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 Boston Later, used chloroform and ether in combination with nitrous oxide.
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
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 Analgesia Amnesia Somatic muscle relaxation Myocardial depression Uterine Atony Interference with cellular growth & replication Inhibition of mitochondrial respiration ? ConvulsionsAny 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 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 transmissiono Poor correlation of anaes. potency with hydrate dissociation pressure (ether, sulphahexafluride)o Combination of agents producing small & large clathrateso 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 ileumo Non-opioid receptor??o In vivo nuclear MRI findings
Physical Properties: not reliableNeurophysiological 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 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 unknowno 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 ratioPressure 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
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
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%
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 effectso Advantages: o Good analgesic o Sympathetic stimulation o Bronchodilatation o Autoregulation o 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 depressionTrichloroethylene(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”
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