Pharm Exam 1.2

Electrophysiological Effects of Anesthetics

• Anesthetic potency increases with chain length but has a cutoff effect.
• Enantiomers exhibit different anesthetic potency despite identical octanol:water partition coefficient.
• Meyer-Overton Rule and its exceptions are explained by anesthetic binding of specific lipophilic amino acids.
• Anesthetics hyperpolarize nerves and this effect correlates with anesthetic potency.
• General anesthetics primarily act at the synapse, inhibiting glutamate release and potentiating GABA.
• Anesthetics target ion channels including Na+, K+, HCN, and GABA-activated chloride channels.
• Anesthetics also affect ligand-gated ion channels such as glutamate-activated NMDA and GABA-activated channels.
• Different anesthetics act at different subtypes of the GABA receptor, leading to potentiation, direct gating, or inhibition.
• Anesthetics affect other ligand-gated ion channels like nicotinic acetylcholine, 5-HT3, and glycine receptors.
• Volatile anesthetics, propofol, barbiturates, and neurosteroids potentiate glycine receptors but not etomidate or ketamine.
• There are graphic summaries available on the topic.
• Sources include Barash Clinical Anesthesia, Flood Stoelting’s Pharmacology and Physiology in Anesthetic Practice, and Evers Anesthetic Pharmacology.

Understanding General Anesthesia and Anesthetic Targets

• General anesthesia is a reversible depression of the CNS, causing loss of response to external stimuli and consists of components such as unconsciousness, amnesia, analgesia, immobility, and attenuation of the autonomic response.
• Unconsciousness involves impairment of connectivity and integration between cortical structures, similar to NREM sleep, and likely interferes with thalamic input to the cerebral cortex and other subcortical structures.
• The sleep/wake cycle involves the interaction between the tuberomammillary nucleus (TMN) and ventrolateral preoptic nucleus (VLPO), with orexin from the perifornical area activating various brain regions and stabilizing the sleep-wake switch.
• Likely anesthetic targets for unconsciousness include the cerebral cortex, thalamus, TMN, VLPO, perifornical area, and locus coeruleus, with GABAergic inhibition and cholinergic stimulation affecting these areas.
• Anesthesia generally prevents the formation of new memories, but leaves previous memories intact, with different mechanisms involved in short-term and long-term memory.
• Long-term memory formation involves critical steps in the hippocampus and amygdala, and the conversion of short-term to long-term memory requires anatomical changes in the synapse and takes time.
• General anesthesia ablates conscious memory (explicit) and unconscious memory (implicit), with varying incidences of awareness with recall observed in different patient groups.
• Awareness monitoring during anesthesia is based on processed EEG and BIS (Bispectral Index), but studies have shown that the BIS monitor is not more successful in preventing awareness than a protocol using MAC.
• Volatile anesthetics exhibit a biphasic dose response for analgesia, while opioids, non-opioids, α2 agonists, neostigmine, ketamine, barbiturates, nitrous oxide, xenon, and adenosine also contribute to analgesia through different mechanisms.
• Immobility during anesthesia is primarily mediated at the spinal cord level, affecting afferent pathways, efferent pathways, and reflex spinal arcs, with different anesthetics working through different mechanisms.
• Multiple anesthetics impair autonomic homeostatic mechanisms, including those related to respiratory, cardiac, and temperature regulation, mediated by the hypothalamus.
• Anesthetic targets sites include the lipid, protein, neuron, synapse, presynaptic, postsynaptic, and ion channels, with the Meyer-Overton Rule initially suggesting a single mechanism of anesthesia, but facing challenges due to the dissimilar effects of halogenated anesthetics with similar structures and octanol:water partition coefficients.

Test your knowledge about the components of general anesthesia and the mechanisms of consciousness. Learn about unconsciousness, amnesia, analgesia, immobility, and the effects of anesthetics on the sleep-wake cycle.