Pharmacology_Katzung

Pharmacology_Katzung. Anesthetics Glutamate or ACh Action potential Postsynaptic neuron nACh receptor NMDA receptor B Presynaptic neuron Ca2+ Ca2+ Mg2+ Ca2+ Mg2+ Mg2+Na+ Ca2+ Na+ Ca2+ Ca2+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Na+ Anesthetics GABA or Glycine Action potential A Presynaptic neuron Mg2+ Ca2+ Ca2+ Postsynaptic neuron Glycine receptor channelK+ K+ K+ K+ K+K+K+ K+ K+ Cl– Cl– Cl– Cl– Cl– Cl– Cl– Cl– Cl–Cl– Cl– GABAA receptor FIGURE 25–1 Putative targets of anesthetic action. Anesthetic drugs may (A) enhance inhibitory synaptic activity or (B) diminish excitatory activity. ACh, acetylcholine; GABAA, γ-aminobutyric acid-A. A. Factors Controlling Uptake 1. Inspired concentration and ventilation—The driving force for uptake of an inhaled anesthetic into the body is the ratio between inspired and alveolar concentration. The most important FIGURE 25–2 Chemical structures of inhaled anesthetics.


Pharmacology_Katzung

Pharmacology_Katzung. parameter that can be controlled by the anesthesiologist to change alveolar concentration quickly is the inspired concentration or partial pressure. The partial pressure is the fraction of a gas mixture that a particular component comprises. For example, a mixture of gases that may be delivered by an anesthesia machine—70% nitrous oxide, 29% oxygen, and 1% isoflurane at normal barometric pressure (760 mm Hg)—contains partial pressures of 532 mm Hg nitrous oxide, 220 mm Hg oxygen, and 7.6 mm Hg isoflurane. The partial pressure of anesthetic in the inspired gas mixture determines the maximum partial pressure that can be achieved in the alveoli as well as the rate of rise of the partial pressure in the alveoli. To accelerate induction, the anesthesiologist increases the inspired anesthetic partial pressure to create a steeper gradient between inspired and alveolar partial pressure. This fractional rise of anesthetic partial pressure during induction is usually expressed as a ratio of


Pharmacology_Katzung

Pharmacology_Katzung. partial pressure to create a steeper gradient between inspired and alveolar partial pressure. This fractional rise of anesthetic partial pressure during induction is usually expressed as a ratio of alveolar concentration (FA) over inspired concentration (FI); the faster FA/FI approaches 1 (representing inspired-toalveolar equilibrium), the faster anesthesia onset will be during an inhaled induction.


Pharmacology_Katzung

Pharmacology_Katzung. The other parameter under control of the anesthesiologist that directly determines the rate of rise of FA/FI is alveolar ventilation. The anesthesiologist can increase the tidal volume and respiratory rate to deliver larger amounts of anesthetic agent faster. The magnitude of the effect is much greater for inhaled anesthetics with high blood solubility than for those with low blood solubility. The tendency for a given inhaled anesthetic to pass from the gas phase of the alveolus into the pulmonary capillary blood is determined by the blood:gas partition coefficient (see following section on Solubility and Table 25–1). As increased ventilation supplies more anesthetic molecules to the alveolus, a more soluble anesthetic (blood:gas partition coefficient > 1) will traverse the alveolar capillary membrane more readily, preventing a rise in its alveolar partial pressure. Thus, increased ventilation will replenish the alveolar anesthetic concentration for a highly soluble anesthetic but is


Pharmacology_Katzung

Pharmacology_Katzung. membrane more readily, preventing a rise in its alveolar partial pressure. Thus, increased ventilation will replenish the alveolar anesthetic concentration for a highly soluble anesthetic but is not necessary for an anesthetic with low solubility. Therefore, an increase in ventilation produces only a small change in alveolar partial pressure of an anesthetic with low blood solubility, but can significantly increase the partial pressure of agents with moderate to high blood solubility such as halothane. As seen in Figure 25–3, a fourfold increase in the ventilation rate almost doubles the FA/FI ratio for halothane during the first 10 minutes


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 25–1 Pharmacologic properties of inhaled anesthetics. Halothane 2.30 2.9 0.75 >40% Medium rate of onset and recovery 1Partition coefficients (at 37°C) are from multiple literature sources. 2MAC is the anesthetic concentration that produces immobility in 50% of patients exposed to a noxious stimulus. 1.0 0.5 FIGURE 25–3 Effect of ventilation on FA/FI and induction of anesthesia. Increased ventilation (8 L/min versus 2 L/min) accelerates the rate of rise toward equilibration of both halothane and nitrous oxide but results in a larger percentage increase for halothane in the first few minutes of induction. of administration but increases the FA/FI ratio for nitrous oxide by only 15%. Thus, hyperventilation increases the speed of induction of anesthesia with inhaled anesthetics that would normally have a slow onset.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Solubility—As described above, the rate of rise of FA/FI is an important determinant of the speed of induction, but is opposed by the uptake of anesthetic into the blood. Uptake is determined by pharmacokinetic characteristics of each anesthetic agent as well as patient factors.


Pharmacology_Katzung

Pharmacology_Katzung. One of the most important factors influencing the transfer of an anesthetic from the lungs to the arterial blood is its solubility characteristics (Table 25–1). As described above, the blood:gas partition coefficient is a useful index of solubility and defines the relative affinity of an anesthetic for the blood compared to the affinity for inspired gas. Desflurane and nitrous oxide, which are relatively insoluble in blood, display low partition coefficients. When an anesthetic with low blood solubility partitions between gas in the lung and pulmonary capillary blood, equilibrium is quickly established and the blood concentration rises rapidly (Figure 25–4, top; nitrous oxide, desflurane, sevoflurane). Conversely, for anesthetics with greater solubility (Figure 25–4, bottom; halothane, isoflurane), more molecules dissolve in the blood before partial pressure changes significantly, and arterial concentration of the gas increases less rapidly. A blood:gas partition coefficient of 0.47


Pharmacology_Katzung

Pharmacology_Katzung. more molecules dissolve in the blood before partial pressure changes significantly, and arterial concentration of the gas increases less rapidly. A blood:gas partition coefficient of 0.47 for nitrous oxide means that at equilibrium, the concentration in blood is less than half the concentration in the alveolar space (gas). A larger blood:gas partition coefficient causes a greater uptake of anesthetic into the pulmonary blood flow and therefore increases the time required for FA/FI to approach equilibrium (Figure 25–4).


Pharmacology_Katzung

Pharmacology_Katzung. 0.5 FIGURE 25–4 The alveolar anesthetic concentration (FA) approaches the inspired anesthetic concentration (FI) fastest for the least soluble agents. 3.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 25–4 The alveolar anesthetic concentration (FA) approaches the inspired anesthetic concentration (FI) fastest for the least soluble agents. 3. Cardiac output—Changes in the flow rate of blood through the lungs also affect the uptake of anesthetic gases from the alveolar space. An increase in pulmonary blood flow (ie, increased cardiac output) will increase the uptake of anesthetic, thereby slowing the rate by which FA/FI rises and decreasing the rate of induction of anesthesia. Furthermore, one should consider the effect of cardiac output in combination with the tissue distribution and uptake of anesthetic into other tissue compartments. The increased uptake of anesthetic into the blood caused by increased cardiac output will be distributed to all tissues. Since cerebral blood flow is well regulated, the increased anesthesia uptake caused by increased cardiac output will predominantly be distributed to tissues that are not involved in the site of action of the anesthetic.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Alveolar-venous partial pressure difference—The anesthetic partial pressure difference between alveolar and mixed venous blood is dependent mainly on uptake of the anesthetic by the tissues, including nonneural tissues. Depending on the rate and extent of tissue uptake, venous blood returning to the lungs may contain significantly less anesthetic than arterial blood Anesthetic uptake into tissues is influenced by factors similar to those that determine transfer of the anesthetic from the lung to the intravascular space, including tissue:blood partition coefficients (Table 25–1), rates of blood flow to the tissues, and concentration gradients. The greater this difference in anesthetic gas concentrations, the more time it will take to achieve equilibrium with brain tissue.


Pharmacology_Katzung

Pharmacology_Katzung. During the induction phase of anesthesia (and the initial phase of the maintenance period), the tissues that exert greatest influence on the arteriovenous anesthetic concentration gradient are those that are highly perfused (eg, brain, heart, liver, kidneys, and splanchnic bed). Combined, these tissues receive over 75% of the resting cardiac output. In the case of volatile anesthetics with relatively high solubility in highly perfused tissues, venous blood concentration initially is very low, and equilibrium with the alveolar space is achieved slowly.


Pharmacology_Katzung

Pharmacology_Katzung. During maintenance of anesthesia with inhaled anesthetics, the drug continues to be transferred between various tissues at rates dependent on the solubility of the agent, the concentration gradient between the blood and the respective tissue, and the tissue blood flow. Although muscle and skin constitute 50% of the total body mass, anesthetics accumulate more slowly in these tissues than in highly perfused tissues (eg, brain) because they receive only one fifth of the resting cardiac output. Although most anesthetic agents are highly soluble in adipose (fatty) tissues, the relatively low blood perfusion to these tissues delays accumulation, and equilibrium is unlikely to occur with most anesthetics during a typical 1to 3-hour operation.


Pharmacology_Katzung

Pharmacology_Katzung. The combined effect of ventilation, solubility in the different tissues, cardiac output, and blood flow distribution determines the rate of rise of FA/FI characteristic of each drug. Figure 25–5 schematically compares how uptake and distribution proceed with two widely different agents. The anesthetic state is achieved when the partial pressure of the anesthetic in the brain reaches a threshold concentration determined by its potency (MAC; see Table 25–1 and Box: What Does Anesthesia Represent & Where Does It Work?). For an insoluble agent like desflurane, the alveolar partial pressure can quickly equilibrate through the blood and brain compartments to reach anesthetizing concentrations. However, for an agent like halo-thane, its greater solubility in blood and other tissue compartments (higher partition coefficients) produces a steeper decline in the concentration gradient from lung to brain, causing a delayed onset of anesthesia. Therefore, administering a larger concentration of


Pharmacology_Katzung

Pharmacology_Katzung. (higher partition coefficients) produces a steeper decline in the concentration gradient from lung to brain, causing a delayed onset of anesthesia. Therefore, administering a larger concentration of halothane and increasing alveolar ventilation are the two strategies that can be used by anesthesiologists to speed the rate of induction with halothane.


