Nitrates have been used under many forms for the treatment and prevention of angina for more than 100 years. Nitrates are potent dilators of the vascular smooth muscle that affect venous capacitance more than arterial resistance. By causing pooling in the peripheral veins, nitrates cause decreases in preload and ventricular volumes. At higher doses, nitrates may cause decreases in systemic and pulmonary vascular resistance.78 Low doses of nitrates have little effect on cardiac output and heart rate in patients with normal or increased intravascular volume. Rapid administration or high doses of nitrates, especially in patients with volume-contracted states, may decrease left ventricular end-diastolic pressure, stroke volume, cardiac output, and mean arterial pressure and cause reflexive increases in heart rate and sympathetic tone. Nitroglycerin inhibits hypoxic pulmonary vasoconstriction, but to a lesser extent than nitroprusside.
The antianginal use of nitroglycerin stems from its effect on the relationship between myocardial oxygen supply and demand. By increasing venous capacitance, and thus decreasing left ventricular end-diastolic pressure and volume, nitroglycerin decreases systolic ventricular wall tension, which is the major determinant of myocardial oxygen demand. Nitrates improve oxygen supply by increasing blood flow to areas of ischemia through several mechanisms. By lowering the left ventricular end-diastolic pressure and decreasing the resistance in collateral vessels, nitrates result in redistribution of coronary blood flow to the subendocardial tissue and increased ratio of endocardial-to-epicardial blood flow. Nitroglycerin is also a direct coronary arterial vasodilator, especially of large epicardial vessels.79 Dilation of large coronary arteries explains the beneficial effects of nitrates in patients with angina caused by coronary vasospasm. However, in patients with angina caused by coronary insufficiency, the administration of nitroglycerin does not result in net coronary blood flow increase. It has been postulated that dilation of large epicardial vessels in patients with coronary insufficiency causes an autoregulated increase in coronary vascular resistance in well-perfused arteriolar resistance vessels distal to large coronary arteries. This increased resistance shunts coronary flow to areas of ischemia, where the arterioles are already maximally dilated. Effects of nitrates on coronary blood flow distribution are different (indeed opposite) from those of sodium nitroprusside and dipyridamole. The latter drugs dilate arteriolar resistance vessels and can lead to myocardial steal phenomenon.
The mechanism of action of nitrates is by providing an exogenous source of the vasodilator nitric oxide. Nitrates enter the vessel wall and are ultimately converted in nitric oxide. Nitric oxide together with tissue thiols forms s-nitroso-thiol; nitrosothiols in turn activate guanylate cyclase, the enzyme that catalyzes the formation of cGMP (Fig. 44-2).80 Increased cGMP causes smooth muscle relaxation. Higher intracellular levels of cGMP also mediate bronchial, biliary, gastrointestinal, ureteral, and uterine smooth muscle relaxation. Nitrates also have beneficial antiplatelet and antithrombotic properties. The antiplatelet effect of nitrates seems to be due to an increased cGMP level in platelets resulting in a reduction in fibrinogen binding to the platelet glycoprotein IIb/IIIa receptor, which is essential for platelet aggregation.81
Cellular mechanism of action of nitroglycerin and nitroprusside. [Reproduced with permission from Ignarro LJ, Lippton H, Edwards JC, et al. Mechanism of vascular smooth muscle relaxation by nitrates, nitroprusside and nitric oxide. J Pharmacol Exp Ther. 1981;218:739.]
Nitrate therapy has an important role in the management of patients with an acute coronary syndrome, despite the absence of a mortality benefit.82,83 It can be used for reducing or potentially eliminating pain (either initial or recurrent) due to myocardial ischemia, improving symptoms of pulmonary congestion, lowering blood pressure in hypertensive patients, and aiding in the diagnosis and management of the rare patient who presents with variant angina (coronary artery spasm). Nitrates can be used transdermally or orally for chronic therapy, on an intermittent basis via the sublingual route, or intravenously for acute therapy (Table 44-8).
Table 44-8 Nitrate Preparations ||Download (.pdf)
Table 44-8 Nitrate Preparations
| Sublingual tablets—Nitrostat||0.3-0.6 mg PRN (up to 3 tablets)|
| Translingual spray—Nitrolingual||0.4 mg/spray (up to 3 sprays)|
| Transmucosal tablets—Nitrogard (Forest)||1-3 mg q5h TID|
| Oral extended-release||2.5-6.5 BID to QID|
| Ointment—2%||1" to 2" q4h for 12-14 h/d|
| Transdermal patches||1 patch 12-14 h/d|
| Sublingual tablets—immediate release||2.5-10 mg q2-3h|
| Oral tablets||30 mg BID or 20 mg TID in morning and afternoon|
| Extended-release tablets and capsules||40-80 mg once daily to TID|
| Immediate release||20 mg in morning and afternoon, 7 h apart|
| Extended-release||60-120 mg once daily|
| Sublingual||10 mg PRN|
| Sublingual||5-10 mg PRN|
| Oral||10-30 mg TID|
Continuous administration of nitrates is associated with tolerance, which is characterized by blunting of the hemodynamic response seen with nitrate therapy. The exact mechanism of tolerance is not known but may involve impaired bioconversion of nitrates to the active form, vascular sulfhydryl depletion or activation of RAAS, and the more recently described formation of free radicals through oxidative stress, resulting in endothelial dysfunction.84 Common adverse effects in patients taking nitrate therapy are headache, flushing, and hypotension. Nitrates must be used cautiously in patients with severe aortic stenosis and volume depletion.
In the perioperative period, patients taking nitrates should continue to receive therapy until and possibly throughout surgery. If a substantial perioperative or postoperative lapse is expected, nitrate ointments or IV nitroglycerin may be used.
