GenAnesth406_2011_Updated(1)

GenAnesth406_2011_Updated(1) - General Anesthetics History...

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Unformatted text preview: General Anesthetics History - diethyl ether (1846), Chloroform (1847), nitrous oxide (1863, initially 1845), thiopental (1935), curare, halothane (1956), desflurane, sevoflurane Neurophysiological changes - unconsciousness, analgesia, inhibition of sensory and motor reflexes, skeletal muscle relaxation Ideal characteristics - rapid onset and recovery, good safety margin, less adverse effects Inhalation and intravenous anesthetics Balanced anesthesia 1 Mechanisms of action No specific chemical class, shape or molecular configuration Solubility in membrane lipids is an important factor for action Does it mean that there is no specific receptor? 2 How general anesthetics work I think you should be more explicit here in step two The lipid solubility hypothesis The unitary hypothesis: all general anesthetics act by a common mode perturbation of the lipid bilayer Based on the relationship between anesthetic potency and lipid solubility (Overton & Meyer) 10,000 Thiomethoxyflurane 1,000 100 10 1 0.1 Nitrogen 0.01 0.01 0.1 1 10 100 1,000 10,000 Methoxyflurane Halothane Isoflurane Diethylether Enflurane Cyclopropane Xenon Nitrous oxide Potency (1/atm) Oil/Gas partition coefficient 4 Figure 14-3. The Meyer-Overton Rule. Molecules with a larger oil/gas partition coefficien potent general anesthetics. This log-log plot shows the very tight correlation between lipid so The earlier belief: only lipid solubility, without any protein interaction, is important for action Lipid solubility plus interaction with proteins Binding of anesthetic agents to protein molecules observed - hemoglobin, myoglobin, luciferase Interaction with other proteins observed Possible interaction with hydrophobic domains of proteins 5 Action on neuronal membranes The drugs act on neuronal membrane Effect on ionic currents Fast neurotransmitter-gated channels Reduce excitatory input or enhance inhibitory input Excitatory receptors (nicotinic acetylcholine, 5HT, NMDA) Inhibitory receptors (GABAA, glycine) 6 d rug therapy Inhibitory synapse Presynaptic neuron Action potential Excitatory synapse Presynaptic neuron Release of acetylcholine Action potential Ca2+ Ca2+ GABA release K+ ClClClClCl ClClClClClNa+ Na+ Na+ Postsynaptic + membrane Na Na+ Na+ Na+ K+ K+ K+ Na+ Na+ Na+ Na+ Postsynaptic membrane Agonist binding sites Anesthetic site on GABAA receptor Anesthetic site on nicotinic acetylcholine receptor Inhibitory Postsynaptic GABAergic Currents No anesthetic 0.1 second With anesthetic Excitatory Postsynaptic Cholinergic Currents No anesthetic With anesthetic 2 milliseconds Membrane Current With anesthetic No anesthetic Membrane Current Transmembrane element Pore No anesthetic With anesthetic Log GABA Log Acetylcholine 150 Inhibitory synapse with general anesthetic 125 Relative response (%) 100 Control 75 EC50 EC50 Excitatory synapse with general anesthetic 50 25 EC50 0 0.01 0.1 1.0 10 100 Relative agonist concentration Action of general anesthetics Minimum Alveolar Concentration (MAC): Minimum concentration of drug in the alveolar air that will produce immobility in 50% of patients exposed to a painful stimulus Notice the low therapeutic index 100 MAC Non-responsive to trapezius squeeze LD50 Percentage of patients exhibiting each endpoint 80 Non-responsive to skin incision 60 Non-responsive to Intubation 40 Cardiac arrest (death) 20 0 0.01 0.02 0.03 0.04 0.05 Alveolar partial pressure of isoflurane (atm) 10 Depth of anesthesia CNS concentration determines depth of anesthesia From lungs to blood From blood to CNS 11 Factors affecting transfer of the drug Partial pressure LEARNING AND MEMORY, SPEECH AND LANGUAGE. BASAL GANGLIA Structures believed to be imporand memor y include the cerebral cortex, amygdala, hippocampus, cerebellum and basal ganglia. Areas of the left tant for various kinds of learning Caudate nucleus Putamen Globus pallidus Amygdala Hippocampus Caudate nucleus Broca’s area Wernicke’s area Putamen Angular Globus gyrus Cerebellum pallidus Amygdaloid nucleus Solubility - blood:gas partition coefficient hemisphere (inset) are known to be active in speech and lanLEARNING form and meaning guage. The AND MEMORY, of SPEECH AND L believed to an utterance is ANGUAGE. arise Structures believed to then in Wernicke’s area and be imporand memor y Wernicke’s cerevocalization. include the area is bral cortex, amygdala, hipalso important for language pocampus, cerebellum and comprehension. basal ganglia. Areas of the left hemisphere (inset) are known to be active in speech and language. The form and meaning of an utterance is believed to arise in Wernicke’s area and then Broca’s area, which is related to vocalization. Wernicke’s area is also important for language comprehension. Amygdaloid nucleus BASAL GANGLIA AREAS OF SPEECH AND L ANGUAGE tant for vrea, which