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Introduction to General Anesthesia

Introduction to General Anesthesia. Özge Köner, MD Anesthesiology Dept. Overview. Historical Perspective Definition of General Anesthesia Mechanism of Anesthesia Anesthetic Agents (volatile & intravenous). Surgery before 1846.

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Introduction to General Anesthesia

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  1. Introduction to General Anesthesia Özge Köner, MD Anesthesiology Dept.

  2. Overview • Historical Perspective • Definition of General Anesthesia • Mechanism of Anesthesia • Anesthetic Agents (volatile & intravenous)

  3. Surgery before 1846 • Hippocrates (460-377, BC) a treatise on surgery, but little sympathy for the patient. • Greek surgeon Dioscorides (40-70, AD) His book “Materia Medica” described the effects of mandroga & wine to produce anesthesia.

  4. Surgery before 1846 • Middle ages: Alcohol fumes as an analgesic during surgery, soporific sponge (opium & scopolamine). marijuana, belladonna and jimsonweed. • Hypnosis, strangulation…

  5. History • Crawford Long, 1842: Ether anesthesia first ideal anesthetic. • Dt.Horace Wells, 1846: Nitrous Oxide • Unsuccessful demo in Boston Mass general

  6. Public Demo of Ether Anesthesia“Gentlemen, this is no Humbug” • Dt. William Morton, October 16, 1846 Ether anesthesia in ETHER DOME (MASS General Hospital) Patient Gilbert Abbot

  7. Ether “Letheon” Inhaler “The Letheon” In classical Greek mythology, the waters of the River Lethe expunged painful memories.

  8. Ether “Letheon” • Flammable • Prolonged induction • Unpleasant odor • High incidence of nausea-vomiting

  9. Chloroform, 1847: James Simpson; Hepatotoxic, ventricular fibrillation • Cyclopropane, 1929: Most widely used general anesthetic for the following 30 years, explosive ! • Halothane, 1956: Although widely replaced with new generation volatiles, it is still in use. • Methoxyflurane, 1960: Nephrotoxicity. Most potent of all the volatiles. • Sevoflurane & Desflurane, late 1960s • Thiopental, intravenous anesthetic, synthesized in the early 1930s by Ernest H Volwiler

  10. Anesthesia • Greek: an- “without” & aisthesis- “sensation”. Blocked or temporarily taken sensation (including the feeling of pain). Name is suggested by Oliver W. Holmes. • Reversible, drug-induced loss of consciousness. • Amnesia & unconsciousness • Analgesia • Muscle relaxation • Attenuation of autonomic responses to noxious stimulation

  11. Sleep & death are brothers(Ancient Greek proverb) • The god of Sleep “Hypnos” is the younger brother of the god of death “Thanatos”. Both of them are the children of Nyx, the goddess of night.

  12. Theories of general anesthetic action • Lipid solubility-anesthetic potency correlation “The Meyer-Overton correlation” Anesthetic potency is related to lipid solubility. The greater is the lipid solubility of the compound in olive oil, the greater is its anesthetic potency. • Modern interpretation of the theory; general anesthetics dissolve in lipid-bilayer regions of nerve cell membranes and alter the properties of lipids surrounding crucial membrane proteins that protein function is compromised. Meyer HH: "Zur Theorie der Alkoholnarkose". 1899.

  13. Theories of general anesthetic action Alternative idea that proteins are directly affected: • Membrane protein hypothesis*: • Some class of proteins might be sensitive to general anesthetics. Inhalation agents may primarily interact with receptor proteins & produce conformational changes in their molecular structure. These changes affect the function of ion channels or enzymes. • GABAA, glycine, glutamate, Nicotinic receptors can be selectively modified by clinical concentrations of volatiles. * Franks NP. Nature, 300: 1982.

