1 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 (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: [Anesthetic]Blood λ = [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).2 IV. Structures of Inhaled Anesthetics Agents Once in Clinical Use:Agents in Clinical Use Today:Experimental: Xenon III. Guedel’s Signs and Stages of Anesthesia3V. MECHANISM OF ACTIONA. MEYER-OVERTON RULE (1899-1901)B. POTENTIAL TARGET SITES FOR GENERAL ANESTHETICS4 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 neuro-transmitters (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.5 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 GAS6 0 2 4 6 8 10 12 14 16 18 20 22 24 26Number of Breaths0.00.20.40.60.81.0FA/FI 048121620Time, min0.00.20.40.60.81.0FA/FI 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 Therefore: FA1/FI = 0.16 Plotting FA /FI vs. number of breaths or time gives these idealized curves: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)EXAMPLE: Assume two anesthetic gases have equal potencies (or MAC). For gas A, Î (blood/gas) = 1 For gas B, Î (blood/gas) = 10.PA(Gas)PA(Liquid)5A10AÎ = 10 = 25110 ml A55 ml A55 ml APA=55/1000 x 760 = 41.8 mm Hg110 ml B10 ml B100 ml BPB=10/1000 x 760 = 7.6 mm Hg605 ml B55 ml B550 ml BPB=55/1000 x 760 = 41.8 mm HgGasvol=1 LBloodvol=1 LEffect of the Blood:Gas Partition Coefficient on EquilibrationEXAMPLE: II Assume two anesthetic gases have MACs = 5%, but ; For gas A, Î = 1 and for gas B, Î = 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.II. Equilibration into Brain: Assume equal vol. for blood and gas phase200 ml A100 ml APBlood=100/1000 = 10%Lung 1 LBlood1L100 ml A200 ml B18 ml BPBlood=18/1000 = 1.8%182 ml B50 ml A"Gas" 1 L(100 ml A)Blood1L50 ml APBrain=50/1000 = 5%16 ml B(182 ml B)166 ml BPBrain=16/1000 = 1.6%92. Concentration of Inspired Anesthetic Gasa) Effect on the maximum alveolar concentrationb) Effect on the rate at which equilibration is achieved1) Concentration
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