is related to Broca’s aarious kinds of learning AREAS OF SPEECH AND L ANGUAGE Low coefficient: fast rise High coefficient: slow rise Amygdala Hippocampus Broca’s area Wernicke’s area Angular gyrus Cerebellum ssing systems involved in the perception, prol y sis of the mater ial being learned. In shor t, rain most likely contributes di∑erently to perstorage. ost prominent intellectual activities depeny is language. W hile the neural basis of lanl y understood, scientists have learned much of the brain from studies of patients who have nguage abilities due to stroke, and from behavnal neuroimaging studies of normal people. ssing synfluential model, the peron studies ot and i stems involved in based ception, pr of loposes tthat mater ial bying sltructure of sshor t, y sis of he the underl eing earned. In peech rises in W ikely contr ea, a ortion o he eft arain most lernicke’s aributespdi∑erentlfytto plertorage. esbrain. This temporal lobe region is connected iostherorminentobe where a pactivities orepenn t p f ontal l intellectual rogram f d vocal yated. This progrhile ithe neural basis of ltanis language. W am s then transmitted o a l y motor cor scientists have learned outh, theunderstood,tex that activates the mmuch o x.f the brain from studies of patients who have nguage abilities due to str k e and r m behavodel proposes that, whenowe, readfaoword, the nal neuroimaging primar of normal tex to t ansmitted from thestudies y visual corpeople.he terend influential smomehow matchedtudiesthe a the message i s odel, based on s with of oposes that poken. The auditor y f e m peech ords when sthe underlying structurorof sof the arises in Wernicke’s area, a portion of the left e brain. This temporal lobe region is connected in the frontal lobe where a program for vocal ated. This program is then transmitted to a the motor cor tex that activates the mouth, x. odel proposes that, when we read a word, the ansmitted from the primar y visual cortex to the ere the message is somehow matched with the ords when spoken. The auditor y form of the word is then processed for comprehension in Wernicke’s area as if the word had been heard. Writing in response to an oral instruction requires information to be passed along the same pathways in the opposite direction—from the auditor y cortex to Wernicke’s area to the angular g yrus. This model accounts for much of the data from patients, and is the most widely used model for c linic al diagnosis and prognosis. Howe ver, some refinements to this model may be necessar y due to both recent studies with patients and functional neuroimaging studies in normal people. word or then processed fan cmaging techniqueWalled ke’s aron F is example, using or i omprehension in c ernic posit ea as if the word h phy (PET), scientists h in esponse to an oral emission tomograad been heard. Writingave rdemonstrated that instruction requires erformed by normal people activated neisome reading tasks pinformation to be passed along the same pathways in the o ea nor he angular g yrus. These results s tex ther Wernicke’s arpposite tdirection—from the auditor y corugto W hat ther rea o he r ngular r yrus. hat oes not involve gest ternicke’seais a tdirtect aeading goute tThisdmodel accounts for mh h of the data fro o the visual s is he most widely prospeecucsound recoding mfpatients, andtimtulus before the used model of either diagnosis speaking. O ther we ver, with cessing for c linic almeaning orand prognosis. Hostudies some refinements o this model may b s likely hat o both words patients alsothave indicated that eitniecessar ytdue ftamiliar recent studies with patients and functional hey can be u studies in need not be recoded into sound beforenteuroimagingnderstood. normal people.the understanding of how language is impleAlthough For exampleain is f a f i m complete, there c e no osit ron mented in the br, usingar nromaging technique aralledwpseveral emission tomogr phy be used to gain impor demonstrated techniques thatamay (PET), scientists havetant insights. that some reading tasks performed by normal people activated neither Wernicke’s area nor the angular g yrus. These results sug19 gest that there is a direct reading route that does not involve speech sound recoding of the visual stimulus before the processing of either meaning or speaking. O ther studies with patients also have indicated that it is likely that familiar words need not be recoded into sound before they can be understood. Although the understanding of how language is implemented in the brain is far from complete, there are now several techniques that may be used to gain important insights. 