Perioperatively, IV nitroglycerin may be used for treatment of myocardial ischemia, CHF, acute volume overload, systemic and pulmonary hypertension, and coronary artery spasm. Patients receiving acute nitroglycerin therapy may exhibit exaggerated hemodynamic responses to anesthetics, possibly related to its effects on preload. Prolonged use or excessive doses of nitroglycerin rarely may cause methemoglobinemia,85 but to a much lesser extent than sodium nitroprusside. More recently, the Evaluation of Clevidipine in the Perioperative Treatment of Hypertension Assessing Safety Events (ECLIPSE) trial was performed to compare the safety and efficacy of the ultra–short-acting calcium channel blocker clevidipine with nitroglycerin, sodium nitroprusside, and nicardipine in the treatment of perioperative acute hypertension in patients undergoing cardiac surgery. There was no difference in the incidence of myocardial infarction, stroke, or renal dysfunction for clevidipine-treated patients compared with the other treatment groups. There was no difference in mortality rates between the clevidipine, nitroglycerin, and nicardipine groups. Mortality was significantly higher, though, for nitroprusside-treated patients. Clevidipine was more effective compared with nitroglycerin or nitroprusside in maintaining blood pressure within a prespecified range.86
β-Adrenergic Blocking Agents
β-Adrenergic blocking agents are among the most widely prescribed cardiac medications and have a wide spectrum of therapeutic uses beyond treatment of hypertension, angina, and dysrhythmias.
There are at least 3 distinct types of β receptors:
- Activation of β1 receptors, found primarily in the heart muscle, increases heart rate, contractility, and AV conduction and decreases AV node refractoriness.
- Activation of β2 receptors, present in cardiac muscle but more prominently found in bronchial and peripheral vascular smooth muscle, results in bronchodilatation and vasodilatation.
- Activation of β3 receptors, found in adipose tissue and the heart, may induce thermogenesis87 and may have cardiodepressant effects.88
The major therapeutic effects of β-adrenergic blockers are on the cardiovascular system.
Variations among β-adrenergic blocking agents result from their differing pharmacologic properties in regard to β1 selectivity, α-adrenergic blocking activity, presence of intrinsic sympathomimetic activity (ISA) or membrane-stabilizing activity (MSA), potency, lipid solubility, first-pass effect, half-life, and mode of metabolism and excretion. All β-adrenergic blocking agents competitively block effects of catecholamines on receptors in the heart, lung, vasculature, kidney, brain, and eye, and their therapeutic value stems from these effects.
β-Adrenergic blockers lower blood pressure in patients with hypertension, although the mechanism is still debated. β-Blockers decrease myocardial contractility and heart rate, and thus cardiac output, but even at dosages lower than necessary to cause substantial decreases in cardiac output, they can be effective antihypertensives. β-Blockers with ISA such as pindolol decrease cardiac output less, yet are similarly effective antihypertensives. β-Blockers decrease the release of renin from the juxtaglomerular apparatus. This action contributes to the antihypertensive effect. However, even though hypertensive patients with high plasma renin activity (PRA) respond well to propranolol, which decreases PRA, β-blockers that do not decrease PRA (eg, pindolol) are also effective.
Evidence suggests that β-blockers cross the blood–brain barrier, and a CNS mechanism involving reduction in receptor-mediated sympathetic outflow has been proposed. On the other hand, lipophilic drugs such as propranolol and metoprolol are no more effective than hydrophilic compounds such as atenolol. Other proposed mechanisms of action include resetting of baroreceptors, attenuation of pressor responses to stress and exercise, and blockade of prejunctional receptors that normally facilitate norepinephrine release.89,90 Despite unclear mechanisms, β-blockers are among the most useful and commonly prescribed cardiovascular medications.
With the recent introduction of the so-called third-generation β-blockers, other additional antihypertensive mechanisms have been proposed, such as release of nitric oxide, antioxidant action, Ca entry blockade, and opening of K channels.91
In angina pectoris, β-adrenergic blocking agents decrease heart rate, blood pressure, and contractility and therefore reduce myocardial O2 consumption. They may improve perfusion by increasing diastolic coronary filling time. Although β-blockers have little effect on the factors influencing plaque vulnerability, they may decrease the incidence of plaque rupture by reducing mechanical stress.92 Other mechanisms have been suggested (Box 44-1). Not all the actions of β-blockers are beneficial in all patients. In patients with very poor ventricular function, worsening failure may negate other gains. Similarly, in Prinzmetal angina, β-blockade is ineffective and may even be harmful because of unopposed α-tone in the large coronary arteries.93 Treatment of angina pectoris with β-blockers, in combination with nitrates, aspirin, and/or calcium channel blockers, represents the current standard of care, if no contraindications exist. Competitive β-receptor inhibition has useful antidysrhythmic effects. β-Blockers decrease the phase IV depolarization slope of the action potential and thus decrease automaticity. They slow the rate of discharge of the sinus and ectopic pacemakers and increase the effective refractory period of the AV node. The membrane-stabilizing effect of β-blockers does not appear to be relevant in the management of arrhythmias because it is manifested at concentrations well above therapeutic levels. β-Blockers are particularly effective in dysrhythmias caused by increased circulating catecholamines such as pheochromocytomas, anxiety, exercise, myocardial ischemia, and heart failure caused by cardiomyopathy; in those caused by increased cardiac sensitivity to catecholamines such as thyrotoxicosis; and in the dysrhythmias of mitral valve prolapse. They control heart rate in atrial fibrillation, flutter, and paroxysmal atrial tachycardia.94,95 β-Blockers reduce sudden death, especially in patients with prior myocardial infarction or heart failure.96 Survivors of myocardial infarctions have decreased morbidity, less sudden death, and fewer recurrent infarctions when treated with β-blockers. Although the reasons for this are not completely clear, a combination of the anti-ischemic and antidysrhythmic effects seems to play a key role.97
Box 44-1 ||Download (.pdf)
Possible Mechanisms by Which β-Blockers Protect the Ischemic Myocardium
Reduction in myocardial oxygen consumption, heart rate, blood pressure, and myocardial contractility
Augmentation of coronary blood flow
Increase in diastolic perfusion time by reducing heart rate
Augmentation of collateral blood flow
Redistribution of blood flow to ischemic areas
Alterations in myocardial substrate utilization
Decrease in microvascular damage
Stabilization of cell and lysosomal membranes
Shift to oxyhemoglobin dissociation curve to the right
Inhibition of platelet aggregationReproduced with permission from Frishman WH. Clinical Pharmacology of the β-Adrenoceptor Blocking Drug. 2nd ed. Norwalk, CT: Appleton-Century-Crofts; 1984:306.
