2. Introduction
ď˘ First Anaesthetic Agents
ď˘ Inhalational anaesthesia refers to the
delivery of gas or vapors to the
respiratory system to produce generalised
anaesthesia in the body.
ď˘ *Continued dominance over regional and
intravenous agents
ď˘ Inherent safety
ď˘ Universal applicability
ď˘ Better control
ď˘ No significant metabolism
ď˘ Easy administration
ď˘ Better acceptance
3. History
ď˘ Early attempts at anaesthesia â Barbaric
ď˘ Gases
ď˘ Joseph Priestly â
⢠1771- âDephlogisticated airâ â Oxygen
⢠1772- âDephlogisticated nitrous airâ
Nitrous Oxide
⢠But, these were all, forgottenâŚ
o Antoine Lavoisier
o Thomas Beddoes
4. History (contd.)
ď˘ Humphry Davy (1799-1801) â
ď˘ Acquainted to Beddoes, deeply interested
in Priestleyâs âdephlogisticated nitrous airâ
ď˘ Experiments â on animals, on himselfâŚ
ď˘ âLaughing Gasâ
ď˘ Stepping Stone for further research
ď˘ Horace Wells â
ď˘ Gardner Quincy Colton- 11 Dec 1844
ď˘ Jan 1845 â Disastrous Demonstration in
Boston
ď˘ Later, used chloroform and ether in
combination with nitrous oxide.
5. History (contd.)
ď˘ Ether-
ď˘ Already in use â oral, topical
ď˘ Pneumatic medicine
ď˘ âEther Frolicsâ
ď˘ Crawford Williamson Long (1842)
ď˘ William Thomas Green Morton-
ď˘ Apprentice of Horace Wells, Charles
Jackson (ether)
ď˘ Experiments on animals, humans-
unsuccessful
ď˘ Fateful Day â 16
th October 1846
6.
7. History (contd.)
ď˘ Chloroform â James Y. Simpson (4th Nov 1847)
ď˘ Jacob Bell, William Lawrence
ď˘ John Snow
ď˘ Cyclopropane â August Freund (1881)
ď˘ Henderson & Lucas (1929)
ď˘ Trichloroethylene â 1941 â Second World War
ď˘ Halothane â C. W. Suckling (1951)
ď˘ M. Johnstone (1956)
ď˘ Methoxyflurane â late 1940âs
ď˘ Joseph F. Artusio (1960)
8. Properties of Ideal Anaes. Agent
ď˘ Pleasant Odor
ď˘ Rapid induction, rapid recovery
ď˘ Non-flammable in presence of O2 & N2O
ď˘ Chemically & Biochemically Stable
ď˘ Minimal/no absorption or biotransformation in
body or metabolism
ď˘ Good Analgesia, amnesia
(unconsciousness), muscle relaxation
ď˘ High oil solubilty, high potency
ď˘ Easy administration, depth easily alterable
ď˘ No deleterious effects on vital systems, safe in all
ages
ď˘ No increase in secretions
9. ď˘ No sensitization of heart to catecholamines
ď˘ No environmental hazards
ď˘ No stimulant effects on EEG
ď˘ No interaction with other agents
ď˘ No alteration in cerebral flow, ICP, no nausea-
vomiting
ď˘ No toxic effects on liver, kidney
ď˘ Long shelf life
ď˘ Low cost
10. Mechanism of Action
ď˘ âTheories of Narcosisâ
ď˘ Inhalational Anaes. Agents produce
ď˘ Analgesia
ď˘ Amnesia
ď˘ Somatic muscle relaxation
ď˘ Myocardial depression
ď˘ Uterine Atony
ď˘ Interference with cellular growth &
replication
ď˘ Inhibition of mitochondrial respiration
ď˘ ? Convulsions
Any theory of narcosis should be able to explain all
these actions
11. Problems:
ď˘ No common chemical or structural properties
ď˘ Effects not mediated through single specific
receptor or related to stereospecificity
ď˘ GA does not result from strong chemical bonds
â˘E.g. Xenon
ď˘ Variable EEG studies
ď˘ Variable potency
ď˘ Ability of high atmospheric pressure to reverse
some, but not all, effects
ď˘ Relation between anaes. effect & molecular size
ď˘ Rapid onset & termination
âit is probably naĂŻve to attempt an elucidation of
a single or unitary mechanism of actionâ
12. Site of Action
ď˘ Unknown even after 166 years
ď˘ Could it be-
o RAS or other group of CNS synapses?
