Pharmacology of General Anesthetics

Introduction / Overview

General anesthetics constitute a diverse group of agents that produce a reversible, drug‑induced, loss of consciousness and immobility, accompanied by analgesia, amnesia, and muscle relaxation. Their clinical relevance is underscored by the requirement for safe and effective induction and maintenance of anesthesia during elective and emergency surgical procedures. Understanding the pharmacological principles that govern their action is essential for clinicians who administer these agents and for pharmacists who prepare and dispense them.

Learning objectives for this monograph include:

• Describe the classification and chemical diversity of general anesthetic agents.
• Explain the principal mechanisms of action at molecular and cellular levels.
• Summarize the pharmacokinetic properties that influence dosing and monitoring.
• Identify therapeutic indications, common adverse effects, and major drug interactions.
• Apply special considerations for vulnerable populations such as pregnant, pediatric, geriatric, and patients with organ impairment.

Classification

Drug Classes and Categories

General anesthetics are traditionally classified according to their route of administration and physical properties:

• Inhalational agents – volatile gases or liquids delivered via breathing circuits (e.g., sevoflurane, desflurane, isoflurane, halothane).
• Intravenous agents – compounds administered directly into the bloodstream, subdivided into:
• Induction agents (propofol, thiopental, ketamine).
• Maintenance agents (midazolam, fentanyl, remifentanil).
• Opioid analgesics (morphine, fentanyl, sufentanil).
• Adjunctive agents – medications that modify the effects of primary anesthetics, such as neuromuscular blockers (succinylcholine, rocuronium) and reversal agents (neostigmine, sugammadex).

Chemical Classification

From a chemical standpoint, general anesthetics fall into several categories:

• Alkane derivatives (halogenated hydrocarbons).
• Alkylamides (sevoflurane, desflurane).
• Alkylphenols (halothane).
• Barbiturates (thiopental).
• Propofol – a phenol‑based analog of benzyl alcohol.
• Ketamine – an arylcyclohexylamine.
• Opioid alkaloids and synthetic analogs.

Mechanism of Action

Pharmacodynamics of Inhalational Anesthetics

Volatile agents exert their effects primarily through modulation of neuronal ion channels and receptor complexes. Evidence suggests that these agents enhance the inhibitory activity of γ‑aminobutyric acid type A (GABA_A) receptors and inhibit excitatory glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors. The degree of potentiation is concentration‑dependent and correlates with the agent’s lipid solubility.

Additionally, volatile anesthetics activate two-pore domain potassium channels (K_2P), including TREK-1 and TASK-3, leading to hyperpolarization and reduced neuronal excitability. The net effect is a shift in the balance of synaptic transmission toward inhibition, which underlies the loss of consciousness and immobility.

Pharmacodynamics of Intravenous Anesthetics

Propofol, the most widely used intravenous induction agent, potentiates GABA_A receptor activity and inhibits NMDA receptors. Its rapid onset is attributed to high lipid solubility, facilitating swift brain penetration. Intravenous barbiturates, such as thiopental, similarly bind to the GABA_A receptor complex but also induce hyperpolarization by opening chloride ion channels, thereby suppressing cortical activity.

Ketamine distinguishes itself by acting as a dissociative anesthetic. It blocks NMDA receptors without significantly affecting GABAergic transmission, producing a state of dissociation and analgesia. The resulting increase in sympathetic tone may be advantageous in hypotensive patients.

Opioid analgesics bind to μ, κ, and δ opioid receptors in the central nervous system, inhibiting descending pain pathways and modulating respiratory centers. Their sedative properties contribute to the overall anesthetic depth.

Molecular and Cellular Mechanisms

At the cellular level, anesthetic agents alter membrane fluidity, thereby influencing the function of embedded ion channels. The Meyer–Overton correlation, which links anesthetic potency to lipid solubility, supports this membrane‑centric model. However, specific protein targets, such as GABA_A and NMDA receptors, provide a more precise understanding of dose–response relationships. The interplay between these targets determines the hemodynamic and respiratory effects observed clinically.

