Aditi m. panditrao explains the various inhalational anesthetics, historical aspects, pharmacology , etc.

1. Inhalational Anaesthetic
Agents

2. Introduction
 First Anaesthetic Agents
 Inhalational anaesthesia refers to the
delivery of gas or vapors to the
respiratory system to produce generalised
anaesthesia in the body.
 *Continued dominance over regional and
intravenous agents
 Inherent safety
 Universal applicability
 Better control
 No significant metabolism
 Easy administration
 Better acceptance

3. History
 Early attempts at anaesthesia – Barbaric
 Gases
 Joseph Priestly –
• 1771- „Dephlogisticated air‟ – Oxygen
• 1772- „Dephlogisticated nitrous air‟
Nitrous Oxide
• But, these were all, forgotten…
o Antoine Lavoisier
o Thomas Beddoes

4. History (contd.)
 Humphry Davy (1799-1801) –
 Acquainted to Beddoes, deeply interested
in Priestley‟s „dephlogisticated nitrous air‟
 Experiments – on animals, on himself…
 „Laughing Gas‟
 Stepping Stone for further research
 Horace Wells –
 Gardner Quincy Colton- 11 Dec 1844
 Jan 1845 – Disastrous Demonstration in
Boston
 Later, used chloroform and ether in
combination with nitrous oxide.

5. History (contd.)
 Ether-
 Already in use – oral, topical
 Pneumatic medicine
 „Ether Frolics‟
 Crawford Williamson Long (1842)
 William Thomas Green Morton-
 Apprentice of Horace Wells, Charles
Jackson (ether)
 Experiments on animals, humans-
unsuccessful
 Fateful Day – 16
th October 1846

7. History (contd.)
 Chloroform – James Y. Simpson (4th Nov 1847)
 Jacob Bell, William Lawrence
 John Snow
 Cyclopropane – August Freund (1881)
 Henderson & Lucas (1929)
 Trichloroethylene – 1941 – Second World War
 Halothane – C. W. Suckling (1951)
 M. Johnstone (1956)
 Methoxyflurane – late 1940‟s
 Joseph F. Artusio (1960)

8. Properties of Ideal Anaes. Agent
 Pleasant Odor
 Rapid induction, rapid recovery
 Non-flammable in presence of O2 & N2O
 Chemically & Biochemically Stable
 Minimal/no absorption or biotransformation in
body or metabolism
 Good Analgesia, amnesia
(unconsciousness), muscle relaxation
 High oil solubilty, high potency
 Easy administration, depth easily alterable
 No deleterious effects on vital systems, safe in all
ages
 No increase in secretions

9.  No sensitization of heart to catecholamines
 No environmental hazards
 No stimulant effects on EEG
 No interaction with other agents
 No alteration in cerebral flow, ICP, no nausea-
vomiting
 No toxic effects on liver, kidney
 Long shelf life
 Low cost

10. Mechanism of Action
 “Theories of Narcosis”
 Inhalational Anaes. Agents produce
 Analgesia
 Amnesia
 Somatic muscle relaxation
 Myocardial depression
 Uterine Atony
 Interference with cellular growth &
replication
 Inhibition of mitochondrial respiration
 ? Convulsions
Any theory of narcosis should be able to explain all
these actions

11. Problems:
 No common chemical or structural properties
 Effects not mediated through single specific
receptor or related to stereospecificity
 GA does not result from strong chemical bonds
•E.g. Xenon
 Variable EEG studies
 Variable potency
 Ability of high atmospheric pressure to reverse
some, but not all, effects
 Relation between anaes. effect & molecular size
 Rapid onset & termination
“it is probably naïve to attempt an elucidation of
a single or unitary mechanism of action”

12. Site of Action
 Unknown even after 166 years
 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:
 Meyer-Overton Hypothesis (1899)
 Narcosis occurs when a critical drug conc. is
attained within a “crucial lipid” in the CNS
 Thus, anaes. doses could be expressed as a
constant molar or volume fraction
 Can be correlated to both in vivo and in vitro
potency
 Suggests that, anaes agent dissolves in
lipophilic portion of the membrane, blockade of
essential pore, prevents depolarization
 Site of Action? Molecular mechanism of
action?
 Vapors or aqueous solutions of agents? Other
lipophilic drugs?

