GENERAL ANESTHETICS I II Randal A Skidgel PhD Dept of Pharmacology rskidgel uic edu I LEARNING OBJECTIVES Definitions partial pressure MAC blood gas partition coefficient oil gas partition coefficient What determines anesthetic potency What are the 4 potential targets for the action of general anesthetics How do blood gas solubility ventilation rate and cardiac output affect equilibration of anesthetics rate of induction of anesthesia What is the mechanism of the concentration effect and the related second gas effect What factors determine the rate of anesthetic equilibration into different tissues What is the route of elimination of general anesthetics and how is recovery from anesthesia affected by the blood gas partition coefficient ventilation rate and cardiac output What are the common pharmacological effects of inhalational anesthetics Know the major differences between the inhalational anesthetics e g which is most least potent induction recovery rate don t need to memorize numbers What are the major uses of the various intravenous anesthetic agents discussed and their major advantages and disadvantages II STRUCTURES OF INHALED ANESTHETICS III DEFINITIONS Definition Of Anesthesia or Anesthetic State 1 Immobile to Noxious Stimuli 2 Unconscious 3 Lack of autonomic response to noxious stimulus 4 State of Analgesia 5 Amnesia PARTIAL PRESSURE OR GAS TENSION For gas A the partial pressure in a mixture of 3 gases A B and C is PA of Molecules of gas A x 760 mm Hg Total of molecules of gases A B C BLOOD GAS PARTITION COEFFICIENT Also called Ostwald Coefficient After an anesthetic is allowed to equilibrate between an equal volume of gas and blood the amount of anesthetic in the blood phase divided by the amount of anesthetic in the gas phase Anesthetic Blood Anesthetic Gas This number an indication of blood solubility is inversely correlated with equilibration rate but has no relation to potency MINIMUM ALVEOLAR CONCENTRATION MAC The alveolar concentration of an anesthetic at 1 atmosphere that prevents movement in 50 of patients in response to a noxious stimulus e g surgical incision The MAC is a measure of the potency of an anesthetic A low MAC means high potency An anesthetic s potency is correlated with its lipophilicity i e low MAC very lipophilic Dose response curve is steep 99 patients immobile by 1 3 MAC MACs of two different agents are additive i e 0 5 MAC anesthetic A 0 5 MAC anesthetic B effectiveness of 1 0 MAC of A or B MAC is age dependent Highest in infants drops to about half by age 80 Analgesia begins at about 0 3 MAC Amnesia at about 0 5 MAC Oil Gas Partition Coefficient Concentration of anesthetic in olive oil divided by its concentration in gas at equilibrium This number correlates directly with potency or inversely with MAC see below V MECHANISM OF ACTION A MEYER OVERTON RULE 1899 1901 B POTENTIAL TARGET SITES FOR GENERAL ANESTHETICS 3 C THEORIES OF ANESTHETIC ACTION 1 Change in Membrane Dimension Critical Volume Hypothesis Anesthetics expand the volume of membranes beyond a critical amount and thereby obstruct ion channels or alter electrical properties 2 Change in Membrane Physical State a Fluidization Theory Anesthetics increase the general fluidity of plasma membranes b Lateral Phase Separation Theory Anesthetics inhibit the formation of an ordered low volume gel phase around ion channels normally required for channel opening 3 Protein Interaction Theory Anesthetics bind to specific proteins that affect ion flux during membrane excitation resulting in either potentiation of inhibitory neurotransmitters e g GABA glycine or inhibition of excitatory neurotransmitters e g glutamate NMDA receptors Currently Known Targets of General Anesthetics GOALS OF GENERAL ANESTHESIA 1 Rapid Induction 2 Use the minimal level of anesthetic that will give analgesia unconsciousness amnesia 3 Minimal depression of cardiovascular system 4 Rapid recovery COMMON PRACTICE TODAY Anesthesiologists use a combination of drugs Premedication e g sedatives opioid analgesics IV anesthetic for induction Muscle relaxants so a lighter level of general anesthesia can be used a mixture of volatile anesthetic gases to maintain anesthesia Initiate Inhaled anesthetic at concentration than MAC reduce for maintenance Guedel s Signs and Stages of Anesthesia 5 PHARMACOKINETICS OF INHALATIONAL ANESTHETICS Equilibration of Alveolar Gas with Inspired Gas For equilibration in the lung alone Assumptions 1 No uptake of gas into bloodstream 2 Total Lung Volume VT 5 L 3 Inspired Volume VI 0 8 L Definitions FA Alveolar Gas Concentration FI Inspired Gas Concentration Plotting FA FI vs time gives this idealized curve 1 0 FA FI 0 8 0 6 0 4 0 2 0 0 0 4 8 12 16 20 Time min Actual Equilibration curves for some Inhalational Anesthetics Inhalational anesthetics diffuse freely across cell membranes in the gas phase down their concentration gradient Thus they equlibrate according to their relative partial pressures e g PA alveolar partial pressure Tissues Tissues Because of uptake of anesthetic gas by the blood the inhaled partial pressure also called inspired fractional concentration or FI will be higher than end tidal alveolar concentration FA FA will also be higher than the concentration of anesthetic returning to the lung because of uptake of anesthetic from the blood into the tissues Thus complete equilibration where FI FA FTissue will not be achieved until all tissues and blood are saturated with anesthetic In practical terms this will not happen in the time frame of most surgeries Tissues Halothane Blood N2O A relatively soluble anesthetic like halothane will take longer to approach equilibrium because it is much more soluble in blood and tissues than the relatively insoluble nitrous oxide As a result the blood and tissues represent a larger reservoir for halothane than for nitrous oxide as schematically illustrated here FA Halothane N2O Henry s Law Partial pressure of a gas in a liquid is equal to its Partial pressure in the gas phase in equilibrium with that liquid Does not mean an equal number of molecules in each phase see below PA Gas 5A PA Liquid 10A 10 5 2 Example Assume 2 anesthetic gases have equal potencies MAC For Gas A blood gas 1 For Gas B blood gas 10 110 ml A 110 ml B 605 ml B 55 ml A 10 ml B 55 ml B Blood 55 ml A vol 1 100 ml B 550 ml Gas vol 1 PA 55 1000 x 76 PB 10 1000 x 76 41 8 mm Hg 7 6 mm Hg PB 55 1000 x 76 41 8 mm Hg Effect of the Blood Gas Partition Coefficient on Equilibration EXAMPLE II
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