Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Inhalational Agents

  • Login to see the comments

Inhalational Agents

  1. 1. Inhalational Anaesthetic Agents Dr. Nigel Harper 2011
  2. 2. Physicochemical Properties • halogenat edhydrocarbons • moredenset hanwat er • st ruct uralisomerism
  3. 3. Physicochemical Properties • halogenat edhydrocarbons • moredenset hanwat er • st ruct uralisomerism • similar molecular weight s (168-220) • 1ccproduces approx200 ccsat urat edvapour
  4. 4. Obsolete theories of anaesthesia Meyer Overton (potency ∝ lipid solubility) – BUT! – anaesthetics work in the absence of lipid (firefly luciferase) – many long chain molecules do not fit the relationship
  5. 5. Mechanisms of Anaesthesia • facilitation at inhibitory (chloride) GABAa channels • facilitation at inhibitory glycine (chloride) channels • inhibition of excitatory NMDA (cation) channels - nitrous oxide and xenon
  6. 6. MAC • The concentration in volumes percent of an agent in oxygen that will prevent movement in response to a standard surgical incision in 50% of the population
  7. 7. MAC skin incision MAC awake Halothane 0.74 0.38 Enflurane 1.7 0.5 Isoflurane 1.2 0.36 Sevoflurane 2.0 0.36 Desflurane 6.0 2.6 MAC awake
  8. 8. MAC skin incision MAC awake Halothane 0.74 0.38 Enflurane 1.7 0.5 Isoflurane 1.2 0.36 Sevoflurane 2.0 0.36 Desflurane 6.0 2.6 (s-a)/s 0.49 0.7 0.7 0.82 0.56 Margin of anaesthetic depth MAC – MAC awake MAC
  9. 9. Factors affecting MAC • age: MAC maximum at 1 year. Compared with MAC at 20yrs, MAC reduced 20% at 40yrs and by 40% at 80 years • 60% Nitrous oxide reduces MAC isoflurane by 40% and MAC sevoflurane by 24% • opioids and other sedatives
  10. 10. Uptake and Distribution • depth of anaesthesia depends on the partial pressure of the agent at the effect site • a poorly soluble agent needs fewer molecules of drug per volume blood to achieve a given partial pressure • transport depends on (blood solubility x blood flow)
  11. 11. Blood flow as a percentage of Cardiac Output • vessel rich group (brain & viscera) 75% • muscle (23%) • fat (2%)
  12. 12. Mapleson water analogue • diameter of the cylinders ∝ capacity of the tissue for the agent • height of water ∝ partial pressure of the agent in that tissue • pipe diameter ∝ (blood flow x blood gas partition coefficient)
  13. 13. lungs viscera inc brain muscle fat fresh gas flow ventilation
  14. 14. lungs viscera inc brain muscle fat fresh gas flow ventilation
  15. 15. lungs viscera inc brain muscle fat fresh gas flow ventilation
  16. 16. lungs viscera inc brain muscle fat fresh gas flow ventilation
  17. 17. lungs viscera inc brain muscle fat fresh gas flow ventilation
  18. 18. lungs viscera inc brain muscle fat fresh gas flow ventilation
  19. 19. Why is a low cardiac output associated with rapid induction of anaesthesia?
  20. 20. lungs viscera inc brain muscle fat fresh gas flow ventilation
  21. 21. lungs viscera inc brain muscle fat fresh gas flow ventilation
  22. 22. Concentration Effect 1. uptake of agent › uptake of O2 and nitrogen 2. PAagent falls progressively until a new breath arrives bringing more agent 3. effect is more marked if the Cinsp is small because the PAagent is reduced to a greater extent before the next inspiration “the higher the inspired concentration the faster the rise in alveolar (end-tidal) concentration”
  23. 23. Second Gas Effect • rate of uptake of volatiles depends on alveolar ventilation • N2O taken up in large quantities because lack of solubility more than outweighed by high alveolar concentration • high N2O uptake effectively increases alveolar ventilation • effect more marked with more soluble agents “The addition of nitrous oxide increases the rate of uptake of the volatile agents”
  24. 24. Sodalime constituents • Calcium Hydroxide 70% to 80 % • Sodium Hydroxide and/or Potassium Hydroxide. 1.5% - 5 % • Indicator dye < 0.05 % • Zeolite (Spherasorb only) 5 % • Water 14 to 16 % • Barium Hydroxide ( Baralyme only) 11 %
  25. 25. Carbon Dioxide absorption 1) H2O + CO2 ====> H2CO3 high pH 2) H2CO3 + 2 NaOH ====> Na2CO3 + 2H2O high pH 3) Na2CO3 + Ca(OH)2====> CaCO3 + 2 NaOH high pH •CarbonDioxideis ult imat elyconvert edt oCalciumCarbonat e(CaCO3). •CarbonDioxideabsorpt ionwill ceasewhenreact ion3 st ops (Calcium Hydroxidelevels aret oolow).
