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Inhaled AnestheticsHistory and Pharmacology
Inhaled AnestheticsHistory and Pharmacology
Rafael Ortega, MDProfessor of Anesthesiology
Rafael Ortega, MDProfessor 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
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.
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
The Great Moment
• John C. Warren (Surgeon)
• William T.G. Morton (Dentist)
• Gilbert Abbott (Patient)
October 16th, 1846(166 years ago…)
The Great Moment (1944) Directed by: Preston Surges
Morton’s Ether Inhaler
C C O C C
H
H
H
H
H
H
H
H
H
H
Ether
diethyl ether
Isoflurane
C C O C
F
F
F
H
Cl
F
F
H
1-chloro-2,2,2-trifluoroethyl difluoromethyl ether
2-chloro-1,1,2-trifluoroethyl difluoromethyl ether
Enflurane
C C O C
F
Cl
H
F
F
F
F
H
Desflurane
C C O C
F
F
F
H
F
F
F
H
1-Fluoro-2,2,2-trifluoro-ethyl difluoromethyl ether
Sevoflurane
C C O C
F
F
F
C
H
H
H
F
FF F
Fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl) ethyl ether
“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
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
1846-1848
Diethyl Ether
Vapor PressuremmHg
Temperature 0C1040F
““Pain, the highest consciousness of our earthly Pain, the highest consciousness of our earthly existence, the most distinct sensation of the existence, the most distinct sensation of the
imperfection of our body, must bow before the power imperfection of our body, must bow before the power of the human mind, before the power of ether vapor.” of the human mind, before the power of ether vapor.”
Johann Friedrich DieffenbachJohann Friedrich Dieffenbach
““This event heralded the end of surgery as torture, This event heralded the end of surgery as torture, when all but the simplest procedures were to be when all but the simplest procedures were to be
dreaded only less than death itself.” dreaded only less than death itself.”
Boston Daily Globe Boston Daily Globe
Lyons AS: Medicine, an illustrated history. New York, H.N. Abrams, 1978Honoring the Conqueror of Pain, Boston Daily Globe. Boston, October 17, 1896
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
Who was the first anesthesiologist?
““the LORD God caused a deep sleep to fall the LORD God caused a deep sleep to fall upon Adam and he slept: and he took one of upon Adam and he slept: and he took one of
his ribs, and closed up the flesh instead his ribs, and closed up the flesh instead thereof”thereof”
Genesis 2:21
Anesthesia: definition
Inhaled Anesthetics
1830 1850 1870 1890 1910 1930 1950 1970 1990 2000
20
15
10
5
0N2O
Ether
ChloroformEthyl chloride Ethylene
Vinithene
CyclopropaneTrichloroethylene
Isopropenyl vinyl ether
Propyl methyl ether Fluoroxene
Ethyl vinyl etherHalothane
Methoxyflurane
Sevoflurane
Desflurane
Isoflurane
Enflurane
Year Introduced
XENON
?
Lower Solubility
3
2
1
0
1960 1980 2000
Halothane
Enflurane
Isoflurane
Desflurane
Why the newer anesthetics?
Ether and cyclopropaneflammable
Chloroform cardiac arrest
Trichloroethylene phosgene, CO
Methoxyflurane renal failure
Why is it still used today?
Rapid inductionRapid recoveryEasy titrationMeasurable concentrationInhalation route readily availableRespiration controlled while delivering gases
Theories of Anesthesia
Diverse group of substances
No specific chemical class
Molecule shape unimportant
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).
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
Lipid solubility and potency
Halogens
Halogenated Agents
Physical PropertiesAnesthetic Boling Point
(0C)Vapor Pressure (mm Hg @ 200C)
Desflurane 22.8 669
Enflurane 56.5 175
Halothane 50.2 241
Isoflurane 48.5 240
Sevoflurane 58.5 160
Blood/Gas Partition CoefficientsAgent Coefficient
Desflurane 0.42
Nitrous Oxide 0.47
Sevoflurane 0.6
Isoflurane 1.4
Enflurane 1.9
Halothane 2.4
Brain Blood Flow
Equilibration
Lungs Arterial Blood Brain
The Tissue GroupsVessel Rich
Group
Muscle Group
Fat Group
Vessel PoorGroup
% Body Mass
9 50 19 22
% Cardiac Output
75 18 7 0
Liters/Min4.0 1.0 0.4 0
Anesthetic UptakeUptake = λ x Q x (A-v)
Where λ = blood/gas partition coefficient Q= cardiac output A-v = alveolar to venous anesthetic
partial pressure difference
Minimal Alveolar ConcentrationMinimal 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
Understanding MAC
The relevant units are partial pressure1 atmosphere = 760 mm Hg1 % of 760 mm Hg = 7.6 mm HgThus, MAC increases at higher altitudes
Factors Affecting MAC
Increase Decrease
MAO Inhibitors Opiods
Cocaine Barbiturates
Amphetamines Benzodiazepines
Chronic Alcoholism Hyponatremia
Hyperthermia Hypothermia
Ephedrine Hypoxia
Other Other
Where do they work?
CNS Sensitive Areas
Reticular Formation
Hypothalamus
Thalamus
Stages of AnesthesiaStage 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.
Awareness Under Anesthesia
Intraoperative EEG Monitoring
Ideal Inhalation AnestheticPleasant and rapid inductionNon-flammable and chemically stableNon-toxicNo biotransformationGood amnesiaAnalgesia and relaxationPotent, allowing high oxygen concentrationNo adverse cardiac or pulmonary effectsNo adrenergic stimulationInexpensive
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)
Inhibits methionine synthetase
May cause bone marrow depression, megaloblastic anemia, leukopenia and neuropathy
Associated with higher incidence of abortions
Nitrous Oxide (dinitrogen monoxide)
Enters body cavities faster than nitrogen
Can distend any air filled space in the body
May cause nausea and vomiting
Nitrous Oxide (dinitrogen monoxide)
Laughing Gas
HalothaneWidely used
Non-irritating to airway
Depresses cardiac output
Sensitizes heart to catecholamines
Halothane hepatitis
Isoflurane (1-chloro-2,2,2-trifluroethyl difluoromethyl ether)
Widely used in the U.S.A. Not hepatotoxicCommonly used in patients with CADRapid inductionCardiac output is maintainedInhibition of pulmonary hypoxic
vasoconstriction EEG slows progressively
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
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