Pharmacology_Katzung

Pharmacology_Katzung. B. Elimination Recovery from inhalation anesthesia follows some of the same principles in reverse that are important during induction. The time to recovery from inhalation anesthesia depends on the rate of elimination of the anesthetic from the brain. One of the most important factors governing rate of recovery is the blood:gas partition coefficient of the anesthetic agent. When the anesthesiologist discontinues the administration of the anesthetic agent to the lung, the alveolar concentration falls rapidly. Insoluble anesthetics that prefer the gas phase over blood will then rapidly diffuse into the alveolus and be removed from the body by the process of lung ventilation. Other factors controlling rate of recovery include pulmonary blood flow and tissue solubility of the anesthetic.


Pharmacology_Katzung

Pharmacology_Katzung. Two features differentiate the recovery phase from the induction phase. First, transfer of an anesthetic from the lungs to blood during induction can be enhanced by increasing its concentration in inspired air, but the reverse transfer process cannot be enhanced because the concentration in the lungs cannot be reduced below zero. Second, at the beginning of the recovery phase, the anesthetic gas tension in different tissues throughout the body may be quite variable, depending on the specific agent and the duration of anesthesia. In contrast, at the start of induction of anesthesia, the initial anesthetic tension is zero in all tissues.


Pharmacology_Katzung

Pharmacology_Katzung. Inhaled anesthetics that are relatively insoluble in blood (ie, possess low blood:gas partition coefficients) and brain are eliminated faster than the more soluble anesthetics. The washout of nitrous oxide, desflurane, and sevoflurane occurs at a rapid rate, leading to a more rapid recovery from their anesthetic effects compared with halothane and isoflurane. Halothane is approximately twice as soluble in brain tissue and five times more soluble in blood than nitrous oxide and desflurane; its elimination therefore takes place more slowly, and recovery from halothaneand isoflurane-based anesthesia is predictably less rapid.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 25–5 Why induction of anesthesia is slower with more soluble anesthetic gases. In this schematic diagram, solubility in blood is represented by the relative size of the blood compartment (the more soluble, the larger the compartment). Relative partial pressures of the agents in the compartments are indicated by the degree of filling of each compartment. For a given concentration or partial pressure of the two anesthetic gases in the inspired air, it will take much longer for the blood partial pressure of the more soluble gas (halothane) to rise to the same partial pressure as in the alveoli. Since the concentration of the anesthetic agent in the brain can rise no faster than the concentration in the blood, the onset of anesthesia will be slower with halothane than with nitrous oxide.


Pharmacology_Katzung

Pharmacology_Katzung. The duration of exposure to the anesthetic can have a significant effect on the speed of emergence from anesthesia, especially in the case of the more soluble anesthetics. Accumulation of anesthetics in muscle, skin, and fat increases with prolonged exposure (especially in obese patients), and blood concentration may decline slowly after discontinuation as the anesthetic is slowly eliminated from these tissues. Although recovery after a short exposure to anesthesia may be rapid even with the more soluble agents, recovery is slow after prolonged administration of halothane or isoflurane. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Ventilation—Two parameters that can be manipulated by the anesthesiologist are useful in controlling the speed of induction of and recovery from inhaled anesthesia: (1) concentration of anesthetic in the inspired gas and (2) alveolar ventilation. As stated above, since the concentration of anesthetic in the inspired gas cannot be reduced below zero, hyperventilation is the only way to speed recovery. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Metabolism—Modern inhaled anesthetics are eliminated mainly by ventilation and are only metabolized to a very small extent; thus, metabolism of these drugs does not play a significant role in the termination of their effect. However, metabolism may have important implications for their toxicity (see Toxicity of Anesthetic Agents). Hepatic metabolism may also contribute to the elimination of and recovery from some older volatile anesthetics. For example, halothane is eliminated more rapidly during recovery than enflurane, which would not be predicted from their respective tissue solubility. This increased elimination occurs because over 40% of inspired halothane is metabolized during an average anesthetic procedure, whereas less than 10% of enflurane is metabolized over the same period.


Pharmacology_Katzung

Pharmacology_Katzung. In terms of the extent of hepatic metabolism, the rank order for the inhaled anesthetics is halothane > enflurane > sevoflurane > isoflurane > desflurane > nitrous oxide (Table 25–1). Nitrous oxide is not metabolized by human tissues. However, bacteria in the gastrointestinal tract may be able to break down the nitrous oxide molecule. Organ System Effects of Inhaled Anesthetics A. CNS Effects Anesthetic potency is currently described by the minimal alveolar concentration (MAC) required to prevent a response to a surgical incision (see Box: What Does Anesthesia Represent & Where Does It Work?). This parameter was first described by investigators in the 1960s and remains the best clinical guide for administering inhaled anesthetics, especially since improved medical technology can now provide instantaneous, accurate determination of gas concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. Inhaled anesthetics (and intravenous anesthetics, discussed later) decrease the metabolic activity of the brain. A decreased cerebral metabolic rate (CMR) generally causes a reduction in blood flow within the brain. However, volatile anesthetics may also produce cerebral vasodilation, which can increase cerebral blood flow. The net effect on cerebral blood flow (increase, decrease, or no change) depends on the concentration of anesthetic delivered. At 0.5 MAC, the reduction in CMR is greater than the vasodilation caused by anesthetics, so cerebral blood flow is decreased. Conversely, at 1.5 MAC, vasodilation by the anesthetic is greater than the reduction in CMR, so cerebral blood flow is increased. In between, at 1.0 MAC, the effects are balanced and cerebral blood flow is unchanged. An increase in cerebral blood flow is clinically undesirable in patients who have increased intracranial pressure because of brain tumor, intracranial hemorrhage, or head injury. Therefore,


Pharmacology_Katzung

Pharmacology_Katzung. An increase in cerebral blood flow is clinically undesirable in patients who have increased intracranial pressure because of brain tumor, intracranial hemorrhage, or head injury. Therefore, administration of high concentrations of volatile anesthetics is best avoided in patients with increased intracranial pressure. Hyperventilation can be used to attenuate this response; decreasing the Paco2 (the partial pressure of carbon dioxide in arterial blood) through hyperventilation causes cerebral vasoconstriction. If the patient is hyperventilated before the volatile agent is started, the increase in intracranial pressure can be minimized.


Pharmacology_Katzung

Pharmacology_Katzung. Nitrous oxide can increase cerebral blood flow and cause increased intracranial pressure. This effect is most likely caused by activation of the sympathetic nervous system (as described below). Therefore, nitrous oxide may be combined with other agents (intravenous anesthetics) or techniques (hyperventilation) that reduce cerebral blood flow in patients with increased intracranial pressure.


Pharmacology_Katzung

Pharmacology_Katzung. Potent inhaled anesthetics produce a basic pattern of change to brain electrical activity as recorded by standard electroencephalography (EEG). Isoflurane, desflurane, sevoflurane, halothane, and enflurane produce initial activation of the EEG at low doses and then slowing of electrical activity up to doses of 1.0–1.5 MAC. At higher concentrations, EEG suppression increases to the point of electrical silence with isoflurane at 2.0–2.5 MAC. Isolated epileptic-like patterns may also be seen between 1.0 and 2.0 MAC, especially with sevoflurane and enflurane, but frank clinical seizure activity has been observed only with enflurane. Nitrous oxide used alone causes fast electrical oscillations emanating from the frontal cortex at doses associated with analgesia and depressed consciousness.


Pharmacology_Katzung

Pharmacology_Katzung. Traditionally, anesthetic effects on the brain produce four stages or levels of increasing depth of CNS depression (Guedel’s signs, derived from observations of the effects of inhaled diethyl ether): Stage I—analgesia: The patient initially experiences analgesia without amnesia. Later in stage I, both analgesia and amnesia are produced. Stage II—excitement: During this stage, the patient appears delirious and may vocalize but is completely amnesic. Respiration is rapid, and heart rate and blood pressure increase. Duration and severity of this light stage of anesthesia are shortened by rapidly increasing the concentration of the agent. Stage III—surgical anesthesia: This stage begins with slowing of respiration and heart rate and extends to complete cessation of spontaneous respiration (apnea). Four planes of stage III are described based on changes in ocular movements, eye reflexes, and pupil size, indicating increasing depth of anesthesia. Stage IV— medullary depression: This deep


Pharmacology_Katzung

Pharmacology_Katzung. Four planes of stage III are described based on changes in ocular movements, eye reflexes, and pupil size, indicating increasing depth of anesthesia. Stage IV— medullary depression: This deep stage of anesthesia represents severe depression of the CNS, including the vasomotor center in the medulla and respiratory center in the brainstem. Without circulatory and respiratory support, death would rapidly ensue in stage IV.


Pharmacology_Katzung

Pharmacology_Katzung. What Does Anesthesia Represent & Where Does It Work?


Pharmacology_Katzung

Pharmacology_Katzung. Anesthetic action has three principal components: immobility, amnesia, and unconsciousness. Immobility Immobility is the easiest anesthetic end point to measure. Edmond Eger and colleagues introduced the concept of minimal alveolar concentration (MAC) to quantify the potency of an inhalational anesthetic. They defined 1.0 MAC as the partial pressure of an inhalational anesthetic in the alveoli of the lungs at which 50% of a population of nonrelaxed patients remained immobile at the time of surgical skin incision. Anesthetic immobility is mediated primar-ily by neural inhibition within the spinal cord but may also include inhibited nociceptive transmission to the brain. Amnesia The ablation of memory arises from several locations in the CNS, including the hippocampus, amygdala, prefrontal cortex, and regions of the sensory and motor cortices. Memory research-ers differentiate two types of memory: (1) explicit memory, ie, specific awareness or consciousness under anesthesia; and (2)


Pharmacology_Katzung

Pharmacology_Katzung. cortex, and regions of the sensory and motor cortices. Memory research-ers differentiate two types of memory: (1) explicit memory, ie, specific awareness or consciousness under anesthesia; and (2) implicit memory, the unconscious acquisition of information under adequate levels of anesthesia. Their studies have found that formation of both types of memory is reliably prevented at low MAC values (0.2–0.4 MAC). Prevention of explicit memory (awareness) has spurred the development of monitors such as the bispectral index, electroencephalogram (EEG), and entropy moni-tor of auditory evoked potentials to help recognize inadequate planes of anesthesia. Consciousness The ability of anesthetic drugs to abolish consciousness requires action at anatomic locations responsible for the formation of human consciousness. Leading neuroscientists study-ing consciousness identify three regions in the brain involved in generating personal awareness: the cerebral cortex, the thalamus, and the reticular


Pharmacology_Katzung

Pharmacology_Katzung. consciousness. Leading neuroscientists study-ing consciousness identify three regions in the brain involved in generating personal awareness: the cerebral cortex, the thalamus, and the reticular activating system. Neural pathways emanating from these regions seem to interact as a cortical system to produce the mental state in which humans are awake, aware, and perceiving. Our current state of understanding supports the following framework: sensory stimuli conducted through the reticular for-mation of the brainstem into supratentorial signaling loops, con-necting the thalamus with various regions of the cortex, are the foundation of consciousness. These neural pathways involved in the development of consciousness are reversibly disrupted by anesthetic agents.


