵ (see Chapters 7 and 9).

Calcium channel blockers interact with the L-type calcium channel and are composed of drugs from four different classes: (1) the 1,4-dihydropyridine (DHP) derivatives (nifedipine, nimodipine, nicardipine, isradipine, amlodipine, and felodipine); (2) the phenylalkyl-amines, (verapamil); (3) the benzothiazepines (diltiazem); and (4) a diarylaminopropylamine ether (bepridil).¹⁵ The L-type calcium channel has specific receptors, which bind to each of the different chemical classes of calcium channel blockers.¹⁹⁶ The binding to calcium blocker receptors by dihydropyridine derivatives (nifedipine) is voltage dependent.¹⁹⁷ Calcium channels transform from a closed resting form that can potentially open, to an activated open form, to an inactive conformation that cannot open, and finally back to the closed resting form. Nifedipine binds preferentially to the inactive receptor that has just recently undergone activation and cannot open. Nifedipine essentially acts as a plug to block the channel. Verapamil binds to the L-type channel preferentially when it is active or open.¹⁹⁸ The greater the period of activation of the channel, the more effective is the blockade (use dependent). Any repetitive activity, such as cardiac pacemaker activity, is sensitive to use-dependent agents.

Physiologic Effects

Hemodynamic Effects

Systemic hemodynamic effects of calcium channel blockers in vivo represent a complex interaction among myocardial depression, vasodilation, and reflex activation of the autonomic nervous system (Table 10-5).

TABLE 10-5 Calcium Channel Blocker Vasodilator Potency and Inotropic, Chronotropic, and Dromotropic Effects on the Heart

Nifedipine, like all dihydropyridines, is a potent arterial dilator with few venodilating effects.¹⁹⁹ Reflex activation of the sympathetic nervous system (SNS) may increase HR. The intrinsic negative inotropic effect of nifedipine is offset by potent arterial dilation, which results in decline of BP and increase in CO in patients.²⁰⁰ Dihydropyridines are excellent antihypertensive agents because of their arterial vasodilatory effects. Antianginal effects result from reduced myocardial oxygen requirements secondary to the afterload-reducing effect and to coronary vascular dilation, resulting in improved myocardial oxygen delivery.

Verapamil is a less potent arterial dilator than the dihydropyridines and results in less reflex sympathetic activation. In vivo, verapamil generally results in moderate vasodilation without significant change in HR, CO, or SV ²⁰¹ (Table 10-6). IV administration of verapamil in the catheterization laboratory causes increases in RV pressure and LVEDP, decreases in SVR, improvement in ejection fraction (EF), and little change in PAPs.²⁰² Verapamil can significantly depress myocardial function in patients with preexisting ventricular dysfunction.²⁰³

TABLE 10-6 Hemodynamic Effects of Intravenous Administration of Verapamil in 20 Patients with Coronary Artery Disease

Diltiazem is a less potent vasodilator and has fewer negative inotropic effects compared with verapamil. Studies in patients show reductions in SVR and BPs, with increases in CO, PAWP, and EF ²⁰⁴ (Figure 10-14). Diltiazem attenuates baroreflex increases in HR secondary to NTG and decreases in HR secondary to phenylephrine.²⁰⁵ Regional blood flow to the brain and kidney increases, whereas skeletal muscle flow does not change.²⁰⁶ In contrast with verapamil, diltiazem is not as likely to aggravate CHF, although it should be used carefully in these patients.²⁰⁷

Figure 10-14 Effects of intravenous diltiazem on systemic and coronary hemodynamics and left ventricular ejection fraction in patients with coronary artery disease. Ao, mean aortic pressure; CI, cardiac index; CSF, coronary sinus flow; HR, heart rate; LVEF, left ventricular ejection fraction; MVO₂, myocardial oxygen consumption; P, mean pulmonary artery pressure; PW, mean pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; R, mean right atrial pressure; SVR, systemic vascular resistance; SWI, stroke work index.

(Modified from Josephson MA, Singh BN: Use of calcium antagonists for ventricular dysfunction. Am J Cardiol 55:81B, 1985; and Abrams J: Nitrates. In Chatterjee K, Cheitlin MD, Karliner J, et al [eds]: Cardiology: An illustrated text/reference, vol 1. Philadelphia: JB Lippincott, 1991, pp 2.75–2.90.)

Coronary Blood Flow

Coronary artery dilation occurs with the calcium channel blockers with increases in total CBF (Figure 10-15). Nifedipine is the most potent coronary vasodilator, especially in epicardial vessels, which are prone to coronary vasospasm. Diltiazem is effective in blocking coronary artery vasoconstriction caused by a variety of agents, including α-agonists, serotonin, prostaglandin, and acetylcholine.^178,^208,²⁰⁹

Figure 10-15 Coronary blood flow responses to intravenous diltiazem, nifedipine, and verapamil in the conscious normal dog. In contrast with nitroglycerin and β-blockers, calcium-channel blockers increase total coronary flow. Data are mean values ± standard error (n = 4).

(Reproduced by permission of Millard RW, Grupp G, Grupp IL, et al: Chronotropic, inotropic, and vasodilator actions of diltiazem, nifedipine, and verapamil. A comparative study of physiological responses and membrane receptor activity. Circ Res 52[Suppl I]:29, 1983. Copyright 1983 American Medical Association.)

Calcium channel blockers also may dilate the coronary artery at the stenotic site, thus reducing the pressure gradient across the coronary lesion.¹⁷⁸ Diltiazem preferentially dilates coronary arteries compared with other peripheral vessels.²¹⁰ Animal studies demonstrate that nifedipine, verapamil, and diltiazem increase coronary collateral flow distal to coronary ligation in animals and improve subendocardial flow relative to subepicardial flow²¹¹^–²¹⁴ (Figure 10-16).

Figure 10-16 Ratio of subendocardial to subepicardial blood flow during resting control conditions and in the presence of proximal stenosis, which prevented arterial inflow from increasing above the preocclusion control after a 10-second coronary artery occlusion in animals. Diltiazem increased subendocardial to subepicardial blood flow ratio in the ischemic area. Values are mean ± standard error of the mean. *P < 0.05 compared with measurements during control conditions with unimpeded arterial inflow. ^†P < 0.05 compared with the control stenosis.

