18. Inhalational Anaesthetic Agents (Volatile Agents) Flashcards
Explain the term ‘blood:gas’ partition coefficient
’
A partition coefficient is the ratio of the amount of substance in one phase to the amount of it in another at a stated temperature, when the two phases are in equilibrium and of equal volumes and pressures.
At a steady state, the partial pressure of volatile anaesthetic agents within the alveoli (PA) is in equilibrium with that in the arterial blood (Pa) and subsequently the brain (PB).
As such, PA gives an indirect measure of PB.
The blood:gas (B:G) coefficient is a measure of the solubility of a substance in blood and influences anaesthetic onset and offset times.
> The more soluble an
inhalational agent, the slower
its onset and offset times.
This is because its effects
on the central nervous system depend
on its partial pressure in blood
(and subsequently its partial pressure in
the brain) and
not on the absolute amount dissolved in blood.
> Highly soluble agents (halothane and isoflurane) have low partial pressures in blood and more molecules are required to saturate the liquid phase before the PA can be increased.
> As the molecules within the alveoli are readily taken up into the blood, the alveolar concentration and partial pressure remain low, and it takes longer to reach equilibrium (FA/Fi ratio of 1).
> Consequently, the brain
partial pressure rises
more slowly and the onset
of anaesthesia is slower.
> Conversely, poorly soluble agents
(desflurane and sevoflurane) have
alveolar concentrations that
rise rapidly
towards inspired concentrations,
achieving higher partial pressures in alveoli, blood and brain, and onset of anaesthesia is more rapid.
The wash-in curves (FA/Fi ratio over time)
graphically demonstrate
the effect of B:G coefficients
on onset times for different agents.
FA/Fi represents the ratio of fractional alveolar to fractional inspired concentrations, and different agents achieve an FA/Fi ratio of 1 (equilibrium) at different rates.
Fig. 18.1 Wash in curves showing the inspired concentration of inhalational agent (Fi) against alveolar concentration (FA) over time
Explain the term ‘oil:gas’ partition coefficient
The oil:gas (O:G) coefficient
is a measure of lipid solubility
and an indicator of potency.
It is inversely related to MAC. > Highly lipid-soluble agents are more potent and a lower MAC is required to achieve central nervous system effects.
Meyerton Overton theory
> The Meyer–Overton theory (see p. 57) suggests that when sufficient amount of agent dissolves into a neuronal lipid membrane, anaesthesia is achieved.
Using logarithmic scales,
MAC can be plotted against
O:G for various agents.
If this hypothesis were correct,
then the product of MAC and O:G
would be a single constant.
In fact, for the older agents,
the product equates to 100,
whereas for the newer agents,
it equals 200,
suggesting there may be
different sites or mechanisms of action.
Compare the uptake and excretion of isoflurane and
sevoflurane.
Property Isoflurane Sevoflurane
Blood:Gas coefficient 1.4 0.6
Onset/offset Slower Faster
Oil:Gas coefficient 98 53
MAC (in 100% O2) 1.15 2.05
MAC (in 70% N2O) 0.56 0.66
Metabolism (%) 0.2 3–5
Isoflurane is more soluble in blood
and
exerts a lower partial pressure in blood.
As it easily diffuses out of the alveoli,
it takes longer than sevoflurane
to achieve a high alveolar partial pressure.
Consequently its ratio of alveolar
concentration to inspired concentration
(FA/Fi) takes longer to approach 1
and its speed of onset of anaesthesia is slower.
The converse applies at the
end of anaesthesia when the
offset time of isoflurane is slower.
Which factors, other than blood:gas coefficient, affect the speed of onset of anaesthesia when using volatiles?
The increase in alveolar partial pressure (PA)
is a balance between the delivery of the drug
to the alveolus and the
loss from the alveolus to the
arterial blood (input minus uptake).
1.