Other cardiovascular syndromes in which β-blocker therapy has proved useful include mitral valve prolapse, preexcitation syndromes, hypertrophic cardiomyopathy,98 tetralogy of Fallot, aortic aneurysm, prolonged QT interval syndromes, and advanced cardiomyopathies. Noncardiac uses have included prevention of bleeding in patients with portal hypertension and treatment of glaucoma, thyrotoxicosis, migraines, essential tremors, delirium tremens, and anxiety.
These important drugs are not without significant side effects. β-Blockers may precipitate CHF in patients with preexisting ventricular dysfunction. Patients with sinus node dysfunction or AV block may develop symptomatic bradycardias; consequently, β-blockers are relatively contraindicated in patients with sick sinus syndrome. Stimulation of β2 receptors in lungs causes bronchodilation; conversely, treatment with β-blockers may induce bronchospasm. Even β-blockers with relative β1 selectivity (eg, metoprolol, atenolol, betaxolol, esmolol, acebutolol, bisoprolol) occasionally induce bronchoconstriction in therapeutic doses. Nevertheless, they are preferred in patients with chronic lung disease.99 β-Blockade may decrease cardiac output and block β2-mediated coronary or peripheral arterial dilation, allowing unopposed constriction (eg, spasm). Symptoms of peripheral vascular disease may worsen after β-blocker therapy, although this concern might be overstated in patients with mild to moderate peripheral vascular disease.100 Additional concerns include impotence and decreased sympathetic manifestations of hypoglycemia in patients taking insulin or hypoglycemic agents. CNS effects such as depression, psychosis, and obtundation may occur. Depression, fatigue, and sexual dysfunction are common causes of β-blocker discontinuation.
Multiple interactions between β-adrenergic blocking agents and other drugs have been described, particularly ones that depress myocardial function and automaticity, such as calcium channel blockers and antiarrhythmic drugs.
Propranolol is the prototype against which all other β-adrenergic blocking agents are measured. It is noncardioselective and has no ISA. Although propranolol possesses MSA, this occurs only at doses far beyond therapeutic and is not clinically relevant except after massive overdoses. Propranolol is almost completely absorbed after oral administration, but undergoes extensive first-pass hepatic metabolism. Thus the usual oral dosage of propranolol is 40 to 320 mg/d, whereas the IV dosage is only 0.025 to 0.15 mg/kg. Cimetidine decreases hepatic metabolism and blood flow and may decrease propranolol's therapeutic dose. Propranolol is highly lipophilic and crosses the blood–brain barrier, which may explain its many CNS effects. Its usual oral half-life is approximately 4 hours. Propranolol is available as a long-acting preparation, a marked advantage for treatment of patients with angina pectoris.101 Propranolol may be slowly administered intravenously to patients under anesthesia in incremental doses of 1 mg with frequent monitoring of blood pressure.
Metoprolol is a moderately β1 selective blocker with no ISA or MSA. It is primarily metabolized by the hepatic cytochrome P450 system with a half-life of 3 to 7 hours. When used in low doses, metoprolol may be preferable to propranolol for smokers and other patients who may have bronchospastic diseases but who require therapy with β-blockers. Although relatively cardioselective, metoprolol still may precipitate bronchospasm. It is less likely than propranolol to mask symptoms of hypoglycemia. Its usual oral dosage is 50 to 200 mg twice daily, although an extended-release formulation is also available and widely prescribed. Like propranolol, metoprolol is available in IV form, with usual dosage of 0.025 to 0.15 mg/kg. Metoprolol is used in the treatment of hypertension, stable angina, acute myocardial infarction, and chronic heart failure. The efficacy of metoprolol in heart failure management was studied in several randomized clinical trials, which showed an improved survival, reduced need for hospitalizations as a consequence of worsening heart failure, improved New York Heart Association (NYHA) functional class, and beneficial effects on patient well-being.102,103
Atenolol is a long-acting, cardioselective β-blocker with no ISA or MSA. It is eliminated by renal excretion and has a half-life of 6 to 7 hours. Its usual dosage is 50 to 200 mg daily. It is available in an IV form, with a recommended dosage of 5 to 10 mg given slowly. Besides being cardioselective and requiring only a single daily intake, other possible advantages include relative hydrophilia and minimal blood–brain barrier crossing. Unfortunately, in clinical trials with atenolol, this has not been reflected by a lower incidence of CNS side effects.104
Bisoprolol is a very highly selective, long-acting, cardioselective β-blocker, without any ISA or MSA. It is well-absorbed after oral administration and is eliminated by renal excretion, with 50% unchanged in the urine and the remaining 50% eliminated as inactive metabolites.105 Its half-life of 9 to 13 hours makes it suitable for once-daily administration. Recent randomized clinical trials show that bisoprolol prevents major cardiovascular events in patients with CHF.106
Betaxolol is an oral, long-acting, cardioselective β-blocker with no ISA or MSA. Undergoing mainly hepatic metabolism, its half-life of 16 to 22 hours makes it suitable for once-daily administration. As with timolol, betaxolol is available for topical ophthalmic use and may be better tolerated by patients with bronchospastic disease because of its β1 selectivity.
Nadolol is a long-acting, noncardioselective β-blocker with no ISA or MSA. Unlike propranolol, it is renally excreted, with a half-life of 20 to 24 hours, allowing for once-daily administration. The usual dosage is 40 to 240 mg/d; dosage should be reduced in patients with renal failure.