o Cellular or subcellular structures like
acetlycholine, serotonin, etc?
o An area responsible for synthesis of an
important but unknown neurotransmitter?
o A particular molecule such as a specific
phospholipid, an ion- channel, or perhaps an
enzyme whose structure is altered by the
agent?
o Does the agent decrease the mitochondrial
oxygen uptake or alter CNS electrical activity
or cause changes in a certain area of the cell
membrane?
13. Lipid Solubility:
ď˘ Meyer-Overton Hypothesis (1899)
ď˘ Narcosis occurs when a critical drug conc. is
attained within a âcrucial lipidâ in the CNS
ď˘ Thus, anaes. doses could be expressed as a
constant molar or volume fraction
ď˘ Can be correlated to both in vivo and in vitro
potency
ď˘ Suggests that, anaes agent dissolves in
lipophilic portion of the membrane, blockade of
essential pore, prevents depolarization
ď˘ Site of Action? Molecular mechanism of
action?
ď˘ Vapors or aqueous solutions of agents? Other
lipophilic drugs?
14.
15. Action on Water Molecules:
ď˘ Concepts of Pauling & Miller â Action through
aqueous rather than lipid site within CNS
o Pauling â Hydrated anaes. agent molecule or
âClathrateâ can stabilise membrane or occlude
essential pores, interference with
depolarization, producing anaesthesia
o Miller â physical interaction between water molecule
& anaes. molecule results in âIcebergâ which âstiffens-
upâ the membrane, prevents neuronal transmission
o Poor correlation of anaes. potency with
hydrate dissociation pressure
(ether, sulphahexafluride)
o Combination of agents producing small & large
clathrates
o Ambient pressure & body temperature
16. Binding to Specific Receptors:
ď˘ Microtubules?
ď˘ Receptors made up of proteins, lipids or water
ď˘ Protein receptors for Ach, GABA, Glutamate, G-
protein??
ď˘ Opioid receptors?? (exogenous opioids or
endorphins)
o Development of tolerance to analgesia & righting
reflex produced by N2O (rats)
o Naltrexone antagonizes analgesia by N2O (rats)
o Naloxone â halothane,enflurane,cyclopropane (rats)
o But not in dogs or pig ileum
o Non-opioid receptor??
o In vivo nuclear MRI findings
17. Physical Properties: not reliable
Neurophysiological Theory:
o Effect on Synaptic transmission > Axonal
transmission
o Likely site of action â RAS??
o Problems â
o How does it act?
o Surgical removal of RAS does not affect action of
agent
o Changes in EEG vary with different agents â
multiplicity of site of action
o Other actions?
o Muscular relaxation â Spinal monosynaptic H-
reflex⌠mechanism unknown
o Change in Ca++ channel permeability??
18. Biochemical Theory:
ď˘ Effect on intermediary metabolism â decrease O2
uptake
ď˘ Inhibit mitochondrial respiration in a dose-
dependant & reversible manner (even Xenon)
ď˘ In vitro potencies related to in vivo potencies &
lipid solubility â cut-off molecular size for in
vivo CNS effects same as in vitro inhibition of
mitochondrial respiration
ď˘ Rate of synthesis & utilization of ATP &
Creatine Phosphate in CNS is proportionately
decreased. Thus in vivo & in vitro sites of action
may be similar but not identical.