> Inspired concentration (Fi):
2
> Alveolar minute ventilation:
3
> Functional residual capacity (FRC):
4
> Cardiac output and pulmonary blood flow:
5
> V /Q mismatch and diffusion defects: These are rarely significant.
6
> C oncentration and second gas effect
1.
> Inspired concentration (Fi):
1.
> Inspired concentration (Fi): If high, there is an increased delivery
of drug to the alveolus and a more rapid rise in PA. In turn, Fi depends
on the:
• Concentration set on the vaporiser
• Fresh gas flow rate
• Volume of the breathing circuit
• Amount absorbed by the anaesthetic machine and breathing circuit.
2
> Alveolar minute ventilation
> Alveolar minute ventilation:
If high, the delivery of volatile agent to the
alveolus is increased.
In turn, this is influenced by:
• Respiratory depressant effects
of the volatile agents with increasing
depth of anaesthesia as
hypocapnia causes a reduced cerebral blood
flow and reduced delivery of agent to the brain
• Ventilatory settings in ventilated patients.
3
> Functional residual capacity (FRC):
A large FRC will
dilute the inspired concentration,
resulting in a slower rise in PA
and a slower onset,
whereas a small FRC leads to a
rapid rise in PA and a faster onset.
4
> Cardiac output and pulmonary blood flow:
if high, the agent is taken up from the
alveolus more effectively and
so the PA rises more slowly,
leading to a slower onset of anaesthesia.
A low cardiac output results in a
slower uptake into the circulation,
achieving a higher PA more quickly.
The onset of anaesthesia is more rapid.
The myocardial depressant effects
of volatile agents thus
have a positive feedback effect on their onset.
5
> V. /Q. mismatch and diffusion defects:
> V. /Q. mismatch and diffusion defects: These are rarely significant
> Concentration and second gas effect:
The concentration effect
occurs when N2O is used
in high concentration and
refers to the
disproportionate rise in
alveolar partial pressures
of other gases.
N2O is much more soluble than
N2 (35×) and O2 (20×) and
results in a reduced alveolar volume
as it diffuses out of the alveoli
more rapidly than N2 can diffuse back in.
The reduced alveolar volume results
in a rise in alveolar partial pressure
and concentration of the remaining gases.
The second gas effect refers to the effect
that N2O has on the speed of
onset of anaesthesia of the
second gas (volatile).
As a consequence of the concentration effect,
the volatile agents achieve a rapid rise in PA,
and
their FA/Fi ratio approaches 1 more quickly,
leading to a faster onset of action.
The same factors will affect the
speed of offset (elimination) of
inhalational anaesthetic agents.
How does the structure of an inhalational agent influence its effects?
> All volatile agents,
except halothane and nitrous oxide,
are halogenated ethers.
> An ether is a link between
two carbon-containing compounds (C–O–C).
> Ethers are lipid soluble
but not water soluble.
> A halogen is a member of group VII of the periodic table, which includes fluorine (F), chlorine (Cl) and bromine (Br).
> Fluorine is the lightest of the three
and lowers the molecular weight (MW)
of the compound.
A lower MW increases blood solubility,
and a higher MW increases potency.
Fluorine is the most electronegative halogen
and stabilises ethers.
It increases the saturated vapour pressure and therefore the compound evaporates less easily (e.g. desflurane).
> Halothane is a halogen-substituted
alkane (halogenated hydrocarbon).
An alkane is a hydrocarbon with fully saturated bonds, such as methane (CH4) and ethane (CH3CH3).
Alkanes are lipid soluble
and precipitate arrhythmias.
> Halogenation reduces flammability.
> Halothane is a halogen-substituted alkane
(MW = 197).
> Isoflurane is a halogenated
methyl ethyl ether (MW = 184).
> Enflurane is a halogenated
methyl ethyl ether (MW = 184).
Isoflurane and enflurane are structural isomers.
> Desflurane is a fluorinated
methyl ethyl ether (MW = 168).
> Sevoflurane is a polyfluorinated
isopropyl methyl ether (MW = 200).