Electrophysiologic Effects

Calcium channel blockers exert their primary electrophysiologic effects on tissue of the conducting system that is dependent on calcium for generation of the action potential, primarily at the sinoatrial (SA) and AV nodes. They do not alter the effective refractory period (ERP) of atrial, ventricular, or His-Purkinje tissue. Diltiazem and verapamil exert these electrophysiologic effects in vivo and in vitro, whereas the electrophysiologic depression of dihydropyridines (nifedipine) is completely attenuated by reflex sympathetic activation. Nifedipine actually can enhance SA and AV node conduction, whereas verapamil and diltiazem slow conduction velocity and prolong refractoriness of nodal tissue.²¹⁵^–²¹⁷

Atherosclerosis

Calcium is involved in the generation of atherosclerotic plaque and in damaged atherosclerotic tissue (calcification).²¹⁸ Verapamil and nifedipine have been found to have antiatherogenic effects.²¹⁸ Nifedipine has been shown to retard angiographic progression of CAD in humans.²¹⁹ Diltiazem also may reduce atherosclerotic progression after heart transplantation.²²⁰ Diltiazem suppresses aortic atherosclerosis, but not that of coronary arteries, inhibits spontaneous calcinosis in hypertensive rats, and prevents vitamin D–induced calcinosis in arterial elastic tissue.²²¹^–²²³ Diltiazem also suppresses necrosis of aortic smooth muscle cells by hyperlipidemia serum²²⁴ and intimal thickening in rabbit carotid arteries.²²⁵

Platelet Aggregation

Calcium antagonists, nitrates, and β-adrenergic blockers all inhibit platelet aggregation. This could be a most important effect of all anti-ischemic drugs, especially in the treatment of chronic disease. Calcium is a mediator involved in the release of platelet aggregatory factors, such as ADP, and verapamil inhibits calcium-induced release of these factors.²²⁶ Diltiazem inhibition of platelet aggregation correlates with changes in intracellular calcium levels.²²⁷ In vivo, diltiazem inhibits platelet aggregation after 24 hours in healthy volunteers.²²⁸ Similar antiaggregatory effects of diltiazem were seen in patients with unstable angina, but no inhibitory effect of platelet aggregation was found with verapamil. Diltiazem metabolites are even more effective in inhibiting platelet aggregation than diltiazem.²²⁹

Metabolic Effects

Nifedipine may be associated with decreases in serum glucose levels in patients with diabetes, but glucose levels in healthy volunteers generally increase slightly with nifedipine and in hypertensive patients with diltiazem.^230,²³¹ Diltiazem reportedly has no effect on insulin, glucagon, growth hormone, or cortisol levels.^232,²³³ However, nifedipine apparently delays insulin release in patients with diabetes.²³³

Pharmacology

Table 10-7 illustrates pharmacokinetic parameters for the U.S. Food and Drug Administration–approved anti-ischemic calcium channel blockers.

TABLE 10-7 Properties of Calcium Antagonists in Clinical Use

Nifedipine

Nifedipine was the first dihydropyridine derivative to be used clinically. Other dihydropyridines available for clinical use include nicardipine, isradipine, amlodipine, felodipine, and nimodipine.²³⁴ In contrast with the other calcium channel blockers, nimodipine is highly lipid soluble and penetrates the blood–brain barrier. It is indicated for vascular spasm after intracerebral bleeding.

Nifedipine’s oral bioavailability is approximately 70%, with peak plasma levels occurring within 30 to 45 minutes. Protein binding is 95%, and elimination half-life is approximately 5 hours. Nifedipine is available for oral administration in capsular form. The compound degenerates in the presence of light and moisture, preventing commercially available IV preparations. Puncture of the capsule and sublingual administration provide an onset of effects in 2 to 3 minutes. Nifedipine GITS (GastroIntestinal Therapeutic System, Procardia XL), a long-acting, controlled-release delivery system, is available for single daily dosing and is now the preferred preparation. It has an onset of action of 20 minutes, with steady-state plasma levels being reached in 48 hours.

Nicardipine

Nicardipine is a dihydropyridine agent with a longer half-life than nifedipine and with vascular selectivity for coronary and cerebrovascular beds. Nicardipine may be the most potent overall relaxant of vascular smooth muscle among the dihydropyridines.²³⁵ Peak plasma levels are reached 1 hour after oral administration, with bioavailability of 35%.²³⁶ Plasma half-life is approximately 8 to 9 hours. Although the drug undergoes extensive hepatic metabolism with less than 1% of the drug excreted renally, greater renal elimination occurs in some patients.²³⁷ Plasma levels may increase in patients with renal failure; reduction of the dose is recommended in these patients.²³⁶

Nicardipine is a potent cerebrovascular vasodilator and may prevent ischemia-related neuronal necrosis in animal studies.^238,²³⁹ Marked improvements in CBF occur with nicardipine.²⁴⁰ Although coronary vasodilation is one explanation, positive inotropic effects with either PDE activity or calcium channel agonist (as well as antagonist) activity resulting in autoregulatory increases in blood flow may be an additional mechanism.²⁴¹

Verapamil

The structure of verapamil is similar to that of papaverine. Verapamil exhibits significant first-pass hepatic metabolism, with a bioavailability of only 10% to 20%.²⁴² One hepatic metabolite, norverapamil, is active and has a potency approximately 20% of that of verapamil.²⁴² Peak plasma levels are reached within 30 minutes. Bioavailability markedly increases in hepatic insufficiency, mandating reduced doses. ²⁴² IV verapamil achieves hemodynamic and dromotropic effects within minutes, peaking at 15 minutes and lasting up to 6 hours. Accumulation of the drug occurs with prolonged half-life during long-term oral administration.²⁴³

Verapamil’s metabolism is dependent on hepatic blood flow and may decrease in the presence of H₂-receptor blockers. Increased metabolism may occur when hepatic enzyme-inducible agents like phenobarbital are given concomitantly. Seventy percent of verapamil’s metabolites are recovered in the urine and 15% in feces.

Diltiazem

After oral dosing, the bioavailability of diltiazem is greater than verapamil’s, varying between 25% and 50%.²⁴⁴ Peak plasma concentration is achieved between 30 and 60 minutes, and elimination half-life is 2 to 6 hours.²⁴⁴ Protein binding is approximately 80%. As with verapamil, hepatic clearance is flow dependent and major hepatic metabolism occurs, with metabolites having 40% of the clinical activity of diltiazem.^245,²⁴⁶ Hepatic disease may require decreased dosing, whereas renal failure does not affect dosing.²⁴⁷

Significant Adverse Effects

Most significant adverse hemodynamic effects can be predicted from the calcium channel blockers’ primary effects of vasodilation, and negative inotropy, chronotropy, and dromotropy. Hypotension, HF, bradycardia and asystole, and AV nodal block have occurred with calcium channel blockers.²⁴⁸ These side effects are more likely to occur with combination therapy with β-blockers or digoxin, in the presence of hypokalemia.²⁴⁸

Verapamil increases digoxin levels, whereas diltiazem has variable effects and nifedipine no effect on digoxin levels.²⁴⁹^–²⁵¹ Cimetidine and ranitidine increase calcium blockers’ serum levels either by liver enzyme induction or reductions of hepatic blood flow.²⁵² The physiologic effects of calcium blockers may be additive to those of anesthetic agents in animal studies, but clinically significant effects are variable.^253,²⁵⁴ The cautious use of IV verapamil with a β-adrenergic receptor antagonist is necessary because of the increased risk for AV block or severe myocardial depression.