Timolol is a noncardioselective β-blocker with no MSA or ISA. Its usual dosage is 10 to 30 mg twice a day, with a half-life of 4 to 5 hours. It undergoes both hepatic and renal excretion. Otherwise, it is similar to propranolol. Timolol is frequently used as an eye-drop therapy for open-angle glaucoma. In this form, it is often systemically absorbed and produces effects similar to those after oral ingestion.
Acebutolol, carteolol, penbutolol, and pindolol are nonselective β-blockers with ISA and partial agonist effects. With the patient at rest, these drugs may decrease heart rate to a lesser extent than other β-blockers. They are efficacious in blunting exercise-induced hemodynamic response. These drugs are thought to produce fewer lipid abnormalities and peripheral vascular complications, with less myocardial depression and bronchospasm. Specifically, pindolol produces less depression of heart rate and fewer nocturnal pauses in patients with sick sinus syndrome as compared with agents lacking agonist effects.107,108 Another possible advantage may be the absence of rebound after discontinuation; however, no large-scale trials are available to support these claims. No data are available to support the use of these drugs after myocardial infarction (MI). Table 44-9 lists the dosages for these drugs.
Table 44-9 Pharmacologic Properties of β-Blockers ||Download (.pdf)
Table 44-9 Pharmacologic Properties of β-Blockers
|Agent||Relative β1 Selectivity||ISA||MSA||α Activity||Elimination Half-Life Charts||Predominant Mode of Elimination||Oral Dosage (mg)||IV Dosage|
|Acebutolol||+||+||+||–||3-4 h||Renal/hepatic||200-600 BID|
|Atenolol||++||–||–||–||6-7 h||Renal||50-200 daily||5-10 titrated at 1 mg/min|
|Betaxolol||++||–||+||–l||16-22 h||Hepatic/renal||10-40 daily|
|Bisoprolol||++||–||–||–||9-13 h||Renal/hepatic||10-20 daily|
|Carteolol||–||+||–||–||5-6 h||Renal||2.5-10 daily|
|Carvedilol||–||–||+||+||7-10 h||Hepatic||3.125-25 BID|
|Esmolol||++||–||9 min||Red blood cell esterases||–||0.5-1 mg/kg bolus, then 100-300 μg/kg/min|
|Labetalol||–||–||–||+||6-8 h||Hepatic||200-1200 BID||5-20 mg initially, then 40 mg q10min up to 300 mg as boluses or 2 mg/min as infusion|
|Metoprolol||+||–||–||–||3-7 h||Hepatic||50-200 BID||0.1-0.15 mg/kg titrated slowly to effect|
|Metoprolol extended release||++||–||–||–||?||Hepatic||50-400 daily|
|Nadolol||–||–||–||–||20-24 h||Renal||40-240 daily|
|Penbutolol||–||+||–||–||5 h||Renal||20 daily|
|Pindolol||–||++||+||–||3-4 h||Renal/hepatic||5-30 BID|
|Propranolol||–||–||++||–||4 h||Hepatic||40-320 daily, 0.1-0.15 mg/kg BID or QID titrated slowly to effect|
|Propanolol extended release||–||–||++||–||10 h||Hepatic||80-320 daily, BID|
|Timolol||–||–||–||–||4-5 h||Renal||10-30 BID|
Labetalol is a nonselective β-blocker unique among β-blockers for its β-adrenergic blocking properties in a ratio of approximately 7:1(β:α). In addition, labetalol has partial agonist activity at β2 receptors.109 This blocking can be used to decrease arterial pressure with somewhat better maintenance of cardiac output. Labetalol is available in both IV and oral forms, and its use is well established in acute therapy of severe hypertension in the emergency room, operating room, and recovery suite, but it is seldom used as a long-term medication.
Esmolol is a highly cardioselective adrenergic blocker with little ISA and no MSA. It has a distribution half-life of 2 minutes and an elimination half-life of 9 minutes as a result of rapid hydrolysis by red blood cell (RBC) esterases. Its short duration of action makes it particularly valuable in management of perioperative patients. Esmolol is typically used as a bolus, with or without an infusion. Steady-state plasma levels are obtained within 5 minutes. Usual bolus dosages are 0.5 to 1 mg/kg. Infusion rates of 50 to 300 μg/kg/min are titrated to clinical effect. On discontinuation of an esmolol infusion, significant recovery occurs within 10 to 20 minutes, and blood concentrations are undetectable within 30 minutes. Because esmolol is metabolized by red blood cell esterase, plasma cholinesterase inhibitors do not affect metabolism and elimination. Esmolol has been used intraoperatively to attenuate response to intubation, prevent and/or treat tachycardia and ischemia, and produce deliberate hypotension. The time course for attainment of decreases in heart rate is faster than that for changes in blood pressure.110 It has been used to attenuate the increased heart rate and mean arterial pressure associated with rapidly increased desflurane concentrations.111 Postoperatively, it has been used in treatment of hypertension, myocardial ischemia, and supraventricular dysrhythmias.