ď˘ High pressure â unconsciousness, but not
inhibition of O2 uptake or analgesia
ď˘ Ca++ influx altered
ď˘ GABA conc. at synaptic areas increased
19. Molecular Theory:
ď˘ Susceptible phospholipid membrane â altering its
physical status
ď˘ Phospholipid bilayer of the cell membrane can
exist in 2 forms:
ď˘ Tightly ordered Gel phase
ď˘ Structurally disoriented Fluid phase
âLateral Phase Separationâ
ď˘ Gel phase â Fluid phase interchangeable
ď˘ Opening of channel = conversion to gel phase
ď˘ Anaes. Agents increase Fluid : Gel ratio
Pressure reversal Theory:
ď˘ A. A. expands vol. of hydrophobic region
20. Minimum Alveolar Concentration
ď˘ Merkel & Eger (1963)
ď˘ It is the minimum concentration of anaes.
agent in the alveoli at 1 atmosphere that
produces immobility in 50% subjects when
exposed to noxious stimuli.
ď˘ Measure/index of anaes. potency
ď˘ Inversely proportional to potency
ď˘ Directly proportional to Oil/Gas solubility
coefficient
ď˘ Equally applicable to all inhalational agents
ď˘ Gives better control over dose of drug required
ď˘ Used to compare Anaes. Effects & side effects
of various agents
22. Nitrous Oxide (N2O)
ď˘ History
ď˘ Non-irritating, colorless, slightly sweet-smelling
inorganic gas. Heavier than air
ď˘ Oil/gas solubility ratio = 3.2
ď˘ Blood/gas solubility coeff. = 0.47
ď˘ MAC = 105
ď˘ Second Gas Effect
ď˘ Stored in blue cylinders
ď˘ Pharmacokinetics:
ď˘ Rapidly taken up
ď˘ no metabolism
ď˘ Eliminated completely unchanged
24. Diethyl Ether (C2H5)2O
ď˘ Colorless, volatile liquid, characteristic
pungent smell, inflammable, explosive
ď˘ Pharmacokinetics:
ď˘ Highly soluble in blood- induction prolonged,
unpleasant
ď˘ Blood/gas solubility coeff = 12.1
ď˘ Oil/gas solubility = 65 (low)
ď˘ MAC = 3-5
ď˘ Metabolism â 5-10% via skin, secretions, urine.
Rest excreted unchanged
ď˘ Pharmacodynamics:
ď˘ CNS â Depression
Stage I at 0.5-1%
Stage II at 1-2.5%
Stage III at 2.5-4%
Stage IV at 4-5%
25. o CVS â Minimal change
o Respiratory System â Irritant
Increased Secretions
o Neuromuscular junction â relaxation
o GIT â vomiting
o Kidney â decreases renal blood flow
albuminuria
o Uterus â relaxes
o Liver â minimal effects
o Advantages:
o Good analgesic
o Sympathetic stimulation
o Bronchodilatation
o Autoregulation
o Economical, easy availabilty, storage
26. Ethyl Chloride (C2H5Cl):
ď˘ Refrigeration anaesthesia; MAC = 2.55
ď˘ 3-5% conc. in inspired air can produce
anaesthesia
ď˘ Rapid effect
ď˘ Local as well as General anaesthesia
ď˘ Myocardial depression
Trichloroethylene(CCl2CHCl):
ď˘ Most potent â oil/gas solubility = 960
ď˘ MAC = 0.17 ; blood/gas sol. Coeff. = 9.15
ď˘ Cranial Nerve lesions (sensory)
ď˘ Very slow induction, prolonged recovery
ď˘ Partly metabolised (urine), partly excreted
ď˘ Cardiac Dysrhythmias, tachypnea, circumoral
herpes, increased ICP
ď˘ âPhosgeneâ
35. Role in Balanced General Anaesthesia
ď˘ Capable of producing almost all
components of Balanced General
Anaesthesia by themselves
ď˘ Modern Balanced GA â combination of
Inhalational & Intravenous
ď˘ Irreplaceable part of anaesthesia