Sweet Dreams are Made of These These are my drowsy days: In vain do I now awake - to sleep again Sir Thomas Browne: Religi...
Anaesthesia   <ul><li>From the Greek </li></ul><ul><ul><ul><ul><li>‘ absence or loss of sensation’ </li></ul></ul></ul></u...
Conciousness <ul><li>What is it and how do we alter it? </li></ul><ul><li>Any chemical reaction in the body can be targete...
Why Anaesthesia? <ul><li>No surgery – no anaesthesia? </li></ul><ul><ul><ul><li>Type of anaesthetic depends on the procedu...
Pre 17 th  Century <ul><li>Possible ‘choices’ </li></ul><ul><ul><li>No anaesthesia or analgesia </li></ul></ul><ul><ul><li...
17 th /18 th  Centuries <ul><li>The European revolution in chemistry </li></ul><ul><ul><li>Black, Priestly, Lavoisier et a...
The   American   Dream <ul><li>Humanitarianism had travelled from England to the East Coast </li></ul><ul><li>Religious ob...
19 th  Century Europe <ul><li>Antisepsis allowed more complex and invasive surgical procedures </li></ul><ul><li>Ether sup...
1900 to present <ul><li>Anaesthetic techniques improved eg spinal anaesthesia and muscle relaxants </li></ul><ul><li>Antib...
Types of Anaesthesia <ul><li>General </li></ul><ul><ul><ul><li>Volatile gases </li></ul></ul></ul><ul><ul><ul><li>Muscle r...
The Chemist’s Dilemma <ul><li>How to get a drug, that will produce effective anaesthesia, without killing the patient, thr...
Perioperative Drugs <ul><li>Induction agents  </li></ul><ul><ul><li>etomidate, ketamine, propofol, thiopentone, methohexit...
Induction agents <ul><li>Total anaesthesia – agony or ecstasy? </li></ul><ul><li>Induction or maintenance? </li></ul><ul><...
GABA Receptors <ul><li>Receptor video </li></ul>
Thiopentone <ul><li>Highly fat soluble </li></ul><ul><li>90% in the cerebral capillaries crosses the blood brain barrier <...
Propofol <ul><li>Short acting </li></ul><ul><ul><li>redistribution half-life of 2 – 8 min </li></ul></ul><ul><li>Primary e...
Etomidate and Ketamine <ul><li>Etomidate </li></ul><ul><li>A carboxylated imidazole </li></ul><ul><li>Half life 75 minutes...
Volatile agents <ul><li>Derivatives of halothane (halogenated methyl ethers) </li></ul><ul><li>Non-flammable, non-explosiv...
What the Patient Wants <ul><li>Pleasant to inhale, non-irritant </li></ul><ul><li>Fast onset (Low blood/gas solubility) </...
Minimum Alveolar Concentration <ul><li>Determined by testing  in non medicated animals </li></ul><ul><li>Inversely related...
Modes of Action <ul><li>No-one really knows! </li></ul><ul><li>Cross blood brain barrier </li></ul><ul><li>Affect synaptic...
The Practicality <ul><li>Any anaesthetic agent breathed into the lungs will </li></ul><ul><li>Dissolve in the blood  </li>...
One Theory <ul><li>Fat in the cell walls swells up </li></ul><ul><li>Nerve conduction is affected and activity is reduced ...
Solubility <ul><li>Bl ood-gas partition coefficient  </li></ul><ul><ul><li>ratio of the amount dissolved in a volume of bl...
Uptake <ul><li>High uptake means slow recovery </li></ul><ul><ul><li>During induction and maintenance, a large reservoir o...
Preferences? <ul><li>Low blood/gas partition coefficient (solubility) e.g. Nitrous oxide, sevoflurane and desflurane </li>...
Neuromuscular blockers <ul><li>Reduce acetylcholine at nicotinic receptors, so reducing muscle tone </li></ul><ul><li>Non ...
Suxamethonium <ul><li>Initial overstimulation of ACH receptors </li></ul><ul><ul><li>Fasiculations </li></ul></ul><ul><ul>...