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects Halothane, enflurane, isoflurane, desflurane, and sevoflurane all depress normal cardiac contractility (halothane and enflurane more so than isoflurane, desflurane, and sevoflurane). As a result, all volatile agents tend to decrease mean arterial pressure in direct proportion to their alveolar concentration. With halothane and enflurane, the reduced arterial pressure is caused primarily by myocardial depression (reduced cardiac output) and there is little change in systemic vascular resistance. In contrast, isoflurane, desflurane, and sevoflurane produce greater vasodilation with minimal effect on cardiac output. These differences may have important implications for patients with heart failure. Because isoflurane, desflurane, and sevoflurane better preserve cardiac output as well as reduce preload (ventricular filling) and afterload (systemic vascular resistance), these agents may be better choices for patients with impaired myocardial function.


Pharmacology_Katzung

Pharmacology_Katzung. Nitrous oxide also depresses myocardial function in a concentration-dependent manner. This depression may be significantly offset by a concomitant activation of the sympathetic nervous system resulting in preservation of cardiac output. Therefore, administration of nitrous oxide in combination with the more potent volatile anesthetics can minimize circulatory depressant effects by both anesthetic-sparing and sympathetic-activating actions.


Pharmacology_Katzung

Pharmacology_Katzung. Because all inhaled anesthetics produce a dose-dependent decrease in arterial blood pressure, activation of autonomic nervous system reflexes may trigger increased heart rate. However, halothane, enflurane, and sevoflurane have little effect on heart rate, probably because they attenuate baroreceptor input into the autonomic nervous system. Desflurane and isoflurane significantly increase heart rate because they cause less depression of the baroreceptor reflex. In addition, desflurane can trigger transient sympathetic activation—with elevated catecholamine levels—to cause marked increases in heart rate and blood pressure during administration of high desflurane concentrations or when desflurane concentrations are changed rapidly.


Pharmacology_Katzung

Pharmacology_Katzung. Inhaled anesthetics tend to reduce myocardial oxygen consumption, which reflects depression of normal cardiac contractility and decreased arterial blood pressure. In addition, inhaled anesthetics produce coronary vasodilation. The net effect of decreased oxygen demand and increased coronary flow (oxygen supply) is improved myocardial oxygenation. However, other factors, such as surgical stimulation, intravascular volume status, blood oxygen levels, and withdrawal of perioperative β blockers, may tilt the oxygen supply-demand balance toward myocardial ischemia.


Pharmacology_Katzung

Pharmacology_Katzung. Halothane and, to a lesser extent, other volatile anesthetics sensitize the myocardium to epinephrine and circulating catecholamines. Ventricular arrhythmias may occur when patients under anesthesia with halothane are given sympathomimetic drugs or have high circulating levels of endogenous catecholamines (eg, anxious patients, administration of epinephrine-containing local anesthetics, inadequate intraoperative anesthesia or analgesia, patients with pheochromocytomas). This effect is less marked for isoflurane, sevoflurane, and desflurane. C. Respiratory Effects


Pharmacology_Katzung

Pharmacology_Katzung. C. Respiratory Effects All volatile anesthetics possess varying degrees of bronchodilating properties, an effect of value in patients with active wheezing and in status asthmaticus. However, airway irritation, which may provoke coughing or breath-holding, is induced by the pungency of some volatile anesthetics. The pungency of isoflurane and desflurane makes these agents less suitable for induction of anesthesia in patients with active bronchospasm. These reactions rarely occur with halothane and sevoflurane, which are considered nonpungent. Therefore, the bronchodilating action of halothane and sevoflurane makes them the agents of choice in patients with underlying airway problems. Nitrous oxide is also nonpungent and can facilitate inhalational induction of anesthesia in a patient with bronchospasm.


Pharmacology_Katzung

Pharmacology_Katzung. The control of breathing is significantly affected by inhaled anesthetics. With the exception of nitrous oxide, all inhaled anesthetics in current use cause a dose-dependent decrease in tidal volume and an increase in respiratory rate, resulting in a rapid, shallow breathing pattern. However, the increase in respiratory rate varies among agents and does not fully compensate for the decrease in tidal volume, resulting in a decrease in alveolar ventilation. In addition, all volatile anesthetics are respiratory depressants, as defined by a reduced ventilatory response to increased levels of carbon dioxide in the blood. The degree of ventilatory depression varies among the volatile agents, with isoflurane and enflurane being the most depressant. By this hypoventilation mechanism, all volatile anesthetics increase the resting level of Paco2 in spontaneously breathing patients.


Pharmacology_Katzung

Pharmacology_Katzung. Volatile anesthetics also raise the apneic threshold (Paco2 level below which apnea occurs through lack of CO2-driven respiratory stimulation) and decrease the ventilatory response to hypoxia. Clinically, the respiratory depressant effects of anesthetics are overcome by assisting (controlling) ventilation mechanically. The ventilatory depression produced by inhaled anesthetics may be counteracted by surgical stimulation; however, low, subanesthetic concentrations of volatile anesthetic present after surgery in the early recovery period can continue to depress the compensatory increase in ventilation normally caused by hypoxia. Inhaled anesthetics also depress mucociliary function in the airway. During prolonged exposure to inhaled anesthetics, mucus pooling and plugging may result in atelectasis and the development of postoperative respiratory complications, including hypoxemia and respiratory infections. D. Renal Effects


Pharmacology_Katzung

Pharmacology_Katzung. D. Renal Effects Inhaled anesthetics tend to decrease glomerular filtration rate (GFR) and urine flow. Renal blood flow may also be decreased by some agents, but filtration fraction is increased, implying that autoregulatory control of efferent arteriole tone helps compensate and limits the reduction in GFR. In general these anesthetic effects are minor compared with the stress of surgery itself and usually reversible after discontinuation of the anesthetic. E. Hepatic Effects


Pharmacology_Katzung

Pharmacology_Katzung. E. Hepatic Effects Volatile anesthetics cause a concentration-dependent decrease in portal vein blood flow that parallels the decline in cardiac output produced by these agents. However, total hepatic blood flow may be relatively preserved as hepatic artery blood flow to the liver may increase or stay the same. Although transient changes in liver function tests may occur following exposure to volatile anesthetics, persistent elevation in liver enzymes is rare except following repeated exposures to halothane (see Toxicity of Anesthetic Agents). F. Effects on Uterine Smooth Muscle


Pharmacology_Katzung

Pharmacology_Katzung. F. Effects on Uterine Smooth Muscle Nitrous oxide appears to have little effect on uterine musculature. However, the halogenated anesthetics are potent uterine muscle relaxants and produce this effect in a concentration-dependent fashion. This pharmacologic effect can be helpful when profound uterine relaxation is required for intrauterine fetal manipulation or manual extraction of a retained placenta during delivery. However, it can also lead to increased uterine bleeding after delivery when uterine contraction is desired. Toxicity of Anesthetic Agents A. Acute Toxicity 1.


Pharmacology_Katzung

Pharmacology_Katzung. Toxicity of Anesthetic Agents A. Acute Toxicity 1. Nephrotoxicity—Metabolism of enflurane and sevoflurane may generate compounds that are potentially nephrotoxic. Although their metabolism can liberate nephrotoxic fluoride ions, significant renal injury has been reported only for enflurane with prolonged exposure. The insolubility and rapid elimination of sevoflurane may prevent toxicity. This drug may be degraded by carbon dioxide absorbents in anesthesia machines to form a nephrotoxic vinyl ether compound termed “compound A,” which, in high concentrations, has caused proximal tubular necrosis in rats. Nevertheless, there have been no reports of renal injury in humans receiving sevoflurane anesthesia. Moreover, exposure to sevoflurane does not produce any change in standard markers of renal function. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Hematotoxicity—Prolonged exposure to nitrous oxide decreases methionine synthase activity, which theoretically could cause megaloblastic anemia. Megaloblastic bone marrow changes have been observed in patients after 12-hour exposure to 50% nitrous oxide. Chronic exposure of dental personnel to nitrous oxide in inadequately ventilated dental operating suites is a potential occupational hazard. All inhaled anesthetics can produce some carbon monoxide (CO) from their interaction with strong bases in dry carbon dioxide absorbers. CO binds to hemoglobin with high affinity, reducing oxygen delivery to tissues. Desflurane produces the most CO, and intraoperative formation of CO has been reported. CO production can be avoided simply by using fresh carbon dioxide absorbent and by preventing its complete desiccation. 3.


Pharmacology_Katzung

Pharmacology_Katzung. Malignant hyperthermia—Malignant hyperthermia is a heritable genetic disorder of skeletal muscle that occurs in susceptible individuals exposed to volatile anesthetics while undergoing general anesthesia (see Chapter 16 and Table 16–4). The depolarizing muscle relaxant succinylcholine may also trigger malignant hyperthermia. The malignant hyperthermia syndrome consists of muscle rigidity, hyperthermia, rapid onset of tachycardia and hypercapnia, hyperkalemia, and metabolic acidosis following exposure to one or more triggering agents. Malignant hyperthermia is a rare but important cause of anesthetic morbidity and mortality. A specific biochemical abnormality—an increase in free cytosolic calcium concentration in skeletal muscle cells—may be the underlying cellular basis of malignant hyperthermia. Treatment includes administration of dantrolene (to reduce calcium release from the sarcoplasmic reticulum) and appropriate measures to reduce body temperature and restore electrolyte and


Pharmacology_Katzung

Pharmacology_Katzung. Treatment includes administration of dantrolene (to reduce calcium release from the sarcoplasmic reticulum) and appropriate measures to reduce body temperature and restore electrolyte and acid-base balance (see Chapter 27).


