Randal A Skidgel Ph D Room 412 CSN x6 9179 GENERAL ANESTHETICS I II I BACKGROUND AND HISTORY II DEFINITIONS M 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 M 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 M 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 M 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 M 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 MAC see below 1 III Guedel s Signs and Stages of Anesthesia IV Structures of Inhaled Anesthetics Agents Once in Clinical Use Agents in Clinical Use Today Experimental Xenon 2 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 acetylcholine Mihic et al Nature 389 385 389 1997 showed that single amino acid substitutions at two positions remove the potentiating effects of volatile anesthetics and ethanol on GABA and glycine receptors a GABA and glycine receptors bind the neurotransmitters that are released at inhibitory chemical synapses and open to allow chloride ions to diffuse across the postsynaptic membrane b The main effect of volatile anaesthetics is to prolong channel opening and hence to increase postsynaptic inhibition c The receptor channels consist of pentamers of closely related subunits and the structure of a single subunit is shown in d The authors suggest that the two critical amino acids may form a binding site for general anaesthetics and ethanol 4 M 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 M 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 Initiate Inhaled anesthetic at concentration than MAC reduce for maintenance VI PHARMACOKINETICS OF INHALATIONAL ANESTHETICS Equilibration Lung Blood and Tissues Cell membranes are not barriers to diffusion of anesthetic gases Partial pressure in brain PB determines anesthesia ANESTHETIC GAS 5 A EQUILIBRATION OF ALVEOLAR GAS WITH INSPIRED GAS IDEALIZED CURVE Assumptions 1 No uptake of gas into bloodstream 2 Total Lung Volume VT 5 L 3 Inspired Volume VI 0 8 L 4 Residual Volume VR 4 2 liters Definitions FA Alveolar Gas Concentration FI Inspired Gas Concentration n number of breaths General Equation FA n VI FI VR FA n 1 VT First Breath FA1 0 8 L FI 4 2 L 0 5L 0 16 FI Plotting FA FI vs number of breaths or time gives these idealized curves 1 0 0 8 1 0 0 6 FA FI 0 8 FA FI Therefore FA1 FI 0 16 0 4 0 6 0 2 0 4 0 0 0 2 0 2 4 6 8 10 12 14 16 Number of Breaths 0 0 0 4 8 12 16 20 Time min 6 18 20 22 24 26 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 PA Gas 5A PA Liquid 10A 10 2 5 EXAMPLE Assume two anesthetic gases have equal potencies or MAC For gas A blood gas 1 For gas B blood gas 10 110 ml A 110 ml B 605 ml B 10 ml B 55 ml B 100 ml B 550 ml B Gas vol 1 L 55 ml A Blood 55 ml A vol 1 L PA 55 1000 x 760 PB 10 1000 x 760 PB 55 1000 x 760 41 8 mm Hg 7 6 mm Hg 41 8 mm Hg Effect of the Blood Gas Partition Coefficient on Equilibration EXAMPLE II Assume two anesthetic gases have MACs 5 but For gas A 1 and for gas B 10 I Uptake from the Lung Assumptions no flow equal volume in Blood and Gas Phase 1 L of both gases administered at 20 concentration 200 ml A 200 ml B 100 ml A 18 ml B 100 ml A 182 ml B PBlood 100 1000 10 PBlood 18 1000 1 8 Lung 1L Blood 1L II Equilibration into Brain Assume equal vol for blood and gas phase PBrain 50 1000 5 Gas 1L Blood 1L PBrain 16 1000 1 6 50 ml A 16 ml B 50 ml A 166 ml B 100 ml A 182 ml B 2 Concentration of Inspired Anesthetic Gas a Effect on the maximum alveolar concentration b Effect on the rate at which equilibration is achieved 1 Concentration Effect 2 Second Gas Effect 9 3 Pulmonary Ventilation 4 Pulmonary Blood Flow Cardiac Output 12 Equilibration of Anesthetic Gases into Tissues FAT 6 C O FI 20 Mass x 50 fold more soluble MG 10 C O 50 Mass VRG Methoxyflurane Nitrous Oxide 75 C O MG muscle group 10 Mass VRG vessel rich group brain heart liver kidney skin and muscle 5 Tissue Uptake of the Anesthetic a Arterial or Alveolar Venous Concentration Gradient
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