Paradoxic aggravation of myocardial ischemia may be seen with the short-acting dihydropyridines (nifedipine).²⁵⁵ This may be secondary to decreased CPP with associated hypotension, selective vasodilation in the nonischemic region (coronary steal), or increased oxygen demand as a result of reflex sympathetic stimulation and tachycardia.

Case reports of a withdrawal syndrome similar to β-blocker withdrawal have been presented. Five of 143 patients had significant ST-segment changes after diltiazem or verapamil withdrawal.²⁵⁶ MI and coronary spasm have been reported after diltiazem withdrawal.^257,²⁵⁸ One study comparing propranolol with verapamil withdrawal in patients with stable angina found that 2 of 20 patients had severe exacerbation of their angina with propranolol withdrawal, and no patients had hemodynamic or symptomatic evidence of a withdrawal phenomenon with verapamil.²⁵⁹

Summary

Calcium antagonists provide excellent symptom control in patients with unstable angina. In the absence of β-adrenergic blockade, the short-acting dihydropyridine nifedipine may increase the risk for MI or recurrent angina. When β-adrenergic blockers cannot be used, and HR slowing is indicated, verapamil and diltiazem may offer an alternative.

Drug Therapy for Systemic Hypertension

Systemic hypertension, long recognized as a leading cause of cardiovascular morbidity and mortality, accounts for enormous health-related expenditures. Nearly a fourth of the U.S. population has hypertensive vascular disease; however, 30% of these individuals are unaware of their condition, and another 30% to 50% are inadequately treated.^260,²⁶¹ On a worldwide basis, nearly 1 billion individuals are hypertensive.²⁶² Based on data from the Framingham Heart Study, normotensive patients at age 55 can expect a 90% lifetime risk for subsequent development of hypertension.²⁶³ Furthermore, hypertension management comprises the most common reason underlying adult visits to primary care physicians, and antihypertensive drugs are the most prescribed medication class.²⁶⁴

Despite the asymptomatic nature of hypertensive disease, with symptom onset delayed 20 to 30 years after development of systemic hypertension, substantial incontrovertible evidence demonstrates a direct association between systemic hypertension and increased morbidity and mortality. The World Health Organization estimates that hypertension underlies one in eight deaths worldwide, making elevated BP the third leading cause of mortality.²⁶² In fact, hypertension accounts for the single most treatable risk factor for MI, stroke, peripheral vascular disease, CHF, renal failure, and aortic dissection.²⁶⁰ In prospective randomized trials, over the course of adult lifetimes, successful treatment of hypertension has been associated with 35% to 40% reductions in the incidence of stroke, 50% reductions in CHF, and 25% reductions in MIs.^260,²⁶² Improved treatment of hypertension has been credited with the major reductions in stroke and cardiovascular mortality occurring since the 1970s in the United States.

Pathophysiologic mechanisms underlying predisposition to hypertension remain, for the most part, unclear. Undoubtedly, both genetic and environmental factors play contributory roles.²⁶⁵ Concordance for hypertension is greater between monozygotic or dizygotic twins, and even siblings within a single family, than that observed between unrelated individuals, supporting a genetic component. However, by some estimates, genetic predeterminants account for only 30% to 40% of hypertensive disease.²⁶⁵ As for environmental factors, a direct association between body mass index and hypertension has been reported, and dietary sodium intake is associated with long-term risk for development of hypertension.^266,²⁶⁷

In most cases, no single reversible mechanism underlying systemic hypertensive disease can be identified—the so-called primary or essential hypertension. In a small subset, perhaps 5% of hypertensive patients, a distinct causative factor promoting systemic hypertension is identified. The most common causative factor underlying secondary hypertension is renal insufficiency. Other less common mechanisms include pheochromocytoma, renal artery stenosis, and hypertension resulting from adrenal cortical abnormalities such as primary aldosteronism or Cushing syndrome. Diagnostic clues suggestive of secondary hypertension include hypertensive disease refractory to medical therapy, unusually abrupt onset with severe associated symptoms, or occurrence of hypertension at a particularly young age.

Definitions for hypertension are somewhat arbitrary, although derived from clinical trials suggesting systemic pressures at which the benefits of treatment outweigh the risk for adverse effects related to antihypertensive therapy. BP varies with normal distribution across the population at large, and aging is associated with progressive increases in systolic pressure. After 50 years of age, reductions in diastolic pressure are commonly observed, resulting in widening of pulse pressure with age. Published evidence suggests that systolic and pulse pressures are better predictors for morbidity and mortality than diastolic pressure.²⁶⁴ Most recently, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7 Report) defined systolic BPs (Table 10-8) exceeding 140 mm Hg and diastolic BPs exceeding 90 mm Hg as stage 1 hypertension. BPs less than 120/80 mm Hg were defined as normal, and those in between as consistent with “prehypertension.”²⁶⁰

TABLE 10-8 Classification and Management of Blood Pressure for Adults Age 18 Years or Older

Although antihypertensive drug therapy is widely regarded as essential for BPs greater than 140/90 mm Hg, recent evidence suggests benefits to more aggressive BP reduction for certain patient subsets. The association between systemic BP and cardiovascular risk has been described as a “J-curve,” with progressive cardiovascular risk reductions accompanying BP reductions until a critical threshold—after which the potential for myocardial ischemia and/or other organ injury increases.²⁶⁸

Risk for cardiovascular disease appears to increase at BPs greater than 115/75 mm Hg, with a doubling in risk associated with each 20/10-mm Hg increment in systemic pressure.²⁶⁰ Thus, the most recent JNC-7 report recommends drug therapy for “prehypertensive” disease in patients with “compelling indications” such as chronic renal disease or diabetes. Antihypertensive therapy generally is targeted to achieve systemic BPs less than 140/90 mm Hg; however, for high-risk patients such as those with diabetes, renal, or cardiovascular disease, lower BP targets are suggested, typically more than 130/80 mm Hg.²⁶⁰

Medical Treatment for Hypertension

Currently, nearly 80 distinct medications are marketed for treatment of hypertension ²⁶⁴ (Table 10-9). Often, combined therapy with two or more classes of antihypertensive medications may be needed to achieve treatment goals²⁶⁹ (Table 10-10). Although the specific drug selected for initial therapy now has been deemed less important than in the past, recognition that specific antihypertensive drug classes alleviate end-organ damage, beyond that simply associated with reductions in systemic BP, has led to targeted selection of antihypertensive drug combinations on the basis of coexisting risk factors such as recent MI, chronic renal insufficiency, or diabetes.

