GENERAL ANESTHETICS I & II Randal A. Skidgel, PhD Dept. of Pharmacology [email protected] 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 ANESTHETICSIII. 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 (λ ): (Also called Ostwald Coefficient): After an anesthetic is allowed to equilibrate between an equal volume of gas and blood, λ = the amount of anesthetic in the blood phase divided by the amount of anesthetic in the gas phase: λ = [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).3V. MECHANISM OF ACTIONA. MEYER-OVERTON RULE (1899-1901)B. POTENTIAL TARGET SITES FOR GENERAL ANESTHETICSC. 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 Anesthetics5 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 Anesthesia048121620Time, min0.00.20.40.60.81.0FA/FI 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: Actual Equilibration curves for some Inhalational AnestheticsTissuesTissuesTissuesFAHalothaneHalothaneN2ON2OTissuesBloodInhalational 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). 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. 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.110 ml A55 ml A55 ml APA=55/1000 x 76 = 41.8 mm Hg110 ml B10 ml B100 ml BPB=10/1000 x 76 = 7.6 mm Hg605 ml B55 ml B550 ml PB=55/1000 x 76 = 41.8 mm
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