Non depolarisers <ul><li>Competitive antagonists of ACH receptors </li></ul><ul><li>Reversed by acetylcholinesterase inhib...
And Finally ......... <ul><li>Any questions? </li></ul>
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Rossgrovesedgehilluni

  1. 1. Sweet Dreams are Made of These These are my drowsy days: In vain do I now awake - to sleep again Sir Thomas Browne: Religio Medici
  2. 2. Anaesthesia <ul><li>From the Greek </li></ul><ul><ul><ul><ul><li>‘ absence or loss of sensation’ </li></ul></ul></ul></ul><ul><li>More commonly thought of as absence of consciousness </li></ul>
  3. 3. Conciousness <ul><li>What is it and how do we alter it? </li></ul><ul><li>Any chemical reaction in the body can be targeted by a drug </li></ul><ul><li>Electrical impulses in the brain are produced by chemical changes </li></ul>
  4. 4. Why Anaesthesia? <ul><li>No surgery – no anaesthesia? </li></ul><ul><ul><ul><li>Type of anaesthetic depends on the procedure </li></ul></ul></ul><ul><ul><ul><ul><li>Dentistry and minor surgery local </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Many internal operations general </li></ul></ul></ul></ul><ul><ul><ul><li>Sophisticated surgery requires a compliant patient </li></ul></ul></ul><ul><ul><ul><li>Fear reduced with anaesthetics and analgesics </li></ul></ul></ul><ul><li>No anaesthesia – no surgery??? </li></ul><ul><ul><ul><li>Would that it were true! </li></ul></ul></ul>
  5. 5. Pre 17 th Century <ul><li>Possible ‘choices’ </li></ul><ul><ul><li>No anaesthesia or analgesia </li></ul></ul><ul><ul><li>Non chemical options </li></ul></ul><ul><ul><ul><li>Concussion, compression, ice, hypnosis, blood letting </li></ul></ul></ul><ul><ul><li>Naturally occurring compounds </li></ul></ul><ul><ul><ul><ul><li>Opium, cannabis, hyoscine, alcohol </li></ul></ul></ul></ul><ul><ul><li>Primitive volatile gases eg Ether (1540) </li></ul></ul><ul><li>None were either adequate or safe! </li></ul>
  6. 6. 17 th /18 th Centuries <ul><li>The European revolution in chemistry </li></ul><ul><ul><li>Black, Priestly, Lavoisier et al synthesised atmospheric gases </li></ul></ul><ul><ul><ul><ul><li>Oxygen, carbon dioxide, nitrogen, nitrous oxide (NO) </li></ul></ul></ul></ul><ul><ul><li>Humphrey Davy noted the analgesic properties of nitrous oxide </li></ul></ul><ul><ul><li>‘ Laughing gas’ used both socially and medically </li></ul></ul><ul><ul><li>Carbon dioxide suggested for pain free surgical manipulation </li></ul></ul><ul><ul><li>IV injection (opium through a quill – 1665) </li></ul></ul><ul><ul><li>Pain relief considered a societal goal </li></ul></ul>
  7. 7. The American Dream <ul><li>Humanitarianism had travelled from England to the East Coast </li></ul><ul><li>Religious objections were ignored </li></ul><ul><li>Ether use became common in dentistry and childbirth </li></ul><ul><li>Medical practices deteriorated from East to West as frontiers advanced </li></ul><ul><li>‘ Mediaeval’ anaesthesia was practiced by pioneers </li></ul>
  8. 8. 19 th Century Europe <ul><li>Antisepsis allowed more complex and invasive surgical procedures </li></ul><ul><li>Ether superseded by chloroform (1831) </li></ul><ul><li>Snow et al described narcosis </li></ul><ul><li>Suitable devices for administration developed </li></ul><ul><li>Experimentation with new agents </li></ul>