Pharmacokinetics

Absorption and Distribution

Inhalational anesthetics are absorbed through alveolar membranes, achieving equilibrium between alveolar and arterial partial pressures. The alveolar concentration (C_Alv) rapidly reflects changes in inspired concentration, allowing for precise titration. Distribution is governed by the agent’s partition coefficients: blood–gas partition coefficient and lipid–blood partition coefficient. Agents with low blood–gas partition coefficients, such as desflurane, exhibit rapid onset and offset due to swift equilibrium with the alveolar gas.

Intravenous agents are absorbed directly into systemic circulation. Propofol’s distribution is characterized by a high volume of distribution (V_d ≈ 0.6 L/kg), reflecting extensive tissue uptake, particularly in adipose tissue. Thiopental displays a V_d of approximately 0.3 L/kg. Ketamine’s distribution is more limited (V_d ≈ 0.5 L/kg). Opioids vary; fentanyl has a V_d of ~2–5 L/kg, whereas morphine’s V_d is around 0.3 L/kg.

Metabolism

Inhalational agents are largely exhaled unchanged, with minimal hepatic metabolism. Occasional metabolites (e.g., halothane metabolites contribute to hepatotoxicity) are clinically insignificant for most agents.

Propofol undergoes hydroxylation and glucuronidation in the liver, producing propofol glucuronide, which is excreted renally. Thiopental is metabolized by hepatic cytochrome P450 enzymes (primarily CYP2B6) into inactive metabolites. Ketamine is metabolized by CYP2B6 and CYP3A4 to norketamine, which retains some anesthetic activity. Opioids are metabolized variably: morphine via conjugation to glucuronides, fentanyl via CYP3A4 oxidation.

Excretion

Inhalational anesthetics are exhaled via the lungs. Intravenous agents are eliminated through renal and hepatic routes. Propofol and its metabolites are cleared renally. Thiopental metabolites are excreted by the kidneys. Ketamine’s metabolites are primarily renally excreted, whereas fentanyl metabolites are eliminated hepatically.

Half‑life and Dosing Considerations

For inhalational agents, the effective half‑life (t_1/2,eff) is influenced by the blood–gas partition coefficient and the rate of ventilation. Agents such as desflurane have t_1/2,eff < 2 min, enabling rapid emergence. Intravenous agents’ half‑lives vary: propofol t_1/2 ≈ 1–4 min, thiopental t_1/2 ≈ 4–6 min, ketamine t_1/2 ≈ 2–3 min. Opioids possess longer durations, with fentanyl t_1/2 ≈ 3–4 h, morphine t_1/2 ≈ 2–3 h. Dosing regimens are tailored to the desired depth of anesthesia, the patient’s organ function, and the surgical context.

Therapeutic Uses / Clinical Applications

Approved Indications

General anesthesia is indicated for surgeries requiring complete unconsciousness, immobility, and analgesia. Volatile anesthetics are used for maintenance of anesthesia during procedures ranging from minor outpatient surgeries to major spinal or cardiac operations. Intravenous agents are employed for induction, maintenance, or rapid‑sequence induction in patients with contraindications to inhalation. Ketamine is particularly useful in trauma, pediatric, and pediatric sedation, as well as in patients with compromised cardiovascular function.

Off‑Label Uses

In certain settings, general anesthetics are used off‑label to manage severe agitation, refractory seizures, or to provide procedural sedation in interventional radiology. Propofol infusion syndrome has been a concern when propofol is administered at high doses for extended periods, leading to cautious use in intensive care units.

Adverse Effects

Common Side Effects

Respiratory depression, hypotension, and post‑operative nausea and vomiting (PONV) are frequently observed. The incidence of PONV varies with the choice of agent: volatile agents, particularly desflurane, are associated with higher rates compared to propofol, which has antiemetic properties. Hypotension is more pronounced with propofol and ketamine due to vasodilatory effects, whereas volatile agents cause dose‑dependent vasodilation.

