General Anesthesia

Propofol (2,6-diisopropylphenol) produces anesthesia through positive allosteric modulation of the gamma-aminobutyric acid type A receptor, enhancing chloride conductance and prolonging channel opening time. At clinical concentrations it can also directly activate the receptor in the absence of gamma-aminobutyric acid. Onset is within 30 to 60 seconds of an induction bolus. The initial offset after a single dose (5 to 10 minutes) is driven by redistribution from the brain to muscle — not by elimination. Hepatic glucuronidation and sulfation are the primary elimination pathways.

For infusion-based anesthesia, the clinically relevant parameter is the context-sensitive half-time: the time for plasma concentration to fall 50% after stopping a continuous infusion. Propofol's context-sensitive half-time rises modestly with infusion duration (approximately 10 minutes after 1 hour; approximately 40 minutes after 8 hours), making it suitable for prolonged total intravenous anesthesia with reasonably predictable emergence.

Propofol reduces cerebral metabolic rate and cerebral blood flow without cerebral vasodilation, preserving cerebrovascular coupling — making it favorable for neuroanesthetic applications and superior to volatile agents in patients with elevated intracranial pressure. It also produces antiemetic effects (through serotonin type 3 receptor antagonism and dopaminergic inhibition at the chemoreceptor trigger zone), contributing to its preference over volatile agents in high-risk postoperative nausea and vomiting patients.

Propofol causes dose-dependent hypotension through peripheral vasodilation and modest myocardial depression, without the compensatory reflex tachycardia seen with isoflurane. Elderly, hypovolemic, and patients with impaired cardiac function require substantially reduced induction doses. Propofol is a potent respiratory depressant — apnea is common after induction doses.

Etomidate is a carboxylated imidazole that produces anesthesia through gamma-aminobutyric acid type A receptor potentiation, binding to beta subunits. Its clinical niche rests on a single property: exceptional hemodynamic stability. Unlike propofol, thiopental, or ketamine (in catecholamine-depleted patients), etomidate causes minimal change in cardiac output, heart rate, systemic vascular resistance, or mean arterial pressure. It is the preferred induction agent when cardiovascular reserve is severely compromised — cardiogenic shock, severe aortic stenosis, cardiac tamponade, right heart failure.

Etomidate blocks 11-beta-hydroxylase (the enzyme that converts 11-deoxycortisol to cortisol in the final step of cortisol synthesis) and also inhibits aldosterone synthase. A single induction dose suppresses cortisol production for 6 to 24 hours in most patients. In healthy elective surgical patients this transient suppression is clinically insignificant. In patients with septic shock — where adrenal reserve may already be compromised — even brief adrenal suppression from a single dose may worsen outcomes. Many centers therefore avoid etomidate in septic shock patients and use ketamine as the hemodynamically stable alternative.

Etomidate is not used for maintenance infusion because cumulative adrenal suppression becomes clinically significant with prolonged use.

Myoclonus on induction occurs in 30 to 70% of patients not premedicated with an opioid or benzodiazepine. It is a cortical disinhibition phenomenon, not seizure activity, and is substantially reduced by fentanyl or midazolam pretreatment. Postoperative nausea and vomiting incidence is higher with etomidate than with propofol. Pain on injection occurs in approximately 20% of patients.

Benzodiazepines are positive allosteric modulators of the gamma-aminobutyric acid type A receptor, binding at the alpha-gamma subunit interface and increasing the frequency of chloride channel opening in response to gamma-aminobutyric acid. Unlike barbiturates and propofol, they do not directly activate the receptor in the absence of gamma-aminobutyric acid. They cannot reliably produce surgical anesthesia as sole agents at standard doses. Their clinical value in anesthesia is as adjuncts: anxiolysis, anterograde amnesia, anticonvulsant activity, and reduction of volatile agent minimum alveolar concentration.

Midazolam is water-soluble at its formulation pH but becomes lipid-soluble at physiological pH after injection, allowing rapid central nervous system penetration (onset 2 to 3 minutes intravenously). It is metabolized by cytochrome P450 3A4 to 1-hydroxymidazolam, an active metabolite. In renal failure, metabolite accumulation can prolong sedation unexpectedly.

Perioperative uses of midazolam: premedication (1 to 2 mg intravenously — anxiolysis and reliable anterograde amnesia within 5 minutes); co-induction with propofol (reduces propofol induction dose by 25 to 30%); prevention of ketamine emergence reactions (substantially reduces incidence of hallucinations and dysphoria in adults); and supplemental sedation during regional or monitored anesthesia care.

Flumazenil is a competitive benzodiazepine receptor antagonist. Reversal onset is 1 to 2 minutes intravenously. Its duration (30 to 60 minutes) is considerably shorter than most benzodiazepines, so resedation can occur — patients require monitoring for at least 60 to 120 minutes after flumazenil administration. Flumazenil can precipitate acute withdrawal seizures in patients physically dependent on benzodiazepines and should be used with caution in this population.

Total intravenous anesthesia uses intravenous agents exclusively — no inhalational agents. The standard combination is propofol (hypnotic) plus remifentanil (analgesic). Remifentanil is a mu-opioid receptor agonist with a pharmacokinetic property unique among clinical opioids: its ester linkage makes it susceptible to hydrolysis by nonspecific esterases in plasma and tissues, producing a pharmacologically inactive metabolite. This metabolism is independent of hepatic and renal function, yielding an ultrashort context-sensitive half-time of approximately 3 to 5 minutes regardless of infusion duration. Remifentanil can be infused for 8 hours and will still clear within minutes of stopping — making analgesia precisely titratable and emergence rapid.

Because remifentanil provides no residual postoperative analgesia, transition to longer-acting analgesia must be planned and initiated before or immediately at emergence to prevent an analgesic gap. This is the primary practical challenge of remifentanil-based total intravenous anesthesia.

The principal challenge of total intravenous anesthesia relative to volatile agents is the absence of end-tidal gas concentration as a real-time surrogate for anesthetic depth. With volatile agents, the end-tidal concentration provides a continuous, reliable pharmacodynamic measure. With total intravenous anesthesia, plasma propofol concentration can be estimated by pharmacokinetic models but cannot be measured at the bedside, and model predictions may diverge 20 to 30% from true concentrations in individual patients. Processed electroencephalography monitors (such as bispectral index) provide an objective measure of cortical activity reflecting anesthetic depth and are considered standard of care for total intravenous anesthesia in many centers, reducing the risk of intraoperative awareness.