Inhalation Annnnn

HISTORY
diethyl ether first used by William T.G. Morton in the USA in 1846
ether survived as a viable agent for many years because it,
a. is readily made in pure form
b. is a volatile liquid, therefore easily vaporised
c. is potent, only a few volumes % required, averting hypoxia
d. supported respiration and the circulation
chloroformwas the next agent to receive attention, by James Simpson in 1847
apart from its pleasant odour and nonflammability, it had major problems,
a. severe cardiovascular depression (sudden death ? VF)
b. dose dependent hepatotoxicity
cyclopropanewas discovered accidentally in 1929 and was very popular for almost 30 yrs
however, the increasing use of electronic equipment necessitated the production of a
nonflammable agent
a variety of other agents were investigated but discarded for various reasons,
a. explosivemixtures with oxygen - diethyl ether
- ethyl chloride
- divinyl ether
- cyclopropane
b. postoperative liver necrosis / sudden death - chloroform
c. postoperative renal failure - methoxyflurane
halothane, developed by ICI, was introduced in 1956 and revolutionised anaesthetic practice
this recently has come in to some disrepute for postoperative liver failure
enfluranehas been in use since 1970
difficulties with purification and suspected cardiotoxicity delayed the introduction of its isomer,
isoflurane, until recently (1981)
desfluraneis expected to be released for use in Australia, possibly by 1996
this will provide an agent with the kinetics of cyclopropane without the flammability
Inhalational Anaesthetics
MINIMUM ALVEOLAR CONCENTRATION
Def'n: the minimum alveolar concentration of anaesthetic, at equilibrium, at one
atmosphere pressure, which produces immobility in 50% of subjects exposed to
a standard noxious stimulus, which, for humans is surgical incision of the skin
the rationale for this measure of anaesthetic potency is,
a. alveolar concentration can be easily measured
b. near equilibrium, alveolar and brain tensions are virtually equal
c. the high cerebral blood flow produces rapid equilibration
factors which support the use of this measure are,
a. MAC is invariant with a variety of noxious stimuli
b. individual variability is small
c. sex, height, weight & anaesthetic duration do not alter MAC
d. doses of anaesthetics in MAC's are additive
for a number of anaesthetic gases, 1.3 MAC ~ 21 mmol/l in brain lipids
the slopes of the dose/response curves are steep
although only 50% of subjects do not respond at 1 MAC, 99% are unresponsive at 1.3 MAC
another measure is the ED
50
, which for the common inhalational agents is ~ MAC + 20%
this is a less accurate measure as it does not refer to the alveolar concentration, which for a given
inhalational dose will vary with agent solubility and patient uptake
all the inhalational agents have a low margin of safety, with therapeutic indices of 2 to 4
NB: MAC represents only a single point on the dose response curve for the production
of anaesthesia;
other effects, such as cardiovascular depression, may not be proportional
2
Factors Which Affect MAC
Increase MAC
i. hyperthermia
ii. hypernatraemia
iii. drug induced elevation of CNS catecholamine stores
iv. chronic alcohol abuse ? chronic opioid abuse (MCQ)
v. increases in ambient pressure (experimental)
Decrease MAC
i. hypothermia - halothane MAC
27C
~ 50% MAC
37C
- decrease is ~ linear
ii. hyponatraemia
iii. increasing age - MAC
Hal
< 3 mths ~ 1.1 %
- MAC
Hal
> 60 yrs ~ 0.64 %
iv. hypoxaemia - P
aO2
40 mmHg
v. hypotension
vi. anaemia
vii. pregnancy ? progesterone
viii. CNS depressant drugs - opioids
- benzodiazepines
- major tranquilizers
- TCA's
ix. other drugs - lithium
- lignocaine
- magnesium
- pancuronium (?)
x. acute alcohol abuse
No Change in MAC
i. sex
ii. weight, BSA
iii. type of supramaximal stimulus
iv. duration of anaesthesia
v. hypo/hyperkalaemia
vi. hypo/hyperthyroidism
vii. P
aCO2
~ 15-95 mmHg
viii. P
O2
> 40 mmHg
ix. MAP > 40 mmHg
3
MOLECULAR ACTION OF INHALATIONAL ANAESTHETICS
Interruption of Neuronal Transmission
NB: there is no experimental data to support an action of the inhaled agents at
specialised peripheral receptors,
there is good evidence for differential sensitivity of various neuronal groups to the
action of the inhaled agents,
this would be in keeping with a membrane siteof action (see later)
postsynaptic potentials are depressed to a proportionately greater extent than fibre compound
action potentials
depending upon the fibre group, the former may be almost totally abolished in the absence of any
significant effect on axonal AP's
axons may actually show a biphasic response, with initial enhanced excitability, followed by
depression
although axonal transmission appears affected to a lesser extent, this may still be significant in
terms of transmitter release and the effects upon synaptic transmission may be, in part, due to this
the following factors also influence susceptibility,
a. fibre diameter MAC
fibre
1/~diameter
b. stimulation frequency MAC
fibre
1/freq. Hz
c. axonal region branch pts. > axons
the action of the inhaled agents on synaptic transmission may be due to alteration of either,
a. presynaptic transmitter release
b. reuptake of transmitter following release
c. binding to post/pre-synaptic receptor sites
d. membrane conductance following receptor activation
in contrast to what might be expected from the above, polysynaptic pathways are not depressed
to a greater extent than monosynaptic pathways
the inhaled agents appear to equally depress monosynaptic and polysynaptic responses recorded
from the ventral root of the spinal cord (Miller)
4
Alterations of Neuroregulators with Anaesthesia
in addition to the "classical" neurotransmitters, there is an ever-growing list of endogenous
peptides, amino-acids, etc., which modulate neuronal transmission
further, the postsynaptic action potential results in the formation of second mesengers which
further mediate changes in neuronal transmission
acetylcholinelevels are not affected by any of the volatile agents, however, there is a decrease in
