Pharmacology of Anesthetic Drugs

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Chapter 7 Pharmacology of Anesthetic Drugs

Kelly Grogan, MD, Daniel Nyhan, MD, Dan E. Berkowitz, MD

An enormous body of literature has accumulated describing the effects of the different anesthetic agents on the heart and the regional vascular beds. Recently, this has been due to the great interest in anesthesia-induced preconditioning (APC).

VOLATILE AGENTS

The influence of volatile anesthetics on contractile function has been investigated extensively, and it is now widely agreed that volatile agents cause dose-dependent depression of contractile function (Box 7-1). Moreover, different volatile agents are not identical in this regard and the preponderance of information indicates that halothane and enflurane exert equal but more potent myocardial depression than do isoflurane, desflurane, or sevoflurane.¹ This reflects in part reflex sympathetic activation with the latter agents. It is also widely accepted that in the setting of preexisting myocardial depression, volatile agents have a greater effect than in normal myocardium. At the cellular level, volatile anesthetics exert their negative inotropic effects mainly by modulating sarcolemmal (SL) L-type Ca²⁺ channels, the sarcoplasmic reticulum (SR), and the contractile proteins. However, the mechanisms whereby anesthetic agents modify ion channels are not completely understood.

BOX 7-1 Volatile Anesthetic Agents

• All volatile anesthetic agents cause dose-dependent decreases in systemic blood pressure, which for halothane and enflurane are predominantly due to attenuation of myocardial contractile function and which for isoflurane, desflurane, and sevoflurane are predominantly due to decreases in systemic vascular resistance. Moreover, volatile agents obtund all components of the baroreceptor reflex arc.

• The effects of volatile agents on myocardial diastolic function are not yet well characterized and await the application of “bedside” emerging technologies that have the sensitivity to quantitate indices of diastolic function.

• Volatile anesthetics lower the arrhythmogenic threshold to catecholamines. However, the underlying molecular mechanisms are not well understood.

• When confounding variables are controlled (e.g., systemic blood pressure), isoflurane does not cause “coronary steal” by a direct effect on coronary vasculature.

• The effects of volatile agents on systemic regional vascular beds and on the pulmonary vasculature are complex and depend on variables that include, but are not confined to, the specific anesthetic under study, the specific vascular bed, the vessel size, and whether endothelial-dependent or endothelial-independent mechanisms are being investigated.

Cardiac Electrophysiology

Volatile anesthetic agents lower the arrhythmogenic threshold for epinephrine. Moreover, not all volatile agents are similar, with the order of sensitization being halothane > enflurane > sevoflurane > isoflurane = desflurane. The molecular mechanisms underlying this effect of volatile anesthetics are poorly understood.

Coronary Vasoregulation

Volatile anesthetic agents modulate several determinants of both myocardial oxygen supply and demand. Moreover, it is now established that volatile agents also directly modulate the response of myocytes to ischemia.

The effect of isoflurane on coronary vessels was controversial and dominated much of the literature in this area in the 1980s and early 1990s. The current assessments of the effects of isoflurane have been succinctly detailed by Tanaka and associates.² Several reports had indicated that it caused direct coronary arteriolar vasodilatation in vessels of 100 μm or less and that isoflurane could cause “coronary steal” in patients with “steal-prone” coronary anatomy. Several studies in which potential confounding variables were controlled indicated clearly that isoflurane did not cause coronary steal. Studies of sevoflurane and desflurane showed similar results and are consistent with a mild direct coronary vasodilator effect of these agents.

Systemic Vascular Effects

All volatile anesthetic agents decrease systemic blood pressure (BP) in a dose-dependent manner. With halothane and enflurane, the decrease in systemic BP is primarily due to decreases in stroke volume (SV) and cardiac output (CO) whereas isoflurane, sevoflurane, and desflurane decrease overall systemic vascular resistance (SVR) while maintaining CO.

Baroreceptor Reflex

All volatile agents attenuate the baroreceptor reflex. Baroreceptor reflex inhibition by halothane and enflurane is more potent than that observed with isoflurane, desflurane, or sevoflurane, each of which has a similar effect. Each component of the baroreceptor reflex arc (afferent nerve activity, central processing, efferent nerve activity) is inhibited by volatile agents.