Celiprolol is a third-generation cardioselective β-blocker without MSA but with evidence of ISA at the β2 receptor. It is an effective drug in the treatment of hypertension and angina.112 It is a weak bronchodilator and vasodilator as a result of its β2-receptor effect. It may prove superior to other β-blockers for asthmatic patients.113
Carvedilol is a nonselective β-blocker that also blocks α1 receptors in a manner similar to that of labetalol. It has MSA but no ISA. Carvedilol is also a potent antioxidant and antiproliferative, which inhibits vascular smooth muscle proliferation.114 This property makes it useful in the treatment of chronic CHF. In numerous clinical trials, carvedilol significantly reduced morbidity and mortality in patients with heart failure.115 Favorable effects on the remodeling process in heart failure were seen, with a decrease in left ventricular size and improvement in ejection fraction.116 A recent clinical trial comparing metoprolol and carvedilol in patients with chronic heart failure showed that carvedilol extends survival.117
Bucindolol is a third-generation nonselective β-blocker with α1 blocking and β2-agonist capabilities. In contrast to other β-blockers studied, bucindolol failed to show any significant overall survival benefit in patients with advanced cardiac failure.118
Nebivolol is a third-generation, highly selective β1-receptor blocker, which can be distinguished from other β-blockers by its hemodynamic profile. It combines β-blocking activity with a vasodilating effect, which is mediated at least in part by endothelial NO. The blood-pressure-lowering effect of nebivolol is linked to a reduction in peripheral resistance and an increase in stroke volume with preservation of cardiac output.119 Recent clinical trials show that it is an effective and well-tolerated treatment for heart failure in the elderly (age >65 years).120 It may reduce mortality in patients with heart failure.121
Anesthetic considerations regarding β-blocker therapy are numerous. Initially, β-blockers and antihypertensives were discontinued before anesthesia and surgery because of concerns that their effects would be additive with those of general anesthetic agents. Unfortunately, this sudden withdrawal tended to result in rebound effects with worsening of both angina and hypertension. There is little doubt that preoperative initiation of β-blocker therapy decreases the risk of perioperative ischemia and MI. Nevertheless, there is a raging controversy over whether acute perioperative β-blockade should be initiated in patients who have high or intermediate risk for a perioperative MI. Earlier research supported such of administration of β-blockers in these patients, demonstrating a decreased incidence of postoperative ischemia and lower mortality at 2-year follow-up in the group of patients who received β-blockers.122,123 More recently, the POISE study and others raise the question of whether the reduced incidence of perioperative ischemia and nonfatal MI occurs at the expense of increased stroke risk and death rates in patients randomized to receive β-blockers compared to with controls.124,125 Other investigators disagree, saying that the purported increased stroke and death rates are due to study design. They say that moderate rather than high-dose β-blockers administered starting 30 days before rather than the day of surgery improves cardiac outcomes without any increased risk in both high- and intermediate-risk patients undergoing noncardiac surgery.126-128 Badgett et al129 conducted a meta-analysis of existing trials and suggested that disparate results between trials may be due to differences between individual β-blockers. Trials using β-blockers with reduced β1 selectivity and increased metabolic dependence on cytochrome P450, with its high degree of genetic polymorphism, seem to result in poorer outcomes than those which are more selective and less cytochrome P450 dependent. Hence bisoprolol, which is not cytochrome dependent and highly β1 selective, may be a better choice than metoprolol, which is less β1 selective and very cytochrome dependent as compared with bisoprolol. Atenolol is intermediate with respect to these properties. Badgett et al129 recommend comparison of metoprolol with other β-blockers in survival and morbidity trials. Whether these differences are due to study design, including dosage and timing of various β-blockers, remains to be determined. As of this writing, the American Heart Association 2009 guidelines aver that several class IIa recommendations exist to initiate β-blockade in patients with inducible ischemia, known coronary disease, or multiple risk factors who are undergoing intermediate-risk surgery. In light of the conflicting results outlined previously, they suggest considering early preoperative initiation of β-blockers in such patients in doses titrated to avoid bradycardia and hypotension. They specifically do not advocate high-dose regimens initiated on the day of surgery, such as that of the POISE study.130
There is, however, a strong consensus that β-blockers should be continued in patients who are chronically β-blocked.130,131 Abrupt discontinuation of β-blockers can result in a withdrawal syndrome caused by upregulation of β-receptors. This increased sensitivity to endogenous catecholamines can result in hypertension, tachycardia, or exacerbation of anginal syndromes, and even MI or death.
The β-adrenergic blocking agents most frequently used in the United States today are described in the following sections (Table 44-9).
Because of their pharmacologic effects, β-blockers interact with many anesthetic agents. β-Blockers have additive negative inotropic effects with potent inhalation agents. In dogs at 1.0 MAC of enflurane, propranolol causes mild decreases in myocardial contractility, heart rate, and cardiac output. These changes are more pronounced at deeper anesthetic concentrations. Circulatory depression, although present, is less when halothane or isoflurane is combined with propranolol compared with enflurane. In dogs anesthetized with halothane, isoflurane, or enflurane, propranolol produces additive slowing of heart rate and AV node conduction.132
Patients maintained on β-blockers, particularly when combined with calcium channel blockers, are at risk for severe bradyarrhythmias when anesthesia is induced with high-dose fentanyl or sufentanil. These bradyarrhythmias especially occur when muscle relaxants lacking vagolytic effects are used. When high-dose narcotics are given to patients who take β-blockers, with or without calcium channel blockers, it is recommended that vagolytic muscle relaxants (eg, pancuronium) be used.133 β-Blockers are also associated with bradycardia during neuraxial anesthesia.134
The currently available IV β-blockers—propranolol, metoprolol, atenolol, labetalol, and esmolol—may be administered perioperatively to attenuate hemodynamic responses to intubation or surgical stress, treat hypertension and ischemia, slow heart rates, or treat dysrhythmias, in addition to the prophylactic uses described earlier.
The calcium channel blockers represent a diverse group of compounds with dissimilar structures and pharmacologic effects (Table 44-10). They inhibit voltage-sensitive calcium channel function (L-type or slow channels), which mediates the entry of extracellular calcium into smooth muscle (Fig. 44-3), cardiac myocytes, and SA and AV nodal cells in response to electrical depolarization. They therefore have vasodilatory properties, especially in arterial beds, and have negative chronotropic and inotropic effects to varying degrees.135,136 Unlike β-blockers, which all depend on blockade of receptors for their activity, the sites and mechanisms of action of the individual calcium channel blockers vary, as do their individual actions on different tissues. They are not nearly as interchangeable as β-blockers.