  14. Anatomic regions of brain responsible for the general anesthetic action • THALAMUS (Inhibition of Ni Ach receptors) • HIPOTHALAMUS (Histaminergic, orexinergic neurons) • BRAIN STEM (Noradrenergic neurons of LC. α2-agonists) • LIMBIC SYSTEM (Hippocampus and Amygdala; memory function and anesthetic mediated amnesia)

  15. Mechanism of Anesthesia • Anesthetic action on spinal cord probably inhibits purposeful responses to noxious stimulation. • Inhalational agents can “depress the exitability ofthalamic neurons”, “block thalamocortical communication”, the potential result is loss of consciousness. • Existing evidence provides no basis for a single anatomic site responsible for anesthesia.

  16. Anesthetic effects on synaptic level:Cellular mechanism • SYNAPSE is thought to be the most relevant site of anesthetic action: (by means of anesthetic effects on sodium channels) • Presynaptic inhibition of neurotransmitter release, • Inhibition of excitatory neurotransmitter effect, • Enhancement of inhibitory neurotransmitter effect.

  17. Molecular mechanismGABAA receptor, ligand gated ion channel • GABA is the major inhibitory neurotransmitter. GABAA receptor is abundant in brain and located in the post-synaptic membrane. • Glycine, • 5-HT3, • Neuronal nicotinic receptors.

  18. GABA receptor binding & anesthetic action • Binding of GABA causes a conformational change in the receptor. The central pore is opened, • Chloride ions are passed down electrochemical gradient, • Net inhibitory effect is the reduced neuronal activity.

  19. Consciousness Movement Excitatory neuro- transmission Neuronal excitability GABAA receptors NMDA receptors Na channels K channels Etomidate Propofol Barbiturates Volatile Anesthetics N2O Xenon Ketamine

  20. Anesthetics divide into 2 classes • Inhalation Anesthetics • Gases or Vapors • Usually Halogenated • Intravenous Anesthetics • Injections • Anesthetics or induction agents

  21. BARBITURATES • Depress RAS located in the brainstem & affect the synaptic function. • Sodium salt is alkaline, pH=10. • IV or rectal application is possible. • Duration of action is determined by redistribution. • Onset time of action 30-45 sec.

  22. BARBITURATES USES 1. Anesthesia 2. Medically induced coma 3. Euthanasia 4. Lethal injection 5. Truth serum 6. Psychiatry

  23. BENZODIAZEPINES • Related Neurotransmitters • GABA • Benzodiazepines facilitate GABA binding • Agonistic action on GABA may account for the sedative-hypnotic and anesthetic properties

  24. BENZODIAZEPINES(Diazepam, Midazolam) • Absorbtion: Oral, IM, IV, SL, rectal, buccal. • Highly protein bounded, rapid of onset & duration of action relatively long. Metabolized in liver, excreted in the urine. • Midazolam: elimination half life 2 hrs. Renal failure prolongs sedation (α-OH-midazolam) • Controls grand mal seizures. Antegrade amnesia. Mild muscle relaxation, anxiolysis, sedation.

  25. Midazolam is used for: • Emergency treatment of seizures • Sedation during medical procedures • Premedication prior to medical procedures

  26. Buccal Midazolam for epilepsy treatment • Midazolam can be: • Trickled inside the cheek – buccal • Dripped into the nose – intranasal • Injected into a vein (IV) or muscle (IM)

  27. KETAMINE(PHENCYCLIDINE ANALOGUE) • IV, IM, oral. • NMDA-Antagonist (glutamate subtype) • Functionally dissociates the THALAMUS from the LIMBIC cortex. • Dissociative anesthesia. • Analgesic, amnestic, hypnosis. • Ketamine anesthesia was first given to American soldiers during the Vietnam War.

  28. ETOMIDATE • Depresses RAS, • Myoclonic activity (decreased with opioids), • Pain on injection, • Rapid onset of action, • Hydrolysed by hepatic microsomal enzyme & plasma esterases, • Excreted in urine.