Pharmacology_Katzung

Pharmacology_Katzung. Malignant hyperthermia susceptibility is characterized by genetic heterogeneity, and several predisposing clinical myopathies have been identified. It has been associated with mutations in the gene coding for the skeletal muscle ryanodine receptor (RyR1, the calcium release channel on the sarcoplasmic reticulum), and mutant alleles of the gene encoding the α1 subunit of the human skeletal muscle l-type voltage-dependent calcium channel. However, the genetic loci identified to date account for less than 50% of malignant hyperthermia-susceptible individuals, and genetic testing cannot definitively determine malignant hyperthermia susceptibility. Currently, the most reliable test to establish susceptibility is the in vitro caffeine-halothane contracture test using skeletal muscle biopsy samples. Genetic counseling is recommended for family members of a person who has experienced a well-documented malignant hyperthermia reaction in the operating room. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Hepatotoxicity (halothane hepatitis)—Hepatic dysfunction following surgery and general anesthesia is most likely caused by hypovolemic shock, infection conferred by blood transfusion, or other surgical stresses rather than by volatile anesthetic toxicity. However, a small subset of individuals previously exposed to halo-thane developed fulminant hepatic failure. The incidence of severe hepatotoxicity following exposure to halothane is estimated to be in the range of 1 in 20,000–35,000. The mechanisms underlying halothane hepatotoxicity remain unclear, but studies in animals implicate the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radicals) or initiate immune-mediated responses. Cases of hepatitis following exposure to other volatile anesthetics, including enflurane, isoflurane, and desflurane, have rarely been reported. B. Chronic Toxicity 1. Mutagenicity, teratogenicity, and reproductive effects—


Pharmacology_Katzung

Pharmacology_Katzung. B. Chronic Toxicity 1. Mutagenicity, teratogenicity, and reproductive effects— Under normal conditions, inhaled anesthetics including nitrous oxide are neither mutagens nor carcinogens in patients. Nitrous oxide can be directly teratogenic in animals under conditions of extremely high exposure. Halothane, enflurane, isoflurane, desflurane, and sevoflurane may be teratogenic in rodents as a result of physiologic changes associated with the anesthesia rather than through a direct teratogenic effect.


Pharmacology_Katzung

Pharmacology_Katzung. The most consistent finding in surveys conducted to determine the reproductive success of female operating room personnel has been a questionably higher-than-expected incidence of miscarriages. However, there are several problems in interpreting these studies. The association of obstetric problems with surgery and anesthesia in pregnant patients is also an important consideration. In the United States, at least 50,000 pregnant women each year undergo anesthesia and surgery for indications unrelated to pregnancy. The risk of abortion is clearly higher following this experience. It is not obvious, however, whether the underlying disease, surgery, anesthesia, or a combination of these factors is the cause of the increased risk.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Carcinogenicity—Epidemiologic studies suggested an increase in the cancer rate in operating room personnel who were exposed to trace concentrations of anesthetic agents. However, no study has demonstrated the existence of a causal relationship between anesthetics and cancer. Many other factors might account for the questionably positive results seen after a careful review of epidemiologic data. Anesthesia machines are now equipped with gas scavenging systems to remove concentrations of anesthetics administered to patients, and operating rooms rely on high air exchange rates to remove any trace concentrations of anesthetics released from anesthesia machines.


Pharmacology_Katzung

Pharmacology_Katzung. Intravenous nonopioid anesthetics play an essential role in the practice of modern anesthesia. They are used to facilitate rapid induction of anesthesia and have replaced inhalation as the preferred method of anesthesia induction in most settings except for pediatric anesthesia. Intravenous agents are also commonly used to provide sedation during monitored anesthesia care and for patients in ICU settings. With the introduction of propofol, intravenous anesthesia also became a good option for the maintenance of anesthesia. However, similar to the inhaled agents, the currently available intravenous anesthetics are not ideal anesthetic drugs in the sense of producing all and only the five desired effects (unconsciousness, amnesia, analgesia, inhibition of autonomic reflexes, and skeletal muscle relaxation). Therefore, balanced anesthesia employing multiple drugs (inhaled anesthetics, sedative-hypnotics, opioids, neuromuscular blocking drugs) is generally used to minimize unwanted


Pharmacology_Katzung

Pharmacology_Katzung. muscle relaxation). Therefore, balanced anesthesia employing multiple drugs (inhaled anesthetics, sedative-hypnotics, opioids, neuromuscular blocking drugs) is generally used to minimize unwanted effects.


Pharmacology_Katzung

Pharmacology_Katzung. The intravenous anesthetics used for induction of general anesthesia are lipophilic and preferentially partition into highly perfused lipophilic tissues (brain, spinal cord), which accounts for their rapid onset of action. Regardless of the extent and speed of their metabolism, termination of the effect of a single bolus is determined by redistribution of the drug into less perfused and inactive tissues such as skeletal muscle and fat. Thus, all drugs used for induction of anesthesia have a similar duration of action when administered as a single bolus dose despite significant differences in their metabolism. Figure 25–6 shows the chemical FIGURE 25–6 Chemical structures of some intravenous anesthetics. structures of common clinically used intravenous anesthetics. Table 25–2 lists pharmacokinetic properties of these and other intravenous agents.


Pharmacology_Katzung

Pharmacology_Katzung. In most countries, propofol is the most frequently administered drug for induction of anesthesia, and it has largely replaced barbiturates in this setting. Because its pharmacokinetic profile allows for continuous infusions, propofol is a good alternative to inhaled anesthetics for maintenance of anesthesia and is a common choice for sedation in the setting of monitored anesthesia care. When used during maintenance of anesthesia, propofol infusion can be supplemented with intravenous opioids and neuromuscular blockers as needed to completely avoid the use of inhaled anesthetics (total intravenous anesthesia, TIVA). Alternatively, a propofol infusion might be used to reduce the required concentration of inhaled anesthetics so that undesired effects can be minimized. Increasingly, propofol is also used for sedation in the ICU as well as conscious sedation and TABLE 25–2 Pharmacokinetic properties of intravenous anesthetics.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 25–2 Pharmacokinetic properties of intravenous anesthetics. Note: The duration of action reflects the duration after a typical single IV dose given for induction of anesthesia. Data are for average adult patients. CL, clearance; NA, not applicable; Vdss, volume of distribution at steady state. short-duration general anesthesia in locations outside the operating 100 room (eg, interventional radiology suites, emergency department; see Box: Sedation & Monitored Anesthesia Care, earlier). Propofol (2,6-diisopropylphenol) is an alkyl phenol with hyp- 0.125 0.5 1 4 16 64 256 notic properties that is chemically distinct from other groups of intravenous anesthetics (Figure 25–6). Because of its poor solubility in water, it is formulated as an emulsion containing 10% soybean oil, 2.25% glycerol, and 1.2% lecithin, the major component of


Pharmacology_Katzung

Pharmacology_Katzung. Percent of dose the egg yolk phosphatide fraction. Hence, susceptible patients may experience allergic reactions. The solution appears milky white and slightly viscous, has a pH of approximately 7, and has a propofol concentration of 1% (10 mg/mL). In some countries, a 2% formulation is available. Although retardants of bacterial growth are added to the formulations, solutions should be used as soon as possible (unused drug must be discarded 12 hours after opening the vial), and proper sterile technique is essential. The addition of metabisulfite in one of the formulations has raised concern regarding its use in patients with reactive airway disease (eg, asthma) or sulfite allergies. The presumed mechanism of action of propofol is through potentiation of the chloride current mediated through the GABAA receptor complex.


Pharmacology_Katzung

Pharmacology_Katzung. Propofol is rapidly metabolized in the liver; the resulting water-soluble compounds are presumed to be inactive and are excreted through the kidneys. Plasma clearance is high and exceeds hepatic blood flow, indicating the importance of extrahepatic metabolism, which presumably occurs in the lungs and may account for the elimination of up to 30% of a bolus dose of the drug (Table 25–2). The recovery from propofol is more complete, with less “hangover” than that observed with thiopental, likely due to the high plasma clearance. However, as with other intravenous drugs, transfer of propofol from the plasma (central) compartment and the associated termination of drug effect after a single bolus dose are mainly the result of redistribution from highly perfused (brain) to less-wellperfused (skeletal muscle) compartments (Figure 25–7). As with other intravenous agents, awakening after an induction dose of propofol usually occurs within 8–10 minutes. The kinetics of


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 25–7 Redistribution of thiopental after an intravenous bolus administration. The redistribution curves for bolus administration of other intravenous anesthetics are similar, explaining the observation that recovery times are the same despite remarkable differences in metabolism. Note that the time axis is not linear.


Pharmacology_Katzung

Pharmacology_Katzung. movement are occasionally observed during induction of anesthesia. These effects may resemble seizure activity; however, most studies support an anticonvulsant effect of propofol, and the drug may be safely administered to patients with seizure disorders. Propofol decreases cerebral blood flow and the cerebral metabolic rate for oxygen (CMRO2), which decreases intracranial pressure (ICP) and intraocular pressure; the magnitude of these changes is comparable to that of thiopental. Although propofol can produce a desired decrease in ICP, the combination of reduced cerebral blood flow and reduced mean arterial pressure due to peripheral vasodilation can critically decrease cerebral perfusion pressure.


Pharmacology_Katzung

Pharmacology_Katzung. When administered in large doses, propofol produces burst suppression in the EEG, an end point that has been used when propofol (and other intravenous anesthetics) after a single bolus dose or continuous infusion are best described by means of a three-compartment model. Such models have been used as the basis for developing systems of target-controlled infusions. The context-sensitive half-time of a drug describes the elimination half-time after discontinuation of a continuous infusion as a function of the duration of the infusion. It is an important parameter in assessing the suitability of a drug for use as maintenance anesthetic. The context-sensitive half-time of propofol is brief, even after a prolonged infusion, and therefore, recovery occurs relatively promptly (Figure 25–8). A. CNS Effects Propofol acts as hypnotic but does not have analgesic properties. Although the drug leads to a general suppression of CNS activity, excitatory effects such as twitching or spontaneous


Pharmacology_Katzung

Pharmacology_Katzung. Propofol acts as hypnotic but does not have analgesic properties. Although the drug leads to a general suppression of CNS activity, excitatory effects such as twitching or spontaneous FIGURE 25–8 The context-sensitive half-time of common intravenous anesthetics. Even after a prolonged infusion, the half-time of propofol is relatively short, which makes propofol the preferred choice for intravenous anesthesia. Ketamine and etomidate have similar characteristics, but their use is limited by other effects. administering intravenous anesthetics for neuroprotection during neurosurgical procedures. Evidence from animal studies suggests that propofol’s neuroprotective effects during focal ischemia are similar to those of thiopental and isoflurane. B. Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects Compared with other induction drugs, propofol produces the most pronounced decrease in systemic blood pressure; this is a result of profound vasodilation in both arterial and venous circulations leading to reductions in preload and afterload. This effect on systemic blood pressure is more pronounced with increased age, in patients with reduced intravascular fluid volume, and with rapid injection. Because the hypotensive effects are further augmented by the inhibition of the normal baroreflex response, the vasodilation only leads to a small increase in heart rate. In fact, profound bradycardia and asystole after the administration of propofol have been described in healthy adults despite prophylactic anticholinergic drugs. C. Respiratory Effects


Pharmacology_Katzung

Pharmacology_Katzung. C. Respiratory Effects Propofol is a potent respiratory depressant and generally produces apnea after an induction dose. A maintenance infusion reduces minute ventilation through reductions in tidal volume and respiratory rate, with the effect on tidal volume being more pronounced. In addition, the ventilatory response to hypoxia and hypercapnia is reduced. Propofol causes a greater reduction in upper airway reflexes than thiopental does, which makes it well suited for instrumentation of the airway, such as placement of a laryngeal mask airway. D. Other Effects


Pharmacology_Katzung

Pharmacology_Katzung. D. Other Effects Although propofol, unlike volatile anesthetics, does not augment neuromuscular block, studies have found good intubating conditions after propofol induction without the use of neuromuscular blocking agents. Unexpected tachycardia occurring during propofol anesthesia should prompt laboratory evaluation for possible metabolic acidosis (propofol infusion syndrome). An interesting and desirable side effect of propofol is its antiemetic activity. Pain on injection is a common complaint and can be reduced by premedication with an opioid or coadministration with lidocaine. Dilution of propofol and the use of larger veins for injection can also reduce the incidence and severity of injection pain.