Table 44-10 Pharmacologic Effects of the Calcium Channel Blockers ||Download (.pdf)
Table 44-10 Pharmacologic Effects of the Calcium Channel Blockers
|HR Acute||SA Node||AV Node||Myocardial Contractility||PVR||CO||CBF||MVO2||Oral Dosage||Intravenous Dosage||T1/2 (h)|
|Diltiazem||↓||↓||↓||↓||↓||V||↓||30-90 mg q6-8h||0.25 mg/kg (bolus) then 0.15 ng/kg/h||2–6|
|Bepridil||↓||↓||↓||V||–||V||↓||200-400 mg QD||–||24-48|
|Verapamil||↓||↓||↓||↓↓||↓||↓||↓||80-120 mg q6-2h||0.75-0.15 mg/kg (bolus) then 0.075-0.15 ng/kg/h||3–7|
|Amlodipine||–||–||↓–||↓↓||V||2.5-10 mg QD||–||36-45|
|Felodipine||–||–||–||↓↓||V||2.5-10 mg QD||–||tri-exponential: 4.8 min; 1.5 h; 9.1 h|
|Isradipine||–||–||–||↓↓||V||2.5-10 mg QD||–||6-11|
|Nicardipine||–||–||–||↓↓||V||10-20 mg q8h||5-15 mg/h||2|
|Nifedipine||–||–||↓–||↓↓||V||10-40 mg q8h||–||1.5-5|
|Nisoldipine||–||–||–||↓↓||V||20-40 mg QD||–||10|
Activation sequence of mechanical contraction in vascular smooth muscle. The calcium (Ca2|m+) calmodulin complex (1) activates myosin light-chain kinase (2), which catalyzes the phosphorylation of myosin (P-myosin). Cross-bridge formation between P-myosin and actin produces mechanical contraction.
Used predominantly in antianginal and antihypertensive therapy (Fig. 44-4), calcium channel blockers are also used in the treatment of syndromes as diverse as paroxysmal supraventricular tachycardia, hypertrophic obstructive cardiomyopathy, Raynaud phenomenon, preterm labor, and migraine headache prophylaxis.137,138 The currently available calcium channel blockers can be categorized into 4 groups based on different chemical structures: dihydropyridines (which include nifedipine, nisoldipine, nicardipine, nimodipine, amlodipine, isradipine, felodipine, nitrendipine), verapamil (a phenylalkylamine), diltiazem (a benzothiazepine), and bepridil (a diarylaminopropylamine).
Consequences of calcium channel blockers on myocardial O2 balance. Because of reflex responses, negative chronotropism and inotropism may not be important. [Reproduced with permission from Nayler WG, Dillon JS, Daly MF. Cellular sites of action of calcium antagonists and β-adrenoceptor blockers. In: Opie LH, ed. Perspectives in Cardiovascular Research. Vol 9. Calcium Antagonists and Cardiovascular Disease. New York, NY: Raven Press; 1984:188.]
Verapamil, which is structurally similar to papaverine, has a complex mode of action. It is a racemic mixture, with l-verapamil being a more potent calcium channel blocker than d-verapamil.139 The net effect is depression of both slow channel activation and recovery from inactivation. Via its effects on the calcium channels, verapamil decreases myocardial contractility and dilates coronary and peripheral vascular beds, increasing coronary blood flow and decreasing systemic vascular resistance. Reflex tachycardia, secondary to decreased systemic vascular resistance, does not occur as a result of its negative chronotropic effect. Like other calcium channel blockers, verapamil has little effect on venous capacitance vessels in clinical doses. By decreasing heart rate, contractility, and peripheral resistance, verapamil decreases myocardial O2 consumption. By increasing diastolic filling time and coronary blood flow while decreasing coronary vascular resistance, it increases myocardial O2 delivery. In patients with CHF, intravenous verapamil can cause a marked decrease in contractility and left ventricular function. By directly antagonizing coronary vascular spasm, verapamil is useful in treatment of classic and Prinzmetal angina. Verapamil is useful in managing patients after myocardial infarction without CHF, and its use may decrease long-term mortality.140
The electrophysiologic effects of verapamil are substantial. It slows spontaneous rates of firing and increases SA node recovery time, thereby decreasing heart rate. The velocity of AV node conduction decreases as a consequence of both decreased conduction and increased refractoriness. Because of this effect on the AV node conduction, verapamil can terminate paroxysmal supraventricular tachycardia and slow the ventricular response in atrial flutter, fibrillation, and multifocal atrial tachycardia. It can successfully convert paroxysmal supraventricular tachycardias (PSVTs) to sinus rhythm with an effectiveness of greater than 90%. It is also of prophylactic value in preventing recurrences of PSVT and controlling the ventricular response in atrial flutter and fibrillation during long-term oral therapy.141 It should be noted that in patients with Wolff-Parkinson-White syndrome, verapamil might increase heart rate by preferential AV slowing, which may increase conduction through accessory pathways in patients who develop atrial fibrillation.
The net effect of verapamil in lowering both systolic and diastolic blood pressure with few side effects makes it efficacious for treatment of hypertension, although calcium channel blockers are currently not recommended as first-line therapy for hypertension. Possibly as a result of its improvement in diastolic function, verapamil improves exercise tolerance and decreases the severity of symptoms in patients with hypertrophic obstructive cardiomyopathy (HOCM). It is mainly used in HOCM patients who cannot tolerate β-blockers.114
In acute IV therapy, the recommended dose of verapamil is 0.075 to 0.15 mg/kg titrated to effect. Peak vasodilatory effect occurs at approximately 5 minutes and may persist for 30 minutes, although the antidysrhythmic effect may persist substantially longer. IV distribution half-life is 3.5 minutes and elimination half-life 110 minutes. Anesthetics or other drugs that decrease liver blood flow will increase the half-life of verapamil.
The side effects of verapamil are related to its pharmacologic and therapeutic actions. Verapamil may exacerbate SA and AV node dysfunction, especially in patients with underlying disease or those treated with digitalis or β-blockers. Verapamil may worsen symptoms of CHF, especially if used in combination with β-blockers.147 Digitalis levels increase by an average of 70% after initiation of therapy with verapamil.
Diltiazem, a benzothiazepine, is a calcium channel blocker with a spectrum of pharmacologic effects between verapamil and the dihydropyridines. Diltiazem, like all calcium channel blockers, is an effective coronary artery dilator, but has less effect on peripheral vessels than the dihydropyridines. It is a mild negative inotrope, but less so than verapamil.142 Reflex tachycardia is also blunted because diltiazem decreases sinus node automaticity and AV nodal conduction, albeit to a lesser extant than verapamil. Although diltiazem can be used in combination with β-blockers, the effects may be additive, causing SA and AV node dysfunction in patients with underlying conduction disease.