19 12 Alveolar Pressure Ventilation brings anesthetic into alveoli Palv The balance between input and output sets the level of Palv Uptake into bloodstream removes anesthetic from alveoli Smaller λ(Blood/Gas) have Faster Induction Times A Initial Palv = 0.1 atm λ (blood/gas) = 0.5 Final Palv = Part = 0.067 atm B Initial Palv = 0.1 atm λ (blood/gas) = 11 Final Palv = Part = 0.0083 atm Anesthetic Alveolus Capillary Figure 14-8. Why Do Anesthetics with Smaller λ(Blood/Gas) have Faster Induction T The role of blood:gas partition coefficient 1.0 Alveolar partial pressure as % of inspired partial pressure (Palv/PI) Nitrous oxide, λ = 0.47 Desflurane, λ = 0.45 0.8 Isoflurane, λ = 1.4 63% equilibration 0.6 Halothane, λ = 2.3 0.4 0.2 Ether, λ = 12.0 0.0 0 10 20 30 16 Minutes of administration The role of pulmonary ventilation A Ventilation Effects 1.0 Nitrous oxide 63% equilibration Palv/PI 0.5 Halothane Diethyl ether 0.0 0 2 L/min ventilation 20 40 8 L/min ventilation 17 Minutes Minutes The role of cardiac output B Cardiac Output Effects 1.0 Nitrous oxide 2 L/min ventilation 8 L/min ventilation Palv/PI 63% equilibration 0.5 Halothane Diethyl ether 0.0 0 2 L/min cardiac output 20 40 18 L/min cardiac output 18 Minutes Effects of age 0.9 Children (1–5 years) 0.8 0.7 Palv/PI Adults 0.6 0.5 0.4 0 10 20 30 40 50 60 19 Minutes of anesthesia Factors affecting transfer of the drug Anesthetic concentration in the inspired air Pulmonary ventilation Pulmonary blood flow Transfer from blood to the tissues 20 LEARNING AND MEMORY, BASAL GANGLIA Action of general anesthetics SPEECH AND LANGUAGE. Structures believed to be important for various kinds of learning and memor y include the cerebral cortex, amygdala, hippocampus, cerebellum and basal ganglia. Areas of the left hemisphere (inset) are known to be active in speech and language. The form and meaning of an utterance is believed to arise in Wernicke’s area and then Broca’s area, which is related to vocalization. Wernicke’s area is also important for language comprehension. Caudate nucleus Putamen Globus pallidus Uptake: Amygdaloid nucleus AREAS OF SPEECH AND L ANGUAGE Amygdala Hippocampus Broca’s area Wernicke’s area Angular gyrus Cerebellum BASAL GANGLIA ssing systems involved in the perception, prol y sis of the mater ial being learned. In shor t, rain most likely contributes di∑erently to perstorage. ost prominent intellectual activities depeny is language. W hile the neural basis of lanl y understood, scientists have learned much of the brain from studies of patients who have nguage abilities due to stroke, and from behavnal neuroimaging studies of normal people. t and influential model, based on studies of oposes that the underlying structure of speech arises in Wernicke’s area, a portion of the left e brain. This temporal lobe region is connected Hippocampus Amygdala in the frontal lobe where a program for vocal ated. This program is then transmitted to a Cerebellum the motor cor tex that activates the mouth, x. odel proposes that, when we read a word, the ansmitted from the primar y visual cortex to the ere the message is somehow matched with the ords when spoken. The auditor y form of the word is then processed for comprehension in Wernicke’s area tant for various kinds of learning as if the word had been heard. Writing in response to an oral and memor y include the cereCaudate instruction requires information to be passed along the same bral cortex, amygdala, hipnucleus pathways in the opposite direction—from the auditor y cortex pocampus, cerebellum and Putamen to Wernicke’s area to the angular g yrus. This model accounts basal ganglia. Areas of the left Globus for much of theallidus from patients, and is the most widely used data p hemisphere (inset) are known to model for c linic al diagnosis and prognosis. Howe ver, some Amygdaloid be active in speech and lanrefinements tonucleusmodel may be necessar y due to both recent this guage. The form and meaning of studies with patients and functional neuroimaging studies in an utterance is believed to arise normal people. in Wernicke’s area and then AREAS OF using For example, SPEECH an imaging technique c alled posit ron AND L ANGUAGE Broca’s area, which is related to emission tomography (PET), scientists have demonstrated that vocalization. Wernicke’s area is some reading tasks performed by normal people activated neialso important for language Broca’s area ther Wernickeernicke’s area the angular g yrus. These results sug’s area nor W comprehension. gest that there is Angularect reading route that does not involve a dir gyrus speech sound recoding of the visual stimulus before the processing of either meaning or speaking. O ther studies with patients also have indicated that it is likely that familiar words LEARNING AND MEMORY, need not be recoded into sound before they can be understood. Although tBASAL GANGLIA he understandingSPEECHw languageAGE.mpleof ho AND LANGU is i Structur there a ed to be everal mented in the brain is far from complete,es believre now simportant for various insights. techniques that may be used to gain important kinds of learning Caudate nucleus Putamen Globus pallidus Concentration, pulmonary ventilation, solubility in blood, blood flow LEARNING AND MEMORY, SPEECH AND LANGUAGE. Structures