Bases of anesthetic pharmacology

Mechanism

Biophysical mechanisms of narcosis

Historically, the correlation between the lipid solubility of anesthetic gases and their anesthetic potency (Meyer-Overton hydrophobic hypothesis) suggested that these agents acted through nonspecific perturbation of the lipid bilayer of neuronal membranes. Contemporary research has shown that the interaction is highly specific and occurs directly with channel proteins and membrane receptors in specific hydrophobic domains.

This equation represents the Meyer-Overton rule, where the minimum alveolar concentration (MAC) correlates inversely with the lipid solubility of the compound. The main target receptors identified in the CNS are:

• GABA_A receptor (γ-aminobutyric acid type A): Ionotropic chloride channel (Cl^-). Halogenated hypnotic agents, propofol, barbiturates, and etomidate act as positive allosteric modulators, prolonging the channel opening time or increasing its affinity for the ligand. This results in a sustained hyperpolarization of the postsynaptic membrane, decreasing neuronal excitability.
• NMDA (N-methyl-D-aspartate) receptor: Ionotropic channel permeable to calcium (Ca²⁺) and sodium (Na⁺), mediator of excitatory neurotransmission by glutamate. Ketamine, nitrous oxide and xenon act as non-competitive antagonists of this receptor, blocking the ion channel directly.
• Two-Pore Potassium Channels (K2P - TREK/TRAAK): Halogenated anesthetics activate these leak channels, promoting the efflux of potassium (K⁺) to the extracellular space, which stabilizes the resting membrane potential near its reversible equilibrium potential and prevents the generation of the action potential.

Synaptic Mechanism of Immuno-suppression and Hypnosis

At the molecular level, the GABA_A receptor consists of a pentamer that typically has the 2α1β2γ configuration. Intravenous anesthetics such as propofol bind with high specificity to the hydrophobic cavity located between the β and α subunits. This allosteric binding stabilizes the open state of the channel in the presence of basal GABA, causing a massive flow of Cl^- into the neuronal cell. The membrane potential decreases from -70 mV to values close to -90 mV, inducing a blockage of impulse conduction in the cerebral cortex, the thalamus and the ascending reticular activating system (RAAS).

Pharmacokinetics

Dynamics of compartment distribution

The distribution and elimination of intravenous anesthetic drugs is governed by three-compartmental kinetic models. Following a rapid intravenous bolus, the drug is distributed almost instantaneously to the central compartment (V1), which includes highly perfused organs (brain, heart, kidneys, and liver). Subsequently, it is reversibly transferred to the fast peripheral compartment (V2) (skeletal muscle and skin) and the slow peripheral compartment (V3) (adipose and bone tissue, with low perfusion but high physical storage capacity).