Delayed Effects

Reversible Myocardial Ischemia

Prolonged ischemia results in irreversible myocardial damage and necrosis (Box 7-2). Shorter durations of myocardial ischemia can, depending on the duration and sequence of ischemic insults, lead to either preconditioning or myocardial stunning (Fig. 7-1). Stunning, first described in 1975, occurs after brief ischemia and is characterized by myocardial dysfunction in the setting of normal restored blood flow and by an absence of myocardial necrosis. Ischemic preconditioning (IPC) was first described by Murray and colleagues in 1986 and is characterized by an attenuation in infarct size after sustained ischemia, if this period of sustained ischemia is preceded by a period of brief ischemia. Moreover, this effect is independent of collateral flow. Thus, short periods of ischemia followed by reperfusion can lead to either stunning or preconditioning with a reduction in infarct size (Fig. 7-2).³

BOX 7-2 Volatile Agents and Myocardial Ischemia

• Volatile anesthetic agents have been demonstrated to attenuate the effects of myocardial ischemia (acute coronary syndromes).

• Nonacute manifestations of myocardial ischemia include hibernating myocardium, stunning, and preconditioning.

• Halothane and isoflurane facilitate the recovery of stunned myocardium.

• Preconditioning, a profoundly important adaptive protective mechanism in biologic tissues, can be provoked by protean nonlethal stresses, including but not confined to ischemia.

• Volatile anesthetic agents can mimic preconditioning (anesthetic preconditioning), an observation that could have important clinical implications, as well as providing insight into the cellular mechanisms of action of volatile agents.

Figure 7-1 Effects of ischemia and reperfusion on the heart based on studies in anesthetized canine model of proximal coronary artery occlusion. Brief periods of ischemia of less than 20 minutes followed by reperfusion are not associated with development of necrosis (reversible injury). Brief ischemia/reperfusion results in the phenomenon of stunning and preconditioning. If duration of coronary occlusion is extended beyond 20 minutes, a wavefront of necrosis marches from subendocardium to subepicardium over time. Reperfusion before 3 hours of ischemia salvages ischemic but viable tissue. (This salvaged tissue may demonstrate stunning.) Reperfusion beyond 3 to 6 hours in this model does not reduce myocardial infarct size. Late reperfusion may still have a beneficial effect on reducing or preventing myocardial infarct expansion and left ventricular (LV) remodeling.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Kloner RA, Jennings RB: Consequences of brief ischemia: Stunning, preconditioning, and their clinical implications: I. Circulation 104:2981, 2001.)

Figure 7-2 Schematic of stunning and preconditioning. Short coronary artery occlusions result in stunning, in which there is prolonged regional wall motion abnormality, despite presence of reperfusion and viable myocardial cells. Brief episodes of ischemia/reperfusion also precondition the heart. When the heart is then exposed to a longer duration of ischemia and reperfusion, myocardial infarct size is reduced.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Kloner RA, Jennings RB: Consequences of brief ischemia: Stunning, preconditioning, and their clinical implications: I. Circulation 104:2981, 2001.)

Anesthetic Preconditioning

Volatile agents can elicit delayed (late), as well as classic (early), preconditioning. Moreover, APC is dose dependent, exhibits synergy with ischemia in affording protection, and, perhaps not surprisingly in view of differential uptake and distribution of volatile agents, has been demonstrated to require different time intervals between exposure and the maintenance of a subsequent benefit that is agent dependent. Volatile agents that exhibit APC activate mitochondrial K⁺_ATP channels, and this effect is blocked by specific mitochondrial K⁺_ATP channel antagonists. However, the precise relative contributions of SL versus mitochondrial K⁺_ATP channel activation to APC remain to be elucidated (Fig. 7-3).

