Chapter 25: General Anesthetics

Modern anesthetics act very rapidly and achieve deep anesthesia quickly. With older and more slowly acting anesthetics, the progressively greater depth of central depression associated with increasing dose or time of exposure is traditionally described as stages of anesthesia.

A. Stage 1: Analgesia

In stage 1, the patient has decreased awareness of pain, sometimes with amnesia. Consciousness may be impaired but is not lost.

B. Stage 2: Disinhibition

In stage 2, the patient appears to be delirious and excited. Amnesia occurs, reflexes are enhanced, and respiration is typically irregular; retching and incontinence may occur.

C. Stage 3: Surgical Anesthesia

In stage 3, the patient is unconscious and has no pain reflexes; respiration is very regular, and blood pressure is maintained.

D. Stage 4: Medullary Depression

In stage 4, the patient develops severe respiratory and cardiovascular depression that requires mechanical and pharmacologic support.

Anesthesia protocols vary according to the proposed type of diagnostic, therapeutic, or surgical intervention. For minor procedures, conscious sedation techniques that combine intravenous agents with local anesthetics (see Chapter 26) are often used. These can provide profound analgesia, with retention of the patient's ability to maintain a patent airway and respond to verbal commands. For more extensive surgical procedures, anesthesia protocols commonly include intravenous drugs to induce the anesthetic state, inhaled anesthetics (with or without intravenous agents) to maintain an anesthetic state, and neuromuscular blocking agents to effect muscle relaxation (see Chapter 27). Vital sign monitoring remains the standard method of assessing depth of anesthesia during surgery. Cerebral monitoring, automated techniques based on quantification of anesthetic effects on the electroencephalograph (EEG), is also useful.

The mechanisms of action of general anesthetics are varied. As CNS depressants, these drugs usually increase the threshold for firing of CNS neurons. The potency of inhaled anesthetics is roughly proportional to their lipid solubility. Mechanisms of action include effects on ion channels by interactions of anesthetic drugs with membrane lipids or proteins with subsequent effects on central neurotransmitter mechanisms. Inhaled anesthetics, barbiturates, benzodiazepines, etomidate, and propofol facilitate γ-aminobutyric acid (GABA)-mediated inhibition at GABA_A receptors. These receptors are sensitive to clinically relevant concentrations of the anesthetic agents and exhibit the appropriate stereospecific effects in the case of enantiomeric drugs. Ketamine does not produce its effects via facilitation of GABA_A receptor functions, but possibly via its antagonism of the action of the excitatory neurotransmitter glutamic acid on the N-methyl-d-aspartate (NMDA) receptor. Most inhaled anesthetics also inhibit nicotinic acetylcholine (ACh) receptor isoforms at moderate to high concentrations. The strychnine-sensitive glycine receptor is another ligand-gated ion channel that may function as a target for certain inhaled anesthetics. CNS neurons in different regions of the brain have different sensitivities to general anesthetics; inhibition of neurons involved in pain pathways occurs before inhibition of neurons in the midbrain reticular formation.

A. Classification and Pharmacokinetics

The agents currently used in inhalation anesthesia are nitrous oxide (a gas) and several easily vaporized liquid halogenated hydrocarbons, including halothane, desflurane, enflurane, isoflurane, sevoflurane, and methoxyflurane. They are administered as gases; their partial pressure, or “tension,” in the inhaled air or in blood or other tissue is a measure of their concentration. Because the standard pressure of the total inhaled mixture is atmospheric pressure (760 mm Hg at sea level), the partial pressure may also be expressed as a percentage. Thus, 50% nitrous oxide in the inhaled air would have a partial pressure of 380 mm Hg. The speed of induction of anesthetic effects depends on several factors, discussed next.

1. Solubility

The more rapidly a drug equilibrates with the blood, the more quickly the drug passes into the brain to produce anesthetic effects. Drugs with a low blood:gas partition coefficient (eg, nitrous oxide) equilibrate more rapidly than those with a higher blood solubility (eg, halothane), as illustrated in Figure 25–1. Partition coefficients for inhalation anesthetics are shown in Table 25–1.

2. Inspired gas partial pressure

A high partial pressure of the gas in the lungs results in more rapid achievement of anesthetic levels in the blood. This effect can be taken advantage of by the initial administration of gas concentrations higher than those required for maintenance of anesthesia.

3. Ventilation rate

The greater the ventilation, the more rapid is the rise in alveolar and blood partial pressure of the agent and the onset of anesthesia (Figure 25–2). This effect is taken advantage of in the induction of the anesthetic state.