Serious / Rare Adverse Reactions

Allergic reactions, though uncommon, can occur with halothane and other halogenated agents. Propofol infusion syndrome (Propofol Infusion Syndrome; PIS) is a rare but potentially fatal complication characterized by metabolic acidosis, rhabdomyolysis, cardiac failure, and renal failure. Ketamine can induce psychotomimetic effects, including hallucinations and dysphoria, particularly when used in higher doses or in patients with pre‑existing psychiatric disorders.

Black Box Warnings

Propofol carries a black‑box warning for PIS when administered at doses > 4 mg/kg/h for more than 48 h. Halothane is associated with idiosyncratic hepatitis and thus is rarely used in contemporary practice. Ketamine’s potential for abuse and dissociative effects necessitates careful monitoring.

Drug Interactions

Major Drug–Drug Interactions

Inhalational agents potentiate the effects of neuromuscular blockers, prolonging paralysis. Volatile anesthetics inhibit cytochrome P450 enzymes, potentially increasing plasma concentrations of drugs metabolized by CYP3A4 and CYP2B6, such as benzodiazepines and opioids. Propofol has minimal drug interactions but may enhance the sedative effects of CNS depressants. Ketamine’s interaction profile includes additive sympathomimetic effects with other stimulants and potential for GABAergic antagonism with benzodiazepines, leading to altered anesthetic depth.

Contraindications

Patients with known hypersensitivity to the anesthetic or its excipients should avoid the agent. Severe hepatic failure contraindicates the use of agents with significant hepatic metabolism (e.g., thiopental). Propofol is contraindicated in patients with a history of propofol infusion syndrome. Ketamine is contraindicated in patients with uncontrolled hypertension or elevated intracranial pressure due to its sympathomimetic effects.

Special Considerations

Use in Pregnancy / Lactation

Inhalational anesthetics cross the placenta; however, their rapid elimination reduces fetal exposure. Propofol is considered relatively safe in pregnancy but should be used with caution due to potential maternal hypotension. Ketamine is not recommended during pregnancy owing to its central nervous system effects on the fetus. During lactation, propofol and many volatile agents are excreted in minimal amounts, but caution is advised until more definitive data are available.

Pediatric / Geriatric Considerations

Pediatric patients exhibit higher metabolic rates and lower body water content, affecting the pharmacokinetics of intravenous anesthetics. Geriatric patients often have reduced hepatic and renal function, necessitating dose adjustments. Both populations are more susceptible to postoperative delirium and PONV; propofol’s antiemetic properties may be advantageous in elderly patients.

Renal / Hepatic Impairment

Hepatic impairment may prolong the half‑life of agents metabolized by the liver. Propofol’s metabolism is hepatic; caution is warranted in cirrhosis. Intravenous opioids, particularly fentanyl, rely on hepatic metabolism; thus, dose reductions or alternative agents may be required. Renal impairment affects the excretion of propofol metabolites and opioids; monitoring for accumulation is essential.

Summary / Key Points

• General anesthetics are classified by route of administration and chemical structure, influencing their pharmacodynamic and pharmacokinetic profiles.
• Volatile agents primarily enhance GABA_A receptor activity and inhibit NMDA receptors, while intravenous agents modulate similar pathways with distinct mechanisms.
• Pharmacokinetics are governed by lipid solubility, partition coefficients, and organ metabolism, dictating onset, duration, and clearance.
• Therapeutic applications span induction and maintenance of anesthesia, with specific agents favored for particular clinical scenarios.
• Adverse effects include hypotension, PONV, and rare severe reactions such as propofol infusion syndrome; careful monitoring mitigates risk.
• Drug interactions with neuromuscular blockers, CYP450 substrates, and CNS depressants necessitate vigilant dose adjustment.
• Special populations—pregnant, pediatric, geriatric, and those with organ dysfunction—require individualized dosing strategies.

Clinicians and pharmacists should remain apprised of evolving evidence regarding the safety profiles and pharmacologic nuances of general anesthetic agents to optimize patient outcomes and minimize complications.

References

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