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Inhaled Anesthetics History and Pharmacology Inhaled Anesthetics History and Pharmacology Rafael Ortega, MD Professor of Anesthesiology Rafael Ortega,

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Presentation on theme: "Inhaled Anesthetics History and Pharmacology Inhaled Anesthetics History and Pharmacology Rafael Ortega, MD Professor of Anesthesiology Rafael Ortega,"— Presentation transcript:

1 Inhaled Anesthetics History and Pharmacology Inhaled Anesthetics History and Pharmacology Rafael Ortega, MD Professor of Anesthesiology Rafael Ortega, MD Professor of Anesthesiology Boston University School of Medicine February 6th, 2013 Boston University School of Medicine February 6th, 2013 College of Pharmacy University of Rhode Island

2 Objectives To understand the evolution, the role and the indications of inhalation anesthetics today. To learn how the properties of general anesthetics influence their onset, uptake, potency and mode of delivery. To know the characteristics, indications and effects of the currently used inhalation anesthetics. To prepare participants for clinical experiences with inhalation general anesthetics.

3 A Brief History of Anesthesia Ancient World:Egypt, Greece, Rome, etc. 10th Century:Soporific Sponge Middle Ages: Alcohol Fumes 16th Century:Paracelsus: Tincture of Laudanum 1804:Seishu Hanaoka: “Tsusensan” 1842:Crawford W. Long: Diethyl Ether 1844:Horace Wells: Nitrous Oxide


5 The Great Moment John C. Warren (Surgeon) William T.G. Morton (Dentist) Gilbert Abbott (Patient) October 16th, 1846 (166 years ago…)

6 The Great Moment (1944) Directed by: Preston Surges

7 Morton’s Ether Inhaler

8 C C O C C H H H H H H H H H H Ether diethyl ether

9 Isoflurane C C O C F F F H Cl F F H 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether

10 2-chloro-1,1,2-trifluoroethyl difluoromethyl ether Enflurane C C O C F Cl H F F F F H

11 Desflurane C C O C F F F H F F F H 1-Fluoro-2,2,2-trifluoro-ethyl difluoromethyl ether

12 Sevoflurane C C O C F F F C H H H F F F F Fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether

13 “Anesthesia” before 1846 Davy ---------- “Destruction of Pain” Hickman ----- “Suspended Animation” Wells: --------- “Influence of Gas” Morton: --------“Ether Sleep” David Shephard: From Craft to Specialty. York Point Publishing. Ontario, 2009

14 Oliver Wendell Holmes (1809–1894) Oliver Wendell Holmes (1809–1894) “Everybody wants to have a hand in a great discovery. All I will do is to give you a hint or two as to the names — or the name — to be applied to the state produced and the agent. The state should, I think, be called Anesthesia.” Letter from Holmes to Morton, Boston, Nov 21, 1846


16 1846-1848

17 Diethyl Ether Vapor Pressure mmHg Temperature 0 C 104 0 F

18 “Pain, the highest consciousness of our earthly existence, the most distinct sensation of the imperfection of our body, must bow before the power of the human mind, before the power of ether vapor.” Johann Friedrich Dieffenbach Johann Friedrich Dieffenbach “This event heralded the end of surgery as torture, when all but the simplest procedures were to be dreaded only less than death itself.” “This event heralded the end of surgery as torture, when all but the simplest procedures were to be dreaded only less than death itself.” Boston Daily Globe Boston Daily Globe Lyons AS: Medicine, an illustrated history. New York, H.N. Abrams, 1978 Honoring the Conqueror of Pain, Boston Daily Globe. Boston, October 17, 1896

19 Written in Granite: An Illustrated History of the Ether Monument, by Rafael A. Ortega, 71 pp, with illus, ISBN 0- 87270-142-5, Boston, Mass, Plexus Management, 2006

20 Who was the first anesthesiologist?

21 “the LORD God caused a deep sleep to fall upon Adam and he slept: and he took one of his ribs, and closed up the flesh instead thereof” Genesis 2:21

22 Anesthesia: definition A loss of sensation in a part of the body or in body generally, induced by the administration of a drug. (Stedman’s Medical Dictionary) –General Anesthesia blocks: »Sensory »Reflex »Mental »Motor

23 Inhaled Anesthetics 183018501870189019101930195019701990 2000 20 15 10 5 0 N2ON2O Ether Chloroform Ethyl chloride Ethylene Vinithene Cyclopropane Trichloroethylene Isopropenyl vinyl ether Propyl methyl ether Fluoroxene Ethyl vinyl ether Halothane Methoxyflurane Sevoflurane Desflurane Isoflurane Enflurane Year Introduced XENON ?

