ANESTHETICS

• General anesthetics


  Depress the central nervous system to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures
• General anesthetics have low therapeutic indices and thus require great care in administration
• While all general anesthetics produce a relatively similar anesthetic state, they are quite dissimilar in their secondary actions (side effects) on other organ systems
• Selection of specific drugs and routes of administration to produce general anesthesia

  Based on their pharmacokinetic properties and on the secondary effects of the various drugs, in the context of the proposed diagnostic or surgical procedure and with the consideration of the individual patient's age, associated medical condition, and medication use
• Agents employed by anesthesiologists

  • Sedatives
  • Neuromuscular blocking agents
  • Local anesthetics
• General principles of surgical anesthesia

  • Minimizing the potentially deleterious direct and indirect effects of anesthetic agents and techniques
  • Sustaining physiologic homeostasis during surgical procedures that may involve major blood loss, tissue ischemia, reperfusion of ischemic tissue, fluid shifts, exposure to a cold environment, and impaired coagulation
  • Improving postoperative outcomes by choosing techniques that block or treat components of the surgical stress response, which may lead to short- or long-term sequelae
• Hypothermia


  Body temperature <36˚C during surgery, due to low ambient temperature, exposed body cavities, cold intravenous fluids, altered thermoregulatory control, and reduced metabolic rate
• General anesthetics lower the core temperature set point at which thermoregulatory vasoconstriction is activated to defend against heat loss
• Vasodilation produced by both general and regional anesthesia offsets cold-induced peripheral vasoconstriction, thereby redistributing heat from central to peripheral body compartments, leading to a decline in core temperature
• Metabolic rate and total body oxygen consumption decrease with general anesthesia by about 30%, reducing heat generation
• Even small drops in body temperatures may lead to an increase in perioperative morbidity, including cardiac complications, wound infections
• Anesthetic state


  A collection of "component" changes in behavior or perception, including amnesia, immobility in response to noxious stimulation, attenuation of autonomic responses to noxious stimulation, analgesia, and unconsciousness
• Cellular mechanisms of anesthesia

  • General anesthetics can hyperpolarize neurons, which may be important on neurons serving a pacemaker role and on pattern-generating circuits, and in synaptic communication
  • At anesthetizing concentrations, both inhalational and intravenous anesthetics have substantial effects on synaptic transmission and much smaller effects on action-potential generation or propagation
• Inhalational anesthetics


  • Inhibit excitatory synapses and enhance inhibitory synapses
  • Can inhibit neurotransmitter release, and the reduction in presynaptic action potential amplitude substantially inhibits neurotransmitter release
  • Can act postsynaptically, altering the response to released neurotransmitter
• Intravenous general anesthetics


  • Act predominantly through GABAA receptors and perhaps through some interactions with other ligand-gated ion channels
• Nitrous oxide, ketamine, and xenon

  • Likely produce unconsciousness via inhibition of the NMDA receptor and/or activation of two-pore-domain K+ channels
• Parenteral anesthetics


  Small, hydrophobic, substituted aromatic or heterocyclic compounds, where hydrophobicity is the key factor governing their pharmacokinetics
• After a single intravenous bolus, parenteral anesthetics preferentially partition into the highly perfused and lipophilic tissues of the brain and spinal cord where they produce anesthesia within a single circulation time
• Termination of anesthesia after single boluses of parenteral anesthetics primarily reflects redistribution out of the CNS rather than metabolism
• Parenteral anesthetic half-lives are "context-sensitive," and the degree to which a half-life is contextual varies greatly from drug to drug, as might be predicted based on their differing hydrophobicities and metabolic rates
• Most individual variability in sensitivity to parenteral anesthetics can be accounted for by pharmacokinetic factors
• Ketamine


  An arylcyclohexylamine, a congener of phencyclidine, supplied as a racemic mixture even though the S-isomer is more potent with fewer side effects
• Ketamine


  Rapidly produces a hypnotic state quite distinct from that of other anesthetics, with profound analgesia, unresponsiveness to commands, and amnesia, but patients may have their eyes open, move their limbs involuntarily, and breathe spontaneously
• Local anesthetics


  Bind reversibly to a specific receptor site within the pore of the Na+ channels in nerves and block ion movement through this pore, reversibly blocking the action potentials responsible for nerve conduction
• Local anesthetics can bind to other membrane proteins, such as blocking K+ channels, but this requires higher concentrations and is not the primary mechanism of conduction block
• Lidocaine & Procaine


  Check drug metabolism notes