the turnover rate
synthesis is impaired by N
2
O 70% or halothane 3%
levels of catecholamines are similarly unaffected, however drugs which alter the availability of
NA significantly alter anaesthetic requirement
in contrast, CNS levels of dopamineappear to be inversely related to anaesthetic requirement
administration of levodopa produces a dose-dependent reduction of MAC
H
in rats
the administration of
2
-adrenergic agonists markedly reduces MAC
clonidinereduces the MAC
H
in dogs by up to 42%
d-medetomidine, a more selective
2
-agonist, produces a MAC
H
reduction in dogs to ~ 10% of
the control value
this is supposedly due to presynaptic inhibition of NA release, in addition to postsynaptic
depression of neuronal excitability
serotonin levels are unaltered generally, though, may increase in specific regions
substantia nigra & dorsal raphe nucleus
gabba-aminobutyric-acid metabolism is depressed and content increases with halothane 3%
however, uptake and release are unaffected, and the significance of the accumulation of GABA in
inhibitory neurones is uncertain
most studies demonstrate an increase in CNS cyclic AMP
this results from a reciprocal activation of adenylate cyclase and inhibition of phosphodiesterase
levels of cGMP are reduced by the volatile agents
these may, via phosphorylation, alter macromolecules involved in neuronal transport
it was hypothesised in the late 1970's that the volatile agents acted via the opiate receptors
supporting this was the reduction in MAC with the use of opiates and the partial reversal of
volatile agent action with the administration of naloxone
this later event more likely represents a general increased CNS excitation, rather than competition
for the opiate receptor
another mechanism for this hypothesis was that volatile agents acted via release of endogenous
opioids within the CNS
there is some animal data to support this, however there is no elevation of opioid peptides in the
CSF of human subjects anaesthetised with volatile agents
NB: in summary, the predominant effects of the volatile agents cannot at present be
explained by depletion, production, or release of a single neurotransmitter
5
Theories of Anaesthetic Action
1. Lipid Solubility - Overton & Meyer
2. Alterations to Lipid Bilayers
i. lipid perturbation - dimensional change
ii. lipid phase transition - "lateral phase separation"
iii. lipid-protein interactions
3. Alteration to Protein Function - luciferase inhibition
The Physicochemical Basis of Anaesthetic Action
a myriad of molecular species can produce general anaesthesia, including inert gases, simple
inorganic and organic molecules, haloalkanes, and ethers
the simple additive action of the anaesthetic agents suggests a nonspecific role, ie. their action is
likely to be a physical process, not a drug receptor interaction
NB: the idea that all anaesthetics have a common mode of action on a specific molecular
structure, is called the unitary theory of narcosis
the best correlation with anaesthetic potency was noted to be the olive oil:gas partition
coefficient by Meyer and Overton, 1899-1901
the product of the anaesthetising partial pressure and the oil:gas partition coefficient varies little
over ~ a 100,000 fold range of anaesthetising partial pressures
this is species dependent, and in humans is,
P
Gas
x
O:G
~ 1.28 0.09 bar
the amazing closeness of this relationship supports a unitary molecular site of action and suggests
that anaesthesia results when a critical number of anaesthetic molecules occupy a crucial
hydrophobic region in the CNS
this relationship has led a search for the molecular basis in cellular hydrophobic regions
the Meyer-Overton rule postulates that it is the number of molecules which are present at the site
of action which is important and not their type
thus, this hypothesis supports the additive nature of anaesthetic agents
6
Exceptions to the Meyer-Overton Rule
enflurane and isoflurane are structural isomers and have similar oil:gas partition coefficients,
however, the MAC for isoflurane is only ~ 70% of that for enflurane
thus, it would appear that there are other factors which influence potency, these include,
1. convulsant properties
complete halogenation, or complete end-methyl halogenation on alkanes & ethers
results in decreased anaesthetic potency and the appearance of convulsant activity
2. the "cutoff effect"
increasing homologues of alkane series a display cutoff point, beyond which
anaesthetic potency sharply decreases
one postulate is that the larger members of a series are to large to fit into the
"anaesthetic site"
3. specific receptors
for a given MAC reduction, plasma levels of morphine, alfentanyl, sufentanyl, and
fentanyl vary ~ 5000 fold
levels of these four agents in brain lipid vary 10 fold
thus, studies of the reduction in MAC by opioids suggests two sites of action,
i. the opioid receptor
ii. some hydrophobic site
d-medetomidine, an
2
-agonist results in a marked reduction in MAC, whereas its
optical isomer, with identical lipid solubility has no effect
Hydrophillic Site Of Action
L. Pauling & S. Miller (1961) independently proposed that anaesthesia may result from the
formation of clatharates of water in membranes
anaesthetic molecules acting as seeds for crystals of water which subsequently alter membrane
ion transport
this is less likely than the unitary theory, as there is a poor correlation between the ability of
agents to form clatharates and their anaesthetic potency
Traube (1904) and Clements & Wilson (1962) proposed that potency correlated with reduction
of surface tension
however, these later physical properties are closely related to those physical properties which
determine hydrophobicity
7
Critical Volume Hypothesis
although the Meyer-Overton rule postulates that anaesthesia results when a certain number of
molecules dissolve at a certain site, it does not explain why anaesthesia results
as anaesthetic action displays pressure reversal, Mullins (1954) proposed that anaesthetic
potency should correlate directly with both lipid solubility and molar volume