4. Pulmonary blood flow

At high pulmonary blood flows, the gas partial pressure rises at a slower rate; thus, the speed of onset of anesthesia is reduced. At low flow rates, onset is faster. In circulatory shock, this effect may accelerate the rate of onset of anesthesia with agents of high blood solubility.

5. Arteriovenous concentration gradient

Uptake of soluble anesthetics into highly perfused tissues may decrease gas tension in mixed venous blood. This can influence the rate of onset of anesthesia because achievement of equilibrium is dependent on the difference in anesthetic tension between arterial and venous blood.

B. Elimination

Inhaled anesthesia is terminated by redistribution of the drug from the brain to the blood and elimination of the drug through the lungs. The rate of recovery from anesthesia using agents with low blood:gas partition coefficients is faster than that of anesthetics with high blood solubility. This important property has led to the introduction of several newer inhaled anesthetics (eg, desflurane, sevoflurane), which, because of their low blood solubility, are characterized by recovery times that are considerably shorter than is the case with older agents. Halothane and methoxyflurane are metabolized by liver enzymes to a significant extent (Table 25–1). Metabolism of halothane and methoxyflurane has only a minor influence on the speed of recovery from their anesthetic effect but does play a role in potential toxicity of these anesthetics.

C. Minimum Alveolar Anesthetic Concentration

The potency of inhaled anesthetics is best measured by the minimum alveolar anesthetic concentration (MAC), defined as the alveolar concentration required to eliminate the response to a standardized painful stimulus in 50% of patients. Each anesthetic has a defined MAC (Table 25–1), but this value may vary among patients depending on age, cardiovascular status, and use of adjuvant drugs. Estimations of MAC value suggest a relatively “steep” dose–response relationship for inhaled anesthetics. MACs for infants and elderly patients are lower than those for adolescents and young adults. When several anesthetic agents are used simultaneously, their MAC values are additive.

D. Effects of Inhaled Anesthetics

1. CNS effects

Inhaled anesthetics decrease brain metabolic rate. They reduce vascular resistance and thus increase cerebral blood flow. This may lead to an increase in intracranial pressure. High concentrations of enflurane may cause spike-and-wave activity and muscle twitching, but this effect is unique to this drug. Although nitrous oxide has low anesthetic potency (ie, a high MAC), it exerts marked analgesic and amnestic actions.

2. Cardiovascular effects

Most inhaled anesthetics decrease arterial blood pressure moderately. Enflurane and halothane are myocardial depressants that decrease cardiac output, whereas isoflurane, desflurane and sevoflurane cause peripheral vasodilation. Nitrous oxide is less likely to lower blood pressure than are other inhaled anesthetics. Blood flow to the liver and kidney is decreased by most inhaled agents. Inhaled anesthetics depress myocardial function—nitrous oxide least. Halothane, and to a lesser degree isoflurane, may sensitize the myocardium to the arrhythmogenic effects of catecholamines.

3. Respiratory effects

Although the rate of respiration may be increased, all inhaled anesthetics cause a dose-dependent decrease in tidal volume and minute ventilation, leading to an increase in arterial CO₂ tension. Inhaled anesthetics decrease ventilatory response to hypoxia even at subanesthetic concentrations (eg, during recovery). Nitrous oxide has the smallest effect on respiration. Most inhaled anesthetics are bronchodilators, but desflurane is a pulmonary irritant and may cause bronchospasm. The pungency of enflurane causes breath-holding, which limits its use in anesthesia induction.

4. Toxicity

Postoperative hepatitis has occurred (rarely) after halothane anesthesia in patients experiencing hypovolemic shock or other severe stress. The mechanism of hepatotoxicity is unclear but may involve formation of reactive metabolites that cause direct toxicity or initiate immune-mediated responses. Fluoride released by metabolism of methoxyflurane (and possibly enflurane and sevoflurane) may cause renal insufficiency after prolonged anesthesia. Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anemia. Susceptible patients may develop malignant hyperthermia when anesthetics are used together with neuromuscular blockers (especially succinylcholine). This rare condition is thought in some cases to be due to mutations in the gene loci corresponding to the ryanodine receptor (RyR1). Other chromosomal loci for malignant hyperthermia include mutant alleles of the gene-encoding skeletal muscle L-type calcium channels. The uncontrolled release of calcium by the sarcoplasmic reticulum of skeletal muscle leads to muscle spasm, hyperthermia, and autonomic lability (Table 16-2). Dantrolene is indicated for the treatment of this life-threatening condition, with supportive management.