TABLE 10-9 Oral Antihypertensive Drugs

TABLE 10-10 Combination Drugs for Hypertension

Combination Type	Fixed-Dose Combination, mg*	Trade Name
ACEIs and CCBs	Amlodipine-benazepril hydrochloride (2.5/10, 5/10, 5/20, 10/20)	Lotrel
	Enalapril-felodipine (5/5)	Lexxel
	Trandolapril-verapamil (2/180, 1/240, 2/240, 4/240)	Tarka
ACEIs and diuretics	Benazepril-hydrochlorothiazide (5/6.25, 10/12.5, 20/12.5, 20/25)	Lotensin HCT
	Captopril-hydrochlorothiazide (25/15, 25/25, 50/15, 50/25)	Capozide
	Enalapril-hydrochlorothiazide (5/12.5, 10/25)	Vaseretic
	Fosinopril-hydrochlorothiazide (10/12.5, 20/12.5)	Monopril/HCT
	Lisinopril-hydrochlorothiazide (10/12.5, 20/12.5, 20/25)	Prinzide, Zestoretic
	Moexipril-hydrochlorothiazide (7.5/12.5, 15/25)	Uniretic
	Quinapril-hydrochlorothiazide (10/12.5, 20/12.5, 20/25)	Accuretic
ARBs and diuretics	Candesartan-hydrochlorothiazide (16/12.5, 32/12.5)	Atacand HCT
	Eprosartan-hydrochlorothiazide (600/12.5, 600/25)	Teveten-HCT
	Irbesartan-hydrochlorothiazide (150/12.5, 300/12.5)	Avalide
	Losartan-hydrochlorothiazide (50/12.5, 100/25)	Hyzaar
	Olmesartan medoxomil-hydrochlorothiazide (20/12.5, 40/12.5, 40/25)	Benicar HCT
	Telmisartan-hydrochlorothiazide (40/12.5, 80/12.5)	Micardis-HCT
	Valsartan-hydrochlorothiazide (80/12.5, 160/12.5, 160/25)	Diovan-HCT
BBs and diuretics	Atenolol-chlorthalidone (50/25, 100/25)	Tenoretic
	Bisoprolol-hydrochlorothiazide (2.5/6.25, 5/6.25, 10/6.25)	Ziac
	Metoprolol-hydrochlorothiazide (50/25, 100/25)	Lopressor HCT
	Nadolol-bendroflumethiazide (40/5, 80/5)	Corzide
	Propranolol LA-hydrochlorothiazide (40/25, 80/25)	Inderide LA
	Timolol-hydrochlorothiazide (10/25)	Timolide
Centrally acting drug and diuretic	Methyldopa-hydrochlorothiazide (250/15, 250/25, 500/30, 500/50)	Aldoril
	Reserpine-chlorthalidone (0.125/25, 0.25/50)	Demi-Regroton, Regroton
	Reserpine-chlorothiazide (0.125/250, 0.25/500)	Diupres
	Reserpine-hydrochlorothiazide (0.125/25, 0.125/50)	Hydropres
Diuretic and diuretic	Amiloride-hydrochlorothiazide (5/50)	Moduretic
	Spironolactone-hydrochlorothiazide (25/25, 50/50)	Aldactazide
	Triamterene-hydrochlorothiazide (37.5/25, 75/50)	Dyazide, Maxzide

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; BB, β-blocker; CCB, calcium channel blocker.

* Some drug combinations are available in multiple fixed doses. Each drug dose is reported in milligrams.

Reproduced from Chobanian AV, Bakris GL, Black HR, et al: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42:1206–1252, 2003, by permission.

Diuretics

Thiazide diuretic therapy comprises the cornerstone of most antihypertensive regimens.^270,²⁷¹ Three classes of diuretics have proved efficacious in reducing systemic BP—the thiazide and related sulfonamide compounds, loop diuretics, and potassium-sparing agents. All classes of diuretics initially reduce BP by increasing urinary excretion of sodium, with resultant reductions in plasma volume and CO; however, over a period of 6 to 8 weeks, diuretic therapy leads to reductions in SVR—hypothesized to relate to activation of vascular endothelial potassium channels.

Thiazide diuretics remain the first-choice medical therapy for the majority of patients with hypertension.²⁷² Although the natriuretic effect achieved by blockade of sodium and chloride transport in the distal convoluted tubule is relatively weak, thiazide diuretics generally produce 10-mm Hg reductions in BP and have proved efficacious in numerous randomized trials to reduce morbidity and mortality related to hypertensive vascular disease.^264,²⁶⁹

Loop diuretics, the most potent natriuretics of this class, block sodium, potassium, and chloride transport in the thick ascending loop of Henle. The loop diuretics typically are reserved for patients with renal insufficiency (serum creatinine > 2 mg/dL or creatinine clearance < 25 mL/min) or CHF, conditions for which thiazide diuretics are relatively ineffective. The short duration of action of loop diuretics (e.g., furosemide: 4 to 6 hours) and greater likelihood for adverse effects limit more widespread application.

Potassium-sparing and aldosterone-receptor–blocking diuretics are among the weakest natriuretics of this class. These drugs act by a variety of mechanisms to inhibit sodium reabsorption from the distal collecting duct while simultaneously reducing urinary potassium excretion. These drugs are most commonly administered in combination with a thiazide diuretic in an effort to reduce the incidence of hypokalemia or for their salutary effects in chronic HF.

Low doses of diuretic are well tolerated; however, common adverse effects related to this drug class include hypokalemia (secondary to renal potassium wasting), impaired glucose tolerance and insulin resistance, hyperuricemia, hypercalcemia, hyperlipidemia, and, rarely, hyponatremia. The potassium-sparing and aldosterone-receptor–blocking drugs are contraindicated in patients at risk for hyperkalemia, in particular, patients with renal insufficiency.

β-Blockers

β-Adrenergic receptor blockers, which reduce sympathetic stimulation of the heart and vasculature, comprise another common antihypertensive therapy, particularly in settings of CAD or CHF.²⁷³^–²⁷⁷ More specifically, β-blockers inhibit myocardial and peripheral β₁-adrenergic receptors to reduce CO. As well, β-blockers reduce renin release from renal juxtaglomerular cells and norepinephrine release by inhibition of prejunctional β₂-adrenergic receptors in the peripheral vasculature. β-Blockers traditionally are classified on the basis of cardioselectivity, lipid solubility, and intrinsic sympathetic activity, with first-generation agents such as propranolol nonselectively blocking both β₁– and β₂-adrenergic receptors. Second-generation agents (e.g., metoprolol or atenolol) exhibit a relatively cardioselective preference for β₁-adrenergic receptor blockade at low doses. Pindolol, a novel β-blocker with ISA, stimulates vasodilation by activation of β₂-adrenergic receptors. Combination agents, such as labetalol, provide mixed β- and α₁-adrenergic blocking properties resulting in inhibition of sympathetic activity, as well as direct vasodilatory effects.

As with the diuretics, β-blockers typically are well tolerated at low doses; however, the potential for nonselective blockade of β-adrenergic receptors may result in bronchospasm, Raynaud’s phenomenon, depression, and HF or heart block. β-Blockers are relatively contraindicated in patients with asthma or reactive airways disease, heart block, or depression. Rapid withdrawal of β-blockers may be associated with rebound adrenergic stimulation and potential for exacerbating myocardial and/or peripheral vascular ischemia; therefore, β-blocker discontinuation must occur by gradual stepped reductions in dose.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors reduce peripheral vascular resistance by inhibiting conversion of angiotensin I (Ang I) to the highly vasoconstrictive angiotensin II (Ang II).²⁷⁸ Recent evidence suggests that much of the long-term antihypertensive effect of ACE inhibitors derives from protective effects on bradykinin de-gradation. Bradykinin, a potent vasodilator under normal conditions, undergoes degradation by the action of ACE. Therefore, ACE inhibition results in increased plasma and tissue concentrations of bradykinin.