  9. 9. 1900 to present <ul><li>Anaesthetic techniques improved eg spinal anaesthesia and muscle relaxants </li></ul><ul><li>Antibiotics developed </li></ul><ul><li>Effective monitoring of patient developed </li></ul><ul><li>Anaesthetic professionalism allowed more dangerous compounds to be utilised </li></ul><ul><li>Volatile gases formulated as liquids (e.g. ethyl chloride) </li></ul><ul><li>War and terrorism have led to innovation and discovery of new possibilities </li></ul>
  10. 10. Types of Anaesthesia <ul><li>General </li></ul><ul><ul><ul><li>Volatile gases </li></ul></ul></ul><ul><ul><ul><li>Muscle relaxants </li></ul></ul></ul><ul><ul><ul><li>Neurological agents </li></ul></ul></ul><ul><ul><ul><li>Opioid narcotics </li></ul></ul></ul><ul><li>Local/regional </li></ul><ul><ul><ul><li>Spinal/limb blockers </li></ul></ul></ul><ul><ul><ul><li>Local agents </li></ul></ul></ul><ul><ul><ul><li>Additive drugs </li></ul></ul></ul>
  11. 11. The Chemist’s Dilemma <ul><li>How to get a drug, that will produce effective anaesthesia, without killing the patient, through the body’s defences and barriers, to the place where it will work </li></ul><ul><li>Variables </li></ul><ul><li>Drug </li></ul><ul><li>Form </li></ul><ul><li>Management </li></ul>
  12. 12. Perioperative Drugs <ul><li>Induction agents </li></ul><ul><ul><li>etomidate, ketamine, propofol, thiopentone, methohexitone </li></ul></ul><ul><li>Inhalation agents (Volatile anaesthetics) </li></ul><ul><ul><li>isoflurane, sevoflurane, desflurane </li></ul></ul><ul><li>Neuromuscular blockers (Muscle relaxants) </li></ul><ul><ul><li>Suxamethonium (depolarising), pancuronium, vecuronium, mivacurium, rocuronium, cisatracurium, atracurium </li></ul></ul><ul><li>Opoids </li></ul><ul><ul><li>fentanyl, alfentanil, remifentanil, morphine, pethidine </li></ul></ul><ul><li>Non Steroidal Anti-inflammatory Drugs (NSAID) </li></ul><ul><ul><li>ketorolac, diclofenac </li></ul></ul>
  13. 13. Induction agents <ul><li>Total anaesthesia – agony or ecstasy? </li></ul><ul><li>Induction or maintenance? </li></ul><ul><li>IV injection for all? </li></ul><ul><li>Airway support possible? </li></ul><ul><li>Swift onset desirable? </li></ul><ul><li>Resuscitation equipment to hand? </li></ul><ul><li>Accurate assessment of depth of anaesthesia possible? </li></ul><ul><li>Patient benefit? </li></ul>
  14. 14. GABA Receptors <ul><li>Receptor video </li></ul>
  15. 15. Thiopentone <ul><li>Highly fat soluble </li></ul><ul><li>90% in the cerebral capillaries crosses the blood brain barrier </li></ul><ul><li>Rapid onset of action at GABA receptors </li></ul><ul><li>Diffuses slowly into less well–perfused tissues, such as muscles </li></ul><ul><li>This decreases blood concentration </li></ul><ul><li>Thiopentone leaves brain tissues to return to the blood - patient shows signs of waking (redistribution) </li></ul><ul><li>Ultimately destroyed in the liver – 10-15% broken down per hour </li></ul>
  16. 16. Propofol <ul><li>Short acting </li></ul><ul><ul><li>redistribution half-life of 2 – 8 min </li></ul></ul><ul><li>Primary effect may be potentiation of GABA-A receptor </li></ul><ul><ul><li>possibly slows the channel closing time </li></ul></ul><ul><li>Some research suggests the endocannabinoid system may be involved </li></ul><ul><li>Conjugated in the liver </li></ul><ul><ul><li>Rate of clearance exceeds hepatic blood flow, suggesting an additional extrahepatic site of elimination </li></ul></ul><ul><li>Inactive metabolites excreted by the kidneys </li></ul><ul><li>Elimination half-life estimated to be between 2–24 hours </li></ul>