24 Lower Solubility 3 2 1 0 196019802000 Halothane Enflurane Isoflurane Desflurane

25 Why the newer anesthetics? Ether and cyclopropaneflammable Chloroformcardiac arrest Trichloroethylenephosgene, CO Methoxyfluranerenal failure

26 Why is it still used today? Rapid induction Rapid recovery Easy titration Measurable concentration Inhalation route readily available Respiration controlled while delivering gases

27 Theories of Anesthesia Diverse group of substances No specific chemical class Molecule shape unimportant

28 Theories of Anesthesia Four possible target sites for inhaled anesthetic molecules (solid circles) in a neuronal membrane include the lipid bilayer as a whole (a), lipids at a protein-lipid interface (b), a protein site bounded by lipid (c), and a protein site exposed to an aqueous environment (d).

29 Theories of Anesthesia Lipid Theory: by dissolving in membrane lipid, anesthetics affect its physical state altering membrane function. Protein Theory: the interaction of anesthetic molecules with membrane proteins can affect their function

30 Lipid solubility and potency

31 Halogens

32 Halogenated Agents

33 Physical Properties AnestheticBoling Point ( 0 C)Vapor Pressure (mm Hg @ 20 0 C) Desflurane22.8669 Enflurane56.5175 Halothane50.2241 Isoflurane48.5240 Sevoflurane58.5160

34 Blood/Gas Partition Coefficients AgentCoefficient Desflurane0.42 Nitrous Oxide0.47 Sevoflurane0.6 Isoflurane1.4 Enflurane1.9 Halothane2.4

35 Brain Blood Flow

36 Equilibration Lungs Arterial Blood Brain

37 The Tissue Groups Vessel Rich Group Muscle Group Fat Group Vessel Poor Group % Body Mass 9501922 % Cardiac Output 751870 Liters/Min

38 Anesthetic Uptake Uptake = λ x Q x (A-v) Where λ = blood/gas partition coefficient Q= cardiac output A-v = alveolar to venous anesthetic partial pressure difference

39 Minimal Alveolar Concentration Minimal Alveolar Concentration (MAC) is the minimum alveolar concentration of anesthetic that prevents movement in 50% of subjects in response to a standard surgical incision. The concentration in the alveoli is a reasonable approximation of the concentration in the brain. Lungs Arterial Blood Brain

40 Understanding MAC The relevant units are partial pressure 1 atmosphere = 760 mm Hg 1 % of 760 mm Hg = 7.6 mm Hg Thus, MAC increases at higher altitudes

41 Factors Affecting MAC IncreaseDecrease MAO InhibitorsOpiods CocaineBarbiturates AmphetaminesBenzodiazepines Chronic AlcoholismHyponatremia HyperthermiaHypothermia EphedrineHypoxia Other

42 Where do they work?

43 CNS Sensitive Areas Reticular Formation Hypothalamus Thalamus

44 Stages of Anesthesia Stage 1 – Analgesia: the subject is conscious but drowsy. Responses to painful stimuli are reduced. Stage 2 – Excitement: the subject loses consciousness. Responds only in a reflex fashion to painful stimuli. Stage 3 – Surgical Anesthesia: spontaneous movement cease. Respirations become regular. Stage 4 – Medullary Paralysis: respiration and vasomotor control cease. Cardiovascular collapse. Death.

45 Awareness Under Anesthesia

46 Intraoperative EEG Monitoring

47 Ideal Inhalation Anesthetic Pleasant and rapid induction Non-flammable and chemically stable Non-toxic No biotransformation Good amnesia Analgesia and relaxation Potent, allowing high oxygen concentration No adverse cardiac or pulmonary effects No adrenergic stimulation Inexpensive

48 Low blood:gas partition coefficient Allows for fast onset and termination of action Effective as an analgesic Commonly used as an adjuvant in combination with a potent halogenated agent Nitrous Oxide (dinitrogen monoxide)

49 Inhibits methionine synthetase May cause bone marrow depression, megaloblastic anemia, leukopenia and neuropathy Associated with higher incidence of abortions Nitrous Oxide (dinitrogen monoxide)

50 Enters body cavities faster than nitrogen Can distend any air filled space in the body May cause nausea and vomiting Nitrous Oxide (dinitrogen monoxide)

51 Laughing Gas

52 Halothane Widely used Non-irritating to airway Depresses cardiac output Sensitizes heart to catecholamines Halothane hepatitis

53 Isoflurane (1-chloro-2,2,2-trifluroethyl difluoromethyl ether) Widely used in the U.S.A. Not hepatotoxic Commonly used in patients with CAD Rapid induction Cardiac output is maintained Inhibition of pulmonary hypoxic vasoconstriction EEG slows progressively

54 Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) Least soluble in blood Can trigger coughing and breath holding Circulatory actions similar to isoflurane Minimal biotransformation Expensive if not used properly

55 Sevoflurane (fluoromethyl 2,2,2-trifluoro 1-(trifluoromethyl) ethyl ether) Latest agent introduced Low solubility Smooth inhalation induction Undergoes significant biotransformation Caution in renal insufficiency


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