Persistent dry cough accounts for the most common adverse effect associated with ACE inhibitor administration. Attributed to increased concentrations of bradykinin, this side effect frequently leads to discontinuation of ACE inhibitor therapy. Much rarer, although substantially more serious, is the potential for angioedema, again attributable to increased bradykinin concentrations. Angioedema may occur at any time during therapy, occurs most frequently in African Americans, and may prove fatal because of airway compromise. Increased potential for hyperkalemia occurs in patients with renal insufficiency and those receiving potassium supplements or potassium-sparing diuretics. ACE inhibitors have been reported to induce renal failure in patients with bilateral renal artery stenosis and may potentiate severe intractable hypotension in patients with particularly elevated renin activity (e.g., decompensated HF or intravascular volume depletion). Finally, ACE inhibitors pose a teratogenic risk and are therefore contraindicated in pregnancy.

Adverse effects associated with α₁-blockers include orthostatic hypotension, fluid retention, and reflex tachycardia.²⁸⁴ Although rarely administered as monotherapy, α₁-blockers continue to prove useful in combination with other antihypertensives because of their lack of metabolic side effects and propensity to dilate urethral smooth muscle, alleviating symptoms of prostatism.²⁶⁴

Central α₂-Agonists and Other Centrally Acting Drugs

Centrally acting antihypertensive agents, such as clonidine and methyldopa, stimulate α₂-adrenergic and imidazoline receptors within the CNS to reduce sympathetic outflow and SVR. In the case of clonidine, activation of presynaptic α-adrenergic receptors inhibits norepinephrine release and subsequent catecholamine generation.²⁸⁵ Reserpine differs from the α₂-agonists in that it inhibits reuptake of norepinephrine by storage vesicles in the postganglionic adrenergic neurons, depleting norepinephrine. As opposed to the α₂-agonists, reserpine’s peripheral effects predominate over central activity.

More widespread use of centrally acting antihypertensives has been limited by CNS-mediated adverse effects including sedation, depression, and dry mouth. In addition, autoimmune hemolytic anemia has been reported with methyldopa. Despite these limitations, however, pregnancy-induced hypertension remains a common indication for this agent because long-term use has indicated no adverse effects toward the fetus. Abrupt discontinuation of clonidine frequently results in rebound hypertension, but this effect may be alleviated with transdermal clonidine patches or the longer-acting oral agent guanfacine. All centrally acting antihypertensives are contraindicated in the setting of depression.

Direct Vasodilators

Both hydralazine and minoxidil produce potent direct arterial vasodilation mediated by activation of ATP-sensitive potassium channels within the arterial vasculature. The relative lack of effect on venous capacitance vessels by direct vasodilators reduces the potential for orthostatic hypotension. The potency and relatively adverse side-effect profile for direct vasodilators limit applications to hypertensive disease resistant to standard pharmacologic approaches, most often in the setting of severe hypertension associated with chronic renal failure.

Both hydralazine and minoxidil cause peripheral edema formation and profound reflex sympathetic activation manifested as tachycardia, headaches, and flushing. Minoxidil, a more potent antihypertensive than hydralazine, frequently is associated with excessive growth of facial hair. Reflex sympathetic responses to direct vasodilators necessitate concomitant administration of diuretics and β-adrenergic blockers to alleviate the potential for fluid retention and myocardial ischemia.

Novel Approaches to Antihypertensive Therapy

Despite the array of antihypertensive medications currently available, heterogeneity of treatment effects and adverse effects of current drugs on quality-of-life measures suggest the need for alternative approaches to antihypertensive therapy.²⁸⁶ Promising approaches include both aldosterone-receptor blockers and renin inhibitors. With the exception of potential for hyperkalemia, aldosterone-receptor inhibitors have proved well tolerated, and renin inhibitors administered in concert with Ang II inhibitors alleviated the compensatory increase in plasma renin activity. Third-generation β-blockers incorporating vasodilatory activity offer particular promise for treating hypertension in the setting of concomitant HF. Further modifications to endothelin-receptor antagonists and dual vasopeptidase inhibitors offer novel antihypertensive approaches for the future. Ultimately, gene therapy may prove the definitive solution to essential hypertension. It appears likely that environmental factors interacting with multiple genetic polymorphisms contribute to overall risk for hypertension. Gene therapy offers a viable approach to long-term management of hypertension but will prove dependent on further identification of target genes, improvements in gene transfer efficiency, and development of safer transfer vectors. Near term, advances in personalized medicine offer potential for DNA testing of genetic polymorphisms to identify antihypertensive drugs most likely to benefit specific patients.²⁸⁷

Management of Severe Hypertension

For purposes of characterizing treatment urgency, severe hypertension is characterized as either a hypertensive emergency with target-organ injury (e.g., myocardial ischemia, stroke, pulmonary edema) or hypertensive urgency with severe elevations in BP not yet associated with target-organ damage. Chronic increases in BP, even when of a severe nature, do not necessarily require urgent intervention and often may be managed with oral antihypertensive therapy on an outpatient basis. In contrast, a hypertensive emergency necessitates immediate therapeutic intervention, most often in an intensive care setting, with IV antihypertensive therapy and invasive arterial BP monitoring. In the most extreme cases of malignant hypertension, severe increases in BP may be associated with retinal hemorrhages, papilledema, and evidence of encephalopathy, which may include headache, vomiting, seizure, and/or coma. Progressive renal failure and cardiac decompensation are additional clinical features characteristic of the most severe hypertensive emergencies.

A common therapeutic approach to the hypertensive emergency includes a limited reduction in BP, of perhaps 10%, over the initial 1 to 2 hours of therapy, followed by further reductions to a target diastolic pressure (e.g., 110 mm Hg) during the initial 12 hours of therapy. Further reductions in BP to acceptable target levels should proceed over a period of days to minimize potential for inducing ischemic injury in the setting of altered autoregulatory flow to target organ vascular beds.^264,²⁸⁸

The favored parenteral drug for rapid treatment of hypertensive emergencies remains sodium nitroprusside ²⁶⁴ (Table 10-11). An NO donor, sodium nitroprusside induces arterial and venous dilation, providing rapid and predictable reductions in systemic BP. Prolonged administration of large doses may be associated with cyanide or thiocyanate toxicity; however, rarely is this a concern in the setting of acute hypertensive emergencies. Although less potent and predictable than sodium nitroprusside, NTG, another NO donor, may be preferable in the setting of myocardial ischemia or after CABG. NTG preferentially dilates venous capacitance beds as opposed to arterioles; however, rapid onset of tolerance limits the efficacy of sustained infusions to maintain BP control. Nicardipine, a parenteral dihydropyridine calcium channel blocker, and fenoldopam, a selective dopamine₁-receptor antagonist, have been utilized increasingly in select patient populations after CABG and in the setting of renal insufficiency, respectively.