  29. ENDOCRINE EFFECTS: • Long term infusion leads to adrenocortical suppression and increased mortality in critically ill patients. • Transient inhibition of enzymes involved in “cortisol and aldosterone” synthesis.

  30. PROPOFOL(2,6-DIISOPROPYLPHENOL) • Fascilitates the inhibitory neurotransmission mediated by GABA, • Pain on injection (iv), • Bacterial growth in the formula. Use within 6 hours after opening the formula

  31. IV ANESTHETIC AGENTS

  32. Pharmacokinetics of Inhaled Anesthetics • Amount that reaches the brain is determined by: • Lipid solubility (oil:gas partition ratio) –its related to MAC- • Alveolar partial pressure of anesthetic • Solubility of gas into blood The rate of onset of action is determined by solubility in blood. The lower the solubility in blood, the more anesthetics will arrive at the brain • Cardiac Output: If increased induction time delays.

  33. Pathway for General Anesthetics

  34. Rate of Entry into the Brain: Influence of Blood and Lipid Solubility

  35. Control of Volatile Partial Pressure in Brain • Direct Physician's Control • Solubility of agent • Concentration of agent in inspired gas • Magnitude of alveolar ventilation • Indirect Control • Pulmonary blood flow (function of CO) • Arterio-venous concentration gradient

  36. MAC(minimal alveolar concentration) • A measure of potency • 1MAC is the concentration necessary to preventmovement inresponsetopainfulstimulus in 50% of population.

  37. Systemic Effects of Inhaled Anesthetics • Respiration:Depress respiration and response to CO2 • Kidney:Depress renal blood flow and urine output • Muscle:High concentrations relax skeletal muscle • CNS: Increased cerebral blood flow, decreased cerebral metabolism

  38. Cardiovascular System • Reduced blood pressure and peripheral vascular resistance. Isoflurane maintains CO and coronary function better than other agents.

  39. Nitrous Oxide • Simple linear compound • Not metabolized • Only anesthetic agent that is inorganic • Colorless, odorless, tasteless

  40. Nitrous Oxide • Its potency is low • Weak anesthetic, relatively powerful analgesic • It must be used with other agents for surgical anesthesia • Low blood solubility (quick recovery)

  41. Nitrous Oxide • Minimal effects on heart rate and blood pressure • May cause myocardial depression • Little effect on respiration • Beginning of case: second gas effect • End of case: diffusion hypoxia

  42. Side effects (Nitrous Oxide) • Diffusion into closed spaces

  43. Side effects (Nitrous Oxide) • N2O inhibits methionine synthetase (precursor to DNA synthesis) & vitamin B12metabolism, • Dentists, OR personnel, abusers are at risk.

  44. Methoxyflurane, 1960 • Halogen substituted ethane, not flammable. • Most potent inhalational anesthetic • Prolonged induction & emergence from anesthesia • Nephrotoxic & Hepatotoxic

  45. Methoxyflurane • Since the 1970s it has been used in Australia in lower doses for acute analgesia, largely by paramedic services. • Self administered by the patients.

  46. Halothane, 1956 • Halogen substituted ethane. Stable and nonflammable • Most potent inhalational anesthetic (except for the methoyflurane) • Very soluble in blood and adipose tissue • Prolonged emergence

  47. Sensitizes myocardium to effects of exogenous catecholamines-- ventricular arrhythmias • Depresses myocardium-- lowers BP and slows conduction- • Decreases respiratory drive-- central response to CO2- • Shallow respiration -- atelectasis • Depresses protective airway reflexes

  48. Halothane (Side Effects) • “Halothane Hepatitis” -- 1/10,000 cases (immunologically mediated) • fever, jaundice, hepatic necrosis, death • exposure dependent • metabolic breakdown products are hapten-protein conjugates • Malignant Hyperthermia-- 1/60,000 (with succinylcholine to 1/260,000).

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