believed to be impor- Distribution: Regional blood flow, transfer to tissues and memor y include the cerebral cortex, amygdala, hippocampus, cerebellum and basal ganglia. Areas of the left hemisphere (inset) are known to 19 ssing systems involved in the perception, prol y sis of the mater ial being learned. In shor t, rain most likely contributes di∑erently to perstorage. ost prominent intellectual activities depeny is language. W hile the neural basis of lanl y understood, scientists have learned much of the brain from studies of patients who have Hippocampus Amygdala nguage abilities due to stroke, and from behavnal neuroimaging studies of normal people. Cerebellum t and influential model, based on studies of oposes that the underlying structure of speech arises in Wernicke’s area, a portion of the left e brain. This temporal lobe region is connected in the frontal lobe where a program for vocal ated. This program is then transmitted to a the motor cor tex that activates the mouth, x. Hippocampus Amygdala odel proposes that, when we read a word, the ansmitted from the primar y visual cortexebellum Cer to the ere the message is somehow matched with the ssing systems involved in the perception, proords when spoken. The auditor y form of the l y sis of the mater ial being learned. In shor t, rain most likely contributes di∑erently to perstorage. ost prominent intellectual activities depeny is language. W hile the neural basis of lanl y understood, scientists have learned much of the brain from studies of patients who have nguage abilities due to stroke, and from behavnal neuroimaging studies of normal people. ssing synfluential model, the peron studies ot and i stems involved in based ception, pr of loposes tthat mater ial bying sltructure of sshor t, y sis of he the underl eing earned. In peech rises in W ikely contr ea, a ortion o he eft arain most lernicke’s aributespdi∑erentlfytto plertorage. esbrain. This temporal lobe region is connected iostherorminentobe where a pactivities orepenn t p f ontal l intellectual rogram f d vocal yated. This progrhile ithe neural basis of ltanis language. W am s then transmitted o a l y motor cor scientists have learned outh, theunderstood,tex that activates the mmuch o x.f the brain from studies of patients who have nguage abilities due to str k e and r m behavodel proposes that, whenowe, readfaoword, the nal neuroimaging primar of normal tex to t ansmitted from thestudies y visual corpeople.he terend influential smomehow matchedtudiesthe a the message i s odel, based on s with of oposes that poken. The auditor y f e m peech ords when sthe underlying structurorof sof the arises in Wernicke’s area, a portion of the left e brain. This temporal lobe region is connected in the frontal lobe where a program for vocal ated. This program is then transmitted to a the motor cor tex that activates the mouth, x. odel proposes that, when we read a word, the ansmitted from the primar y visual cortex to the ere the message is somehow matched with the ords when spoken. The auditor y form of the word is then pAmygdaloid for comprehension in Wernicke’s area rocessed be active in speech and lanas if the word nucleusbeen heard. Writing in response to an oral had LEARNING form and meaning guage. The AND MEMORY, of instruction requires information to be passed along the same SPEECH AND L believed to an utterance is ANGUAGE. arise BASAL GANGLIA pathways in the opposite direction—from the auditor y cortex Structures believed to then in Wernicke’s area and be imporAREA a OF SPEE t to Wernicke’s S rea toCH he angular g yrus. This model accounts tant for vrea, which is related to AND L ANGUAGE Broca’s aarious kinds of learning for much of the data from patients, and is the most widely used and memor y Wernicke’s cerevocalization. include the area is Caudat model for c linic al ediagnosis and prognosis. Howe ver, some bral important for language nucleus also cortex, amygdala, hipBroca’s area refinements tWernicke’s arodel may be necessar y due to both recent o this m ea pocampus, cerebellum and comprehension. Putamen Angular studies with patients and functional neuroimaging studies in basal ganglia. Areas of the left Globus gyrus normal people. allidus p hemisphere (inset) are known to For example, using an imaging technique c alled posit ron Amygdaloid be active in speech and lanemission tomognucleus (PET), scientists have demonstrated that raphy guage. The form and meaning of some reading tasks performed by normal people activated neian utterance is believed to arise ther Wernicke’s area nor the angular g yrus. These results sugin Wernicke’s area and then AREA OF a d CH gest that thereS is SPEEirect reading route that does not involve AND L ANGUAGE Broca’s area, which is related to speech sound recoding of the visual stimulus before the provocalization. Wernicke’s area is cessing of either meaning or speaking. O ther studies with also important for language Broca’s area patients