Aditi M. Panditrao's Inhalational anaes agents

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

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Aditi M. Panditrao's Inhalational anaes agents

  1. 1. Inhalational Anaesthetic Agents
  2. 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. 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. 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. 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
  6. 6. 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)
  7. 7. 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
  8. 8.  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
  9. 9. 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
  10. 10. 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”
  11. 11. 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?
  12. 12. 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?
  13. 13. 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
  14. 14. 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
  15. 15. 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??
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. Classification Inorganic  Organic Compounds Compounds (Gases) (Vapors mostly) o N2O o XenonHydrocarbon Halogenated Hydrocarbon Compounds compounds • Diethyl ether • Ethyl Chloride • Divinyl ether • Chloroform • Ethylene (gas) • Trichloroethylene • Cyclopropane (gas) • Methoxyflurane • Halothane • Enflurane, Isoflurane • Sevoflurane • Desflurane
  20. 20. 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
  21. 21.  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
  22. 22. 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%
  23. 23. 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
  24. 24. 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”
  25. 25. 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
  26. 26. 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
  27. 27. 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,
  28. 28.  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
  29. 29.  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
  30. 30. 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
  31. 31.  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
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. Thank You

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