Like most drugs, general anesthetics appear to act via interactions with specific receptor molecules involved in cell signaling (See Chapter 2). For review purposes, list the major types of signaling mechanisms relevant to the actions of drugs that act via receptors. The Skill Keeper Answers appear at the end of the chapter.

A. Propofol

Propofol produces anesthesia as rapidly as the intravenous barbiturates, and recovery is more rapid. Propofol has antiemetic actions, and recovery is not delayed after prolonged infusion. The drug is very commonly used as a component of balanced anesthesia and as an anesthetic in outpatient surgery. Propofol is also effective in producing prolonged sedation in patients in critical care settings. Propofol may cause marked hypotension during induction of anesthesia, primarily through decreased peripheral resistance. Total body clearance of propofol is greater than hepatic blood flow, suggesting that its elimination includes other mechanisms in addition to metabolism by liver enzymes. Fospropofol, a water-soluble prodrug form, is broken down in the body by alkaline phosphatase to form propofol. However, onset and recovery are both slower than propofol. Although fospropofol appears to cause less pain at injection sites than the standard form of the drug, many patients experience paresthesias.

B. Barbiturates

Thiopental and methohexital have high lipid solubility, which promotes rapid entry into the brain and results in surgical anesthesia in one circulation time (<1 min). These drugs are used for induction of anesthesia and for short surgical procedures. The anesthetic effects of thiopental are terminated by redistribution from the brain to other highly perfused tissues (Figure 25–3), but hepatic metabolism is required for elimination from the body. Barbiturates are respiratory and circulatory depressants; because they depress cerebral blood flow, they can also decrease intracranial pressure.

C. Benzodiazepines

Midazolam is widely used adjunctively with inhaled anesthetics and intravenous opioids. The onset of its CNS effects is slower than that of thiopental, and it has a longer duration of action. Cases of severe postoperative respiratory depression have occurred. The benzodiazepine receptor antagonist, flumazenil, accelerates recovery from midazolam and other benzodiazepines.

D. Ketamine

This drug produces a state of “dissociative anesthesia” in which the patient remains conscious but has marked catatonia, analgesia, and amnesia. Ketamine is a chemical congener of the psychotomimetic agent, phencyclidine (PCP), and inhibits NMDA glutamate transmission. The drug is a cardiovascular stimulant, and this action may lead to an increase in intracranial pressure. Emergence reactions, including disorientation, excitation, and hallucinations, which occur during recovery from ketamine anesthesia, can be reduced by the preoperative use of benzodiazepines.

E. Opioids

Morphine and fentanyl are used with other CNS depressants (nitrous oxide, benzodiazepines) in anesthesia regimens and are especially valuable in high-risk patients who might not survive a full general anesthetic. Intravenous opioids may cause chest wall rigidity, which can impair ventilation. Respiratory depression with these drugs may be reversed postoperatively with naloxone. Neuroleptanesthesia is a state of analgesia and amnesia is produced when fentanyl is used with droperidol and nitrous oxide. Newer opioids related to fentanyl have been introduced for intravenous anesthesia. Alfentanil and remifentanil have been used for induction of anesthesia. Recovery from the actions of remifentanil is faster than recovery from other opioids used in anesthesia because of its rapid metabolism by blood and tissue esterases.

F. Etomidate

This imidazole derivative affords rapid induction with minimal change in cardiac function or respiratory rate and has a short duration of action. The drug is not analgesic, and its primary advantage is in anesthesia for patients with limited cardiac or respiratory reserve. Etomidate may cause pain and myoclonus on injection and nausea postoperatively. Prolonged administration may cause adrenal suppression.

G. Dexmedetomidine

This centrally acting α₂-adrenergic agonist has analgesic and hypnotic actions when used intravenously. Its characteristics include rapid clearance resulting in a short elimination half-life. Dexmedetomidine is mainly used for short-term sedation in an ICU setting. When used in general anesthesia, the drug decreases dosage requirements for both inhaled and intravenous anesthetics.

1. A new halogenated gas anesthetic has a blood:gas partition coefficient of 0.5 and a MAC value of 1%. Which prediction about this agent is most accurate? (Refer to Table 25–1 for comparison of agents.)

