PCTH 325 - General Anaesthetics Nov 5 th 2013 (9:30-10:50) Location Woodward 6 M Walker (rsdaa@mail.ubc.ca) Anesthesiology, Pharmacology & Therapeutics, Faculty of Medicine, UBC Slides adapted from, and courtesy of, Dr. Stephan Schwarz 1
General Anaesthesia Anaesthesia (GB) or Anesthesia (US) from Greek αν = an -, "without"; and αἴσθησις, = aisthēsis, "sensation - Wiki. Two types of anaesthesia: General and Local General involves actions on CNS Local involves local actions on nerves at, or close to, site of injection Totally different molecular mechanisms of actions for the two types 2
Historical approaches to managing surgical and other types of pain Use of natural drugs : Opium poppy ( morphine), Mandrake (mandragora) root, Coca leaves, Ethanol, Marijuana Use of physical methods: Nerve compression, Application of cold (cryoanalgesia), Phlebotomy For surgical pain SPEED was of the essence: prior to the use of general anaesthetics surgery could be successful, but painful. 3
Pharmacological progress to modern anaesthesia 1275 Discovery of diethyl ether by alchemist Raymundus Lullus. 1540 First synthesis of diethyl ether ( an easily vapourized liquid) by Valerius Cordus and the discovery of its analgesic properties by Paracelsus, but not used for such. 1776 Synthesis of nitrous oxide (N 2 O, laughing gas) by Priestley (used as a recreational inhaled drug). 1790s suggestions of using ether and N 2 O to reduce consciousness in surgery; instead, used for fun and frolics. 4
Evolution of inhaled general anaesthesia 1842 N 2 O used clinically 1845/6 Wells and Morton (US) introduced N 2 O into dentistry, and diethyl ether into general anaesthesia. 1847 Introduction of chloroform by James Simpson much later was discontinued due to hepato- and lethal cardiac arrhythmias 1929 Another anaesthetic gas cyclopropane (at ICI) 1950 s Halothane invented by Raventos (at ICI) Since then sons and daughters of halothane 5
Progress with general vapour/gaseous general anaesthetic was slow Ether and then chloroform entered regular use but associated with many anaesthesia-related deaths especially chloroform Nitrous oxide unfortunately not sufficiently potent, but a useful adjuvant Cyclopropane a useful flammable addition Injectables introduced slowely (thiopentone) 1950s introduction of HALOTHANE 6
Today general anaesthesia involves: Altering, by pharmacological means, physiological status to produce states characterized by Hypnosis (= loss of consciousness; sleep ) Analgesia Amnesia Immobility Inhibition of autonomic and sensory nerve reflexes Muscle relaxation ( ) 7
Evolution of inhaled vapour general anaesthetics 1956 Introduction of halothane 1981 Introduction of isoflurane 1990s Introduction of sevoflurane & desflurane 8
Structures of some inhaled gaseous or vapour anesthetics 9
Anesthetic uptake: vapourization ventilation lung alveolar into blood - from there to the brain 10
Physiochemical and physiological factors determining inhaled anaesthetic uptake Solubility of general anaesthetic in blood Partial pressure of general anaesthetic in air and blood, i.e. difference between alveolar and pulmonary venous blood concentrations of anaesthetic Ventilation of the alveoli where exchange occurs between blood and air 11
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The higher the blood solubility, the slower the uptake! 13
Solubility of inhaled anesthetics Anaesthetic Agent Blood/Gas Partition Coefficient Nitrous Oxide 0.47 Desflurane 0.42 Sevoflurane 0.6 Isoflurane 1.4 Halothane 2.3 14
Alveolar concentration (FA) versus inspired concentration (Fl ) as FA/Fl ratio over time 15
Possible mechanisms of action of general anaesthetics Classic theories: Lipid theory (Mayer-Overton Rule) Protein theory Inhaled anesthetics suppress excitable tissues, e.g. by: Facilitation of inhibition GABA A receptor-mediated transmission Background ( leak ) K + conductance Inhibition of excitation Glutamate & ACh receptor-mediated transmission 16
The Meyer-Overton rule 17
CNS effects of inhaled general anaesthetics Central nervous system Decrease in cerebral metabolic rate Greatest with isoflurane (no EEG at 2 MAC):?cerebral protection Enflurane: epileptic (spike-wave) EEG activity Cerebral vasodilatation Increase in cerebral blood flow N 2 O: only modest effect (low potency) 18
