Pharmacology of General Anesthetics

Introduction/Overview

General anesthetics represent a pharmacologically diverse group of agents that induce a reversible state of unconsciousness, amnesia, analgesia, and immobility, facilitating surgical and diagnostic procedures. The clinical practice of anesthesia relies on the precise administration of these drugs to achieve a controlled depression of the central nervous system while maintaining vital physiological functions. The development of modern general anesthesia, marked by the public demonstration of ether anesthesia in 1846, fundamentally transformed the scope and safety of surgical medicine. Contemporary anesthetic practice typically involves a balanced approach, combining multiple agents to exploit their complementary pharmacodynamic profiles while minimizing individual drug toxicity.

The clinical relevance of mastering the pharmacology of general anesthetics cannot be overstated. These agents are among the most potent and potentially dangerous drugs used in medicine, with a narrow therapeutic index. Their administration requires a thorough understanding of their effects on all organ systems, pharmacokinetic principles for precise titration, and management of profound physiological alterations. Mastery of this topic is essential for ensuring patient safety, optimizing surgical conditions, and managing the perioperative period effectively.

Learning Objectives

• Classify general anesthetics into major categories based on their chemical structure and route of administration.
• Explain the predominant theories regarding the molecular and cellular mechanisms of action for inhaled and intravenous general anesthetics.
• Analyze the pharmacokinetic principles governing the uptake, distribution, and elimination of inhaled anesthetics, including the concepts of minimum alveolar concentration and context-sensitive half-time.
• Compare and contrast the clinical applications, therapeutic profiles, and major adverse effects of commonly used inhalational and intravenous anesthetic agents.
• Identify significant drug interactions, contraindications, and special population considerations relevant to the administration of general anesthetics.

Classification

General anesthetics are primarily classified by their physical state and route of administration into two broad categories: inhalational agents and intravenous agents. This fundamental distinction dictates their pharmacokinetic behavior and clinical application.

Inhalational Anesthetics

These are volatile liquids or gases administered via the pulmonary route. They are further subdivided based on chemical structure.

• Halogenated Hydrocarbons: Modern agents are primarily halogenated ethers.
  • Fluorinated Methyl Ethyl Ethers: Sevoflurane, Desflurane, Enflurane (largely obsolete), Methoxyflurane (obsolete due to nephrotoxicity).
  • Fluorinated Methyl Isopropyl Ether: Isoflurane.
• Gaseous Anesthetics:
  • Nitrous Oxide (N₂O).
  • Xenon (a noble gas with anesthetic properties; limited clinical use due to high cost).

Intravenous Anesthetics

These agents are administered directly into the bloodstream, providing rapid onset of action. Classification is based on chemical class.

• Barbiturates: Thiopental (largely historical), Methohexital.
• Imidazole Derivatives: Etomidate.
• Arylcyclohexylamines: Ketamine.
• Phenol Derivatives: Propofol.
• Benzodiazepines: Midazolam, Diazepam (used primarily for sedation, not as sole general anesthetics).
• Opioids: Fentanyl, Sufentanil, Remifentanil, Alfentanil (used as potent analgesic components of balanced anesthesia).
• Miscellaneous/Sedative-Hypnotics: Dexmedetomidine (an α₂-adrenergic agonist used for sedation).

Mechanism of Action

The precise molecular mechanisms by which general anesthetics produce their effects remain an area of active research. The unitary theory of anesthesia, which proposed a single mechanism for all agents, has been supplanted by the understanding that different anesthetic classes likely act on distinct but overlapping molecular targets. The predominant hypothesis is that these agents modulate synaptic transmission, primarily by enhancing inhibitory neurotransmission or suppressing excitatory neurotransmission.

Molecular Targets and Receptor Interactions

General anesthetics are thought to act by binding to specific sites on ligand-gated ion channels, altering their function. These agents are generally lipophilic and may interact with hydrophobic pockets within protein complexes.

• Enhancement of GABA_A Receptor Function: This is a primary mechanism for many intravenous agents (propofol, barbiturates, etomidate, benzodiazepines) and contributes to the action of volatile agents. Binding potentiates the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), increasing chloride ion influx, hyperpolarizing the neuron, and inhibiting action potential generation.
• Inhibition of NMDA Receptor Function: Ketamine and nitrous oxide primarily act as non-competitive antagonists at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. This blockade of excitatory neurotransmission, particularly in the thalamocortical and limbic systems, leads to dissociation between the thalamus and the cerebral cortex.
• Modulation of Other Ion Channels: Volatile anesthetics and some intravenous agents may also modulate two-pore domain potassium (K_2P) channels (e.g., TREK-1), leading to hyperpolarization, and inhibit neuronal nicotinic acetylcholine receptors. Dexmedetomidine acts on presynaptic α₂-adrenergic receptors in the locus coeruleus, reducing norepinephrine release and producing sedation.