TABLE 10-11 Parenteral Drugs for Treatment of Hypertensive Emergencies

Several drugs remain available for intermittent parenteral administration in the setting of hypertensive emergencies or urgencies. Enalaprilat, an IV ACE inhibitor, has been administered in settings of severe hypertension complicated by HF. Hydralazine, labetalol, and esmolol provide additional therapeutic options for intermittent parenteral injection for hypertensive control. However, with the exception of sodium nitroprusside, the response to parenteral antihypertensive drugs remains unpredictable, posing the potential for delayed achievement of targeted BP goals or, conversely, severe hypotensive responses. In most cases of emergent or severe hypertension, a diuretic will be required to maintain the prolonged natriuresis needed to sustain an antihypertensive response. In the setting of renal insufficiency or failure, minoxidil and even acute dialysis may be necessary to attain BP control.

Compelling Indications for Specific Antihypertensive Drug Selection

Despite compelling evidence supporting the preferential administration of thiazide diuretics as agents of choice for treatment of hypertension, most patients will require addition of a second nondiuretic antihypertensive drug to achieve desired target BPs.²⁶⁴ Selection of a complementary antihypertensive agent necessitates a thorough understanding of the mechanisms of action to optimize the additive effect of combined therapy. For example, β-blockers, ACE inhibitors, and Ang II antagonists inhibit renin release. Therefore, combinations of these agents are unlikely to achieve a maximal additive antihypertensive response. Similarly, both the diuretics and dihydropyridine calcium channel blockers produce peripheral vasodilation such that combination with other antihypertensive drug classes may prove more efficacious. Increasingly, data derived from ongoing outcomes-based trials of antihypertensive therapy in patients with coexisting diseases suggest that specific antihypertensive drugs reduce morbidity beyond that expected for BP reduction alone²⁶⁴ (Table 10-12).

TABLE 10-12 Clinical Trial and Guideline Basis for Compelling Indications for Individual Drug Classes

For example, in patients with ischemic heart disease, and most especially a recent MI, β-blockers have been demonstrated to reduce mortality and morbidity related to subsequent cardiac events.^86,^275,^277,³⁰⁵ Although precise mechanisms remain unclear, reductions in overall sympathetic stimulation and antiarrhythmic effects presumably play contributory roles. In the setting of renal insufficiency, ACE inhibitors and Ang II antagonists delay progression of both diabetic and nondiabetic-associated renal disease.^305,³⁰⁸^–³¹⁰ Calcium channel blockers have proved efficacious in the setting of peripheral vascular diseases, such as Raynaud syndrome, and α₁-blockers favorably influence symptoms of prostatism. In the setting of hypertension and pregnancy, methyldopa and hydralazine remain preferred antihypertensives for management of chronic hypertension and preeclampsia, respectively.²⁶⁰

Perioperative Implications of Hypertension

There is little evidence to suggest that mild-to-moderate degrees of hypertension adversely affect morbidity and mortality in the perioperative setting. In fact, ACC/AHA guidelines state that mild-to-moderate hypertension does not represent an independent risk factor for perioperative cardiovascular complications.³¹⁴ However, given the strong association between hypertension and cardiovascular diseases, a preoperative diagnosis of hypertension necessitates preoperative assessment for evidence of target-organ damage (e.g., CAD, renal dysfunction, stroke, peripheral vascular disease).³¹⁵ In contrast with isolated hypertension, secondary cardiovascular diseases, in many cases, do pose increased risk for perioperative morbidity and mortality. In patients with a preoperative diagnosis of hypertension, an electrocardiogram (ECG) is performed (to assess for evidence of ischemia, prior MI, or left ventricular [LV] hypertrophy), and a urinalysis and plasma creatinine determination may be obtained to assess renal function. Specific antihypertensive therapies may necessitate additional evaluations such as assessment of plasma potassium and sodium in patients taking diuretics.

In cases of mild-to-moderate hypertension, few controlled trials assessing the association between preoperative hypertension and perioperative morbidity and mortality are available. Most investigations have been observational in nature with no correction for potentially confounding risk factors. In many cases, the number of study participants has been inadequate to ensure statistical power to assess for relevant associations between outcomes and a preoperative diagnosis of hypertension. Howell et al ²⁸⁸ published a meta-analysis summarizing 30 studies including more than 12,995 patients for whom an association between hypertension and perioperative complications could be assessed. These authors calculated an odds ratio of 1.31, suggesting a slightly increased risk for perioperative cardiovascular complications in patients with preexisting hypertension; however, given limitations of the dataset, the authors further concluded that such a small odds ratio in the setting of a “low perioperative event rate” likely represents a clinically insignificant association between preexisting hypertension and cardiac risk. Other investigators have reported similar small associations between isolated systolic hypertension before surgery and subsequent perioperative morbidity.

As opposed to the apparently low perioperative risk posed by mild-to-moderate hypertension, cases of severe hypertension (diastolic BP > 110 mm Hg) frequently lead to questions whether elective surgery should be postponed to allow for titration of antihypertensive therapy to acceptable systemic BPs. Again, although there are little data to support conclusive recommendations regarding acceptable preoperative BPs or the length of antihypertensive therapy necessary to achieve a new “steady state,” patients with poorly controlled BP experience more labile BP responses in the perioperative setting with greater potential for hypertensive or hypotensive episodes, or both.³¹⁵^–³¹⁷ Guidelines published by the ACC/AHA suggest that systemic BPs exceeding 180 mm Hg systolic and/or 110 mm Hg diastolic should be controlled before surgery.³¹⁴ In a review, Howell and colleagues²⁸⁸ concluded that surgery need not be canceled in the setting of severe hypertension; however, a careful preoperative assessment for target organ damage (e.g., cardiovascular, renal, cerebrovascular disease) should be performed before surgery, and intraoperative arterial pressures should be maintained within 20% of preoperative BPs. At a minimum, in patients with severe hypertension, invasive monitoring of arterial pressure with strict control of perioperative BPs, continuing into the postoperative setting, appears justified; given the predilection for CAD in these patients, perioperative therapy with β-blockers may be indicated.^93,⁹⁴

Pharmacotherapy for acute and chronic heart failure

Chronic HF is one major cardiovascular disorder that continues to increase in incidence and prevalence, both in the United States and worldwide. It affects nearly 550 million persons in the United States, and roughly 600,000 new cases are diagnosed each year.^318,³¹⁹ Currently, 1% to 2% of those 40 to 59 years of age and 12% to 14% of individuals older than 80 have HF.³¹⁸ Because HF is primarily a disease of the elderly, its prevalence is projected to increase twofold to threefold over the next decade, as the median age of the U.S. population continues to increase.³²⁰ The increasingly prolonged survival of patients with various cardiovascular disorders that culminate in ventricular dysfunction (e.g., patients with CAD are living longer rather than dying acutely with MI), and the greater diagnostic awareness further compound the HF epidemic. Despite improvements in the understanding of the neurohormonal mechanisms underlying its pathophysiology and remarkable advances made in pharmacologic therapy, HF continues to cost the United States an estimated $38 billion annually in medical expenditures,³²¹ and it contributes to approximately 292,000 deaths per year.³¹⁸ Given the public health impact of the disease and the rapid pace of therapeutic advances, it is essential that the perioperative physician remain aware of contemporary clinical practice for the benefit of those patients with chronic HF presenting to the operating room or intensive care unit.

