Pharmacology of Anesthetic Drugs

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Chapter 7 Pharmacology of Anesthetic Drugs

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

Acute Effects

Myocardial Function

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.

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.

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

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).

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.

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).