Pharmacology_Katzung

Pharmacology_Katzung. The most common use of propofol is to facilitate induction of general anesthesia by bolus injection of 1–2.5 mg/kg IV. Increasing age, reduced cardiovascular reserve, or premedication with benzodiazepines or opioids reduces the required induction dose; children require higher doses (2.5–3.5 mg/kg IV). Generally, titration of the induction dose helps to prevent severe hemodynamic changes. Propofol is often used for maintenance of anesthesia either as part of a balanced anesthesia regimen in combination with volatile anesthetics, nitrous oxide, sedative-hypnotics, and opioids or as part of a total intravenous anesthetic technique, usually in combination with opioids. Therapeutic plasma concentrations for maintenance of anesthesia normally range between 3 and 8 mcg/mL (typically requiring a continuous infusion rate between 100 and 200 mcg/kg/min) when combined with nitrous oxide or opioids.


Pharmacology_Katzung

Pharmacology_Katzung. When used for sedation of mechanically ventilated patients in the ICU or for sedation during procedures, the required plasma concentration is 1–2 mcg/mL, which can be achieved with a continuous infusion at 25–75 mcg/kg/min. Because of its pronounced respiratory depressant effect and narrow therapeutic range, propofol should be administered only by individuals trained in airway management. Subanesthetic doses of propofol can be used to treat postoperative nausea and vomiting (10–20 mg IV as bolus or 10 mcg/kg/ min as an infusion).


Pharmacology_Katzung

Pharmacology_Katzung. Subanesthetic doses of propofol can be used to treat postoperative nausea and vomiting (10–20 mg IV as bolus or 10 mcg/kg/ min as an infusion). As previously noted, injection pain during administration of propofol is often perceived as severe, and the lipid emulsion has several disadvantages. Intense research has focused on finding alternative formulations or related drugs that would address some of these problems. Fospropofol is a water-soluble prodrug of propofol, is rapidly metabolized by alkaline phosphatase, and produces propofol, phosphate, and formaldehyde. The formaldehyde is metabolized by aldehyde dehydrogenase in the liver and in erythrocytes. The available fospropofol formulation is a sterile, aqueous, colorless, and clear solution that is supplied in a single-dose vial at a concentration of 35 mg/mL under the trade name Lusedra.


Pharmacology_Katzung

Pharmacology_Katzung. Because the active compound is propofol and fospropofol is a prodrug that requires metabolism to form propofol, the pharmacokinetics are more complex than for propofol itself. Multicompartment models with two compartments for fospropofol and three for propofol have been used to describe the kinetics. The effect profile of fospropofol is similar to that of propofol, but onset and recovery are prolonged compared with propofol because the prodrug must first be converted into an active form. Although patients receiving fospropofol do not appear to experience the injection pain typical of propofol, a common adverse effect is the experience of paresthesia, often in the perianal region, which occurs in up to 74% of patients. The mechanism for this effect is unknown.


Pharmacology_Katzung

Pharmacology_Katzung. Fospropofol is approved for sedation during monitored anesthesia care. Supplemental oxygen must be administered to all patients receiving the drug. As with propofol, airway compromise is a major concern. Hence, it is recommended that fospropofol be administered only by personnel trained in airway management. The recommended standard dosage is an initial bolus dose of 6.5 mg/kg IV followed by supplemental doses of 1.6 mg/kg IV as needed. For patients weighing more than 90 kg or less than 60 kg, 90 or 60 kg should be used to calculate the dose, respectively. The dose should be reduced by 25% in patients older than 65 years and in those with an American Society of Anesthesiologists status of 3 or 4. This section focuses on the use of thiopental and methohexital for induction of general anesthesia; however, these barbiturate hypnotics have been largely replaced as induction agents by propofol. Other barbiturates and general barbiturate pharmacology are discussed in Chapter 22.


Pharmacology_Katzung

Pharmacology_Katzung. The anesthetic effect of barbiturates presumably involves a combination of enhancement of inhibitory transmission and inhibition of excitatory neurotransmission (Figure 25–1). Although the effects on inhibitory transmission probably result from activation of the GABAA receptor complex, the effects on excitatory transmission are less well understood.


Pharmacology_Katzung

Pharmacology_Katzung. Thiopental and methohexital undergo hepatic metabolism, mostly by oxidation but also by N-dealkylation, desulfuration, and destruction of the barbituric acid ring structure. Barbiturates should not be administered to patients with acute intermittent porphyria because they increase the production of porphyrins through stimulation of aminolevulinic acid synthetase. Methohexital has a shorter elimination half-time than thiopental due to its larger plasma clearance (Table 25–2), leading to a faster and more complete recovery after bolus injection. Although thiopental is metabolized more slowly and has a long elimination half-time, recovery after a single bolus injection is comparable to that of methohexital and propofol because it depends on redistribution to inactive tissue sites rather than on metabolism (Figure 25–7). However, if administered through repeated bolus injections or continuous infusion, recovery will be markedly prolonged because elimination will depend on metabolism under


Pharmacology_Katzung

Pharmacology_Katzung. on metabolism (Figure 25–7). However, if administered through repeated bolus injections or continuous infusion, recovery will be markedly prolonged because elimination will depend on metabolism under these circumstances (see also context-sensitive half-time, Figure 25–8).


Pharmacology_Katzung

A. CNS Effects

Pharmacology_Katzung. A. CNS Effects


Pharmacology_Katzung

Pharmacology_Katzung. Barbiturates produce dose-dependent CNS depression ranging from sedation to general anesthesia when administered as bolus injections. They do not produce analgesia; instead, some evidence suggests they may reduce the pain threshold, causing hyperalgesia. Barbiturates are potent cerebral vasoconstrictors and produce predictable decreases in cerebral blood flow, cerebral blood volume, and ICP. As a result, they decrease CMRO2 consumption in a dose-dependent manner up to a dose at which they suppress all EEG activity. The ability of barbiturates to decrease ICP and CMRO2 makes these drugs useful in the management of patients with space-occupying intracranial lesions. They may provide neuroprotection from focal cerebral ischemia (stroke, surgical retraction, temporary clips during aneurysm surgery), but probably not from global cerebral ischemia (eg, from cardiac arrest). Except for methohexital, barbiturates decrease electrical activity on the EEG and can be used as anticonvulsants. In


Pharmacology_Katzung

Pharmacology_Katzung. but probably not from global cerebral ischemia (eg, from cardiac arrest). Except for methohexital, barbiturates decrease electrical activity on the EEG and can be used as anticonvulsants. In contrast, methohexital activates epileptic foci and may therefore be useful to facilitate electroconvulsive therapy or during the identification of epileptic foci during surgery.


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects The decrease in systemic blood pressure associated with administration of barbiturates for induction of anesthesia is primarily due to peripheral vasodilation and is usually smaller than the blood pressure decrease associated with propofol. There are also direct negative inotropic effects on the heart. However, inhibition of the baroreceptor reflex is less pronounced than with propofol; thus, compensatory increases in heart rate limit the decrease in blood pressure and make it transient. The depressant effects on systemic blood pressure are increased in patients with hypovolemia, cardiac tamponade, cardiomyopathy, coronary artery disease, or cardiac valvular disease because such patients are less able to compensate for the effects of peripheral vasodilation. Hemodynamic effects are also more pronounced with larger doses and rapid injection. C. Respiratory Effects


Pharmacology_Katzung

Pharmacology_Katzung. Barbiturates are respiratory depressants, and a usual induction dose of thiopental or methohexital typically produces transient apnea, which will be more pronounced if other respiratory depressants are also administered. Barbiturates lead to decreased minute ventilation through reduced tidal volumes and respiratory rate and also decrease the ventilatory responses to hypercapnia and hypoxia. Resumption of spontaneous breathing after an anesthetic induction dose of a barbiturate is characterized by a slow breathing rate and decreased tidal volume. Suppression of laryngeal reflexes and cough reflexes is probably not as profound as after an equianesthetic propofol administration, which makes barbiturates an inferior choice for airway instrumentation in the absence of neuromuscular blocking drugs. Furthermore, stimulation of the upper airway or trachea (eg, by secretions, laryngeal mask airway, direct laryngoscopy, tracheal intubation) during inadequate depression of airway reflexes may


Pharmacology_Katzung

Pharmacology_Katzung. drugs. Furthermore, stimulation of the upper airway or trachea (eg, by secretions, laryngeal mask airway, direct laryngoscopy, tracheal intubation) during inadequate depression of airway reflexes may result in laryngospasm or bronchospasm. This phenomenon is not unique to barbiturates but is true whenever the drug dose is inadequate to suppress the airway reflexes.


Pharmacology_Katzung

Pharmacology_Katzung. D. Other Effects Accidental intra-arterial injection of barbiturates results in excruciating pain and intense vasoconstriction, often leading to severe tissue injury involving gangrene. Approaches to treatment include blockade of the sympathetic nervous system (eg, stellate ganglion block) in the involved extremity. If extravasation occurs, some authorities recommend local injection of the area with 0.5% lidocaine (5–10 mL) in an attempt to dilute the barbiturate concentration. Life-threatening allergic reactions to barbiturates are rare, with an estimated occurrence of 1 in 30,000 patients. However, barbiturate-induced histamine release occasionally is seen.