anaesthesia occurring when the volume of the hydrophobic region is caused to expand beyond
some critical volume
this theory is supported by a number of experimental observations,
a. hydrostatic pressure reversal
b. volume expansion of model lipid membranes
c. He & Ne, low lipid solubility gases are not anaesthetics
d. the potency of hydrogen << predicted
NB:
that is, the volume expansion caused by these agents is offset by the compression
resulting from the high hydrostatic pressures required
arguments against this hypothesis include,
a. decreasing temperature should decrease relative volume expansion and increase MAC
requirement
b. that not all lipid soluble agents are anaesthetics
c. the non-linear pressure antagonism for certain agents
Anaesthetic Binding to Membrane Lipids
biological membranes consist of a cholesterol-phospholipid bilayer, having a thickness of ~ 4 nm
peripheral proteins are weakly bound to the exterior hydrophilic membrane
integral proteins are deeply imbedded in, or pass through the lipid bilayer
synaptic membranes are ~ 50:50 lipid bilayer & protein by weight
the correlation of potency and solubility of anaesthetic agents in phospholipid bilayers is at least
as good as that for olive oil
Effects on Membrane Permeability
examining ion fluxes across synthetic liposomes, all inhalational agents increase cation flux
the magnitude of the increase depends upon lipid composition and the agent examined
these increases in cation flux are reversed by high pressures (~ 100 Atm)
these effects are also seen with lipid vesicles, and it has been postulated that the reduction in the
normal transvesicular pH gradient results in inability of the vesicles to retain catecholamines
this leads to intraneuronal depletion of catechol stores and reduced transmission
experimental depletion, however, can only reduce MAC ~ 40% and this can only be a
contributing factor
8
Effects on Membrane Dimension
the absorption of anaesthetic into lipid monolayers increases lateral pressure
theoretically this may affect ion channel function
this effect parallels anaesthetic potency and is a variation of the volume expansion theory
however, the measured increases in volume of prepared monolayers are only small and may be
due to other factors,
a. increased hydration in the bilayer
b. altered lipid water interactions
c. conformational changes in the lipid phase
Alteration of Membrane Physical State
phospholipid membranes undergo a transition with increasing temperature, called the gel-liquid
crystalline transition of the lipid matrix
this transition is associated with an increase in the molar volumeof the lipid
Trudell et al. (1973) showed that in the presence of anaesthetic agents this transition occurs at a
lower temperature, and over a wider temperature range
even small changes in fluidity of the membrane (~ 1-2%) result in increased cation flux across
liposomes
lipids surrounding ion channels are held in the more rigid gel state, dissolution of which allows
channel closure
incompatible with this idea, is the fact that hypothermia decreases fluidity but enhances
anaesthetic action
an alternative proposal, is the "lateral phase separation hypothesis"
using NMR and ESR techniques, these agents cause a local disordering of the phospholipid
matrix and reduce the number of molecules which simultaneously alternate between the gel &
liquid crystalline states
reducing such fluctuations, these agents thereby reduce the magnitude of fluctuations in volume
which probably occur in dynamic biological membranes
such volume fluctuations allowing channel conformational change
both the fluidization and lateral phase separation hypotheses suggest that anaesthesia results
from making the membrane more disorganised, or fluid
this would then be reversible by the application of high pressure
these theories are compromised by,
a. small increases in temperature (~ 1C), result in the same degree of fluidization as
clinical concentrations of inhalational agents and therefore should augment anaesthesia
b. increasing age is accompanied by the progressive accumulation of rigidifying lipids,
which should oppose this action
9
Alteration of Protein Function
NB: most investigators agree that the final common action of inhaled anaesthetic agents
is on specific neuronal membrane proteins involved in ion fluxes
Soluble Proteins
distinct anaesthetic binding sites have been found in a number of proteins,
i. haemoglobin
ii. myoglobin
iii. serum albumin
this binding is readily reversible, and appears to result in virtually no significant alteration in
protein function for most plasma enzymes
other proteins are quite sensitive to anaesthetic binding
the bacterial enzyme luciferaseis readily inhibited at 1 MAC
the "cutoff effect" can be demonstrated with a purified firefly luciferase preparation
this effect may extrapolated in theory to enzymes involved in neuronal excitability
Membrane Proteins
there are two major problems with trying to study membrane bound protein function,
a. isolation of significant numbers is difficult and time consuming
b. proteins then need to be re-incorporated into a lipid membrane to study their function
clearly it is difficult to distinguish between effects on the surrounding membrane lipid and distinct
effect on the proteins themselves
the ACh-receptor/ionophorecomplex is the best characterised with regard to anaesthetic
influence
volatile agents stabilise the receptor in a state which forms high affinity bonds with agonist
molecules, thus producing a desensitised and closed channel state
although there is a fair correlation between anaesthetic potency and increased binding affinity,
minimal desensitisation occurs at clinical concentration
also, very high concentrations actually decrease ACh binding, thus there is no linear
dose-response relationship
interaction with rhodopsin has also been examined but effects are only seen at very high
concentrations
recent work suggests that membrane G-proteins may be a site where significant alteration of
membrane function occurs
these are inhibited by pertussis toxin and intracerebroventricular injection of pertussis toxin