Figure 7-3 Multiple endogenous signaling pathways mediate volatile anesthetic-induced myocardial activation of an end-effector that promotes resistance against ischemic injury. Mitochondrial K⁺_ATP channels have been implicated as the end-effector in this protective scheme, but sarcolemmal K⁺_ATP channels may also be involved in this mechanism of protection. A trigger initiates a cascade of signal transduction events, resulting in the protection. Volatile anesthetics signal through adenosine and opioid receptors, modulate G proteins, stimulate protein kinase C (PKC) and other intracellular kinases, or have direct effects on mitochondria to generate reactive oxygen species (ROS) that ultimately enhance K⁺_ATP channel activity. Volatile anesthetics may also directly facilitate K⁺_ATP channel opening. Dotted arrows delineate the intracellular targets that may be regulated by volatile anesthetics; solid arrows represent potential signaling cascades.

(From Tanaka K, Ludwig LM, Kersten JR, et al: Mechanisms of cardioprotection by volatile anesthetics. Anesthesiology 100:707, 2004.)

INTRAVENOUS INDUCTION AGENTS

The drugs discussed in this section are all induction agents and hypnotics. These drugs belong to different classes (barbiturates, benzodiazepines, N-methyl-D-aspartate [NMDA] receptor antagonists, and α₂-adrenergic receptor agonists). Their effects on the cardiovascular system are therefore dependent on the class to which they belong.

Acute Cardiac Effects

Myocardial Contractility

With regard to propofol, the studies remain controversial as to whether there is a direct effect on myocardial contractile function at clinically relevant concentrations. However, the weight of evidence suggests that the drug has a modest negative inotropic effect, which may be mediated by inhibition of L-type Ca²⁺ channels or modulation of Ca²⁺ release from the sarcoplasmic reticulum.

In one of the few human studies using isolated atrial muscle tissue, no inhibition of myocardial contractility was found in the clinical concentration ranges of propofol, midazolam, and etomidate. In contrast, thiopental showed strong negative inotropic properties whereas ketamine showed slight negative inotropic properties. Thus, negative inotropic effects may explain in part the cardiovascular depression on induction of anesthesia with thiopental but not with propofol, midazolam, and etomidate. Improvement of hemodynamics after induction of anesthesia with ketamine is a function of sympathoexcitation.

The effect of drugs such as propofol may also be markedly affected by the underlying myocardial pathology. For instance, Sprung and coworkers determined the direct effects of propofol on the contractility of human nonfailing atrial and failing atrial and ventricular muscles obtained from the failing human hearts of transplant patients or from nonfailing hearts of patients undergoing coronary artery bypass graft (CABG) surgery.⁴ They concluded that propofol exerts a direct negative inotropic effect in nonfailing and failing human myocardium but only at concentrations larger than typical clinical concentrations. Negative inotropic effects are reversible with β-adrenergic stimulation, suggesting that propofol does not alter the contractile reserve but may shift the dose responsiveness to adrenergic stimulation.

Vasculature

As with the heart, the cumulative physiologic effects in the vasculature represent a summation of the effects of the agents on the central autonomic nervous system, as well as the direct effects of these agents on the vascular smooth muscle, and the modulating effects on the underlying endothelium. It is now well established that propofol decreases SVR in humans. This was demonstrated in a patient with an artificial heart in whom the CO remained fixed. The effect is predominantly mediated by alterations in sympathetic tone; however, in isolated arteries, propofol decreases vascular tone and agonist-induced contraction. The mechanism by which propofol mediates these effects has been attributed in part to inhibition of Ca²⁺ influx through voltage or receptor-gated Ca²⁺ channels, as well as inhibition of Ca²⁺ release from intracellular Ca²⁺ stores.

INDIVIDUAL AGENTS

Thiopental

Thiopental has survived the test of time as an intravenous anesthetic drug (Box 7-3). Since Lundy introduced it in 1934, thiopental was the most widely used induction agent because of the rapid hypnotic effect (one arm-to-brain circulation time), highly predictable effect, lack of vascular irritation, and general overall safety. The induction dose of thiopental is lower for older than for younger healthy patients. Pharmacokinetic analyses confirm that the awakening from thiopental is due to rapid redistribution. Thiopental has a distribution half-life (t½α) of 2.5 to 8.5 minutes, and the total body clearance varies, according to sampling times and techniques, from 0.15 to 0.26 L/kg/hr. The elimination half-life (t½β) varies from 5 to 12 hours. Barbiturates and propofol have increased volumes of distribution (Vd) when used during cardiopulmonary bypass (CPB).