Cellular and Systems-Level Effects

At the cellular level, the net effect is a depression of neuronal excitability and a disruption of communication within neural networks. The ascending reticular activating system (ARAS), crucial for maintaining consciousness, is particularly sensitive. Different components of the anesthetic state are mediated by actions on different brain regions: amnesia involves the hippocampus and amygdala, immobility involves spinal cord motor neurons, and analgesia involves supraspinal and spinal sites. The Meyer-Overton correlation, which noted a relationship between anesthetic potency and lipid solubility, supported the idea of action in hydrophobic sites but did not identify specific protein targets.

Pharmacokinetics

The pharmacokinetics of general anesthetics are critical for understanding their onset, depth, and duration of action. Principles differ significantly between inhalational and intravenous agents.

Inhalational Anesthetics

The pharmacokinetics of inhaled agents are governed by the principles of gas exchange and partial pressures. The primary goal is to achieve and maintain an adequate partial pressure of the anesthetic in the brain (P_br).

Uptake and Distribution

The process is described by the concentration effect and the second gas effect. The rate of rise of alveolar concentration (F_A) toward inspired concentration (F_I) is determined by:

• Inspired Concentration: Higher F_I speeds induction.
• Alveolar Ventilation: Increased ventilation enhances delivery to alveoli.
• Blood:Gas Partition Coefficient (λ_b/g): This is the primary determinant of induction and recovery speed. A low λ_b/g (e.g., desflurane 0.45, sevoflurane 0.65, nitrous oxide 0.47) indicates low solubility in blood, leading to rapid equilibration and fast onset/offset. A high λ_b/g (e.g., older agents like halothane 2.4) results in slower changes.
• Cardiac Output: A high cardiac output slows induction by removing more anesthetic from the alveoli, diluting it in a larger blood volume.
• Alveolar-to-Venous Partial Pressure Gradient: This is influenced by tissue uptake, particularly into the vessel-rich group (brain, heart, liver, kidneys).

The potency of inhaled anesthetics is quantified by the Minimum Alveolar Concentration (MAC), defined as the alveolar concentration (at 1 atmosphere) that prevents movement in 50% of patients in response to a standardized surgical stimulus. MAC is additive; for example, 0.5 MAC of sevoflurane plus 0.5 MAC of nitrous oxide equals 1.0 MAC.

Metabolism and Elimination

Modern volatile agents undergo varying degrees of hepatic metabolism via cytochrome P450 enzymes (primarily CYP2E1). The extent of metabolism correlates with potential for toxicity. Sevoflurane metabolism is approximately 5%, isoflurane less than 1%, and desflurane about 0.02%. Elimination is predominantly via exhalation of the unchanged agent. Recovery depends on the same factors governing uptake: low solubility and high alveolar ventilation promote rapid elimination.

Intravenous Anesthetics

These agents follow multi-compartment pharmacokinetic models after intravenous bolus administration.

Absorption and Distribution

Administration is intravenous, ensuring 100% bioavailability. The rapid onset of action (one arm-brain circulation time) is due to high lipid solubility, leading to quick crossing of the blood-brain barrier. Initial distribution is into the vessel-rich group, followed by redistribution to muscle and eventually fat. Termination of effect after a single bolus is primarily due to redistribution from the brain to other tissues, not elimination.

Metabolism and Excretion

Metabolism occurs mainly in the liver, and metabolites are excreted renally. Important pharmacokinetic parameters include:

• Context-Sensitive Half-Time (CSHT): This is the time required for the plasma concentration to decrease by 50% after discontinuing a continuous infusion. It is more clinically relevant than elimination half-life (t_1/2) for infusions. Propofol and remifentanil have short, stable CSHTs, whereas drugs like diazepam have a CSHT that increases dramatically with infusion duration.
• Hepatic Clearance: Propofol has a very high hepatic clearance, exceeding liver blood flow, suggesting extrahepatic metabolism.
• Special Cases: Remifentanil is metabolized by nonspecific esterases in blood and tissues, giving it an extremely short t_1/2 (3-10 min) independent of hepatic or renal function. Ketamine has high hepatic extraction and active metabolites.

