Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 25. General Anesthetics

General Anesthetics: Introduction

General anesthesia is a state characterized by unconsciousness, analgesia, amnesia, skeletal muscle relaxation, and loss of reflexes. Drugs used as general anesthetics are CNS depressants with actions that can be induced and terminated more rapidly than those of conventional sedative-hypnotics.

High-Yield Terms to Learn

Balanced anesthesia Anesthesia produced by a mixture of drugs, often including both inhaled and intravenous agents Inhalation anesthesia Anesthesia induced by inhalation of drug Minimum alveolar anesthetic concentration (MAC) The alveolar concentration of an anesthetic that is required to prevent a response to a standardized painful stimulus in 50% of patients Analgesia A state of decreased awareness of pain, sometimes with amnesia General anesthesia A state of unconsciousness, analgesia, and amnesia, with skeletal muscle relaxation and loss of reflexes

Stages of Anesthesia

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.

Stage 1: Analgesia

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

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.

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.

Stage 4: Medullary Depression

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

Anesthesia Protocols

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.

Mechanisms of Action

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 -aminobutyric acid (GABA)-mediated inhibition at GABAA 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 GABAA 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.

Inhaled Anesthetics

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.

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.

FIGURE 25-1

Why induction of anesthesia is slower with more soluble anesthetic gases and faster with less soluble ones. In this schematic diagram, solubility is represented by the size of the blood compartment (the more soluble the gas, the larger is the compartment). For a given concentration or partial pressure of the 2 anesthetic gases in the inspired air, it will take much longer with halothane than with nitrous oxide for the blood partial pressure to rise to the same partial pressure as in the alveoli. Because the concentration in the brain can rise no faster than the concentration in the blood, the onset of anesthesia will be much slower with halothane than with nitrous oxide.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 25-3.)

TABLE 25-1 Properties of inhalation anesthetics.

Anesthetic Blood: Gas Partition Coefficient Minimum Alveolar Concentration (%)a

Metabolism Nitrous oxide 0.47 >100 None Desflurane 0.42 6.5 <0.1% Sevoflurane 0.69 2.0 2-5% (fluoride) Isoflurane 1.40 1.4 <2% Enflurane 1.80 1.7 8% Halothane 2.30 0.75 >40% Methoxyflurane 12 0.16 >70% (fluoride)

aMinimum alveolar concentration (MAC) is the anesthetic concentration that eliminates the response in 50% of patients exposed to a standardized painful stimulus. In this table, MAC is expressed as a percentage of the inspired gas mixture.

Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 10th ed. McGraw-Hill, 2007.

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.

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.

FIGURE 25-2

Ventilation rate and arterial anesthetic tensions. Increased ventilation (8 versus 2L/min) has a much greater effect on equilibration of halothane than nitrous oxide.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 25-5.)

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.

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.

Elimination

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.

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.

Effects of Inhaled Anesthetics

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.

Cardiovascular Effects

Most inhaled anesthetics decrease arterial blood pressure moderately. Enflurane and halothane are myocardial depressants that decrease cardiac output, whereas isoflurane, descflurane, 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.

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 causing breath-holding limits its use in anesthesia induction.

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 both 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. Dantrolene is indicated for the treatment of this life-threatening condition, with supportive management.

Skill Keeper: Signaling Mechanisms

(See Chapter 2)

Like most drugs, general anesthetics appear to act via interactions with specific receptor molecules involved in cell signaling. For review purposes, try to recall the major types of signaling mechanismsrelevant to the actions of drugs that act via receptors. The Skill Keeper Answers appear at the end of the chapter.

Intravenous Anesthetics

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.

FIGURE 25-3

Redistribution of thiopental after intravenous bolus administration. Note that the time axis is not linear.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 25-6.)

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.

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). 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.

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.

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 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 rapidly broken down in the body by alkaline phosphatase to form propofol. It is more readily injectable and appears to cause less pain at injection sites than the standard form of the drug.

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.

General anesthesia is a state characterized by unconsciousness, analgesia, amnesia, skeletal muscle relaxation, and loss of reflexes. Drugs used as general anesthetics are CNS depressants with actions that can be induced and terminated more rapidly than those of conventional sedative-hypnotics.

Skill Keeper Answer: Signaling Mechanisms

(See Chapter 2)

1. Receptors that modify gene transcription: adrenal and gonadal steroids

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, and so on

Checklist

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

 Name the 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 point out their main pharmacokinetic and pharmacodynamic characteristics.

Drug Summary Table: General Anesthetics

Subclass Possible Mechanism Pharmacologic Effects Pharmacokinetics Toxicities and Interactions Inhaled anesthetics Desflurane Enflurane Halothane Isoflurane Sevoflurane Nitrous oxide Facilitate GABA-mediated inhibition; block brain NMDA and ACh-N receptors Increase cerebral blood flow; enflurane and halothane decrease cardiac output. Others cause vasodilation; all decrease respiratory functions—lung irritation (desflurane) Rate of onset and recovery vary by blood:gas partition coefficient; recovery mainly due to redistribution from brain to other tissues Toxicity: extensions of effects on brain, heart/vasculature, lungs. Drug interactions: additive CNS depression with many agents, especially opioids and sedative-hypnotics Intravenous anesthetics Barbiturates Thiopental, Thioamylal, Methohexital Barbiturates, benzodiazepines, etomidate and propofol facilitate GABA-mediated inhibition at GABAA receptors

Barbiturates: circulatory and respiratory depression; decrease intracranial pressure Barbiturates: high lipid solubility—fast onset and short action due to redistribution Barbiturates: extensions of CNS depressant actions; additive CNS depression with many drugs Benzodiazepines Midazolam Benzodiazepines: less depressant than barbiturates Slower onset, but longer duration than barbiturates Postoperative respiratory depression reversed by flumazenil Dissociative Ketamine Blocks excitation by glutamate at NMDA receptors Analgesia, amnesia and catatonia but "consciousness" retained; cardiovascular (CV) stimulation! Moderate duration of action—hepatic metabolism Increased intracranial pressure; emergence reactions Imidazole Etomidate Minimal effects on CV and respiratory functions Short duration due to redistribution No analgesia, pain on injection (may need opioid), myoclonus, nausea, and vomiting Opioids Fentanyl Alfentanil Remifentanil Morphine Interact with , and  receptors for endogenous opioid peptides Marked analgesia, respiratory depression (see Chapter 31) Alfentanil and remifentanil fast onset (induction) Respiratory depression—reversed by naloxone Phenols Propofol, Fospropofol Propofol: vasodilation and hypotension; negative inotropy. Fospropofol water-soluble Propofol: fast onset and fast recovery due to inactivation Propofol: hypotension (during induction), cardiovascular depression

ACh, acetylcholine; NMDA, N-methyl-D-aspartate.



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