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