BOX 7-3 Intravenous Anesthetics

Thiopental

Thiopental decreases cardiac output by:

• A direct negative inotropic action

• Decreased ventricular filling, resulting from increased venous capacitance

• Transiently decreasing sympathetic outflow from the central nervous system

Because of these effects, caution should be used when thiopental is given to patients who have left or right ventricular failure, cardiac tamponade, or hypovolemia.

Midazolam

There are only small hemodynamic changes after the intravenous administration of midazolam.

Etomidate

Etomidate is described as the drug that changes hemodynamic variables the least. Studies in noncardiac patients and those who have heart disease document the remarkable hemodynamic stability after administration of etomidate.

Patients who have hypovolemia, cardiac tamponade, or low cardiac output probably represent the population for whom etomidate is better than other induction drugs, with the possible exception of ketamine.

Ketamine

A unique feature of ketamine is stimulation of the cardiovascular system, with the most prominent hemodynamic changes including significant increases in HR, CI, SVR, PAP, and systemic artery pressure. These circulatory changes cause an increase in with an appropriate increase in coronary blood flow.

Studies have demonstrated the safety and efficacy of induction with ketamine in hemodynamically unstable patients. It is the induction drug of choice for patients with cardiac tamponade physiology.

Dexmedetomidine

Dexmedetomidine is a highly selective, specific, and potent adrenoreceptor agonist.

α₂-Adrenergic agonists can safely reduce anesthetic requirements and improve hemodynamic stability. These agents may enhance sedation and analgesia without producing respiratory depression or prolonging recovery period.

Cardiovascular Effects

The hemodynamic changes produced by thiopental have been studied in normal patients and in patients with cardiac disease (Table 7-1). The principal effect is a decrease in contractility, which results from reduced availability of calcium to the myofibrils. There is also an increase in HR. The cardiac index (CI) is unchanged or reduced, and the mean aortic pressure (MAP) is maintained or slightly reduced. In the dose range studied, no relationship between plasma thiopental and hemodynamic effect has been found.

Table 7-1 Induction Agents and Hemodynamic Changes

Mechanisms for the decrease in CO include (1) direct negative inotropic action, (2) decreased ventricular filling, resulting from increased venous capacitance, and (3) transiently decreased sympathetic outflow from the central nervous system. The increase in HR (10% to 36%) that accompanies thiopental administration probably results from the baroreceptor-mediated sympathetic reflex stimulation of the heart. Thiopental produces dose-related negative inotropic effects that appear to result from a decrease in calcium influx into the cells with a resultant diminished amount of calcium at sarcolemma sites. Patients who had compensated heart disease and received 4 mg/kg of thiopental had a greater (18%) BP drop than did other patients. The increase in HR (11% to 36%) encountered in patients with coronary artery disease (CAD), anesthetized with thiopental (1 to 4 mg/kg), is potentially deleterious because of the obligatory increase in myocardial oxygen consumption ().

Despite the well-known potential for cardiovascular depression when thiopental is given rapidly in large doses, this drug has minimal hemodynamic effects in normal patients and in those who have heart disease when it is given slowly or by infusion. Significant reductions in cardiovascular parameters occur in patients who have impaired ventricular function. When thiopental is given to hypovolemic patients, there is a significant reduction in CO (69%), as well as a large decrease in BP, which indicate that patients without adequate compensatory mechanisms may have serious hemodynamic depression with a thiopental induction. Clearly, thiopental produces greater changes in BP and HR than does midazolam when used for induction of ASA Class III and IV patients.

Uses in Cardiac Anesthesia

Thiopental can be used safely for the induction of anesthesia in normal patients and in those who have compensated cardiac disease. Because of the negative inotropic effects, increase in venous capacitance, and dose-related decrease in CO, caution should be used when thiopental is given to patients who have left or right ventricular failure, cardiac tamponade, or hypovolemia. The development of tachycardia is a potential problem in patients with ischemic heart disease.

An additional use for thiopental infusion is cerebral protection during CPB in patients undergoing selected cardiac operations. However, the cerebral protective effect of thiopental during CPB has been challenged by Zaidan and associates,⁵ who demonstrated no differences in outcome between thiopental and control patients undergoing hypothermic CPB for CABG. Although the administration of a barbiturate during CPB may result in myocardial depression, necessitating additional inotropic support, a study by Ito and colleagues suggested beneficial effects of a thiopental infusion during CPB in maintaining peripheral perfusion, which allowed more uniform warming, decreased base deficit, and decreased requirements for postoperative pressor support.