Accordingly, the pharmacologic management of HF as it relates to guidelines published by the ACC/AHA is reviewed.³²² The focus is primarily on chronic HF associated with LV systolic dysfunction, although chronic HF with preserved systolic function (or diastolic heart failure [DHF]) and acute HF also are discussed. For each drug commonly used in clinical practice, the general format of presentation includes whether it alters the progression of myocardial damage (for agents administered chronically), its mechanism(s) of action, current clinical data on trials of its use for HF, and its current place in the treatment of HF. New, non-neurohormonal, pharmacologic options in HF management also are reviewed.

Heart Failure Classification

The ACC/AHA updated guidelines for evaluating and managing HF include a new, four-stage classification system emphasizing both the evolution and progression of the disease (Figure 10-17). It calls attention to patients with preclinical stages of HF to focus on halting disease progression. The staging system is meant to complement, not replace, the widely used New York Heart Association (NYHA) classification, a semiquantitative index of functional classification that categorizes patients with HF by the severity of their symptoms (Box 10-5). NYHA classification remains useful clinically because it reflects symptoms, which, in turn, correlate with quality of life and survival.³²³ The new classification system for HF, recognizing its progressive course and identifying those who are at risk (e.g., the first two stages, A and B, clearly are not HF), reinforces the importance of determining the optimal strategy for neurohormonal antagonism in an attempt to improve the natural history of the syndrome. In this new staging approach, patients would only be expected to either not advance at all or to advance from one stage to the next, unless progression of the disease was halted by treatment. This is in contrast with the NYHA functional classification in which the severity of symptoms characteristically fluctuates depending on changes in diet and medications, even in the absence of measurable changes in LV structure and function.^318,³²² The new HF staging approach may be comparable with that used in such disorders as cancer.

Figure 10-17 American College of Cardiology/American Heart Association Four-Stage Classification and Management Recommendations. Stages in the development of heart failure/recommended therapy. ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blocker; EF, ejection fraction; FHx CM, family history of cardiomyopathy; HF, heart failure; LVH, left ventricular hypertrophy; MI, myocardial infarction.

(Reprinted by permission of Hunt SA: 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 119:e391–e479, 2009; Figure 1.)

BOX 10-5 New York Heart Association Functional Class

Class I: No limitation of functional activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain.

Class II: Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain.

Class III: Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes dyspnea, palpitation, fatigue, or anginal pain.

Class IV: Severe limitation in ability to carry on any physical activity without discomfort. Symptoms of heart failure or anginal pain are present even at rest. If any physical activity is undertaken, discomfort increases.

Although the pathophysiology of HF has been addressed elsewhere, it is important to mention key concepts as the basis of current pharmacologic therapy. To start, HF remains the final common pathway for CAD, hypertension, valvular heart disease, and cardiomyopathy, in which the natural history results in symptomatic or asymptomatic LV dysfunction (specifically, LV systolic dysfunction for the purposes of this discussion). The neurohormonal responses to impaired cardiac performance (salt and water retention, vasoconstriction, sympathetic stimulation) are initially adaptive but, if sustained, become maladaptive, resulting in pulmonary congestion and excessive afterload. This, in turn, leads to a vicious cycle of increases in cardiac energy expenditure and worsening of pump function and tissue perfusion (Table 10-13). Although the cardiorenal and cardiocirculatory branches of this neurohormonal hypothesis of HF were the original foundation for the use of diuretics, vasodilators, and inotropes, respectively, seminal information in the early 1990s emerged from large, randomized clinical trials that showed ACE inhibitors^324,³²⁵ and angiotensin receptor blockers,^293,³²⁶ but not most other vasodilators,³²⁷ prolonged survival in patients with HF. In a similar fashion, the use of β-blockers, despite their negative inotropic effects, improved morbidity and mortality in randomized, controlled trials.^289,^328,³²⁹

TABLE 10-13 Neurohormonal Effects of Impaired Cardiac Performance and Their Effects on the Circulation

Response	Short-Term Effects	Long-Term Effects
Salt and water retention	Augments preload	Pulmonary congestion, anasarca
Vasoconstriction	Maintains blood pressure for perfusion of vital organs (brain, heart)	Exacerbates pump dysfunction (excessive afterload), increases cardiac energy expenditure
Sympathetic stimulation	Increases heart rate and ejection	Increases energy expenditure

The finding that low-dose aldosterone antagonists added to conventional therapy for HF reduce mortality in patients with severe HF suggests that there is more to the neurohormonal hypothesis of drug efficacy than cardiorenal and hemodynamic effects alone.^294,²⁹⁸ Taken together with evidence from basic investigations showing that Ang II is a growth factor and a vasoconstrictor,³³⁰ the clinical data promoted a shift in focus from cardiorenal and cardiocirculatory processes toward cardiac remodeling as the central component in the progression of this neurohormone-mediated cardiac syndrome.³³¹ The renin-angiotensin-aldosterone system, excess sympathetic activity, endothelin, and various cytokines all have been implicated as stimuli of proliferative signaling that contribute to maladaptive cardiac growth. Accordingly, ventricular remodeling, or the structural alterations of the heart in the form of dilatation and hypertrophy (Boxes 10-6 and 10-7), in addition to the counter-regulatory hemodynamic responses, lead to progressive ventricular dysfunction and represent the target of current therapeutic interventions (Figure 10-18).

BOX 10-6 Pathobiology of Left Ventricular Remodeling

From Mann DL: Mechanisms and models in heart failure: An approach. Circulation 100:999–1088, 1999.

Alterations in Myocyte Biology

Excitation contraction coupling

Myosin heavy-chain (fetal) gene expression

β-Adrenergic desensitization

Hypertrophy

Myocytolysis

Cytoskeletal proteins

Myocardial Changes

Myocyte loss

Necrosis

Apoptosis

Alterations in extracellular matrix

Matrix degradation

Replacement fibrosis

Alterations in Left Ventricular (LV) Chamber Geometry

LV dilation

Increased LV sphericity

LV wall thinning

Mitral valve incompetence

BOX 10-7 Mechanical Disadvantage Created by Left Ventricular Remodeling

From Mann DL: Mechanisms and models in heart failure: An approach. Circulation 100:999–1088, 1999.