  17. 17. Etomidate and Ketamine <ul><li>Etomidate </li></ul><ul><li>A carboxylated imidazole </li></ul><ul><li>Half life 75 minutes </li></ul><ul><li>Redistribution rapid so 5-10 minute anaesthesia </li></ul><ul><li>Highly protein bound </li></ul><ul><li>Metabolised by hepatic and plasma esterases </li></ul><ul><li>Ketamine </li></ul><ul><li>Mainly paediatrics </li></ul><ul><li>Blocks MDMA receptors (glutamate) - amnesia </li></ul>
  18. 18. Volatile agents <ul><li>Derivatives of halothane (halogenated methyl ethers) </li></ul><ul><li>Non-flammable, non-explosive at room temperature </li></ul><ul><li>Not degraded by light </li></ul><ul><li>Low latent heat of vaporisation (liquid at room temp) </li></ul><ul><li>Long expiry date </li></ul><ul><li>Stable at room temperature </li></ul><ul><li>Stable with plastics and metals </li></ul><ul><li>Environmentally friendly - no ozone depletion </li></ul><ul><li>Cheap and easy to manufacture </li></ul>
  19. 19. What the Patient Wants <ul><li>Pleasant to inhale, non-irritant </li></ul><ul><li>Fast onset (Low blood/gas solubility) </li></ul><ul><li>Potent but safe (High oil/water solubility) </li></ul><ul><li>No side effects on other systems - e.g. endocrine, cardiovascular, respiratory, hepatic, renal </li></ul><ul><li>No biotransformation - should be excreted, ideally via the lungs, unchanged </li></ul><ul><li>Minimal after effects (Nausea etc) </li></ul><ul><li>Non-toxic to operating theatre personnel </li></ul>
  20. 20. Minimum Alveolar Concentration <ul><li>Determined by testing in non medicated animals </li></ul><ul><li>Inversely related to potency </li></ul><ul><li>The level that prevents movements in response to skin incision in 50% of subjects </li></ul><ul><li>Not affected by gender, weight or height </li></ul><ul><li>Easily measurable in theatre conditions </li></ul><ul><li>Consistently equates to brain concentrations </li></ul>
  21. 21. Modes of Action <ul><li>No-one really knows! </li></ul><ul><li>Cross blood brain barrier </li></ul><ul><li>Affect synaptic transmitters in CNS </li></ul><ul><ul><ul><li>Block pre-synaptic release </li></ul></ul></ul><ul><ul><ul><li>Alter reuptake </li></ul></ul></ul><ul><ul><ul><li>Affect receptor binding </li></ul></ul></ul><ul><ul><ul><li>Disrupt </li></ul></ul></ul><ul><li>Effective agents are oil soluble so a hydrophobic site of action possible </li></ul>
  22. 22. The Practicality <ul><li>Any anaesthetic agent breathed into the lungs will </li></ul><ul><li>Dissolve in the blood </li></ul><ul><li>Be distributed to all parts of the body </li></ul><ul><li>Dissolve in the tissues, including the brain </li></ul><ul><li>Produce anaesthesia with the proportion dissolving in the brain (The brain is mostly fat and fat preferentially absorbs these agents) </li></ul><ul><li>Anaesthetics do not ‘target’ the brain </li></ul>
  23. 23. One Theory <ul><li>Fat in the cell walls swells up </li></ul><ul><li>Nerve conduction is affected and activity is reduced (or stopped altogether in overdose!) </li></ul><ul><li>Higher centres controlling consciousness are affected first </li></ul><ul><li>Vital centres, e.g. respiratory and vasomotor, are luckily more resistant to this effect </li></ul><ul><li>NB – it is assumed that an anaesthetised patient will go on breathing with a near-normal pulse and blood pressure </li></ul>