Pharmacology_Katzung

Pharmacology_Katzung. The principal clinical use of thiopental (3–5 mg/kg IV) or methohexital (1–1.5 mg/kg IV) is for induction of anesthesia (unconsciousness), which usually occurs in less than 30 seconds. Patients may experience a garlic or onion taste after administration. Solutions of thiopental sodium for intravenous injection have a pH range of 10–11 to maintain stability. Rapid co-injection with depolarizing and nondepolarizing muscle relaxants, which have much lower pH, may cause precipitation of insoluble thiopentone acid. Barbiturates such as methohexital (20–30 mg/kg) may be administered per rectum to facilitate induction of anesthesia in mentally challenged patients and uncooperative pediatric patients. When a barbiturate is administered with the goal of neuroprotection, an isoelectric EEG indicating maximal reduction of CMRO2 has traditionally been used as the end point. More recent data demonstrating equal protection after smaller doses have challenged this practice. The use of smaller doses


Pharmacology_Katzung

Pharmacology_Katzung. maximal reduction of CMRO2 has traditionally been used as the end point. More recent data demonstrating equal protection after smaller doses have challenged this practice. The use of smaller doses is less frequently associated with hypotension, thus making it easier to maintain adequate cerebral perfusion pressure, especially in the setting of increased ICP.


Pharmacology_Katzung

Pharmacology_Katzung. Benzodiazepines commonly used in the perioperative period include midazolam, lorazepam, and less frequently, diazepam. Benzodiazepines are unique among the group of intravenous anesthetics in that their action can readily be terminated by administration of their selective antagonist, flumazenil. Their most desired effects are anxiolysis and anterograde amnesia, which are extremely useful for premedication. The chemical structure and pharmacodynamics of the benzodiazepines are discussed in detail in Chapter 22. Pharmacokinetics in the Anesthesia Setting The highly lipid-soluble benzodiazepines rapidly enter the CNS, which accounts for their rapid onset of action, followed by redistribution to inactive tissue sites and subsequent termination of the drug effect. Additional information regarding the pharmacokinetics of the benzodiazepines may be found in Chapter 22.


Pharmacology_Katzung

Pharmacology_Katzung. Despite its prompt passage into the brain, midazolam is considered to have a slower effect-site equilibration time than propofol and thiopental. In this regard, intravenous doses of midazolam should be sufficiently spaced to permit the peak clinical effect to be recognized before a repeat dose is considered. Midazolam has the shortest context-sensitive half-time, which makes it the only one of the three benzodiazepine drugs suitable for continuous infusion (Figure 25–8). A. CNS Effects


Pharmacology_Katzung

Pharmacology_Katzung. A. CNS Effects Benzodiazepines decrease CMRO2 and cerebral blood flow but to a smaller extent than propofol or the barbiturates. There appears to be a ceiling effect for benzodiazepine-induced decreases in CMRO2 as evidenced by midazolam’s inability to produce an isoelectric EEG. Patients with decreased intracranial compliance demonstrate little or no change in ICP after the administration of midazolam. Although neuroprotective properties have not been shown for benzodiazepines, these drugs are potent anticonvulsants used in the treatment of status epilepticus, alcohol withdrawal, and local anesthetic-induced seizures. The CNS effects of benzodiazepines can be promptly terminated by administration of the selective benzodiazepine antagonist flumazenil, which improves their safety profile. B. Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects If used for the induction of anesthesia, midazolam produces a greater decrease in systemic blood pressure than comparable doses of diazepam. These changes are most likely due to peripheral vasodilation inasmuch as cardiac output is not changed. Similar to other intravenous induction agents, midazolam’s effect on systemic blood pressure is exaggerated in hypovolemic patients. C. Respiratory Effects


Pharmacology_Katzung

Pharmacology_Katzung. C. Respiratory Effects Benzodiazepines produce minimal depression of ventilation, although transient apnea may follow rapid intravenous administration of midazolam for induction of anesthesia, especially in the presence of opioid premedication. Benzodiazepines decrease the ventilatory response to carbon dioxide, but this effect is not usually significant if they are administered alone. More severe respiratory depression can occur when benzodiazepines are administered together with opioids. Another problem affecting ventilation is airway obstruction induced by the hypnotic effects of benzodiazepines. D. Other Effects


Pharmacology_Katzung

Pharmacology_Katzung. D. Other Effects Pain during intravenous and intramuscular injection and subsequent thrombophlebitis are most pronounced with diazepam and reflect the poor water solubility of this benzodiazepine, which requires an organic solvent in the formulation. Despite its better solubility (which eliminates the need for an organic solvent), midazolam may also produce pain on injection. Allergic reactions to benzodiazepines are rare to nonexistent.


Pharmacology_Katzung

Pharmacology_Katzung. Benzodiazepines are most commonly used for preoperative medication, intravenous sedation, and suppression of seizure activity. Less frequently, midazolam and diazepam may also be used to induce general anesthesia. The slow onset and prolonged duration of action of lorazepam limit its usefulness for preoperative medication or induction of anesthesia, especially when rapid and sustained awakening at the end of surgery is desirable. Although flumazenil (8–15 mcg/kg IV) may be useful for treating patients experiencing delayed awakening, its duration of action is brief (about 20 minutes) and resedation may occur.


Pharmacology_Katzung

Pharmacology_Katzung. The amnestic, anxiolytic, and sedative effects of benzodiazepines make this class of drugs the most popular choice for preoperative medication. Midazolam (1–2 mg IV) is effective for premedication, sedation during regional anesthesia, and brief therapeutic procedures. Midazolam has a more rapid onset, with greater amnesia and less postoperative sedation, than diazepam. Midazolam is also the most commonly used oral premedication for children; 0.5 mg/kg administered orally 30 minutes before induction of anesthesia provides reliable sedation and anxiolysis in children without producing delayed awakening.


Pharmacology_Katzung

Pharmacology_Katzung. The synergistic effects between benzodiazepines and other drugs, especially opioids and propofol, can be used to achieve better sedation and analgesia but may also greatly enhance their combined respiratory depression and may lead to airway obstruction or apnea. Because benzodiazepine effects are more pronounced with increasing age, dose reduction and careful titration may be necessary in elderly patients. General anesthesia can be induced by the administration of midazolam (0.1–0.3 mg/kg IV), but the onset of unconsciousness is slower than after the administration of thiopental, propofol, or etomidate. Delayed awakening is a potential disadvantage, limiting the usefulness of benzodiazepines for induction of general anesthesia despite their advantage of less pronounced circulatory effects.


Pharmacology_Katzung

Pharmacology_Katzung. Etomidate (Figure 25–6) is an intravenous anesthetic with hypnotic but not analgesic effects and is often chosen for its minimal hemodynamic effects. Although its pharmacokinetics are favorable, endocrine side effects limit its use for continuous infusions. Etomidate is a carboxylated imidazole derivative that is poorly soluble in water and is therefore supplied as a 2 mg/mL solution in 35% propylene glycol. The solution has a pH of 6.9 and does not cause problems with precipitation as thiopental does. Etomidate appears to have GABA-like effects and seems to act primarily through potentiation of GABAA-mediated chloride current, like most other intravenous anesthetics.


Pharmacology_Katzung

Pharmacology_Katzung. An induction dose of etomidate produces rapid onset of anesthesia, and recovery depends on redistribution to inactive tissue sites, comparable to thiopental and propofol. Metabolism is primarily by ester hydrolysis to inactive metabolites, which are then excreted in urine (78%) and bile (22%). Less than 3% of an administered dose of etomidate is excreted as unchanged drug in urine. Clearance of etomidate is about five times that of thiopental, as reflected by a shorter elimination half-time (Table 25–2). The duration of action is linearly related to the dose, with each 0.1 mg/kg providing about 100 seconds of unconsciousness. Because of etomidate’s minimal effects on hemodynamics and short context-sensitive half-time, larger doses, repeated boluses, or continuous infusions can safely be administered. Etomidate, like most other intravenous anesthetics, is highly protein bound (77%), primarily to albumin. A. CNS Effects


Pharmacology_Katzung

Pharmacology_Katzung. A. CNS Effects Etomidate is a potent cerebral vasoconstrictor, as reflected by decreases in cerebral blood flow and ICP. These effects are similar to those produced by comparable doses of thiopental. Despite its reduction of CMRO2, etomidate has failed to show neuroprotective properties in animal studies, and human studies are lacking. The frequency of excitatory spikes on the EEG after the administration of etomidate is greater than with thiopental. Similar to methohexital, etomidate may activate seizure foci, manifested as fast activity on the EEG. In addition, spontaneous movements characterized as myoclonus occur in more than 50% of patients receiving etomidate, and this myoclonic activity may be associated with seizure-like activity on the EEG. B. Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects A characteristic and desired feature of induction of anesthesia with etomidate is cardiovascular stability after bolus injection. In this regard, decrease in systemic blood pressure is modest or absent and principally reflects a decrease in systemic vascular resistance. Therefore, the systemic blood pressure-lowering effects of etomidate are probably exaggerated in the presence of hypovolemia, and the patient’s intravascular fluid volume status should be optimized before induction of anesthesia. Etomidate produces minimal changes in heart rate and cardiac output. Its depressant effects on myocardial contractility are minimal at concentrations used for induction of anesthesia. C. Respiratory Effects


Pharmacology_Katzung

Pharmacology_Katzung. C. Respiratory Effects The depressant effects of etomidate on ventilation are less pronounced than those of barbiturates, although apnea may occasionally follow rapid intravenous injection of the drug. Depression of ventilation may be exaggerated when etomidate is combined with inhaled anesthetics or opioids. D. Endocrine Effects Etomidate causes adrenocortical suppression by producing a dose-dependent inhibition of 11β-hydroxylase, an enzyme necessary for the conversion of cholesterol to cortisol (see Figure 39–1). This suppression lasts 4–8 hours after an induction dose of the drug. Despite concerns regarding this finding, no outcome studies have demonstrated an adverse effect when etomidate is given in a bolus dose. However, because of its endocrine effects, etomidate is not used as continuous infusion.


Pharmacology_Katzung

Pharmacology_Katzung. Etomidate is an alternative to propofol and barbiturates for the rapid intravenous induction of anesthesia, especially in patients with compromised myocardial contractility. After a standard induction dose (0.2–0.3 mg/kg IV), the onset of unconsciousness is comparable to that achieved by thiopental and propofol. Similar to propofol, during intravenous injection of etomidate, there is a high incidence of pain, which may be followed by venous irritation. Involuntary myoclonic movements are also common but may be masked by the concomitant administration of neuromuscular blocking drugs. Awakening after a single intravenous dose of etomidate is rapid, with little evidence of any residual depressant effects. Etomidate does not produce analgesia, and postoperative nausea and vomiting may be more common than after the administration of thiopental or propofol.