Therapeutic Uses/Clinical Applications

General anesthetics are used to facilitate a wide range of surgical and diagnostic procedures. Their application is tailored based on patient factors, procedure type, and duration.

Inhalational Agents

• Sevoflurane: Widely used for both induction (via mask, especially in pediatrics) and maintenance of anesthesia due to its pleasant odor, non-pungency, and rapid onset/offset.
• Desflurane: Favored for maintenance in long surgeries and in obese patients due to its very low blood solubility, facilitating rapid titration and emergence. It is irritating to airways and not used for induction.
• Isoflurane: A cost-effective agent for maintenance, though slower in onset and offset than sevoflurane or desflurane.
• Nitrous Oxide: Used as an adjunct to reduce the MAC requirement of other volatile agents or intravenous anesthetics. Provides rapid onset of analgesia and sedation but cannot produce surgical anesthesia alone at safe concentrations (maximum 70% due to risk of hypoxia).

Intravenous Agents

• Propofol: The most common agent for induction of general anesthesia and for maintenance via continuous infusion (Total Intravenous Anesthesia, TIVA). Also used extensively for procedural sedation in settings like endoscopy and in intensive care units for long-term sedation.
• Etomidate: Used for induction in patients with hemodynamic instability, coronary artery disease, or shock due to its minimal effects on cardiovascular function. Its use as a continuous infusion is avoided due to adrenal suppression.
• Ketamine: Used for induction in hypovolemic or asthmatic patients due to its sympathomimetic and bronchodilatory properties. Provides profound analgesia and is valuable for painful procedures outside the operating room, in burn dressing changes, and as an adjunct for multimodal analgesia. It is a key component of “dissociative sedation.”
• Barbiturates (Methohexital): Primarily used for electroconvulsive therapy (ECT) due to short duration and minimal interference with seizure activity.
• Benzodiazepines (Midazolam): Used for preoperative anxiolysis, sedation, and as a component of balanced anesthesia. Often used in combination with other agents.
• Opioids (Fentanyl, Remifentanil, Sufentanil): Not anesthetics per se, but are integral to balanced anesthesia for providing analgesia, blunting autonomic responses, and reducing MAC requirements for inhaled agents. Remifentanil is used in TIVA techniques for its predictable offset.
• Dexmedetomidine: Used for sedation in the ICU, for procedural sedation, and as an adjunct during general anesthesia to reduce opioid and volatile anesthetic requirements. It produces a unique, cooperative sedation.

Adverse Effects

General anesthetics affect all organ systems, leading to a spectrum of adverse effects ranging from common and mild to rare and life-threatening.

Common Side Effects

• Cardiovascular: Most agents cause dose-dependent myocardial depression and vasodilation, leading to hypotension. Exceptions include ketamine (increases blood pressure and heart rate via sympathomimetic action) and etomidate (minimal cardiovascular effects). Desflurane and isoflurane can cause a transient tachycardia.
• Respiratory: All agents cause dose-dependent respiratory depression, decreased tidal volume, and blunted response to hypercapnia and hypoxia. Airway irritation (coughing, breath-holding, laryngospasm) is common with desflurane and isoflurane.
• Central Nervous System: Emergence delirium (especially with sevoflurane and desflurane in children), postoperative cognitive dysfunction (POCD), nausea and vomiting (PONV), and headaches.
• Pain on Injection: A common complaint with propofol, which can be mitigated by lidocaine admixture or pretreatment.

Serious/Rare Adverse Reactions

• Malignant Hyperthermia (MH): A life-threatening, pharmacogenetic disorder triggered by all volatile inhalational agents and succinylcholine. It involves uncontrolled skeletal muscle metabolism due to ryanodine receptor (RYR1) mutations, leading to hypercapnia, tachycardia, rigidity, and severe hyperthermia. Treatment is immediate cessation of the trigger agent and administration of dantrolene sodium.
• Propofol Infusion Syndrome (PRIS): A rare but frequently fatal syndrome associated with high-dose, prolonged propofol infusion (>48 hours, >4 mg/kg^-1/hr^-1). Features include metabolic acidosis, rhabdomyolysis, hyperlipidemia, and bradyarrhythmias leading to cardiac failure.
• Hepatotoxicity: “Halothane hepatitis” is a rare, immune-mediated fulminant hepatic necrosis associated with halothane metabolism and trifluoroacetylated protein adduct formation. Cross-sensitivity with other volatile agents is possible but exceedingly rare with modern agents.
• Nephrotoxicity: Methoxyflurane caused high-output renal failure due to fluoride ion release. Sevoflurane metabolism produces fluoride and compound A (from reaction with CO₂ absorbents), but clinically significant nephrotoxicity is rare with contemporary fresh gas flows.
• Adrenal Suppression: Etomidate, even after a single induction dose, inhibits 11β-hydroxylase, suppressing cortisol synthesis for up to 24 hours. This may be detrimental in critically ill patients.
• Emergence Psychomimetic Effects: Ketamine can cause vivid dreams, hallucinations, and delirium during emergence, which can be mitigated by co-administration of a benzodiazepine.