increases halothane MAC 70%
the reduction in halothane MAC seen with
2
-agonists is also attenuated by pertussis toxin
NB: in summary, there are a number of possible sites where anaesthetics may have a
significant action, however, good experimental evidence is still wanting
10
UPTAKE AND DISTRIBUTION OF INHALATIONAL AGENTS
NB: the depth of anaesthesia varies directly with the tension of the agent in the brain,
and, therefore, the rates of induction and emergence depend upon the rate of
change of gas tension in the blood and tissues
the alveolar partial pressure is in equilibrium with arterial blood and therefore brain tissue
thus, alveolar concentration is an indirect measure of brain concentration
the factors which determine this may be considered as acting in separate stages,
1. Transfer from Inspired Air to Alveoli
i. the inspired gas concentration F
I
ii. alveolar ventilation V
A

iii. characteristics of the anaesthetic circuit
2. Transfer from Alveoli to Arterial Blood
i. blood:gas partition coefficient
B:G
ii. cardiac output CO
iii. alveoli to venous pressure difference P
A-vGas
3. Transfer from Arterial Blood to Tissues
i. tissue:blood partition coefficient
:
ii. tissue blood flow
iii. arterial to tissue pressure difference P
a-tGas
11
Transfer from Inspired Air to Alveoli
Inspired Gas Concentration
according to Dalton's law of partial pressures, the tension of an individual gas in inspired air is
equal to,
P
Igas
= F
Igas
x Atm

the greater the inspired pressure the greater the approach of F
A
to F
I
= the concentration effect
this is only significant where F
I
is very high, as is the case for N
2
O (or cyclopropane)
when another gas is used in the presence of such an agent, there is increased uptake of the second
gas, the second gas effect
the tension in the inspired gas is frequently limited by agent-induced airways irritability
this can be attenuated partially by adequate premedication
in practice, the inspired concentration is rarely constant
irritating agent concentrations are slowly increased, c.f. agents where rapid induction can be
achieved with "loading doses"
this is why halothane, which should theoretically take longer to induce patients, is more rapid
than the more irritant isoflurane
when a constant tension is inhaled, the tension in arterial blood progressively approaches the
tension in alveolar air (see G&G fig. 13-1)
the rate at which this occurs is determined by the physical properties of the agent, see below
however, during maintenance, F
I
may be considerably greater than F
A
, depending on the solubility
of the agent
Alveolar Ventilation
each inspiration delivers some anaesthetic to the lung and, if unopposed by uptake into the blood,
normal ventilation would increase F
A
/F
I
to 95-98% in 2 minutes
this rate of rise is dependent upon minute ventilation and FRC
the greater the FRC, the slower the rise in F
A
therefore, if minute ventilation is increased, the tension in alveolar air and arterial blood will rise
more quickly lung washin
the effects of the rate of respiration, to speed or slow induction, are transient for gasses such as
N
2
O which are poorly soluble in blood, and thus equilibrate quickly
however, the minute volume of ventilation has a significant effect on the highly solubleagents,
such as methoxyflurane or diethyl-ether
hyperventilation will decrease CBF, and this tends to offset the increased rise of F
A
/F
I
Anaesthetic Circuit (See Later)
three factors are important,
1. the volume of the external breathing system
2. the solubility of the given agent in the rubber and plastic components of the system
3. the gas inflow from the anaesthetic machine
12
Transfer from Alveoli to Arterial Blood
the alveolar membrane poses no barrier to the transfer of anaesthetic gasses in either direction
V/Q mismatch, by effectively increasing shunt flow, will decrease the rate of transfer into blood,
especially for agents of low solubility
in the absence of V/Q inequality, the product of three factors determines the speed of uptake,
where P
Atm
is the barometric pressure
should any of these components 0, then uptake will 0
Blood:Gas Partition Coefficient
the solubility of a gas in liquid is given by its Ostwald solubility coefficient,
this represents the ratio of the concentration in blood to the concentration in the gas phase
(c.f. Bunsen at s.t.p.)
this is independent of pressure, obeying Henry's law
serum proteins and RBC's are the major determinants of solubility
lower B:G coefficients are seen with,
i. haemodilution ~ 20% less when the Hct. = 21% c.f 43%
ii. obesity
iii. hypoalbuminaemia and starvation
higher coefficients are seen in,
i. adults versus children
ii. hypothermia
iii. postprandially
the more soluble an anaesthetic in blood, the more of it which must be dissolved to raise the
partial pressure
stated another way, soluble agents have a larger blood reservoir, the reservoir for insoluble
agents is small and fills more quickly
NB: this is the principal determinant of the approach of F
A
to F
I
Q
.
Gas
=
B:G
CO
P
AvGas
P
Atm
13
Anaesthetic Agent Blood:Gas coefficient at 37C
Methoxyflurane 15
Halothane 2.4
Enflurane 1.8
Isoflurane 1.4
Sevoflurane 0.69
Desflurane (I-653) 0.42
Nitrous Oxide 0.47
Cardiac Output CO
effectively pulmonary blood flow and determines the rate at which agents pass from gas to blood
an increase in flow will slow the initial portion of the arterial tension/time curve by delaying the
approach of F
A
to F
I
a low CO state, conversely, will speed the rise of F
A
/F
I
these effects are greater for highly solubleagents
NB: thus, anaesthetic induced CVS depression may cause a more rapid rise in arterial
tension (Eger 1986)
Shunt
an increase in shunt flow has two effects,
1. increased P
A.Gas
- small for insoluble agents
- moderate for soluble agents
2. decreased P
a.Gas
- very large for insolubleagents
- negligible for soluble agents
NB: a large P
A-a.Gas
gradient develops for insolubleagents
this effectively slows the induction of anaesthesia in the presence of significant shunt, eg.