Midazolam

Midazolam (Versed), a water-soluble benzodiazepine, was synthesized in the United States in 1975. It is unique among benzodiazepines because of its rapid onset, short duration of action, and relatively rapid plasma clearance. The dose for induction of general anesthesia is between 0.05 and 0.2 mg/kg and depends on the premedication and speed of injection.

The pharmacokinetic variables of midazolam reveal that it is cleared significantly more rapidly than are diazepam and lorazepam. The rapid redistribution of midazolam, as well as high liver clearance, accounts for its relatively short hypnotic and hemodynamic effects. The t½β is about 2 hours, which is at least 10-fold less than for diazepam.

Cardiovascular Effects

The hemodynamic effects of midazolam have been investigated in normal subjects, in ASA Class III patients, and in patients who have ischemic and valvular heart disease (VHD). Table 7-1 summarizes the hemodynamic changes after induction of anesthesia with midazolam. In general, there are only small hemodynamic changes after the intravenous administration of midazolam (0.2 mg/kg) in premedicated patients who have coronary artery disease (CAD). Changes of potential importance include a decrease in MAP of 20% and an increase in HR of 15%. The CI is maintained. Filling pressures are either unchanged or decreased in patients who have normal ventricular function but are significantly decreased in patients who have an elevated PCWP (18 mm Hg or higher). As in patients with ischemic heart disease, the induction of anesthesia in patients with VHD is associated with minimal changes in CI, HR, and MAP after midazolam. When intubation follows anesthesia induction with midazolam, significant increases in HR and BP occur, because midazolam is not an analgesic. Adjuvant analgesic drugs are required to block the response to noxious stimuli.

There is a suggestion that midazolam affects the capacitance vessels more than does diazepam, at least during CPB, when decreases in venous reservoir volume of the pump are greater with midazolam than with diazepam. In addition, diazepam decreases SVR more than midazolam during CPB.

Midazolam (0.15 mg/kg) and ketamine (1.5 mg/kg) have proved to be a safe and useful combination for a rapid-sequence induction for emergency surgery. This combination was superior to thiopental alone, because it caused less cardiovascular depression, more amnesia, and less postoperative somnolence. If midazolam is given to patients who have received fentanyl, significant hypotension may occur, as seen with diazepam and fentanyl. However, midazolam is routinely combined with fentanyl for induction and maintenance of general anesthesia during cardiac surgery without adverse hemodynamic sequelae.^6,⁷

Uses

Midazolam is distinctly different from the other benzodiazepines because of its rapid onset, short duration, water solubility, and failure to produce significant thrombophlebitis; it is therefore one of the mainstays of anesthesia in the cardiac operating rooms.

Etomidate

Etomidate is a carboxylated imidazole derivative. It was found that etomidate has a safety margin four times greater than the safety margin for thiopental. The recommended induction dose of 0.3 mg/kg has pronounced hypnotic effects. Etomidate is moderately lipid soluble and has a rapid onset (10 to 12 seconds) and a brief duration of action. It is hydrolyzed primarily in the liver and in the blood as well.

Cardiovascular Effects

In comparative studies with other anesthetic drugs, etomidate is usually described as the drug that changes hemodynamic variables the least. Studies in noncardiac patients and those who have heart disease document the remarkable hemodynamic stability after administration of etomidate. In comparison with other anesthetics, etomidate produces the least change in the balance of myocardial oxygen demand and supply. Systemic BP remains unchanged but may be decreased 10% to 19% in patients who have VHD.

Etomidate (0.3 mg/kg IV), used to induce general anesthesia in patients with acute myocardial infarction undergoing percutaneous coronary angioplasty, did not alter HR, MAP, and rate-pressure product (RPP), demonstrating the remarkable hemodynamic stability of this agent.⁸ However, the presence of VHD may influence the hemodynamic responses to etomidate. Whereas most patients can maintain their BP, patients with both aortic and mitral VHD had significant decreases of 17% to 19% in systolic and diastolic BP and decreases of 11% and 17% in PAP and PCWP, respectively. CI in patients who had VHD and received 0.3 mg/kg either remained unchanged or decreased 13%. There was no difference in response to etomidate between patients who had aortic valve disease and those who had mitral valve disease.