Drug Interactions

The combined use of multiple anesthetic agents and perioperative medications creates a high potential for pharmacodynamic and pharmacokinetic interactions.

Major Drug-Drug Interactions

• Additive CNS Depression: All general anesthetics have additive or synergistic depressant effects with other CNS depressants, including opioids, benzodiazepines, sedating antihistamines, and alcohol. This necessitates dose reduction.
• MAC Reduction: Opioids, benzodiazepines, α₂-agonists (clonidine, dexmedetomidine), lidocaine, and other analgesics significantly reduce the MAC of inhalational anesthetics.
• Cardiovascular Agents: The hypotensive effects of anesthetics are potentiated by antihypertensives, especially β-blockers, calcium channel blockers, and diuretics. Volatile anesthetics sensitize the myocardium to the arrhythmogenic effects of catecholamines.
• Enzyme Induction/Inhibition: Chronic use of enzyme inducers (e.g., phenobarbital, phenytoin, rifampin) may increase the metabolism of volatile anesthetics and some intravenous agents, potentially altering recovery time. Conversely, enzyme inhibitors may prolong effects.
• Neuromuscular Blocking Agents: Volatile anesthetics potentiate the effects of both depolarizing (succinylcholine) and non-depolarizing neuromuscular blockers, reducing their required dose.
• Monoamine Oxidase Inhibitors (MAOIs): Historically associated with severe hypertensive crises with indirect sympathomimetics, but direct-acting vasopressors are considered safer. There is potential for exaggerated CNS depression.

Contraindications

• Malignant Hyperthermia Susceptibility: Absolute contraindication to all volatile inhalational anesthetics and succinylcholine.
• Known Severe Allergy/Hypersensitivity: To a specific agent or its components (e.g., propofol contraindicated in patients with egg or soybean allergy, though refined soybean oil contains minimal protein).
• Acute Intermittent Porphyria: Barbiturates are absolutely contraindicated as they can induce acute attacks. The safety of other agents varies.
• Untreated Closed Space Air Collections: Nitrous oxide is contraindicated in pneumothorax, middle ear surgery, and some intracranial procedures because it diffuses into air-filled spaces faster than nitrogen diffuses out, increasing pressure or volume.
• Significant Hemodynamic Instability (relative): Propofol and thiopental are relatively contraindicated; etomidate or ketamine may be preferred.
• Increased Intracranial Pressure (ICP): Ketamine is relatively contraindicated as it may increase cerebral metabolic rate and ICP, though this is debated in controlled ventilation settings.

Special Considerations

The pharmacokinetics and pharmacodynamics of general anesthetics are altered in specific patient populations, requiring careful dose adjustment and agent selection.

Pregnancy and Lactation

Most general anesthetics cross the placenta freely. Their use during pregnancy is primarily confined to necessary surgical procedures unrelated to delivery or for cesarean section. All agents can cause dose-dependent depression of the fetal CNS. Nitrous oxide, if used for prolonged periods, may inhibit methionine synthase, posing a theoretical risk. For cesarean section, induction is typically performed with a rapid-sequence technique using propofol or thiopental plus succinylcholine, often with low-dose volatile agent for maintenance. Neonatal depression is assessed via Apgar scores. Most anesthetic agents are excreted in breast milk in small amounts, but due to their short clinical use and rapid maternal elimination, interruption of breastfeeding is generally not required after recovery from anesthesia.