also Wernicke’s areaated that it is likely that familiar words have indic comprehension. Angular need not be recoded into sound before they can be understood. gyrus Although the understanding of how language is implemented in the brain is far from complete, there are now several word is then processed for comprehension in Wernicke’s area techniques that may be used to gain important insights. as if the word had been heard. Writing in response to an oral instruction requires information to be passed along the same 19 pathways in the opposite direction—from the auditor y cortex to Wernicke’s area to the angular g yrus. This model accounts for much of the data from patients, and is the most widely used model for c linic al diagnosis and prognosis. Howe ver, some refinements to this model may be necessar y due to both recent studies with patients and functional neuroimaging studies in normal people. word or then processed fan cmaging techniqueWalled ke’s aron F is example, using or i omprehension in c ernic posit ea as if the word h phy (PET), scientists h in esponse to an oral emission tomograad been heard. Writingave rdemonstrated that instruction requires erformed by normal people activated neisome reading tasks pinformation to be passed along the same pathways in the o ea nor he angular g yrus. These results s tex ther Wernicke’s arpposite tdirection—from the auditor y corugto W hat ther rea o he r ngular r yrus. hat oes not involve gest ternicke’seais a tdirtect aeading goute tThisdmodel accounts for mh h of the data fro o the visual s is he most widely prospeecucsound recoding mfpatients, andtimtulus before the used model of either diagnosis speaking. O ther we ver, with cessing for c linic almeaning orand prognosis. Hostudies some refinements o this model may b s likely hat o both words patients alsothave indicated that eitniecessar ytdue ftamiliar recent studies with patients and functional hey can be u studies in need not be recoded into sound beforenteuroimagingnderstood. normal people.the understanding of how language is impleAlthough For exampleain is f a f i m complete, there c e no osit ron mented in the br, usingar nromaging technique aralledwpseveral emission tomogr phy be used to gain impor demonstrated techniques thatamay (PET), scientists havetant insights. that some reading tasks performed by normal people activated neither Wernicke’s area nor the angular g yrus. These results sug19 gest that there is a direct reading route that does not involve speech sound recoding of the visual stimulus before the processing of either meaning or speaking. O ther studies with patients also have indicated that it is likely that familiar words need not be recoded into sound before they can be understood. Although the understanding of how language is implemented in the brain is far from complete, there are now several techniques that may be used to gain important insights. 19 Elimination: Mostly via expiration Toxic metabolites in some cases Recovery depends on duration of exposure (due to accumulation in fat, skin, muscles etc.), longer exposure leading to longer period of recovery 21 Cautions Decrease in blood pressure: caution in case of preexisting myocardial dysfunction, trauma victims Reduced ventilatory drive and reflexes that maintain airway patency: need for airway maintenance Hypothermia Nausea and vomiting 22 Effects of inhalational general anesthetics on the systemic circulation 23 Respiratory effects of inhalational general anesthetics 24 Intravenous anesthetics Thiopental, etomidate, propofol, ketamine Generally used for initial induction of anesthesia Rapid action - can produce anesthesia within a single circulation time Example: thiopental produces unconsiousness in 10 30 seconds Propofol, the most commonly used intravenous anesthetic in the United States Etomidate: primarily for patients at risk for hypotension 25 Distribution of intravenous anesthetic 100 Blood 80 Muscle Group: muscles, skin MG Vessel-Rich Group: brain, liver, kidneys Percent of dose 60 VRG 40 Fat Group: fat FG 20 0 0.1 1 10 100 26 Time (min) Abuse “Propofol abuse …… only a few cc’s more than what’s required to put a person to sleep can trigger fatal respiratory arrest …… 40% of residents who reportedly abused the anesthetic died from the high - the peril of propofol’s exquisitely narrow therapeutic window.” Anesthesia News, 2007 27 Combination of drugs For induction of anesthesia - generally intravenous agents For maintenance of anesthesia - generally inhalalational agents For sedation, anxiolysis & amnesia prior to induction - benzodiazepines For analgesia - generally opioids; NSAIDs for minor procedures For muscle relaxation - suuccinylcholine, pancuronium 28 ...
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This note was uploaded on 03/06/2011 for the course PMY 406 taught by Professor Berman during the Spring '11 term at SUNY Buffalo.

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