endobronchial intubation, CHD
Alveoli to Venous Pressure Difference
this represents tissue uptakeof the inhaled agent
blood cannot approach equilibrium with alveolar air until the distribution of anaesthetic from the
blood to the tissues is nearly complete
with equilibration, the alveolar/mixed venous tension difference progressively falls as tissue
tensions rise
since diffusion is directly proportional to the tension difference, the rate of diffusion into the
blood progressively slows
14
Transfer from Arterial Blood to Brain & Tissues
the rate at which gas passes into the tissues depends on,
i. tissue:blood partition coefficient
ii. tissue blood flow
iii. arterial to tissue pressure difference, P
a-t.Gas
Tissue:Blood Partition Coefficient
for most anaesthetic gasses, this is near unity for lean tissues
the rate of rise of tension in these regions is proportional to the arterial-tissue tension difference
conversely, their solubility in lipid tissues is far greater than that for blood
at equilibrium the concentration in lipid tissues will be far greater than that in blood
the tissue concentration will rise above that of blood well before pressure equilibrium, even
though the tissue tension is lower
Anaesthetic Agent Fat:Blood coefficient at 37C
Methoxyflurane 61
Halothane 62
Enflurane 36
Isoflurane 52
Sevoflurane 55
Desflurane (I-653) 30
Nitrous Oxide 2.3
Tissue Blood Flow
the higher the blood flow to a region, the faster the delivery of anaesthetic and the more rapid
will be equilibration
the total amount of gas dissolved will, however, depend upon the tissue volume and agent
solubility in that tissue
the body tissues have been divided into groups according to their level of perfusion and tissue
blood flow,
a. vessel rich group VRG - brain, heart, kidney & liver
b. the muscle group MG - muscle & skin
c. the fat group FG - large capacity/minimal flow
d. vessel poor group VPG - bone, cartilage & CT
15
Tissue Compartment Kinetics
1
Group Blood Flow % CO Body Mass Flow (l/hr) Equilibration time
2
VRG 75 < 10% 45 3-10 min
MG 18-20 45-50% 2 1-4 hrs
FG 5 15-20% 1.3 5 days
VPG no pharmacokinetic significance (Eger 1974)
1
from Dale et al., Clinical Pharmacokinetics (12:145-167,1987)
2
these variations are more important for the highly soluble, in this case tissue soluble agents
Arterial-Tissue Pressure Difference
with equilibration tissue tension rises and the rate of diffusion slows, as does uptake in the lung
the rate is determined by the tissue time constant, which in turn depends upon both the tissue
capacity (
T:B
) and the tissue blood flow
NB: as for any exponential process, 3 time constants 95% equilibrium point
Brain Compartment Time Constants
Anaesthetic Agent
brain:blood
(37C)
TC (min) Equilibrium
Methoxyflurane 2 3.6 11
Halothane 2.6 4.7 14
Enflurane 2.6 4.7 14
Isoflurane 3.7 6.7 20
Sevoflurane 1.7 3.1 9.3
Desflurane (I-653) 1.3 2.4 7.1
Nitrous Oxide 1.1 2 6
NB: thus, as the VRG receives 75% of the CO, after 3 time constants, 75% of the
returning venous blood will be in equilibrium with P
AGas
TC() =
Tissue Capacity / 100g
Blood Flow/ 100g
16
Other Factors Affecting Uptake & Distribution
Concentration and Second Gas Effects
Def'n: the concentration effect states that with higher inspired concentrations of an
anaesthetic, the rate of rise in arterial tension is greater
eg., during the inhalation of 75% N
2
O/O
2
, initially as much as 1 l/min may diffuse into the
bloodstream across the lungs
this effectively draws more gas into the lungs from the anaesthetic circuit, thereby increasing the
effective minute ventilation
this effect is also important where there is a second gas, such as 1% halothane, in the inspired
mixture
the removal of a large volume of N
2
O from the alveolar air increases the delivery of the second
gas, effectively increasing its delivery to the alveoli and increasing its diffusion into arterial blood
Diffusion Hypoxia
first described by Fink in 1955
this is effectively the reverse of the above
the elimination of a poorly soluble gas, such as N
2
O, from the alveoli may proceed at as greater
rate as its uptake, thereby adding as much as 1 l/min to alveolar air
this gas effectively dilutes alveolar air, and available oxygen, so that when room air is inspired
hypoxia may result
this is usually only mild and rarely clinically significant
although this may occur with any anaesthetic agent, its magnitude is insignificant unless an
insoluble agent, such as nitrous oxide, has been inhaled for some time
under these circumstances as much as 30 l may be dissolved in the blood and tissues
Alterations in Ventilation & Perfusion
previous discussion has assumed independent changes in either of these variables
if both increase proportionately then the rate of rise of F
A
/F
I
might be expected to remain
constant
this would be the case, except for the greater delivery of agent to the tissues and the accelerated
narrowing of P
A-vGas
thus the rate of rise of F
A
/F
I
is increased
the magnitude of this acceleration is dependent upon the distribution of the increase in CO
where this increase is greater to the VRG, a far greater effect is seen
this contributes to the faster induction of children, especially infants, & pregnant women
17
Elimination of Inhaled Anaesthetics
the factors affecting the elimination of an anaesthetic agent are identical to those for uptake and
distribution (see G&G fig. 13-2)
these factors equally apply for changes in the depth of anaesthesia
there are, however, two differences between uptake and elimination,
1. the augmentation of the rise of F
A
/F
I
by overpressureis not possible
2. on induction all tissue groups P
Gas
= 0, whereas, these all vary with elimination
due to the time constants for the tissue groups, neither the MG nor the FG have come to
equilibrium at the end of a halothane anaesthetic
consequently these groups, especially the FG, continue to take up agent and actually contribute
to the decline of F
A
/F
I
during the first few hours
the failure of several tissues to reach equilibrium has two effects,
1. recovery is more rapid than induction (without overpressure)
2. recovery is dependent upon the duration of anaesthesia
the saturation of enzyme systems responsible for metabolism effectively reduces any impact this
might have of the rate of rise of F
A
/F
I
during induction
this limitation does not exist in recovery and results in a faster decline in F
A
for halothane c.f.
enflurane
thus, hepatic metabolism is a significant factor for the elimination of halothane, especially at low,
sub-anaesthetic alveolar concentrations
Intertissue Diffusion
work done by Carpenter et al. (1986) studying washout during recovery from anaesthesia
support a 5 compartment model
the time constants of four of these are in keeping with exchange with lung, VRG, MG and FG
the time constant of the fifth lay between the MG & FG's, being ~ 400 min
Carpenter postulated that anaesthetics diffuse from well perfused tissues to adjacent poorly
perfused tissues which have a high capacity for the agent
eg. from heart to pericardial fat, kidneys to perinephric fat etc.