Increased wall stress (afterload)

Afterload mismatch

Episodic subendocardial hypoperfusion

Increased oxygen utilization

Sustained hemodynamic overloading

Worsening activation of compensatory mechanisms

Figure 10-18 Current and future treatments of heart failure. Currently, heart failure therapies are focused on prevention of disease progression with drugs that antagonize neurohormonal systems. Future therapies may involve antagonists of other biologically active systems (e.g., endothelins, tumor necrosis factor [TNF]-α) and antiremodeling strategies that may reverse the heart failure phenotype. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; NEP, neutral endopeptidase blocker.

(Adapted from Mann DL: Mechanisms and model in heart failure: A combinatorial approach. Circulation 100:999, 1999.)

Pathophysiologic Role of the Renin-Angiotensin System in Heart Failure

The renin-angiotensin system (RAS) is one of several neuroendocrine systems that are activated in patients with HF. The RAS is also an important mediator in the progression of HF. In the short term, the juxtaglomerular cells of the kidney release the proteolytic enzyme, renin, in response to a decrease in BP or renal perfusion (e.g., hemorrhage), generating Ang I from circulating angiotensinogen. ACE cleavage of Ang II from Ang I in the lung produces circulating Ang II. Acutely, Ang II acts as a potent arteriolar and venous vasoconstrictor to return BP and filling pressure to baseline, respectively. Ang II also stimulates the release of aldosterone from the adrenal cortex and antidiuretic hormone (ADH) from the posterior pituitary. Both contribute to increases in blood volume through their effects on the kidney to promote salt and water reabsorption, respectively. In the long term, increases in Ang II lead to sodium and fluid retention, and increases in SVR, which contribute to symptoms of HF, pulmonary congestion, and hemodynamic decompensation (Figure 10-19).

Figure 10-19 Basic pathway of the renin-angiotensin-aldosterone system. ACE, angiotensin-converting enzyme.

(From Jaski BE: Basis of heart failure: A problem solving approach. Boston: Kluwer Academic Publishers, 2000, by permission of Springer Science and Business Media.)

In addition to these cardiorenal and cardiocirculatory effects, most of the hormones and receptors of the RAS are expressed in the myocardium, where they contribute to maladaptive growth or remodeling, key factors in the progression of HF. Increased expression of messenger RNA for angiotensinogen, ACE, and Ang II has been identified in the failing human heart.³³² Correspondingly, increased coronary sinus Ang II concentrations were measured in patients with dilated and ischemic cardiomyopathy, signifying a paracrine or autocrine action of the RAS. Moreover, progressive increases in coronary sinus Ang II production correlated with increases in NYHA functional classification of HF.³³² Taken together, these data provide evidence that intracardiac RAS is involved in the evolution of the disease process.

The effects of Ang II on its receptors, AT₁ and AT₂, are well appreciated. The AT₁ receptor is involved in several effects that lead to adverse cardiovascular outcomes. Activation of AT₁ receptors promotes aldosterone and vasopressin secretion with concomitant increases in salt and water reabsorption through the kidneys, vasoconstriction, catecholamine release, and cell growth and proliferation of cardiovascular tissue (Table 10-14). Stimulation of AT₂ receptors, in contrast, results in natriuresis, vasodilation, release of bradykinin and NO, and cell growth inhibition or apoptosis. The Ang II that is formed locally in the heart acts primarily through AT₁ receptors located on myocytes and fibroblasts, where it participates in the regulation of cardiac remodeling. Through complex cascades of intracellular signal transduction that activate protein transcription factors within the nucleus, initiating the creation of RNA transcripts, the long-term effects of intracardiac Ang II on the AT₁ receptor result in cardiomyocyte hypertrophy, fibroblast proliferation, and extracellular matrix deposition³³³ (Figure 10-20). These processes contribute to progressive LV remodeling and LV dysfunction characteristic of HF.

TABLE 10-14 Cellular and Physiologic Effects of AT₁ and AT₂ Stimulation That Lead to Tissue Remodeling

AT₁ Receptor	AT₂ Receptor
Vasoconstriction Cell growth and proliferation Positive inotropy Aldosterone secretion Catecholamine release	Vasodilation Cell growth inhibition/apoptosis Negative chronotropy Natriuresis Bradykinin release

Figure 10-20 Left ventricular remodeling stimuli.

Angiotensin-Converting Enzyme Inhibitors

Clinical Evidence

Evidence supporting the beneficial use of ACE inhibitors in HF patients comes from various randomized, placebo-controlled clinical trials (Table 10-15). Initially, this class of drugs was evaluated for treatment of symptomatic HF (Studies Of Left Ventricular Dysfunction [SOLVD], Vasodilator-Heart Failure Trial [V-HeFT], Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS]). Patients with NYHA Class II to IV HF treated with ACE inhibitors had reductions in mortality rate ranging from 16% to 31%. Subsequently, ACE inhibitors also were found to improve outcome for asymptomatic patients with LV systolic dysfunction in the following categories: patients with EFs less than 35% because of cardiomyopathy,³³³ patients within 2 weeks after MI with EFs less than 40%,³³⁴ and patients presenting within the first 24 hours of MI regardless of EF.³³⁵ Recent results from the Heart Outcomes Prevention Evaluation (HOPE) study have further expanded the indications for this class of agents to include asymptomatic, high-risk patients to prevent new-onset HF.³³⁶ In patients with diabetes or peripheral vascular disease and an additional atherosclerotic risk factor, but without clinical HF or systolic dysfunction, ramipril (10 mg/day) reduced the HF risk by 23%. More recently, the Prevention of Events with Angiotensin Converting Enzyme (PEACE) trial evaluated the use of angiotensin converting enzyme-inhibitors (ACE-I) in addition to modern conventional therapy in patients with stable CAD with preserved LV function. The results of this trial did not demonstrate any decrease in mortality from cardiovascular causes or nonfatal MI compared with placebo.³³⁷ As a result, the ACC/AHA committee has changed the level of recommendation for the use of ACE-I from Class I to Class IIa for patients with Stage A HF.³²² Together, these data endorse the use of ACE inhibitors as first-line therapy for a broad spectrum of patients including those with LV systolic dysfunction, with or without symptoms, and in high-risk patients with vascular disease, diabetes, or both, in addition to those with the traditional coronary risk factors. Indeed, the addition of ACE-I in patients with stable CAD, preserved LV systolic function, and at low risk for cardiovascular events also can be useful (Class IIa recommendation). Since the commencement of these trials, the rationale for the use of ACE inhibitors has expanded from a reduction in the progression of clinical HF through ACE inhibitor–mediated vasodilatory action, to acknowledgment that ACE inhibitors also directly affect the cellular mechanisms responsible for progressive myocardial pathology.

TABLE 10-15 Selected Clinical Trials of Angiotensin-Converting Enzyme Inhibitors in Heart Failure

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