  24. 24. Solubility <ul><li>Bl ood-gas partition coefficient </li></ul><ul><ul><li>ratio of the amount dissolved in a volume of blood to the amount in the same volume of gas in contact with it </li></ul></ul><ul><li>High blood-gas partition coefficient = slow onset of effect </li></ul><ul><ul><li>ether dissolves in large quantities in blood before the brain levels can rise sufficiently to produce anaesthesia </li></ul></ul><ul><li>Anaesthetic agents do not &quot;target&quot; the brain </li></ul><ul><ul><li>they dissolve everywhere but blood flow, tissue volume and tissue partition coefficients affect distribution </li></ul></ul><ul><li>High cardiac output delays onset of CNS effects </li></ul><ul><ul><li>During fever or fear more agent is dissolved in blood and tissues other than brain </li></ul></ul><ul><ul><li>Paradoxically, although a high uptake means a lot of agent is inhaled, blood levels rise slowly and the patient takes a long time to go to sleep </li></ul></ul>
  25. 25. Uptake <ul><li>High uptake means slow recovery </li></ul><ul><ul><li>During induction and maintenance, a large reservoir of the agent will have accumulated in blood, fat and other tissues like muscle </li></ul></ul><ul><ul><li>At the end of a long operation, this reservoir will slowly give up its stores of anaesthetic agent and thus act like a depot, delaying recovery </li></ul></ul><ul><ul><li>Ether is very blood soluble and so circulates for a long time before it is finally excreted from the lungs, delaying recovery </li></ul></ul><ul><ul><li>Halothane is fat soluble and will remain for hours in the fat of an obese patient at sub-anaesthetic levels but brain clearance is high </li></ul></ul><ul><li>Low uptake e.g. shock </li></ul><ul><ul><li>Low cardiac output </li></ul></ul><ul><ul><li>Blood levels rise quickly </li></ul></ul><ul><ul><li>Induction is fast despite low uptake </li></ul></ul>
  26. 26. Preferences? <ul><li>Low blood/gas partition coefficient (solubility) e.g. Nitrous oxide, sevoflurane and desflurane </li></ul><ul><li>Blood levels rise very rapidly </li></ul><ul><li>Rapid induction of anaesthesia, not dependent on changes in cardiac output </li></ul><ul><li>Blood levels fall very quickly </li></ul><ul><li>Rapid recovery, unrelated to duration of use </li></ul>
  27. 27. Neuromuscular blockers <ul><li>Reduce acetylcholine at nicotinic receptors, so reducing muscle tone </li></ul><ul><li>Non depolarising </li></ul><ul><ul><ul><li>Derivatives of curare </li></ul></ul></ul><ul><ul><ul><li>Competitive receptor inhibition (antagonism) </li></ul></ul></ul><ul><li>Depolarising (suxamethonium) </li></ul><ul><ul><ul><li>Mimic ACH </li></ul></ul></ul><ul><ul><ul><li>Not degraded by acetylcholinesterase </li></ul></ul></ul>
  28. 28. Suxamethonium <ul><li>Initial overstimulation of ACH receptors </li></ul><ul><ul><li>Fasiculations </li></ul></ul><ul><ul><li>Potassium out/sodium in </li></ul></ul><ul><ul><li>Refractory cell </li></ul></ul><ul><li>ACH receptors desensitised so close to new ACH causing paralysis </li></ul><ul><li>Plasma cholinesterases metabolise suxamethonium rapidly </li></ul><ul><li>Receptors return to normal state </li></ul>
  29. 29. Non depolarisers <ul><li>Competitive antagonists of ACH receptors </li></ul><ul><li>Reversed by acetylcholinesterase inhibitors </li></ul><ul><li>Cisatracurium has replaced </li></ul><ul><ul><li>80% metabolised by Hoffman elimination in plasma so safe in hepatic failure </li></ul></ul><ul><ul><li>20% metabolised in liver and excreted in urine </li></ul></ul><ul><ul><li>15% of dose excreted in urine unchanged </li></ul></ul>
  30. 30. And Finally ......... <ul><li>Any questions? </li></ul>

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