4. Physicochemical Properties
• halogenat edhydrocarbons
• moredenset hanwat er
• st ruct uralisomerism
• similar molecular weight s (168-220)
• 1ccproduces approx200 ccsat urat edvapour
5. 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
6. 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
7. 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
9. 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
10. 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
11.
12. 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)
13. Blood flow as a percentage of
Cardiac Output
• vessel rich group (brain & viscera)
75%
• muscle (23%)
• fat (2%)
14. 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)
24. 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”
25. 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”
27. 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).
28. 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
29. Sevoflurane & Compound A
sevoflurane
heat
sodalime
Compound A
Compound A
conjugate
cysteine
beta lyase
toxic
metabolite
Renal toxicity
30. Sevoflurane & Compound A
• Greater in sodalimes which contain KOH
• Less in KOH and NaOH – free sodalimes
35. 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
36. 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
37. Cardiovascular effects
• depression of vasomotor centre
• depression of cardiac contractility
• peripheral dilatation
• autonomic effects (desflurane –
airway receptors?)
• sensitization to catecholamines
• cardioprotection
38. 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
39. • 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
41. 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
42. 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
43. 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
44. 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
45. 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
46. • 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
47. 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
48. Neuromuscular effects
• all inhalational agents potentiate the
effects of neuromuscular blocking
drugs
• reduce contractility
• reduce acetylcholine release
• sevoflurane> isoflurane/desflurane>
halothane
49. 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
50. 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
51.
52. 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
53. • 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
54. 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
55. 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)
57. 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)
58.
59. 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
60. 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
61.
62. 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