Diltiazem is approved for rapid conversion of paroxysmal supraventricular tachycardia to sinus rhythm and for temporary control of rapid ventricular rate in atrial flutter or fibrillation. The usual dose of IV diltiazem is 0.25 mg/kg as a slow loading dose, followed by an infusion of 0.15 mg/kg. An additional bolus of 0.35 mg/kg may be given if needed. Oral diltiazem can be used for the chronic management of these problems.
In vitro, nifedipine has significant effects on both smooth muscle and myocardium. In vivo, however, it is an effective coronary and systemic arterial dilator at doses that have little effect on myocardial contractility or conduction tissue. The vasodilatation and increase in coronary artery blood flow result from the blockade of calcium influx, as well as an increase in the levels of nitric oxide and bradykinin.143 Because of its afterload reduction, nifedipine may cause reflex sympathetic increases in heart rate and cardiac output.144 This sympathetic stimulation is more evident with short-acting preparations than it is with sustained-release nifedipine.145
Clinically, with the exception of short-acting formulations, which may occasionally worsen angina, nifedipine effectively improves exercise tolerance, prolongs the time to the onset of angina in exercise, and decreases the frequency of episodes of angina.147 Concurrent therapy with nifedipine and a β-blocker is more effective than either agent given alone. Indeed, β-blockers eliminate nifedipine's potentially detrimental reflex increases in heart rate.146 Although it is an effective antihypertensive, nifedipine—and generally all calcium channel blockers—is not currently recommended as first-line therapy, unless there are contraindications to other antihypertensives.6 Even though nifedipine has fewer negative chronotropic or inotropic effects than verapamil or diltiazem, in long-term studies, hemodynamic deterioration occurred in some patients with CHF who were treated with dihydropyridines.147
Because it is light sensitive, IV nifedipine is not commercially available in the United States. Nifedipine's side effects include headaches, pedal edema, hypotension, and exacerbation of angina. Like verapamil, nifedipine increases serum digitalis levels. Because a higher rate of cardiac events was reported among patients who were treated with short-acting nifedipine after myocardial infarction, this preparation is no longer recommended in patients with angina.148
Nicardipine has structural and pharmacologic properties similar to those of nifedipine. Like nifedipine, nicardipine is a potent coronary and systemic vasodilator with little effect on contractility. It is available as an IV agent for treatment of hypertension in acute care settings, including the perioperative period and neurologic emergencies.149-151 An initial intravenous bolus of 2 mg is followed by an initial infusion rate of 5 mg/h, which may be increased in 2.5-mg increments every 15 minutes, up to a maximum infusion rate of 15 mg/h. Nicardipine administered intra-arterially reverses vasospasm in subarachnoid hemorrhage and interventional coronary procedures.152,153
Nimodipine, a nifedipine analogue, is a calcium channel blocker with high lipid solubility and apparent preference for cerebrovascular smooth muscle. It is useful in inhibiting cerebral vasospasm and improving outcome in patients with neurologic defects associated with cerebral vasospasm after subarachnoid hemorrhage.154 Its usefulness in patients with acute ischemic stroke has not been proven.155
Amlodipine, isradipine, felodipine, nisoldipine, and nitrendipine are structurally and pharmacologically similar to nifedipine, the dihydropyridine prototype. They dilate coronary and peripheral arteries with minimal effect on cardiac conduction and contractility. Like nifedipine, these drugs are used to treat hypertension and angina and may be safely used in patients with CHF.156
The individual agents are distinct from each other in many ways. Because isradipine has an inhibitory effect on the SA node but not on the cardiac myocytes, it produces little or no reflex tachycardia. Felodipine and nisoldipine have a higher degree of vascular specificity than the rest of the dihydropyridines. Several trials have shown that amlodipine increases exercise duration, decreases the number of anginal attacks, and reduces the consumption of nitroglycerin.157 The Systolic Hypertension in Europe (Syst-Eur) Trial reported that antihypertensive therapy initiated with the nitrendipine reduced the risk of fatal and nonfatal stroke, as well as all cardiovascular events combined, in older patients (age >65 years) with isolated systolic hypertension.158
Clevidipine is a new, lipophilic, short-acting, third-generation dihydropyridine calcium channel blocker. It is an intravenous agent designed for immediate control of blood pressure in a monitored setting. Clevidipine should be initiated with a dose of 1 to 2 mg/h and then titrated to the desired effect. It is a selective arterial dilator without effects on the venous circulation and minimal effects on cardiac contractility or conduction. It has a half-life of approximately 2 minutes, resulting in a rapid onset and offset of its effects. It is metabolized by blood and tissue esterases and is therefore not end-organ dependent for its elimination. Headache, nausea, and vomiting are the most frequent side effects. Patients should be monitored for rebound hypertension once the drug is discontinued.159-161
Mibefradil is an antagonist of T-type calcium channels. This arterial dilator has negative chronotropic effects but minimal inotropic effects. Mibefradil is an effective antianginal whose vasodilatory effects are associated with a reduction in heart rate.162,163 There are case reports of QT interval prolongation and ventricular dysrhythmias during treatment with mibefradil.164
Monatepil is a calcium channel blocker similar to nifedipine, which also has α1-adrenoreceptor–blocking properties. It decreases systolic and diastolic pressure without changes in heart rate. Furthermore, it significantly decreases levels of low-density lipoprotein (LDL) cholesterol, apolipoprotein B, and glycosylated hemoglobin (HgbA1c).165
Bepridil is structurally unrelated to other calcium channel blockers. It blocks slow calcium channels in both cardiac and vascular smooth muscles as well as fast sodium channels in cardiac muscle. It has negative chronotropic and dromotropic and mild negative inotropic effects.166 Bepridil reduces blood pressure and heart rate, improves left ventricular performance in patients with angina, and decreases the frequency of exercise-induced angina attacks. Bepridil can prolong QT interval, especially in the setting of hypokalemia or bradycardia, and can precipitate polymorphic ventricular tachycardia. Bepridil is also associated with agranulocytosis and pancytopenia. Because of these serious side effects, it should be used only in cases of angina refractory to other therapies.