Uses

There are certain situations in which the advantages of etomidate outweigh the disadvantages. Emergency uses include situations in which rapid induction is essential. Patients who have hypovolemia, cardiac tamponade, or low CO probably represent the population for whom etomidate is better than other drugs, with the possible exception of ketamine. The fact that the hypnotic effect is brief means that additional analgesic and/or hypnotic drugs must be administered. Etomidate offers no real advantage over most other induction drugs for patients undergoing elective surgical procedures.

Ketamine

Although ketamine produces rapid hypnosis and profound analgesia, respiratory and cardiovascular functions are not depressed as much as with most other induction agents. Disturbing psychotomimetic activity (described as vivid dreams, hallucinations, or emergence phenomena) remains a problem.

Cardiovascular Effects

The hemodynamic effects of ketamine have been examined in noncardiac patients, critically ill patients, geriatric patients, and patients who have a variety of heart diseases. Table 7-1 contains the range of hemodynamic responses to ketamine. One unique feature of ketamine is stimulation of the cardiovascular system. The most prominent hemodynamic changes are significant increases in HR, CI, SVR, PAP, and MAP. These circulatory changes cause an increase in with an apparently appropriate increase in coronary blood flow (CBE). A second dose of ketamine produces hemodynamic effects opposite to those of the first. Thus, the cardiovascular stimulation seen after ketamine induction of anesthesia (2 mg/kg) in a patient who has VHD is not observed with the second administration, which is accompanied instead by decreases in the BP, PCWP, and CI.

Ketamine produces similar hemodynamic changes in normal patients and in patients who have ischemic heart disease. In patients who have elevated PAP (as with mitral valvular disease), ketamine seems to cause a more pronounced increase in PVR than in SVR. The presence of marked tachycardia after administration of ketamine and pancuronium can also complicate the induction of anesthesia in patients who have CAD or VHD with atrial fibrillation.

One of the most common and successful approaches to blocking ketamine-induced hypertension and tachycardia is the prior administration of benzodiazepines. Diazepam, flunitrazepam, and midazolam all successfully attenuate the hemodynamic effects of ketamine. For example, in a study involving 16 patients with VHD, ketamine (2 mg/kg) did not produce significant hemodynamic changes when preceded by diazepam (0.4 mg/kg). Indeed, HR, MAP, and RPP were unchanged; however, there was a slight but significant decrease in CI. The combination of diazepam and ketamine rivals the high-dose fentanyl technique with regard to hemodynamic stability. No patient had hallucinations, although 2% had dreams and 1% had recall of events in the operating room.

Studies have demonstrated the safety and efficacy of induction with ketamine (2 mg/kg) in hemodynamically unstable patients who required emergency operations. Most of these patients were hypovolemic because of trauma or massive hemorrhage. Ketamine induction was accompanied in the majority of patients by the maintenance of BP and, presumably, of CO as well. In patients who have an accumulation of pericardial fluid, with or without constrictive pericarditis, induction with ketamine (2 mg/kg) maintains CI and increases BP, SVR, and RAP. The HR in this group of patients is unchanged by ketamine, probably because cardiac tamponade already produced a compensatory tachycardia.

Uses

In adults, ketamine is probably the safest and most efficacious drug for patients who have decreased blood volume or cardiac tamponade. Undesired tachycardia, hypertension, and emergence delirium may be attenuated with benzodiazepines.

Propofol

Propofol is the most recent intravenous anesthetic to be introduced into clinical practice, and is the most widely used drug for inductions.

Cardiovascular Effects

The hemodynamic effects of propofol have been investigated in healthy ASA Class I and II patients, elderly patients, patients with CAD and good left ventricular function, and in patients with impaired left ventricular function (see Table 7-1). Numerous studies have also compared the cardiovascular effects of propofol with other commonly used induction drugs, including the thiobarbiturates and etomidate. It is clear that with propofol, systolic arterial pressure falls 15% to 40% after intravenous induction with 2 mg/kg and maintenance infusion with 100 μg/kg/min. Similar changes are seen in both diastolic arterial pressure and MAP.