NB: this may account for as much as 1/3 of the agent taken up
18
Anaesthetic Circuitry
the above discussion assumed that F
I
equals the anaesthetic machine delivered concentration, F
M
this would occur if a non-rebreathing circuit was used, however in practice F
I
is determined by,
a. F
M
b. the washin characteristics of the circuit
c. losses from the circuit by dissolution
d. the effects of rebreathing
Circuit Washin
clearly this is determined by the fresh gas flow and the volume of the circuit
an average circle with a volume of 7l, with a FGF = 6.0 l/min and no uptake from the circuit,
a. corrugated hoses and fittings ~ 3.0 l
b. bag ~ 2.0 l
c. CO
2
absorbers ~ 2.0 l
F
I
/F
M
will be ~ 1.0 at 5-6 minutes
the higher the FGF, the faster the rate of washin
Circuit Losses
both rubber and plastic components of the system may remove agent and slow circuit washin
this is a significant problem for methoxyflurane, less so for halothane or isoflurane, and virtually
insignificant for N
2
O or desflurane
similarly uptake may occur into soda lime
this is small unless the soda lime is dry, when appreciable amounts of agent may be absorbed
both dry & wet soda lime will absorb appreciable amounts of sevoflurane
Circuit Solubility Characteristics
Anaesthetic Agent Polyethylene
(hoses)
Rubber
(bag)
PVC
(ETT)
Methoxyflurane 118 742 -
Halothane 128 190 223
Enflurane - 74 -
Isoflurane 58 49 114
Sevoflurane 31 29 68
Desflurane (I-653) 16 19 35
Nitrous Oxide - 1.2 -
19
The Effect of Rebreathing
as inspired gas is actually fresh gas + exhaled gas, F
I
will be determined by,
a. the amount gas rebreathed
b. the uptake of gas by the lung F
ET
an increase in either uptake or rebreathing will lower the F
I
of a highly soluble gas more than that
for an insoluble gas
this effect may be decreased by decreasing rebreathing
high FGF rates allow predictability of F
I
but are obviously wasteful and result in drier inspired air
Circle Systems
ultimately the amount of anaesthetic required is dictated by patient response, however, an initial
estimate may be made from the "square root of time formula" from Severinghaus
this requires that the first minute uptakebe estimated,
U
1
=
B:G
. CO . (P
A
/Atm)
P
A
/Atm is used as the venous gas concentration may be assumed to be zero and the desired
alveolar concentration is used
uptake at subsequent times is then given by the formula,
thus, for enfluranethis becomes,
U
1
=
B:G
. CO . P
A
/Atm
~ 1.9 . 5,000 . 0.01
~ 95 ml
and subsequently, U
4
~ 47.5 ml
U
16
~ 24 ml
U
25
~ 19 ml
in practice these volumes vary considerably, being affected by body weight, percentage fat,
surface area, hypothermia, hypovolaemia, increasing age etc.
this all becomes academic with the monitoring of F
ET.Gas
U
t
=
U
1
t
20
THE MODERN INHALATIONAL ANAESTHETICS
NB: the ideal inhalational anaesthetic should have the following properties
a. rapid and pleasant induction and emergence from anaesthesia
b. rapid and easily identified changes in the depth of anaesthesia
c. adequate relaxation of skeletal muscles
d. a wide margin of safety
e. the absence of toxic or other adverse effects at normal doses
f. high degree of specificityof action
g. technically easy to administer
h. useful for all agegroups
Physical Properties
halothane is a haloalkane, whereas enflurane and isoflurane are methylethyl ethers
substitution of the hydrogen atoms with halogens, especially fluorine, results in stable,
nonflammable compounds
increasing substitution on the alkanes
a. increasing anaesthetic potency
b. then convulsant activity, and
c. eventually an inert compound at full halogenation
this process also increases the propensity to cause arrhythmias
the ethers, conversely, are less prone to disturbances of cardiac rhythm
all are potent anaesthetic agents, with low molecular weights and low boiling points
they vaporise easily at room temperature from the liquid phase, and in clinical concentrations are
nonflammable and nonexplosive
halothaneis chemically unstable, decomposing to HBr, HCl, and phosgene on exposure to light
halothane is therefore supplied in amber coloured bottles requiring the addition of thymol 0.01%
as a stabilising agent
all have aromatic odours, isoflurane being the most pungent
the relative oil:gas partition coefficients would suggest that induction and emergence should be
most rapid with isoflurane > enflurane >> halothane
toxicity is probably inversely related to chemical stability, and is thought to be caused by active
products of biotransformation
attempts have been made to increase the stability of these agents by deuterium,
2
H, substitution
21
HALOTHANE
Structure:
Chemical name: 2-bromo-2-chloro-1,1,1-trifluoroethane
Introduced: 1956 ICI
MAC: 0.75%
0.29% (70%-N
2
O/O
2
)
Partition Coefficient
Bld-Gas:
Oil-Gas:
Fat-Bld:
2.4 (2.3)
224 (330)
62
Saturated Vapour Pressure: 32% 243 mmHg (20C)
Boiling Point: 50.2 C
Molecular Weight: 197.4 g
Circulatory Effects
as for most volatile anaesthetics, halothane possesses a narrow margin of safety, resulting in
severe cardiovascular depression
hypotension being the best indicator of anaesthetic depth, being dose-dependent
halothane hypotension results from two factors,
a. direct myocardial depression - decreasing CO by 20-50%
b. obtundation of baroreceptor response - no reflex tachycardia
early in halothane anaesthesia there is no decrease in TPR, though, this may fall and the HR rise
with prolonged anaesthesia ( 5hrs)
the order of potency for direct myocardial depression, in decreasing order is,
Enflurane Halothane > Methoxyflurane > Isoflurane > Diethyl Ether
these decreases in LV function are accompanied by increases in LVEDP
cardiovascular depressive effects are exaggerated by -antagonists
however, recent studies show decreasing -blockers prior to CABG surgery results in a greater
incidence of new, perioperative ischaemic changes
the predominant sites of action blocking the baroreceptor response are the effector sites in the
heart controlling cardiac rate and/or contractility
as with other volatile anaesthetics, there is no increased sympathoadrenal activity in response to
cardiovascular depression
22
however, at clinical depths of anaesthesia, the normal SNS response to surgical stimulation
remains
the reduction in CO is proportional to the tension of halothane and is enhanced by a reduced
P
aCO2
