Inhalational Anaesthetic Agents

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

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

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

BostonLater, used chloroform and ether in

combination with nitrous oxide.

History (contd.)

Ether-Already in use – oral, topicalPneumatic medicine ‘Ether Frolics’Crawford Williamson Long (1842)

William Thomas Green Morton-Apprentice of Horace Wells, Charles Jackson

(ether)Experiments on animals, humans-

unsuccessfulFateful Day – 16th October 1846

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)

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

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

Mechanism of Action “Theories of Narcosis” Inhalational Anaes. Agents produce

AnalgesiaAmnesiaSomatic muscle relaxationMyocardial depressionUterine Atony Interference with cellular growth &

replication Inhibition of mitochondrial respiration ? Convulsions

Any theory of narcosis should be able to explain all these actions

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”

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?

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?

Action on Water Molecules:

Concepts of Pauling & Miller – Action through aqueous rather than lipid site within CNSo 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

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

Physical Properties: not reliable

Neurophysiological Theory:o Effect on Synaptic transmission > Axonal

transmissiono Likely site of action – RAS??o Problems –

o How does it act?o Surgical removal of RAS does not affect action of agento Changes in EEG vary with different agents – multiplicity

of site of actiono Other actions?

o Muscular relaxation – Spinal monosynaptic H-reflex… mechanism unknown

o Change in Ca++ channel permeability??

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

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

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

Classification

Inorganic Compounds (Gases)o N2Oo Xenon

Hydrocarbon Compounds• Diethyl ether• Divinyl ether• Ethylene (gas)• Cyclopropane (gas)

Organic Compounds (Vapors mostly)

Halogenated Hydrocarbon compounds

• Ethyl Chloride• Chloroform• Trichloroethylene• Methoxyflurane• Halothane• Enflurane, Isoflurane• Sevoflurane• Desflurane

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

Pharmacodynamics: Weak anaes. Agent Increased ICP, CBF No epileptogenic activity

Anaes. Effect – Potency? Hypoxia? CVS: No effects Toxicity:

HematologicalNeurological ?? TeratogenicAbility to concieve

Uses: Analgesia Dentistry Supplements

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 – DepressionStage I at 0.5-1%Stage II at 1-2.5%Stage III at 2.5-4%Stage IV at 4-5%

o CVS – Minimal changeo Respiratory System – Irritant

Increased Secretionso Neuromuscular junction – relaxationo GIT – vomitingo Kidney – decreases renal blood flow

albuminuriao Uterus – relaxeso Liver – minimal effects

o Advantages:o Good analgesico Sympathetic stimulationo Bronchodilatationo Autoregulationo Economical, easy availabilty, storage

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”

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

Methoxyflurane(CHCl2CF2OCH3):Colorless, fruity odor, non-flammable, non-

irritatingOil/gas solubility coeff. = 825Blood/ gas solubility coeff. = 13MAC = 0.2Slow induction, prolonged recoverySoluble in brain tissueDecreased BP, increased HR, resp.

depressionNephrotoxicHepatotoxic??Muscle relaxation – not adequate

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,

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

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

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

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

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

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

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

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