15. Action on Water Molecules:
 Concepts of Pauling & Miller – Action through
aqueous rather than lipid site within CNS
o Pauling – Hydrated anaes. agent molecule or
“Clathrate” can stabilise membrane or occlude
essential pores, interference with
depolarization, producing anaesthesia
o Miller – physical interaction between water molecule
& anaes. molecule results in “Iceberg” which “stiffens-
up” 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:
 Microtubules?
 Receptors made up of proteins, lipids or water
 Protein receptors for Ach, GABA, Glutamate, G-
protein??
 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 – 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 – RAS??
o Problems –
o How does it act?
o Surgical removal of RAS does not affect action of
agent
o Changes in EEG vary with different agents –
multiplicity of site of action
o Other actions?
o Muscular relaxation – Spinal monosynaptic H-
reflex… mechanism unknown
o Change in Ca++ channel permeability??

18. Biochemical Theory:
 Effect on intermediary metabolism – decrease O2
uptake
 Inhibit mitochondrial respiration in a dose-
dependant & reversible manner (even Xenon)
 In vitro potencies related to in vivo potencies &
lipid solubility – cut-off molecular size for in
vivo CNS effects same as in vitro inhibition of
mitochondrial respiration
 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.
 High pressure – unconsciousness, but not
inhibition of O2 uptake or analgesia
 Ca++ influx altered
 GABA conc. at synaptic areas increased

19. Molecular Theory:
 Susceptible phospholipid membrane – altering its
physical status
 Phospholipid bilayer of the cell membrane can
exist in 2 forms:
 Tightly ordered Gel phase
 Structurally disoriented Fluid phase
“Lateral Phase Separation”
 Gel phase – Fluid phase interchangeable
 Opening of channel = conversion to gel phase
 Anaes. Agents increase Fluid : Gel ratio
Pressure reversal Theory:
 A. A. expands vol. of hydrophobic region

20. Minimum Alveolar Concentration
 Merkel & Eger (1963)
 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.
 Measure/index of anaes. potency
 Inversely proportional to potency
 Directly proportional to Oil/Gas solubility
coefficient
 Equally applicable to all inhalational agents
 Gives better control over dose of drug required
 Used to compare Anaes. Effects & side effects
of various agents

21. Classification
 Inorganic  Organic Compounds
Compounds (Gases) (Vapors mostly)
o N2O
o Xenon
Hydrocarbon
Halogenated Hydrocarbon
Compounds
compounds
• Diethyl ether
• Ethyl Chloride
• Divinyl ether
• Chloroform
• Ethylene (gas)
• Trichloroethylene
• Cyclopropane (gas)
• Methoxyflurane
• Halothane
• Enflurane, Isoflurane
• Sevoflurane
• Desflurane

22. Nitrous Oxide (N2O)
 History
 Non-irritating, colorless, slightly sweet-smelling
inorganic gas. Heavier than air
 Oil/gas solubility ratio = 3.2
 Blood/gas solubility coeff. = 0.47
 MAC = 105
 Second Gas Effect
 Stored in blue cylinders
 Pharmacokinetics:
 Rapidly taken up
 no metabolism
 Eliminated completely unchanged

23.  Pharmacodynamics:
 Weak anaes. Agent
 Increased ICP, CBF
 No epileptogenic activity
 Anaes. Effect – Potency? Hypoxia?
 CVS: No effects
 Toxicity:
 Hematological
 Neurological
 ?? Teratogenic
 Ability to concieve
 Uses:
 Analgesia
 Dentistry
 Supplements

24. Diethyl Ether (C2H5)2O
 Colorless, volatile liquid, characteristic
pungent smell, inflammable, explosive
 Pharmacokinetics:
 Highly soluble in blood- induction prolonged,
unpleasant
 Blood/gas solubility coeff = 12.1
 Oil/gas solubility = 65 (low)
 MAC = 3-5
 Metabolism – 5-10% via skin, secretions, urine.
Rest excreted unchanged
 Pharmacodynamics:
 CNS – 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 – Minimal change
o Respiratory System – Irritant
Increased Secretions
o Neuromuscular junction – relaxation
o GIT – vomiting
o Kidney – decreases renal blood flow
albuminuria
o Uterus – relaxes
o Liver – minimal effects
o Advantages:
o Good analgesic
o Sympathetic stimulation
o Bronchodilatation
o Autoregulation
o Economical, easy availabilty, storage

26. Ethyl Chloride (C2H5Cl):
 Refrigeration anaesthesia; MAC = 2.55
 3-5% conc. in inspired air can produce
anaesthesia
 Rapid effect
 Local as well as General anaesthesia
 Myocardial depression
Trichloroethylene(CCl2CHCl):
 Most potent – oil/gas solubility = 960
 MAC = 0.17 ; blood/gas sol. Coeff. = 9.15
 Cranial Nerve lesions (sensory)
 Very slow induction, prolonged recovery
 Partly metabolised (urine), partly excreted
 Cardiac Dysrhythmias, tachypnea, circumoral
herpes, increased ICP
 “Phosgene”