, evoking a decrease in SNS activity
CVS responses to halothane are less exaggerated during spontaneous respiration, due to,
a. the elevated P
aCO2
& increased SNS activity
b. the absence of the effects of IPPV on CO
the decrease in myocardial contractility can be reversed by increasing [Ca
++
] and, therefore, has
been postulated to be due to a reduced availability of Ca
++
? availability from SR, or decreasing i
SI
halothane is actually a nonspecific Ca
++
influx inhibitor (Dale et al. 1987), and additive effects
with verapamil should be expected (Eger 1984)
the bradycardia seen with halothane is partially reversible with atropine, and is due to,
a. decreased cardiac sympathetic activity with vagal dominance
b. direct slowing of the SA node- decreased phase 4 depolarization
- increased threshold for depolarization*
c. enhanced vagal activity - airway manipulation
NB: sinus bradycardia, wandering pacemaker, or junctional rhythms
these differ from the effects of ACh, which does not alter the threshold V
m
,
but increases resting V
m
and decreases phase 4 V/t
tachyarrhythmias may also occur with halothane and tend to be of the reentrant type, due to,
a. slowing of conduction velocity (AV node & His-Purkinje)
b. increases the refractory period in conducting tissue
NB: predisposition to reentry,
ie., unidirectional block & slow retrograde conduction
halothane increases the automaticity of the myocardium, and when combined with adrenergic
agonists ectopic pacemakers
such tachyarrhythmias are less likely to occur if,
a. anaesthesia is sufficient decreased SNS stimulation
b. ventilation is adequate CO
2
increasing SNS activity
c. use of adrenalinefor haemostasis is limited
i. concentrations < 1:100,000 = 1mg/100 ml
ii. the total dose < 0.1 mg in 10 min = 10 ml
< 0.3 mg in 1 hour = 30 ml

*1:200,000 60 ml/hr, or 1 ml/min
23
coronary autoregulation remains intact and the decrease in coronary flow is due to the reduced
myocardial oxygen consumption & work
the following vascular beds do lose the ability to autoregulate, with perfusion becoming
proportional to MAP,
a. cerebral
b. renal
c. splancnic
d. pulmonary - loss of HPV V/Q mismatch
NB: despite multiple vascular bed changes, TPR remains virtually constant,
the decrease in arterial pressure resulting from decreased contractility
Respiration
halothane influences both the control of ventilation and the efficiency of pulmonary gas exchange
it reduces tracheobronchial secretions, even without atropine
the P
A-aO2
difference increases indicating an increase in shunt flow
the shunt fraction during volatile anaesthesia routinely increases from 2-3% to ~ 10% in
otherwise healthy individuals (Nunn)
further, this increase in shunt occurs early during anaesthesia and is the same for SV & IPPV,
despite the gross V/Q changes demonstrated by Froese & Bryan
respiration characteristically becomes rapid and shallow, "diaphragmatic", with the following
pattern,
a. minute volume is decreased
b. P
aCO2
is increased - from 40 to ~ 50 mmHg
c. dose dependent decreased ventilatory response to CO
2
(and O
2
)
other effects of halothane anaesthesia and the origin of defects in pulmonary oxygen transfer
include,
a. supine position altering regional lung blood flow
b. IPPV
c. altered lung volumes - esp. decreases in FRC
d. changes in relative movements of diaphragm and chest wall
e. bronchodilatation increased V
D
f. depresses mucociliary flow
g. inhibition of hypoxic pulmonary vasoconstriction
NB: effective increase in physiological shunt & dead space
24
Nervous System
EEG shows progressive replacement of fast/low voltage waves with slow waves of increasing
amplitude
surgical stimulation replaces this activity, c.f. normal ARAS arousal
cerebral vessels dilate during halothane anaesthesia with loss of normal autoregulation
CBF & ICP
this is of course unless there is excessive systemic hypotension, further aggravating CPP
CSF formation & reabsorption are both increased minimal net effect
cerebral MRO
2
falls and CBF is adequate for needs
shivering during recovery is common and probably represents a response to heat loss and/or
some ill-defined expression of neurological activity
Muscle
there is some degree of muscle relaxation with halothane
probably due to a central effect but also some increase in end-plate sensitivity to competitive
blockers (?? effects of decreased blood flow)
NB: the main effect is an increase in the duration and magnitude of blockade by
competitive agents
rarely associated with malignant hyperpyrexia, characterised by,
a. a rapid rise in body temperature
b. a massive increase in MRO
2
and/or a low P
aO2
c. an increased P
aCO2
and marked acidosis
this may occur due to failure of uptake of Ca
++
into the SR in genetically susceptible individuals
uterinesmooth muscle is relaxed by halothane, possibly by an action on -adrenergic receptors
this may be useful in manual version of a foetus, however, predisposes to accentuated blood loss
during parturition
Kidney
doses of 1 MAC decrease RBF and GFR by up to 40-50%
this may be greater if there is pre-existing hypovolaemia
in normovolaemic subjects, halothane does not interfere markedly with autoregulation, or the
cortical/medullary distribution of blood flow
there is usually good recovery of function post-operatively
occasionally may produce SIADH with H
2
O retention and hyponatraemia
this usually only occurs in the elderly
25
Liver and GIT
intestinal, and therefore hepatic blood flow are reduced in proportion to perfusing pressure
hepatic blood flow falls by ~ 25-30% with 1.5% inhaled halothane
the liver shows decreased hepatocellular function and MFO activity with reduced drug clearance
these effects are normally rapidly reversed on cessation of anaesthesia
Halothane Hepatotoxicity
the first reports in appeared in 1958
subsequently investigated in the "National Halothane Study (1966)" but toxicity was not
confirmed
this is now accepted but convincing animal models still lacking
most common causes of postoperative hepatic dysfunction are still viral hepatitis, or damage by
known hepatotoxins
rarely, one sees postoperative hepatitis, ~ 1:10,000 anaesthetics, where no other cause can be
identified
this usually occurs at 2-5 days postanaesthesia, and is characterised by,
i. fever
ii. N&V
iii. a rash
iv. an eosinophilic blood picture