There are limited data regarding the risks and benefits of calcium channel blockers in the perioperative setting. Although a classic withdrawal syndrome has not been described, there are case reports of severe coronary vasospasm after abrupt discontinuation of the calcium channel blockers.167 Overall, the continuation of calcium channel blockers in patients already taking them preoperatively is recommended, despite the paucity of information in relation to their interaction with the process of anesthesia and surgery.
There is considerable potential for drug interaction between anesthetic drugs and calcium channel blockers. When used in combination with high-dose narcotics in patients with normal conduction systems and ventricular function, IV verapamil decreases systemic vascular resistance and mean arterial pressure with no change in cardiac output or pulmonary capillary wedge pressure. Although lengthening of the PR interval has been observed, neither first-degree nor more advanced AV block has occurred.
In combination with inhalation agents, verapamil may produce varying degrees of AV block and must be given carefully in patients anesthetized with enflurane, halothane, and, to a lesser degree, isoflurane in patients with AV nodal block or in patients chronically taking β-blockers.168
Verapamil has many perioperative uses. It has been used for intraoperative control of paroxysmal supraventricular tachycardia. During cardiopulmonary bypass, verapamil terminates refractory ventricular fibrillation after aortic cross-clamp removal. Verapamil successfully treats intraoperative myocardial ischemia refractory to IV nitroglycerin.169
In vitro, diltiazem may depress left ventricular function in the presence of enflurane or desflurane, whereas the incidence of bradyarrhythmias is higher with enflurane than with equivalent levels of desflurane.170 Combined with enflurane, diltiazem is particularly depressant to conduction. Together, they may cause first-degree AV block, Mobitz I AV block, or sinus node dysfunction.171
Nifedipine administered in dogs during fentanyl/nitrous oxide anesthesia decreased systemic vascular resistance accompanied by an increase in cardiac index and heart rate. In vitro, the combined treatment of nifedipine and volatile anesthetics, especially enflurane, additively depresses atrial rate and contractility. However, these effects appear less pronounced than the combination of volatile agents with diltiazem and especially verapamil.172
Nicardipine has a longer duration of action in the presence of isoflurane and produces greater initial hypotension with sevoflurane.173
Calcium channel blockers may potentiate effects of depolarizing and nondepolarizing neuromuscular blocking agents, although this is controversial. In contrast with β-adrenergic blocking agents, calcium channel blockers have not been shown to be effective in prevention of intraoperative ischemia.174
Novel therapeutic strategies have been developed for patients with ischemic heart disease and angina pectoris that were unsuccessfully managed with conventional medical or interventional approaches.
Ivabradine is the first of a new class of drugs called If inhibitors. It selectively and specifically inhibits If, a sinus node–specific sodium-potassium inward current. It reduces heart rate at rest or exercise without decreasing myocardial contractility, atrioventricular conduction, and ventricular repolarization duration.175 A double-blind trial comparing the anti-ischemic and antianginal effects of ivabradine to atenolol showed that ivabradine is as effective as atenolol in preventing exercise-induced angina in patients with chronic stable angina.176 Ivabradine preserves ejection fraction better than metoprolol when given to patients who were revascularised after STEMIs.177 Ivabradine has been approved in Europe for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to β-blockers. Ivabradine interacts with retinal currents, causing visual side effect. These include reversible, transient symptoms described mainly as increases in brightness in limited areas of the visual field. Extreme sinus bradycardia is very uncommon.178 No other adverse effects are attributed to ivabradine therapy.
Nicorandil is a nicotinamide ester, which activates the adenosine triphosphate (ATP)–sensitive potassium channel. It dilates peripheral and coronary resistance arterioles, and because of a nitrate-like effect, it dilates systemic veins and epicardial coronary vessels. Consequently, nicorandil increases coronary blood flow, reduces preload and afterload, and has antianginal efficacy similar to that of oral nitrates, β-blockers, and calcium antagonists.179 By opening ATP-dependent potassium channels, nicorandil may also mimic a natural process of ischemic preconditioning, protecting the heart from subsequent ischemic attacks. The IONA (Impact of Nicorandil in Angina) trial showed a significant improvement in outcome as a result of reduction in major coronary events by adding nicorandil to standard antianginal therapy in patients with stable angina.179 Nicorandil is not available in the United States.
Inhibitors of Fatty Acid Oxidation
Two agents, ranolazine and trimetazidine, are presently available and represent this new class of drug. During episodes of acute myocardial ischemia, fatty acid levels rise, promoting their uptake and use as energy source by the myocardium. Because fatty acid oxidation is more oxygen inefficient than carbohydrate oxidation, this abrupt increase in circulating free fatty acids imposes a further deleterious effect on an already imbalanced oxygen supply–demand situation. Inhibition of fatty acid oxidation may increase glucose oxidation, which generates more ATP for each molecule of oxygen than fatty acid oxidation, thereby minimizing lactate accumulation.180 Both drugs are virtually devoid of hemodynamic effects.
The efficacy of ranolazine has been studied in several clinical studies, such as the MARISA (Monotherapy Assessment of Ranolazine in Stable Angina) and CARISA (Combination Assessment of Ranolazine in Stable Angina) trials. Both MARISA and CARISA showed that ranolazine increases exercise capacity and provides antianginal effects on symptomatic patients with chronic angina.181
Similar benefits were shown in the TRIMPOL (Trimetazidine in Poland) II trial, which studied trimetazidine in patients already receiving metoprolol. The addition of trimetazidine produced significant improvement in exercise stress tests and anginal symptoms relative to metoprolol monotherapy.182
Ranolazine but not trimetazidine is available in the United States.