Pharmacology_Katzung

Pharmacology_Katzung. Ketamine (Figure 25–6) is a partially water-soluble and highly lipid-soluble phencyclidine derivative differing from most other intravenous anesthetics in that it produces significant analgesia. The characteristic state observed after an induction dose of ketamine is known as “dissociative anesthesia,” wherein the patient’s eyes remain open with a slow nystagmic gaze (cataleptic state). Of the two stereoisomers, the S(+) form is more potent than the R(−) isomer, but only the racemic mixture of ketamine is available in the USA. Ketamine’s mechanism of action is complex, but the major effect is probably produced through inhibition of the NMDA receptor complex.


Pharmacology_Katzung

Pharmacology_Katzung. Ketamine’s mechanism of action is complex, but the major effect is probably produced through inhibition of the NMDA receptor complex. The high lipid solubility of ketamine ensures a rapid onset of its effect. As with other intravenous induction drugs, the effect of a single bolus injection is terminated by redistribution to inactive tissue sites. Metabolism occurs primarily in the liver and involves N-demethylation by the cytochrome P450 system. Norketamine, the primary active metabolite, is less potent (one third to one fifth the potency of ketamine) and is subsequently hydroxylated and conjugated into water-soluble inactive metabolites that are excreted in urine. Ketamine is the only intravenous anesthetic that has low protein binding (Table 25–2).


Pharmacology_Katzung

Pharmacology_Katzung. If ketamine is administered as the sole anesthetic, amnesia is not as complete as with the benzodiazepines. Reflexes are often preserved, but it cannot be assumed that patients are able to protect the upper airway. The eyes remain open and the pupils are moderately dilated with a nystagmic gaze. Frequently, lacrimation and salivation are increased, and premedication with an anticholinergic drug may be indicated to limit this effect. A. CNS Effects


Pharmacology_Katzung

Pharmacology_Katzung. A. CNS Effects In contrast to other intravenous anesthetics, ketamine is considered to be a cerebral vasodilator that increases cerebral blood flow, as well as CMRO2. For these reasons, ketamine has traditionally not been recommended for use in patients with intracranial pathology, especially increased ICP. Nevertheless, these perceived undesirable effects on cerebral blood flow may be blunted by the maintenance of normocapnia. Despite the potential to produce myoclonic activity, ketamine is considered an anticonvulsant and may be recommended for treatment of status epilepticus when more conventional drugs are ineffective.


Pharmacology_Katzung

Pharmacology_Katzung. Unpleasant emergence reactions after administration are the main factor limiting ketamine’s use. Such reactions may include vivid colorful dreams, hallucinations, out-of-body experiences, and increased and distorted visual, tactile, and auditory sensitivity. These reactions can be associated with fear and confusion, but a euphoric state may also be induced, which explains the potential for abuse of the drug. Children usually have a lower incidence of and less severe emergence reactions. Combination with a benzodiazepine may be indicated to limit the unpleasant emergence reactions and also increase amnesia. B. Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects Ketamine can produce transient but significant increases in systemic blood pressure, heart rate, and cardiac output, presumably by centrally mediated sympathetic stimulation. These effects, which are associated with increased cardiac workload and myocardial oxygen consumption, are not always desirable and can be blunted by coadministration of benzodiazepines, opioids, or inhaled anesthetics. Though the effect is more controversial, ketamine is also considered to be a direct myocardial depressant. This property is usually masked by its stimulation of the sympathetic nervous system but may become apparent in critically ill patients with limited ability to increase their sympathetic nervous system activity. C. Respiratory Effects


Pharmacology_Katzung

Pharmacology_Katzung. C. Respiratory Effects Ketamine is not thought to produce significant respiratory depression. When it is used as a single drug, the respiratory response to hypercapnia is preserved and blood gases remain stable. Transient hypoventilation and, in rare cases, a short period of apnea can follow rapid administration of a large intravenous dose for induction of anesthesia. The ability to protect the upper airway in the presence of ketamine cannot be assumed despite the presence of active airway reflexes. Especially in children, the risk for laryngospasm because of increased salivation must be considered; this risk can be reduced by premedication with an anticholinergic drug. Ketamine relaxes bronchial smooth muscle and may be helpful in patients with reactive airways and in the management of patients experiencing bronchoconstriction.


Pharmacology_Katzung

Pharmacology_Katzung. Its unique properties, including profound analgesia, stimulation of the sympathetic nervous system, bronchodilation, and minimal respiratory depression, make ketamine an important alternative to the other intravenous anesthetics and a desirable adjunct in many cases despite the unpleasant psychotomimetic effects. Moreover, ketamine can be administered by multiple routes (intravenous, intramuscular, oral, rectal, epidural), thus making it a useful option for premedication in mentally challenged and uncooperative pediatric patients. Induction of anesthesia can be achieved with ketamine, 1–2 mg/kg intravenously or 4–6 mg/kg intramuscularly. Although the drug is not commonly used for maintenance of anesthesia, its short context-sensitive half-time makes ketamine a candidate for this purpose. For example, general anesthesia can be achieved with the infusion of ketamine, 15–45 mcg/kg/min, plus 50–70% nitrous oxide or by ketamine alone, 30–90 mcg/kg/min.


Pharmacology_Katzung

Pharmacology_Katzung. Small bolus doses of ketamine (0.2–0.8 mg/kg IV) may be useful during regional anesthesia when additional analgesia is needed (eg, cesarean delivery under neuraxial anesthesia with an insufficient regional block). Ketamine provides effective analgesia without compromise of the airway. An infusion of a subanalgesic dose of ketamine (3–5 mcg/kg/min) during general anesthesia and in the early postoperative period may be useful to produce analgesia or reduce opioid tolerance and opioid-induced hyperalgesia. The use of ketamine has always been limited by its unpleasant psychotomimetic side effects, but its unique features make it a very valuable alternative in certain settings, mostly because of the potent analgesia with minimal respiratory depression. Most recently, it has become popular as an adjunct administered at sub-analgesic doses to limit or reverse opioid tolerance.


Pharmacology_Katzung

Pharmacology_Katzung. Dexmedetomidine is a highly selective α2-adrenergic agonist. Recognition of the usefulness of α2 agonists is based on observations of decreased anesthetic requirements in patients receiving chronic clonidine therapy. The effects of dexmedetomidine can be antagonized with α2-antagonist drugs. Dexmedetomidine is the active S-enantiomer of medetomidine, a highly selective α2-adrenergic agonist imidazole derivative that is used in veterinary medicine. Dexmedetomidine is water soluble and available as a parenteral formulation. Dexmedetomidine undergoes rapid hepatic metabolism involving N-methylation and hydroxylation, followed by conjugation. Metabolites are excreted in the urine and bile. Clearance is high, and the elimination half-time is short (Table 25–2). However, there is a significant increase in the context-sensitive half-time from 4 minutes after a 10-minute infusion to 250 minutes after an 8-hour infusion. A. CNS Effects


Pharmacology_Katzung

Pharmacology_Katzung. A. CNS Effects Dexmedetomidine produces its selective α2-agonist effects through activation of CNS α2 receptors. Hypnosis presumably results from stimulation of α2 receptors in the locus coeruleus, and the analgesic effect originates at the level of the spinal cord. The sedative effect produced by dexmedetomidine has a different quality than that produced by other intravenous anesthetics in that it more completely resembles a physiologic sleep state through activation of endogenous sleep pathways. Dexmedetomidine is likely to be associated with a decrease in cerebral blood flow without significant changes in ICP and CMRO2. It has the potential to lead to the development of tolerance and dependence. B. Cardiovascular Effects


Pharmacology_Katzung

Pharmacology_Katzung. B. Cardiovascular Effects Dexmedetomidine infusion results in moderate decreases in heart rate and systemic vascular resistance and, consequently, a decrease in systemic blood pressure. A bolus injection may produce a transient increase in systemic blood pressure and pronounced decrease in heart rate, an effect that is probably mediated through activation of peripheral α2 adrenoceptors. Bradycardia associated with dexmedetomidine infusion may require treatment. Heart block, severe bradycardia, and asystole have been observed and may result from unopposed vagal stimulation. The response to anticholinergic drugs is unchanged. C. Respiratory Effects


Pharmacology_Katzung

Pharmacology_Katzung. C. Respiratory Effects The effects of dexmedetomidine on the respiratory system are a small to moderate decrease in tidal volume and very little change in the respiratory rate. The ventilatory response to carbon dioxide is unchanged. Although the respiratory effects are mild, upper airway obstruction as a result of sedation is possible. In addition, dexmedetomidine has a synergistic sedative effect when combined with other sedative-hypnotics.


Pharmacology_Katzung

Pharmacology_Katzung. Dexmedetomidine is principally used for the short-term sedation of intubated and ventilated patients in an ICU setting. In the operating room, dexmedetomidine may be used as an adjunct to general anesthesia or to provide sedation, eg, during awake fiberoptic tracheal intubation or regional anesthesia. When administered during general anesthesia, dexmedetomidine (0.5–1 mcg/kg loading dose over 10–15 minutes, followed by an infusion of 0.2–0.7 mcg/kg/h) decreases the dose requirements for inhaled and injected anesthetics. Awakening and the transition to the postoperative setting may benefit from dexmedetomidine-produced sedative and analgesic effects without respiratory depression.


Pharmacology_Katzung

Pharmacology_Katzung. Opioids are analgesic agents and are distinct from general anesthetics and hypnotics. Even when high doses of opioid analgesics are administered, recall cannot be prevented reliably unless hypnotic agents such as benzodiazepines are also used. Opioid analgesics are routinely used to achieve postoperative analgesia and intraoperatively as part of a balanced anesthesia regimen as described earlier (see Intravenous Anesthetics). Their pharmacology and clinical use are described in greater detail in Chapter 31.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to their use as part of a balanced anesthesia regimen, opioids in large doses have been used in combination with large doses of benzodiazepines to achieve a general anesthetic state, particularly in patients with limited circulatory reserve who undergo cardiac surgery. When administered in large doses, potent opioids such as fentanyl can induce chest wall (and laryngeal) rigidity, thereby acutely impairing mechanical ventilation. Furthermore, large doses of potent opioids may speed up the development of tolerance and complicate postoperative pain management. The practice of clinical anesthesia requires integrating the pharmacology and the known adverse effects of these potent drugs with the pathophysiologic state of individual patients. Every case tests the ability of the anesthesiologist to produce the depth of anesthesia required to allow invasive surgery to proceed and to achieve this safely despite frequent major medical problems.


