Pharmacodynamics - Inhaled Anesthetics

PHARMACODYNAMICS

Organ System Effects of Inhaled Anesthetics

A. Cerebral Effects

Anesthetic potency is currently described by the minimal alveolar concentration (MAC) required to prevent a response to a surgical incision (see Topic: What Does Anesthesia Represent & Where Does It Work?).  

Inhaled anesthetics (like intravenous anesthetics, discussed later) decrease the metabolic activity of the brain. Decreased cerebral metabolic rate (CMR) generally reduces blood flow within the brain. However, volatile anesthetics also cause 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 the anesthetic, 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, administration of high concentrations of volatile anes-thetics is undesirable in patients with increased intracranial pressure. Hyperventilation can be used to attenuate this response; decreas-ing 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.

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 above).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.

Potent inhaled anesthetics produce a basic pattern of change to brain electrical activity as recorded by standard electroencephalog-raphy (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 epilep-tic-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.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 analgesiawithout amnesia. Later in stage I, both analgesia and amnesia are produced. Stage II—excitement: During this stage, the patient appears delirious, 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 is 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. StageIV—medullary depression: This deep stage of anesthesia repre-sents 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.

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 out-put as well as reduce preload (ventricular filling) and afterload (systemic vascular resistance), these agents may be better choices for patients with impaired myocardial function.

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

Because all inhaled anesthetics produce a dose-dependent decrease in arterial blood pressure, activation of autonomic ner-vous 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 barore-ceptor reflex. In addition, desflurane can trigger transient sympa-thetic activation—with elevated catecholamine levels—to cause marked increases in heart rate and blood pressure during adminis-tration of high desflurane concentrations or when desflurane concentrations are changed rapidly.

Inhaled anesthetics tend to reduce myocardial oxygen con-sumption, which reflects depression of normal cardiac contractility and decreased arterial blood pressure. In addition, inhaled anes-thetics 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.

Halothane and, to a lesser extent, other volatile anesthetics sensitize the myocardium to epinephrine and circulating catecholamines. Ventricular arrhythmias may occur when patientsunder 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

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 pro-voke coughing or breath-holding, is induced by the pungency of some volatile anesthetics. The pungency of isoflurane and desflu-rane 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 inha-lational induction of anesthesia in a patient with bronchospasm.The control of breathing is significantly affected by inhaled anesthetics. With the exception of nitrous oxide, all inhaled anes-thetics in current use cause a dose-dependent decrease in tidal volume and an increase in respiratory rate (rapid shallow breath-ing 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.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. In practice, the respiratory depressant effects of anesthetics are over-come 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 develop-ment of postoperative respiratory complications, including hypox-emia and respiratory infections.

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

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 func-tion tests may occur following exposure to volatile anesthetics, per-sistent elevation in liver enzymes is rare except following repeated exposures to halothane (see Toxicity of Anesthetic Agents).

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.

Toxicity of Anesthetic Agents

A. Acute Toxicity

Nephrotoxicity—Metabolism of enflurane and sevofluranemay 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. 

Hematotoxicity—Prolonged exposure to nitrous oxidedecreases 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 poten-tial occupational hazard. 

All inhaled anesthetics can produce some carbon monoxide (CO) from their interaction with strong bases in dry carbon diox-ide absorbers. CO binds to hemoglobin with high affinity, reduc-ing oxygen delivery to tissues. Desflurane produces the most CO, and intraoperative formation of CO has been reported. CO pro-duction can be avoided simply by using fresh carbon dioxide absorbent and by preventing its complete desiccation.

Malignant hyperthermia—Malignant hyperthermia is aheritable genetic disorder of skeletal muscle that occurs in susceptibleindividuals exposed to volatile anesthetics while undergoing gen-eral anesthesia (Table 16–4). The depolarizing muscle relaxant succinylcholine may also trigger malignant hyper-thermia. The malignant hyperthermia syndrome consists of mus-cle rigidity, hyperthermia, rapid onset of tachycardia and hypercapnia, hyperkalemia, and metabolic acidosis following exposure to one or more triggering agents. Malignant hyper-thermia is a rare but important cause of anesthetic morbidity and mortality. The specific biochemical abnormality is an increase in free cytosolic calcium concentration in skeletal muscle cells. Treatment includes administration of dantrolene (to reduce cal-cium release from the sarcoplasmic reticulum) and appropriate measures to reduce body temperature and restore electrolyte and acid-base balance .

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 hyper-thermia susceptibility. Currently, the most reliable test to establish susceptibility is the in vitro caffeine-halothane contracture test using skeletal muscle biopsy samples.

Hepatotoxicity (halothane hepatitis)—Hepatic dysfunc-tion 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 halothane has developed fulminant hepatic failure. The incidence of severe hepatotoxicity following exposure to halothane is esti-mated 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, isoflu-rane, and desflurane, have rarely been reported. 

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, desflu-rane, and sevoflurane may be teratogenic in rodents as a result of physiologic changes associated with the anesthesia rather than through a direct teratogenic effect.

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 USA, 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, how-ever, whether the underlying disease, surgery, anesthesia, or a com-bination of these factors is the cause of the increased risk

Carcinogenicity—Epidemiologic studies suggested anincrease 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. Most operating rooms now use scavenging systems to remove trace concentrations of anesthetics released from anesthetic machines.