27. Chloroform (CHCl3)
 1831 – Soubeiran, Liebig, Guthrie
 Colorless, sweet smelling, transparent fluid.
 Oil/gas solubility coeff. = 265
 Blood/gas solubilty coeff. = 10.3
 MAC = 0.5
 Rapid induction, prolonged recovery
 4% metabolized - liver
 Myocardial depression, ventricular fibrillation
 Respiratory depression, central hepatic
necrosis, albuminuria, ketonuria, fatty
degeneration of pancreas & spleen
 Carcinogenic

28. Methoxyflurane(CHCl2CF2OCH3):
 Colorless, fruity odor, non-flammable, non-
irritating
 Oil/gas solubility coeff. = 825
 Blood/ gas solubility coeff. = 13
 MAC = 0.2
 Slow induction, prolonged recovery
 Soluble in brain tissue
 Decreased BP, increased HR, resp.
depression
 Nephrotoxic
 Hepatotoxic??
 Muscle relaxation – not adequate

29. Halothane
 Heavy, colorless, sweet smelling liquid,
 Oil/gas solubility coeff. = 224
 Blood/gas solubility coeff. = 2.3
 MAC = 0.3
 Pharmacokinetics:
 Rapid induction & recovery
 Metabolised in liver microsomes
 Excreted in urine
 Pharmacodynamics:
 CNS – increased ICP, CBF
 Respiratory depression, bronchodilator
Intravenous – pulmonary lesions = death
 Myocardial depression, Dysrhythmias,

30.  Decreased renal blood flow, liver damage
 Uterus – relaxes
 Skeletal – intense shivering post-op
 Advantages:
 Highly potent, non-irritating
 Low PONV
 Good relaxation at low doses
 Decreases BP = decreases blood loss
 Disadvanages:
 Halothane hepatotoxicity
 Malignant hyperthermia
 Arrhythmias
 Headache
 Shivering

31.  Enflurane (CHF2 – O – F2CHFCl):
 Colorless, pleasant
smelling, nonflammable, non-irritating
 Oil/gas solubility coeff. = 98
 Blood/gas solubility coeff. = 1.8
 MAC = 1.68 ; 0.6 (N2O)
 Relatively slow induction & rapid recovery
 Soluble in liver tissue
 Epileptogenic
 Resp. System – non-irritating, no
secretions, breath-holding ++, laryngospasm
 Myocardial depression
 Nephrotoxic, Hepatotoxic

32. Isoflurane
 Ross Terrell – 1965 (Ohio); W.C. Stevens – 1971
 Clear, colorless gas, non-inflammable, pungent
 Oil/gas solubility coeff. = 98
 Blood/gas solubility coeff. = 1.4
 MAC = 1.3
 Pharmacokinetics:
 Rapid induction & recovery
 Breath-holding
 Excretion - 0.2% - urine
 Pharmacodynamics:
 CNS – depression, normal ICP, CBF
 Respiratory depression, irritation –
secretions, bronchodilatation
 Myocardial depression, no dysrhythmias

33.  Advantages:
 Rapid action
 Decreases blood loss
 No PONV
 No hepatotoxicty, nephrotoxicity
 Useful in conditions with raised ICP
 No convulsive activity
 Negligible shivering post-op
 Disadvantages:
 Breath-holding
 Respiratory depression
 Animal studies – Fetal asphyxia

34. Sevoflurane:
 Colorless, sweet smelling, non-irritating, non-
flammable
 Oil/gas solubility coeff. = 47
 Blood/gas solubility coeff. = 0.68
 MAC = 2 – 3.3%
 Fastest induction & recovery
 Resp. depression, rigidity (post-op),
nephrotoxic
 Desflurane:
 Pungent, irritant, global warming gas
 Oil/gas solubility coeff. = 19
 Blood/gas solubility coeff. = 0.42
 MAC = 6
 Rapid onset, recovery
 Low potency, high cost
 Irritant, tachycardia

35. Role in Balanced General Anaesthesia
 Capable of producing almost all
components of Balanced General
Anaesthesia by themselves
 Modern Balanced GA – combination of
Inhalational & Intravenous
 Irreplaceable part of anaesthesia

36. Recent Trends
 Intravenous Halothane
 Intravenous Isoflurane
 Intravenous Sevoflurane
 Xenon:
 1951 – Cullen
 MAC = 71%
 Blood/gas solubility coeff. = 0.115
 Oil/gas solubility coeff. = 20
 „Ideal Anaes. Agent‟
 Respiratory & CNS effects ?? Renal
 Costly, scarce availability

37. Thank You