   • (A) Equilibrium between arterial and venous gas tension will be achieved very slowly

   • (B) It will be metabolized by the liver to release fluoride ions

   • (C) It will be more soluble in the blood than isoflurane

   • (D) Speed of onset will be similar to that of nitrous oxide

   • (E) The new agent will be more potent than halothane

2. Which statement concerning the effects of anesthetic agents is false?

   • (A) Bronchiolar smooth muscle relaxation occurs during halothane anesthesia

   • (B) Chest muscle rigidity often follows the administration of fentanyl

   • (C) Mild, generalized muscle twitching occurs at high doses of enflurane

   • (D) Severe hepatitis has been reported after the use of methoxyflurane

   • (E) The use of midazolam with inhalation anesthetics may prolong postanesthesia recovery

3. A 23-year-old man has a pheochromocytoma, blood pressure of 190/120 mm Hg, and hematocrit of 50%. Pulmonary function and renal function are normal. His catecholamines are elevated, and he has a well-defined abdominal tumor on MRI. He has been scheduled for surgery. Which one of the following agents should be avoided in the anesthesia protocol?

   • (A) Desflurane

   • (B) Fentanyl

   • (C) Isoflurane

   • (D) Midazolam

   • (E) Sevoflurane

4. Which statement concerning nitrous oxide is accurate?

   • (A) A useful component of anesthesia protocols because it lacks cardiovascular depression

   • (B) Anemia is a common adverse effect in patients exposed to nitrous oxide for periods longer than 2 h

   • (C) It is the most potent of the inhaled anesthetics

   • (D) There is a direct association between the use of nitrous oxide and malignant hyperthermia

   • (E) Up to 50% of nitrous oxide is eliminated via hepatic metabolism

5. Which statement concerning anesthetic MAC (minimum anesthetic concentration) value is accurate?

   • (A) Anesthetics with low MAC value have low potency

   • (B) MAC values increase in elderly patients

   • (C) MAC values give information about the slope of the dose–response curve

   • (D) Methoxyflurane has an extremely low MAC value

   • (E) Simultaneous use of opioid analgesics increases the MAC for inhaled anesthetics

6. Total intravenous anesthesia with fentanyl has been selected for a frail elderly woman about to undergo cardiac surgery. Which statement about this anesthesia protocol is accurate?

   • (A) Fentanyl will control the hypertensive response to surgical stimulation

   • (B) Marked relaxation of skeletal muscles is anticipated

   • (C) Opioids such as fentanyl provide useful cardiostimulatory effects

   • (D) Patient awareness may occur during surgery, with recall after recovery

   • (E) The patient is likely to experience pain during surgery

   Questions 7 and 8. A 20-year-old male patient scheduled for hernia surgery was anesthetized with halothane and nitrous oxide; tubocurarine was provided for skeletal muscle relaxation. The patient rapidly developed tachycardia and became hypertensive. Generalized skeletal muscle rigidity was accompanied by marked hyperthermia. Laboratory values revealed hyperkalemia and acidosis.

7. This unusual complication of anesthesia is most likely to be caused by

   • (A) Acetylcholine release from somatic nerve endings at skeletal muscle

   • (B) Activation of brain dopamine receptors by halothane

   • (C) Antagonism of autonomic ganglia by tubocurarine

   • (D) Calcium released within skeletal muscle

   • (E) Toxic metabolites of nitrous oxide

8. The patient should be treated immediately with

   • (A) Atropine

   • (B) Baclofen

   • (C) Dantrolene

   • (D) Edrophonium

   • (E) Flumazenil

9. If ketamine is used as the sole anesthetic in the attempted reduction of a dislocated shoulder joint, its actions will include

   • (A) Analgesia

   • (B) Bradycardia

   • (C) Hypotension

   • (D) Muscle rigidity

   • (E) Respiratory depression

10. Postoperative vomiting is uncommon with this intravenous agent, and patients are often able to ambulate sooner than those who receive other anesthetics.

    • (A) Enflurane

    • (B) Etomidate

    • (C) Midazolam

    • (D) Propofol

    • (E) Thiopental

1. The partition coefficient of an inhaled anesthetic is a determinant of its kinetic characteristics. Agents with low blood:gas solubility have a fast onset of action and a short duration of recovery. The new agent described here resembles nitrous oxide but is more potent, as indicated by its low MAC value. Not all halogenated anesthetics undergo significant hepatic metabolism or release fluoride ions. The answer is D.