> Nitrous oxide exists in two forms as a hybrid.
What are the harmful effects of inhalational anaesthetic agents?
1
> Hepato- and nephrotoxicity
Inhaled anaesthetic agents undergo
metabolism in the liver via
cytochrome P450 system.
The carbon–halogen bond releases
the halogen ion,
which is potentially nephrotoxic.
The C–F bond is more stable and minimally metabolised, whereas the C–Cl and C–Br bonds are more easily metabolised. Inorganic fluoride ions may be nephrotoxic.
2
> Bone marrow depression
Nitrous oxide is only minimally metabolised (0.004%) by gut organisms. Nitrous oxide oxidises the cobalt atom in vitamin B12 complex, which acts as a co-factor for the enzyme methionine synthetase.
The resultant bone marrow
depression may be apparent
by the development of:
• Subacute degeneration of the
spinal cord (dorsal columns)
due to inhibition of methionine synthesis.
• Megaloblastic anaemia due to
impaired tetrahydrofolate production
(important substrate in DNA synthesis).
3 > Compound A Sevoflurane administered via a circle system can react with soda and baralyme used to absorb CO2, resulting in the production of compounds A, B, C, D and E.
Only A is potentially toxic (kidneys, brain, liver), but in clinical practice, the concentrations produced are much lower than the toxic threshold (200 ppm).
4
> Halothane hepatitis
This is thought to manifest in one of two ways:
• Reversible transaminitis due to hepatic hypoxia
• Fulminant hepatitis, which is an antigen–antibody reaction. The metabolite trifluoroacetic acid combines with liver proteins (haptens), stimulating the production of antibodies to hapten, and precipitating hepatic necrosis.
Risk factors include repeated exposure, female sex, obesity and middle age.
Mortality is 50–70%. In theory, it may
occur with other agents,
but their low rates of metabolism make this
less likely.
How do inhalational anaesthetic agents exert their effects?
Different hypotheses have been
put forward,
but no single hypothesis
adequately explains their effects.
1
> Meyer–Overton hypothesis:
This was put forward 100 years ago and
describes a link between lipid solubility
(oil:gas coefficient) and potency (MAC).
The critical volume hypothesis expands on this theory and states that when sufficient amounts of inhalational agents dissolve into the neuronal lipid membrane,
ion channels become distorted
and synaptic transmission is impaired.
The effect of combined inhalational
agents is additive.
2
> Membrane protein receptor hypothesis:
Binding sites for anaesthetic
agents on transmembrane
proteins have been found.
Many ion channels or receptors are likely to be involved including acetylcholine, GABAA, NMDA and voltage-gated ion channels.
3
> Alteration in neurotransmitter availability
and action on receptors:
The breakdown of the inhibitory neurotransmitter gamma amino butyric acid (GABA) is inhibited by volatile agents, leading to an accumulation of GABA within the central nervous system and activation of the GABAA receptor,
causing hyperpolarisation of the cell membrane.
Volatile agents may inhibit certain
calcium channels,
preventing the release of neurotransmitters,
and may inhibit the glutamate receptor.
4 > Multi-site hypothesis: Different inhalational agents alter higher central nervous system function (memory, learning and consciousness)
at different concentrations.
Furthermore, certain agents,
e.g. opiates, may
reduce MAC, although this
effect is neither predictable nor additive.
This implies that there are different sites of action and that inhaled anaesthetics may have both a direct and an indirect effect (via second messengers) on ion channels at various concentrations.
Which neurotransmitters are implicated in the mode of action of inhalational anaesthetic agents?
> Excitatory neurotransmitters,
e.g. glutamate and acetylcholine,
are thought to be inhibited.
> Inhibitory neurotransmitters,
e.g. GABA and glycine, are thought to be activated.
> Nitrous oxide does not appear to affect the
GABAA receptor
but strongly inhibits the NMDA receptor.
It stimulates dopaminergic neurones,
mediating the release of endogenous opioids.