The effect of propofol on HR is variable. The majority of studies have demonstrated significant reductions in SVR (9% to 30%), CI, SV, and left ventricular stroke work index (LVSWI) after propofol. Although controversial, the evidence points to a dose-dependent decrease in myocardial contractility.^9,¹⁰

OPIOIDS IN CARDIAC ANESTHESIA

Terminology and Classification

Various terms are commonly used to describe morphine-like drugs that are potent analgesics. The word narcotic is derived from the Greek word for “stupor” and refers to any drug that produces sleep. In legal terminology, it refers to any substance that produces addiction and physical dependence. Its use to describe morphine or morphine-like drugs is misleading and should be discouraged. Opiates refer to alkaloids and related synthetic and semisynthetic drugs that interact stereospecifically with one or more of the opioid receptors to produce a pharmacologic effect. The more encompassing term, opioid, also includes the endogenous opioids and is used. Opioids may be agonists, partial agonists, or antagonists.

Opioid Receptors

The existence of separate opioid receptors was shown by correlating analgesic activity to the chemical structure of many opioid compounds (Box 7-4). The idea of multiple opioid receptors is an accepted concept, and a number of subtypes for each class of opioid receptors have been identified. Through biochemical and pharmacologic methods, the μ-, δ-, and κ-receptors have been characterized. Pharmacologically, it is well known that δ-opioid receptors consist of two subtypes: δ₁ and δ₂.¹¹

BOX 7-4 Opioids

• The μ-, κ-, and δ-opioid receptors and endogenous opioid precursors have been identified in both cardiac and vascular tissue.

• The functional role of opioid precursors/opioid receptors in the cardiovascular system in physiologic and pathophysiologic conditions (e.g., congestive heart failure, arrhythmia development) are areas of ongoing investigation.

• The predominant cardiovascular effect of exogenously administered opioids is to attenuate central sympathetic outflow

• Endogenous opioids and opioid receptors, especially the delta_-1 receptor, are likely important contributors in effecting both early and delayed preconditioning in the heart.

• Plasma drug concentrations are profoundly altered by cardiopulmonary bypass as a result of hemodilution, altered plasma protein binding, hypothermia, exclusion of the lungs from the circulation, and altered hemodynamics that likely modulate hepatic and renal blood flow. The specific effects are drug dependent.

Opioid receptors involved in regulating the cardiovascular system have been localized centrally to the cardiovascular and respiratory centers of the hypothalamus and brainstem and peripherally to cardiac myocytes, blood vessels, nerve terminals, and the adrenal medulla. It is generally accepted that opioid receptors are differentially distributed between atria and ventricles. The highest specific receptor density for binding of κ-agonists is in the right atrium and least in the left ventricle. As with the κ-opioid receptor, the distribution of the δ-opioid receptor favors atrial tissue and the right side of the heart more than the left.

Cardiac Effects of Opioids

At clinically relevant doses, the cardiovascular actions of opioids are limited. The actions opioids exhibit are mediated both by opioid receptors located centrally in specific areas of the brain and nuclei that regulate the control of cardiovascular function and peripherally by tissue-associated opioid receptors. The opioids in general exhibit a variety of complex pharmacologic actions on the cardiovascular system (Fig. 7-4).¹²

Figure 7-4 Some of the actions of opioids on the heart and cardiovascular system. Opioid actions may either involve direct opioid receptor-mediated actions, such as the involvement of the δ-opioid receptor in ischemic preconditioning (PC) or indirect, dose-dependent, non−opioid receptor−mediated actions such as ion channel blockade associated with the antiarrhythmic actions of opioids.

Most of the hemodynamic effects of opioids in humans can be related to their influence on the sympathetic outflow from the central nervous system. The pharmacologic modulation of sympathetic activity by centrally or peripherally acting drugs elicits cardioprotective effects.