2. Hepatitis after general anesthesia has been linked to use of halothane, although the incidence is very low (1 in 20,00–35,000). Hepatotoxicity has not been reported after administration of methoxyflurane or other inhaled anesthetics. However, fluoride release from prolonged use of methoxyflurane has caused renal insufficiency. The answer is D.

3. Isoflurane sensitizes the myocardium to catecholamines, as does halothane (not listed). Arrhythmias may occur in patients with cardiac disease who have high circulating levels of epinephrine and norepinephrine (eg, patients with pheochromocytoma). Other newer inhaled anesthetics are considerably less arrhythmogenic. The answer is C.

4. Anemia has not been reported in patients exposed to nitrous oxide anesthesia for periods as long as 6 h. Nitrous oxide is the least potent of the inhaled anesthetics, and the compound has not been implicated in malignant hyperthermia. More than 98% of the gas is eliminated via exhalation. The answer is A.

5. MAC value is inversely related to potency; a low MAC means high potency. MAC gives no information about the slope of the dose–response curve. Use of opioid analgesics or other CNS depressants with inhaled anesthetics lowers the MAC value. As with most CNS depressants, the elderly patient is more sensitive, so MAC values are lower. Methoxyflurane has the lowest MAC value of the inhaled anesthetics. The answer is D.

6. Intravenous opioids (eg, fentanyl) are widely used in anesthesia for cardiac surgery because they provide full analgesia and cause less cardiac depression than inhaled anesthetic agents. The opioids are not cardiac stimulants, and fentanyl is more likely to cause skeletal muscle rigidity than relaxation. Disadvantages of this technique are patient recall (which can be decreased by concomitant use of a benzodiazepine) and the occurrence of hypertensive responses to surgical stimulation. The addition of vasodilators (eg, nitroprusside) or a β blocker (eg, esmolol) may be needed to prevent intraoperative hypertension. The answer is D.

7. Malignant hyperthermia is a rare but life-threatening reaction that may occur during general anesthesia with halogenated anesthetics and skeletal muscle relaxants, particularly succinylcholine and tubocurarine. Release of calcium from skeletal sarcoplasmic reticulum leads to muscle spasms, hyperthermia and autonomic instability. Predisposing genetic factors include clinical myopathy associated with mutations in the gene loci for the skeletal muscle ryanodine receptor or L-type calcium receptors. Nitrous oxide is not metabolized! The answer is D.

8. The drug of choice in malignant hyperthermia is dantrolene, which prevents release of calcium from the sarcoplasmic reticulum of skeletal muscle cells. Appropriate measures must be taken to lower body temperature, control hypertension, and restore acid-base and electrolyte balance. The answer is C.

9. Ketamine is a cardiovascular stimulant, increasing heart rate and blood pressure. This results in part from central sympathetic stimulation and from inhibition of norepinephrine reuptake at sympathetic nerve endings. Analgesia and amnesia occur, with preservation of muscle tone and minimal depression of respiration. The answer is A.

10. Propofol is used extensively in anesthesia protocols, including those for day surgery. The favorable properties of the drug include an antiemetic effect and recovery more rapid than that after use of other intravenous drugs. Propofol does not cause cumulative effects, possibly because of its short half-life (2–8 min) in the body. The drug is also used for prolonged sedation in critical care settings. The answer is D.

1. Receptors that modify gene transcription: adrenal and gonadal steroids (See Chapter 2)

2. Receptors on membrane-spanning enzymes: insulin

3. Receptors activating Janus kinases that modulate STAT molecules: cytokines

4. Receptors directly coupled to ion channels: nicotinic (ACh), GABA, glycine

5. Receptors coupled to enzymes via G proteins: many endogenous compounds (eg, ACh, NE, serotonin) and drugs

6. Receptors that are enzymes or transporters: acetylcholinesterase, angiotensin-converting enzyme, carbonic anhydrase, H⁺/K⁺ antiporter, etc

When you complete this chapter, you should be able to:

• ❑ Name the major inhalation anesthetic agents and identify their pharmacodynamic and pharmacokinetic properties.

• ❑ Describe what is meant by the terms (1) blood:gas partition coefficient and (2) minimum alveolar anesthetic concentration.

• ❑ Identify proposed molecular targets for the actions of anesthetic drugs.

• ❑ Describe how the blood:gas partition coefficient of an inhalation anesthetic influences its speed of onset of anesthesia and its recovery time.

• ❑ Identify the commonly used intravenous anesthetics and list their main pharmacokinetic and pharmacodynamic characteristics.