Pediatric Considerations

Pharmacokinetic differences are significant. Neonates and infants have a higher proportion of total body water, reduced plasma proteins, immature hepatic enzyme systems, and a higher cardiac output directed to the vessel-rich group. These factors can lead to higher initial plasma concentrations and prolonged effects of some intravenous agents. The MAC for inhalational agents is highest in infants (≈1.3 MAC) and decreases with age. Sevoflurane is favored for inhalation induction due to its non-pungency. Propofol requirements on a mg/kg basis are higher in children. There is an increased risk of emergence agitation with certain volatile agents. The immature blood-brain barrier and physiology increase susceptibility to drug effects.

Geriatric Considerations

Age-related physiological changes include decreased lean body mass, increased body fat, reduced total body water, decreased hepatic blood flow and metabolic capacity, and reduced renal function. These changes lead to altered pharmacokinetics: smaller central volume of distribution for hydrophilic drugs, larger peripheral volume for lipophilic drugs, and reduced clearance. Pharmacodynamically, the elderly brain is more sensitive to anesthetic agents, resulting in a decreased MAC (approximately 6% per decade after age 40) and increased sensitivity to intravenous agents. Doses for induction and maintenance should be reduced by 20-50%. There is a higher incidence of postoperative delirium and cognitive dysfunction in this population.

Renal and Hepatic Impairment

Renal Impairment: The pharmacokinetics of agents primarily excreted unchanged by the kidneys (e.g., some barbiturate metabolites) may be altered. However, most modern anesthetics are highly lipid-soluble and rely on hepatic metabolism or redistribution. Dosing adjustments are usually not required based on renal function alone, but considerations include the potential for accumulation of active metabolites (e.g., norpethidine from pethidine), electrolyte disturbances affecting drug binding, and altered fluid balance affecting distribution volumes. Sevoflurane use with low fresh gas flows in patients with severe renal impairment is often approached with caution due to compound A, though clinical significance is unclear.

Hepatic Impairment: Liver disease significantly impacts the pharmacokinetics of agents with high hepatic extraction (propofol, most opioids) and those dependent on hepatic metabolism. Reduced hepatic blood flow and enzyme activity can decrease clearance and prolong elimination half-life. Dose reduction and careful titration are essential. Serum albumin reduction may increase the free fraction of highly protein-bound drugs, potentiating their effect. The risk of hepatotoxicity from volatile agents, while extremely low with modern agents, may be theoretically increased in patients with underlying liver disease. Remifentanil, metabolized by blood esterases, is a useful option as its kinetics are unaffected by hepatic disease.

Summary/Key Points

• General anesthetics are classified as inhalational (volatile liquids/gases) or intravenous agents, each with distinct pharmacokinetic profiles governed by factors like blood:gas solubility (for inhalational) and context-sensitive half-time (for intravenous infusions).
• The primary mechanism of action involves modulation of ligand-gated ion channels, particularly potentiation of GABA_A receptors (propofol, barbiturates, volatiles) or antagonism of NMDA receptors (ketamine, N₂O).
• Potency of inhaled agents is measured by Minimum Alveolar Concentration (MAC), which is additive between agents.
• Clinical selection is based on patient factors and procedure: Sevoflurane for smooth induction/maintenance, Desflurane for rapid titration in long cases, Propofol for induction/TIVA, Etomidate in hemodynamically unstable patients, and Ketamine for analgesia/bronchodilation.
• Major adverse effects include dose-dependent cardiorespiratory depression, postoperative nausea/vomiting, and rare but serious events like Malignant Hyperthermia (triggered by volatiles) and Propofol Infusion Syndrome.
• Significant drug interactions occur primarily through additive CNS depression, MAC reduction by adjuncts, and potentiation of neuromuscular blockers.
• Special population dosing is crucial: reduced doses are required in the elderly due to increased sensitivity and altered PK; pediatric patients have higher MAC and different distribution volumes; hepatic impairment significantly affects the clearance of many agents.

Clinical Pearls

• Recovery from a single bolus of intravenous anesthetic is due to redistribution, not metabolism; recovery after a prolonged infusion depends on context-sensitive half-time.
• For rapid induction and emergence with an inhaled agent, choose one with a low blood:gas partition coefficient (e.g., desflurane, sevoflurane).
• Malignant hyperthermia is a clinical diagnosis; immediate treatment with dantrolene takes precedence over laboratory confirmation.
• In patients with significant hepatic disease, consider using agents whose clearance is less dependent on liver function, such as remifentanil or atracurium.
• The “balanced anesthesia” technique, using smaller doses of multiple drugs (e.g., opioid + hypnotic + muscle relaxant), aims to maximize therapeutic effects while minimizing the adverse effects of any single agent.

References

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