All opioids, with the exception of meperidine, produce bradycardia, although morphine given to unpremedicated normal subjects may cause tachycardia. The mechanism of opioid-induced bradycardia is central vagal stimulation. Premedication with atropine can minimize but not totally eliminate opioid-induced bradycardia, especially in patients taking β-adrenoceptor antagonists. Although severe bradycardia should be avoided, moderate slowing of the HR may be beneficial in patients with CAD by decreasing myocardial oxygen consumption.

Hypotension can occur after even small doses of morphine and is primarily related to decreases in SVR. The most important mechanism responsible for these changes is probably histamine release. The amount of histamine release is reduced by slow administration (<10 mg/min). Pretreatment with an H₁ or H₂ antagonist does not block these reactions, but they are significantly attenuated by combined H₁ and H₂ antagonist pretreatment. Opioids may also have a direct action on vascular smooth muscle, independent of histamine release.¹³

Cardioprotective Effects of Exogenous Opioid Agonists

In 1996, Schultz and colleagues were the first to demonstrate that an opioid could attenuate ischemia-reperfusion damage in the heart. Morphine at the dose of 300 μg/kg was given before left anterior descending coronary artery occlusion for 30 minutes in rats in vivo. Infarct area/area at risk was diminished from 54% to 12% by this treatment.¹⁴ The infarct-reducing effect of morphine has been shown in hearts in situ, isolated hearts, and cardiomyocytes. Morphine also improved postischemic contractility. It is now well accepted that morphine provides protection against ischemia-reperfusion injury.¹⁵ Fentanyl has been studied in a limited fashion and has had mixed results as far as its ability to protect the myocardium.¹⁶ This may be due to differences in species studied and/or fentanyl concentrations.

Opioids in Cardiac Anesthesia

A technique of anesthesia for cardiac surgery involving high doses of morphine was developed in the late 1960s and early 1970s. This was based on the observation by Lowenstein and associates that patients requiring mechanical ventilation after surgery for end-stage VHD tolerated large doses of morphine for sedation without discernible circulatory effects. When they attempted to administer equivalent doses of morphine as the anesthetic for patients undergoing cardiac surgery, they discovered serious disadvantages, including inadequate anesthesia, even at doses of 8 to 11 mg/kg, episodes of hypotension related to histamine release, and increased intraoperative and postoperative blood and fluid requirements. Attempts to overcome these problems by combining lower doses of morphine with a variety of supplements (such as N₂O, halothane, or diazepam) proved unsatisfactory, resulting in significant myocardial depression, with decreases in CO and hypotension.

Because of these problems associated with the use of morphine, several other opioids were investigated in an attempt to find a suitable alternative. The use of fentanyl in cardiac anesthesia was first reported by Stanley and Webster in 1978. Since then there have been extensive investigations of fentanyl, as well as sufentanil and alfentanil, in cardiac surgery. The fentanyl group of opioids has proved to be the most reliable and effective for producing anesthesia both for patients with valvular disorders and CABG.

A major advantage of fentanyl and its analogs for patients undergoing cardiac surgery is their lack of cardiovascular depression.¹⁷ This is of particular importance during the induction of anesthesia, when episodes of hypotension can be critical. Cardiovascular stability may be less evident during surgery; in particular, the period of sternotomy, pericardiectomy, and aortic root dissection may be associated with significant hypertension and tachycardia. During and after sternotomy, arterial hypertension, increases in SVR, and decreases in CO frequently occur. The variability in the hemodynamic responses to surgical stimulation, even with similar doses of fentanyl, is probably a reflection of differences in the patient populations studied by different authors. One factor is the influence of β-blocking agents. In patients undergoing CABG anesthetized with fentanyl, 86% of those not taking β-adrenergic blockers became hypertensive during sternal spread versus only 33% of those who were taking these agents.

The degree of myocardial impairment will also influence the response. Critically ill patients or patients with significant myocardial dysfunction appear to require lower doses of opioid for anesthesia. This may reflect altered pharmacokinetics in those patients. A decrease in liver blood flow consequent to decreased CO and congestive heart failure reduces plasma clearance. Thus, patients with poor left ventricular function may develop higher plasma and brain concentrations for a given loading dose or infusion rate than patients with good left ventricular function. Additionally, patients with depressed myocardial function may lack the ability to respond to surgical stress by increasing CO in the presence of progressive increases in SVR.