  26. 26. Sevoflurane Metabolism & Toxicity 1) Biotransformation to fluoride – 3% of sevoflurane biotransformed by Cp450 (2E1) to hexafluoroisopropanol + fluoride – 7 MAC hours sevoflurane → 40 µM fluoride but no proven renal toxicity 2) Reaction with sodalime → Compound A
  27. 27. Sevoflurane & Compound A sevoflurane heat sodalime Compound A Compound A conjugate cysteine beta lyase toxic metabolite Renal toxicity
  28. 28. Sevoflurane & Compound A • Greater in sodalimes which contain KOH • Less in KOH and NaOH – free sodalimes
  29. 29. Low-alkali sodalimes • Spherasorb: no KOH & very little NaOH • LoFloSorb and Amsorb: no KOH or NaOH
  30. 30. Carbon Monoxide and Monday morning
  31. 31. Carbon monoxide 1 • Physiological 0.4 – 0.8% • Headache, nausea & vomiting • Smokers up to 10% • Closed breathing system 0.5 – 1.5% non-smokers 3% smokers • Minimal flow circuit 1 – 1.5%
  32. 32. Carbon monoxide 2 • Desflurane > isoflurane > sevoflurane • Greater with dry sodalime
  33. 33. CNS effects of inhalational agents • all impair autoregulation of CBF (halothane (4x) > enflurane (2x) > isoflurane/sevoflurane/desflurane) • effect on CBF attenuated by prior hyperventilation • enflurane > 1.5 MAC → excitatory spikes (avoid in epileptics) ? sevoflurane • Neuro-protection
  34. 34. Neuroprotection • Modulation of intracellular Ca++ homeostasis • Inhibition of the apoptosis initiator caspase-9 • MCA occlusion studies in rats – Histological & functional protection – Persists up to 8 weeks
  35. 35. Cardiovascular effects • depression of vasomotor centre • depression of cardiac contractility • peripheral dilatation • autonomic effects (desflurane – airway receptors?) • sensitization to catecholamines • cardioprotection
  36. 36. Anaesthetic pre-conditioning • Seen with ALL inhalational agents • Except nitrous oxide • Not seen with propofol • Demonstrable with morphine and ? remifentanil (animal studies) – possibly δ receptor-mediated • Blocked by ketamine
  37. 37. • 20 CABG patients • Either TIVA or sevoflurane • LA and LV pressure catheters • Changes in dP/dtmax with leg elevation • Load dependence of myocardial relaxation R=slope (time constant τ of isovolumetric relaxation / end- systolic pressure) • Post-CABG troponins for 36h sevoflurane pre-conditioning De Hert SG et al. Anesthesiology 2002; 97: 42-49
  38. 38. sevoflurane v propofol and CABG (deHert 2002) Median, 95%CI Individual patients
  39. 39. sevoflurane pre-conditioning • ↑preload resulted in a decrease in dP/dtmax in propofol group but not in sevoflurane group • Load dependence ↑ in propofol group but not in the sevoflurane group • Fewer patients needed inotropic support in sevoflurane group • Lower troponin T post-op, persisting for 36 hours
  40. 40. Priming of mitochondrial and sarcolemmal ATP -sensitive K channels • ↑ Probability of ATP-induced channel opening • Shortening of cardiac action potential • Decreased energy consumption • Reduced cytosolic Ca load • Blunting of mitochondrial K overload • Restoration of membrane function • Restoration of normal ATP consumption
  41. 41. Effects of inhalational agents on respiration • 1 MAC isoflurane completely abolishes response to hypoxia and depresses response to hypercarbia by 50% • enflurane most depressant and halothane least • desflurane most irritant and sevoflurane least • Halothane most bronchodilating
  42. 42. General hepatic effects • cardiac output reduced • hepatic portal flow reduced • increased dependence on hepatic arterial flow • hepatic arterial bed autoregulation impaired by halothane > enflurane> sevoflurane > isoflurane
  43. 43. Anaesthesia Induced Hepatitis • Oxidative metabolism → trifluoroacetyl halide (TFA) • TFA changes structure of CP450 & other proteins to become haptens • dramatic immune response in susceptible individuals • TFA antibodies common in halothane hepatitis
  44. 44. • Halothane most common • Cross-sensitivity between inhalational agents (except sevoflurane which is not metabolised to TFA) • 70% have a history of atopy • More common in obese women • Predisposed by chronic ethanol or isoniazid Anaesthesia Induced Hepatitis
