M3 General anesthesia (multi-target mechanisms)

Topic

The level of consciousness—already defined in another model—is reduced by general anesthesia, which induces a loss of consciousness and a loss of responsiveness to nociceptive stimuli through multiple molecular mechanisms acting simultaneously on the cortical network.

The first of these molecular mechanisms is the potentiation of the cortical network's inhibitory conductance, mediated by a specific type of receptor; this is a direct extension of the synaptic conductance previously described for chemical synapses in another model.

The second molecular mechanism, present in dissociative agents such as ketamine, involves blocking a specific type of glutamate receptor in the cortical network; this is an extension of the receptor-ligand kinetics previously described in another model, paralleling the glutamate receptor hypofunction associated with schizophrenia.

Both molecular mechanisms reduce the effective connectivity of the cortical network until the level of consciousness falls below an operational threshold: as long as the level of consciousness remains above this threshold, the person stays conscious; however, once the cortical network's effective connectivity drops sufficiently for the level of consciousness to cross below that threshold, the loss of consciousness characteristic of general anesthesia occurs.

The relationship between the anesthetic drug concentration and the probability of this loss of consciousness follows a dose-response curve—specifically, the sigmoidal Hill curve previously described for receptor-ligand kinetics in another model: at low drug concentrations, the probability of losing consciousness is low; it then rises rapidly within an intermediate concentration range and finally plateaus near a maximum probability at high drug concentrations.

The pharmacokinetics of the anesthetic drug are, in turn, modeled using a simple compartmental scheme of the same type previously used to describe the kinetics of other substances within the body. Within this pharmacokinetic framework, the context-sensitive half-life of the anesthetic drug reflects how the duration of the infusion prolongs the time required to regain consciousness after the drug is discontinued: the longer the infusion, the more prolonged the recovery of consciousness once the anesthetic is stopped. Ultimately, it is this level of consciousness—reduced through the potentiation of inhibitory conductance and the blockade of glutamate receptors within the cortical network—that determines both the loss of consciousness during general anesthesia and the time required to regain consciousness once the drug is discontinued.

ID:4275