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Pharmacology_Katzung. GENERIC NAME AVAILABLE AS Dexmedetomidine Precedex GENERIC NAME AVAILABLE AS Ketamine Generic, Ketalar Diazepam Generic, Valium Droperidol Generic, Inapsine Enflurane Enflurane, Ethrane Etomidate Generic, Amidate Halothane Generic, Fluothane Isoflurane Generic, Forane, Terrell Lorazepam Generic, Ativan Methohexital Generic, Brevital Midazolam Generic, Versed Nitrous oxide (gas, supplied in blue cylinders) Generic Propofol Generic, Diprivan Sevoflurane Generic, Ultane * See Chapter 31 for names of opioid agents used in anesthesia. Allaert SE et al: First trimester anesthesia exposure and fetal outcome. A review. Acta Anaesthesiol Belg 2007;58:119. Ebert TJ et al: Desflurane-mediated sympathetic activation occurs in humans despite preventing hypotension and baroreceptor unloading. Anesthesiology 1998;85:1227. Eger EI II: Uptake and distribution. In: Miller RD (editor): Anesthesia, 7th ed. Churchill Livingstone, 2010.


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Pharmacology_Katzung. Eger EI II: Uptake and distribution. In: Miller RD (editor): Anesthesia, 7th ed. Churchill Livingstone, 2010. Eger EI II, Saidman LJ, Brandstater B: Minimum alveolar anesthetic concentration: A standard of anesthetic potency. Anesthesiology 1965;26:756. Fraga M et al: The effects of isoflurane and desflurane on intracranial pressure, cerebral perfusion and cerebral arteriovenous oxygen content difference in normocapnic patients with supratentorial brain tumors. Anesthesiology 2003;98:1085. Fragen RJ: Drug Infusions in Anesthesiology. Lippincott Williams & Wilkins, 2005. Hemmings HC et al: Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci 2005;26:503. Hirshey Dirksen SJ et al: Future directions in malignant hyperthermia research and patient care. Anesth Analg 2011;113:1108. Lugli AK, Yost CS, Kindler CH: Anesthetic mechanisms: Update on the challenge of unravelling the mystery of anaesthesia. Eur J Anaesth 2009;26:807.


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Pharmacology_Katzung. Lugli AK, Yost CS, Kindler CH: Anesthetic mechanisms: Update on the challenge of unravelling the mystery of anaesthesia. Eur J Anaesth 2009;26:807. Olkkola KT, Ahonen J: Midazolam and other benzodiazepines. Handb Exp Pharmacol 2008;182:335. Reves JG et al: Intravenous anesthetics. In: Miller RD (editor): Anesthesia, 7th ed. Churchill Livingstone, 2010. Rudolph U et al: Sedatives, anxiolytics, and amnestics. In: Evers AS, Maze M (editors): Anesthetic Pharmacology: Physiologic Principles and Clinical Practice. Churchill Livingstone, 2004. Sjogren D, Lindahl SGE, Sollevi A: Ventilatory responses to acute and sustained hypoxia during isoflurane anesthesia. Anesth Analg 1998;86:403. Stoelting R, Hillier S: Barbiturates. In: Stoelting RK, Hillier SC (editors): Pharmacology and Physiology in Anesthetic Practice. Lippincott Williams & Wilkins, 2005. Yasuda N et al: Kinetics of desflurane, isoflurane, and halothane in humans. Anesthesiology 1991;70:489.


Pharmacology_Katzung

Pharmacology_Katzung. This patient presents with significant underlying cardiac risk and is scheduled to undergo major stressful surgery. Balanced anesthesia would begin with intravenous agents that cause minimal changes in blood pressure and heart rate such as a lowered dose of propofol or etomidate, combined with potent analgesics such as fentanyl (see Chapter 31) to block undesirable stimulation of autonomic reflexes. Main-tenance of anesthesia could incorporate inhaled anesthetics that ensure unconsciousness and amnesia, additional intra-venous agents to provide intraoperative and postoperative analgesia, and, if needed, neuromuscular blocking drugs (see Chapter 27) to induce muscle relaxation. The choice of inhaled agent(s) would be made based on the desire to maintain sufficient myocardial contractility, systemic blood pressure, and cardiac output for adequate perfusion of criti-cal organs throughout the operation. If the patient’s ischemic pain has been chronic and severe, a low-dose ketamine


Pharmacology_Katzung

Pharmacology_Katzung. systemic blood pressure, and cardiac output for adequate perfusion of criti-cal organs throughout the operation. If the patient’s ischemic pain has been chronic and severe, a low-dose ketamine infusion may be administered for additional pain control. Rapid emergence from the combined effects of the chosen anesthetic drugs, which would facilitate the patient’s return to a baseline state of heart function, breathing, and menta-tion, can be attained by understanding the known pharma-cokinetic properties of the anesthetic agents as presented in this chapter.


Pharmacology_Katzung

Pharmacology_Katzung. Kenneth Drasner, MD complications might arise from their use? What anesthet-ics would be most appropriate for providing postoperative analgesia via an indwelling epidural or peripheral nerve catheter? A 67-year-old woman is scheduled for elective total knee arthroplasty. What local anesthetic agents would be most appropriate if surgical anesthesia were to be administered using a spinal or an epidural technique, and what potential


Pharmacology_Katzung

Pharmacology_Katzung. Simply stated, local anesthesia refers to loss of sensation in a limited region of the body. This is accomplished by disruption of afferent neural traffic via inhibition of impulse generation or propagation. Such blockade may bring with it other physiologic changes such as muscle paralysis and suppression of somatic or visceral reflexes, and these effects might be desirable or undesirable depending on the particular circumstances. Nonetheless, in most cases, it is the loss of sensation, or at least the achievement of localized analgesia, that is the primary goal.


Pharmacology_Katzung

Pharmacology_Katzung. Although local anesthetics are often used as analgesics, it is their ability to provide complete loss of all sensory modalities that is their distinguishing characteristic. The contrast with general anesthesia should be obvious, but it is perhaps worthwhile to emphasize that with local anesthesia the drug is delivered directly to the target organ, and the systemic circulation serves only to diminish or terminate its effect. Local anesthesia can also be produced by various chemical or physical means. However, in routine clinical practice, it is achieved with a rather narrow spectrum of compounds, and recovery is normally spontaneous, predictable, and without residual effects. The development of these compounds has a rich history (see Box: Historical Development of Local Anesthesia), punctuated by serendipitous observations, delayed starts, and an evolution driven more by concerns for safety than improvements in efficacy.


Pharmacology_Katzung

Pharmacology_Katzung. Most local anesthetic agents consist of a lipophilic group (eg, an aromatic ring) connected by an intermediate chain via an ester or amide to an ionizable group (eg, a tertiary amine) (Table 26–1). In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers (eg, levobupivacaine, ropivacaine). Because ester links are more prone to hydrolysis than amide links, esters usually have a shorter duration of action. Local anesthetics are weak bases and are usually made available clinically as salts to increase solubility and stability. In the body, they exist either as the uncharged base or as a cation (see Chapter 1, Ionization of Weak Acids and Weak Bases). The relative proportions of these two forms are governed by their pKa and the pH of the body fluids according to the Henderson-Hasselbalch equation, which can be expressed as:


Pharmacology_Katzung

Pharmacology_Katzung. If the concentration of base and conjugate acid are equal, the second portion of the right side of the equation drops out, as log 1 = 0, leaving: TABLE 26–1 Structure and properties of some ester and amide local anesthetics.1 Structure Potency (Procaine = 1) Duration of Action Mepivacaine (Carbocaine, Isocaine) CH3CH3ONHCNCH32 Medium Bupivacaine (Marcaine), 1Other chemical types are available including ethers (pramoxine), ketones (dyclonine), and phenetidin derivatives (phenacaine). 2Data not found.


Pharmacology_Katzung

Pharmacology_Katzung. Although the numbing properties of cocaine were recognized for centuries, one might consider September 15, 1884, to mark the “birth of local anesthesia.” Based on work performed by Carl Koller, cocaine’s numbing effect on the cornea was dem-onstrated before the Ophthalmological Congress in Heidelberg, ushering in the era of surgical local anesthesia. Unfortunately, with widespread use came recognition of cocaine’s significant central nervous system (CNS) and cardiac toxicity, which along with its addiction potential, tempered enthusiasm for this appli-cation. As the early investigator Mattison commented, “the risk of untoward results have robbed this peerless drug of much favor in the minds of many surgeons, and so deprived them of a most valued ally.” As cocaine was known to be a benzoic acid ester, the search for alternative local anesthetics focused on this class of compounds, resulting in the identification of benzocaine shortly before the turn of the last century. However,


Pharmacology_Katzung

Pharmacology_Katzung. acid ester, the search for alternative local anesthetics focused on this class of compounds, resulting in the identification of benzocaine shortly before the turn of the last century. However, benzocaine proved to have limited utility due to its marked hydrophobicity, and was thus relegated to topical anesthesia, a use for which it still finds limited application in current clinical practice. The first useful injectable local anesthetic, procaine, was introduced shortly thereafter by Einhorn, and its structure has served as the template for the development of the most commonly used modern local anesthetics. The three basic structural elements of these compounds can be appreciated by review of Table 26–1: an aromatic ring, conferring lipophilicity; an ionizable tertiary amine, conferring hydrophilicity; and an intermediate chain con-necting these via an ester or amide linkage. One of procaine’s limitations was its short duration of action, a drawback overcome with the introduction of


Pharmacology_Katzung

Pharmacology_Katzung. hydrophilicity; and an intermediate chain con-necting these via an ester or amide linkage. One of procaine’s limitations was its short duration of action, a drawback overcome with the introduction of tetracaine in 1928. Unfortunately, tetracaine demonstrated significant toxicity when employed for high-volume peripheral blocks, ultimately reducing its common usage to spinal anesthesia. Both procaine and tetracaine shared another drawback: their ester linkage conferred instability, and particularly in the case of procaine, the free aromatic acid released during ester hydrolysis of the parent compound was believed to be the source of relatively frequent allergic reactions. Lgren and Lundqvist circumvented the problem of insta-bility with the introduction of lidocaine in 1948. Lidocaine was the first in a series of amino-amide local anesthetics that would come to dominate the second half of the 20th century. Lidocaine had a more favorable duration of action than procaine, and less


Pharmacology_Katzung

Pharmacology_Katzung. was the first in a series of amino-amide local anesthetics that would come to dominate the second half of the 20th century. Lidocaine had a more favorable duration of action than procaine, and less systemic toxicity than tetracaine. To this day, it remains one of the most versatile and widely used anesthetics. Nonetheless, some applications required more prolonged block than that afforded by lidocaine, a pharmacologic void that was filled with the introduction of bupivacaine, a more lipophilic and more potent anesthetic. Unfortunately, bupivacaine was found to have greater propensity for significant effects on cardiac con-duction and function, which at times proved lethal. Recognition of this potential for cardiac toxicity led to changes in anesthetic practice, and significant toxicity became sufficiently rare for it to remain a widely used anesthetic for nearly every regional technique in modern clinical practice. Nonetheless, this inherent cardiotoxicity would drive developmental