  45. 45. Halothane hepatitis: non immume- mediated • transient, minor rise in transaminases more common than fulminant hepatitis • may be associated with a direct hepatotoxic effect of reductive metabolites
  46. 46. Neuromuscular effects • all inhalational agents potentiate the effects of neuromuscular blocking drugs • reduce contractility • reduce acetylcholine release • sevoflurane> isoflurane/desflurane> halothane
  47. 47. Environmental exposure • UK occupational exposure standards (1996) • 8 hour time-weighted average • 20% of the exposure producing no effect in rats • nitrous oxide 100 ppm • enflurane 50 ppm • isoflurane 50 ppm • halothane 10 ppm
  48. 48. Xenon • Very low blood/gas solubility (0.2) • MAC 63-71% Inhibits NMDA channel opening • Very dense • No odour, non-irritant, analgesic • Almost complete cardiorespiratory stability • Cardioprotective • Neuroprotective • CBF ↑ • Some nausea • Can be recycled
  49. 49. Effects of barometric pressure: plenum vaporizers • Depth of anaesthesia depends on partial pressure, not concentration • Partial pressure depends only on temperature • Plenum vaporizers add a fixed mass of saturated vapour to a stream of carrier gas that depends only on the splitting ratio (not the atmospheric pressure) • The splitting ratio will not change with altitude
  50. 50. • At altitude the fixed mass of agent will have the same partial pressure as at sea level but the barometric pressure is lower • The concentration of the agent will increase Concentration = Partial pressure of agent Barometric pressure
  51. 51. example • If the dial setting of a vaporizer is set to "1%" at sea level, it will deliver 1.013 kPa and the concentration will be 1.0% • If the atmospheric pressure is reduced to 80 kPa the vaporizer will continue to deliver 1.013 kPa of vapour and the volume percent will increase to 1.01/80 = 1.26% • The partial pressure of the vapour will be unchanged
  52. 52. Altitude: summary • The delivered concentration is reduced but not the partial pressure • It is not necessary to change the (plenum) vaporizer setting at altitude (except for desflurane)
  53. 53. Formula BP (o C) SVP (kPa at 20o C) Blood gas partition coefficient Oil gas partition coefficient Halothane C2HBrCl3F 50.2 32.4 2.3 224 Enflurane C3H2CF5O 56.5 22.9 1.9 96 Isoflurane C3H2CF5O 48.5 31.9 1.4 91 Sevoflurane C4H3F7O 58.5 21.3 0.6 53 Desflurane C3H2F6O 23.5 88.3 0.42 19
  54. 54. Desflurane vaporizer • Heated vaporization chamber: – Capacity 450ml – Temperature 39o – Pressure 1550 mmHg (206 kPa, 30 psi) • No carrier gas enters the vaporization chamber • Dial controls the flow of saturated vapour into the carrier gas flow (no carrier gas enters the vaporization chamber)
  55. 55. Desflurane vaporizer & altitude • Vaporizer uses a pressure transducer to measure atmospheric pressure • Transducer signal influences the valve which the controls output from the vaporization chamber to maintain the (volume %) concentration of agent constant • The dial setting has to be increased at high altitude to maintain the desired partial pressure of agent
  56. 56. Desflurane vaporizer & altitude • If the vaporizer dial is set to "6%" at sea level it will deliver 6% by volume and the partial pressure of desflurane will be 0.06 x 101.3 = 6.078 kPa • If the atmospheric pressure is reduced to 80 kPa then the vaporizer will continue to deliver 6% desflurane by volume-percent but the partial pressure will be 0.06 x 80 = 4.8 kPa
  57. 57. Formula Boiling point ( o C) SVP at 20 o C (kPa) Blood gas partition coefficient Oil gas partition coefficient Halothane C2HBrClF3 50.2 32.4 2.3 224 Enflurane C3H2CF5O 56.5 22.9 1.9 96 Isoflurane C3H2CF5O 48.5 31.9 1.4 91 Sevoflurane C4H3F7O 58.5 21.3 0.6 53 Desflurane C3H2F6O 23.5 88.3 0.42 19
  58. 58. Ischaemia Receptor activation: α adrenergic opioid bradykinin Activation of: G-proteins protein kinase C (PKC) Ischaemic pre-conditioning Cardio-protection Increased KATP channel opening
  59. 59. Post-conditioning ReperfusionIschaemia Pre-conditioning Early (begins Immediately & lasts 2-3h) Late (begins at 12-24h & lasts 24-72h)

×