Lung effects of inhaled anaesthetics Respiratory system Respiratory depression Increase in rate & decrease in depth of breathing (tidal volume) Net effect: reduction in alveolar ventilation & elevation of PaCO 2 Decrease in respiratory response to elevation of PaCO 2 Decrease in airway resistance Advantage for patients with asthma 19
Cardiovascular effects of inhaled anaesthetics Cardiovascular system Decrease in arterial blood pressure as a result of Reduction of cardiac output (e.g. halothane), and/or Reduction of systemic vascular resistance (e.g. isoflurane) Ventricular arrhythmias (halothane) Sensitization of the myocardium to circulating catecholamines N 2 O: mild sympathetic stimulation 20
Effects on other organs of inhaled anaesthetics Kidneys Reduction in renal blood flow Decrease in glomerular filtration rate & urinary output Skeletal Muscle Muscle relaxation Potentiate effects of non-depolarizing muscle relaxing drugs Uterus Uterine relaxation May lead to uterine atony & severe blood loss in parturition 21
Clinical uses of inhaled general anaesthetics Induction of general anaesthesia Maintenance of general anaesthesia Major component in balanced general anaesthesia 22
Today s General Anaesthesia Currently a Mix and Match of drugs - Inhaled Anaesthetics, Injected General Anaesthetic Drugs, Supplemental Drugs as well as appropriate Devices Inhaled Anaesthetic Mainly halogenated ethers N 2 O, O 2 Anaesthetic injected drugs - propofol, narcotics (morphine-like, e.g. fentanyl). Ancillary drugs - neuromuscular blocking drugs, autonomic drugs, CNS drugs 23
Other injectable anaesthetic injectable drugs (most not given to man) Variety of different non-volatile chemicals produce anaesthesia in animals and man. Barbiturates (thiopental, pentobarbital) Propofol Ketamine Chloralose (chloral hydrate + glucose) Xylazine Urethane Some steroids Alphaxalone/alphadolone, propanidid. Except for steroids, a diverse group of small molecules 24
Intravenous anaesthetic drugs (Thiopental) A barbiturate Now being replaced Useful for rapid induction of hypnosis (lacks analgesic properties!) Mechanism of action {Possibly facilitation of inhibitory neurotransmission via GABA A receptors) 25
Thiopental 1 Pharmacokinetics Rapid induction of anaesthesia (less than 20 seconds) Short duration of action since brain concentration falls rapidly due to redistribution of drug to other tissues Patients normally wakes ~5 min after a single i.v. bolus injection If tissues become saturated with drug, (e.g., as a result of continuous infusion, or repeated doses), the long elimination half-life of 10 hours or more determines recovery of consciousness. 26
Thiopental 2 Adverse effects Hypotension Exaggerated in the presence of blood loss (Pearl Harbor experience) Dose reductions necessary for elderly Respiratory depression Histamine release Arterial occlusion possible 27
Latest and best Propofol 1 2,6-diisopropylphenol 1980 s answer to thiopental Useful for sedation, induction, and maintenance of anaesthesia (TIVA: total intravenous anaesthesia) Smooth induction; pleasant dreams Rapid, clear-headed awakening Antiemetic properties Like halothane, another ICI drug 28
Mechanism of action Propofol 2 Facilitation of inhibitory neurotransmission via GABA A receptors Pharmacokinetics Rapid induction similar to thiopental; more rapid wakening (~3 min after i.v. bolus) Rapid metabolism in the liver; t 1/2 ~1 h No significant redistribution useful for infusion 29
Clinical pharmacodynamics of thiopental versus propofol (Glen et al. 1980) 30
Adverse effects Propofol 3 Respiratory depression & apnea Pronounced hypotension Greater than thiopental Dose reductions required for the elderly Pain possible upon injection Water insoluble, therefore drug is solubilized in an egg lecithin/soy bean oil mixture - a formulation encouraging bacterial growth so drug is only used shortly after opening a sterile ampoule Potential for sepsis 31
Ketamine 1 Phencyclidine (PCP)-derivative ( Angel Dust ) Dissociative anaesthesia Patients appear conscious without responding to sensory input Profound analgesia & amnesia Little cardio-respiratory depression Preserved airway reflexes; bronchodilation Unpleasant dreams are common 32
Ketamine 2 Clinical use Induction of anaesthesia in trauma or shock Battlefield surgery Analgesia in burn patients Intramuscular injection for induction in children Mechanism of action Antagonist at NMDA (N-methyl-D-aspartate) receptors Pharmacokinetics Rapid induction after i.v. bolus (slower than thiopental and propofol) Hepatic metabolism; t 1/2 ~3 h 33