this may progress to fulminant hepatic failure, and of these ~ 50% die
an increased incidence is found after repeated administration of halothane within a short time
interval ?? abnormal immune response
biotransformation and the production of reactive intermediaries is another possible mechanism
however, these are short-lived and bind close to their site of production, hence are very difficult
to study
?? trifluoroacetyl intermediates bind to liver macromolecules which form a hapten and
immunogenic liver damage results in susceptible individuals
two animal models exist,
a. rats, pretreated with phenobarbital and exposed to hypoxia
? reductive pathway & free F
-
production (see below)
b. rats, pretreated with polychlorobiphenyls + halothane 1% / O
2
99%
centrilobular hepatic necrosis
NB: however, both of these are only animal studies and require considerable enzyme
induction, or some other additional factor
26
Biotransformation
60-80% is exhaled unchanged within 24 hours
15% is metabolised by liver MFO system
however, this figure may vary and appears to be inversely proportional to the inspired
concentration
recent mass balance studies in humans 40-50% may be metabolised
initially pulmonary elimination predominates, however as the F
A
falls a greater percentage is
eliminated by hepatic metabolism
halothane is metabolised by two routes,
a. oxidative trifluoroacetic acid
Br
-
& Cl
-
trifluoroacetic acid-ethanolamide conjugate
b. reductive 2-chloro-1,1,1-trifluoroethane*
2-chloro-1,1-difluoroethylene*
Br
-
& F
-
c. soda lime 2-bromo-2-chloro-1,1-difluoroethylene*
?? conjugation with N-acetylcysteine via glutathione
and urinary excretion
NB: * these metabolites are volatile
little F
-
is removed due to the high C-F bond energy (~ 2x C-Cl or C-Br)
blood bromineconcentrations may contribute to postoperative somnolescence
levels as high as 3.0 mmol/l have been recorded
the [metabolites] peaks 24 hours after halothane anaesthesia, and these are eliminated by renal
excretion over the following week
halothane itself is a weak inducing agent, however halothane metabolism can be induced by
phenobarbital, etc.
the major urinary metabolite is trifluoroacetic acid, which itself is not considered to be toxic
however, its trifluoroacetyl intermediatemay play a role in the liver toxicity of halothane
prolonged exposure ? increased incidence of miscarriage in staff
27
Advantages
a. moderately high potency
b. moderately low blood:gas partition coefficient
induction and recovery not prolonged
moderately rapid changes in depth of anaesthesia
c. relatively non-irritant and bronchodilator
laryngospasm and bronchospasm uncommon
d. nonflammable & nonexplosive in combination with O
2
e. hypotensive effect sometimes desirable
f. uterine relaxation sometimes desirable
Disadvantages
a. only sleep is completely obtained
require additional analgesia, muscle relaxation, etc.
b. hypoxia/hypercapnia - respiratory depression
c. hypotension
d. transient arrhythmias - especially with adrenaline
e. post-operative hepatitis
28
ENFLURANE
Structure:
Chemical name: 2-chloro-1,1,2-trifluoroethyl-difluoromethyl ether
Introduced: 1973 ?1972
(synthesised by Terrell 1963)
MAC: 1.68%
0.57% (70%-N
2
O/O
2
)
Bld-Gas:
Oil-Gas:
Fat-Bld:
1.91
98
Boiling Point: 56.5C
Cardiovascular
decreases in BP, baroreceptor responses, preganglionic SNS activity, are approximately the same
as for halothane at MAC equivalent doses
as for halothane the circulatory responses are the best indicators of the depth of anaesthesia
in vitro, enflurane produces a dose-dependent depression of myocardial contractility almost
identical to, or slightly greater than halothane
in vivo, however, enflurane does not decrease the HR and CO as much as halothane, the decrease
in BP being partially due to decreased TPR, thus reducing LV afterload and helping maintain CO
the decrease in myocardial work is paralleled by a reduction in O
2
consumption and there is no
evidence of myocardial ischaemia
both surgical stimulation and hypercarbia reverse the CO to preanaesthetic levels
cardiovascular depressive effects are exaggerated by -antagonists
same precautions regarding -blockers & CABG surgery apply c.f. halothane
enflurane does not appear to significantly interfere with impulse generation, or conduction in the
heart
nor does it appear to sensitise the myocardium to adrenergic agonists
29
Respiration
NB: at 1 MAC, respiratory depression, hypercarbia, and inhibition of chemoreceptor
responses are greater than produced by halothane, or isoflurane
assisted ventilation should nearly always be used,
but hyperventilation avoided due to the possibility of seizure activity
enflurane actually decreases tidal volume the least of the three, however, unlike halothane or
isoflurane there is no increase in respiratory rate,
minute volume is decreased the most by enflurane
as with other anaesthetic gases, pulmonary oxygen exchange is impaired and supplemental O
2
is
employed F
I
O
2
30% in the elderly
as for halothane, enflurane causes bronchodilatation and inhibits bronchoconstriction
Nervous System
a small proportion of subjects tonic-clonic muscle activity
investigation revealed characteristic EEG pattern with higher concentrations or hypocapnia,
high voltage, 14-18 Hz pattern,
progressing to spike-dome complexes,
alternating with periods of electrical silence, or frank "seizure" activity
this is not thought to be especially harmful but avoided in patients with known seizure foci, even
though studies with epileptic patients failed to induce seizure activity
most other CNS effects are similar to halothane,
a. CBF is increased when perfusion pressure is maintained
b. ICP follows changes in CBF and CPP
c. CSF formation is increased & CSF reabsorption decreased
increased CSF volume
d. decreased cerebral MRO
2

in early systemic hypotension, CBF is maintained but then decreases as cerebral perfusion
pressure continues to fall
Muscle
enflurane causes greater muscle relaxation than halothane, and the enhancement of the effects of
the competitive blockers is also greater
this is due to both a CNS effect and an effect at the postjunctional membrane of the NMJ
the later is not reversed by neostigmine
uterine muscle is relaxed, c.f. halothane this may enable foetal version, however is
contraindicated at parturition
30
Renal System
enflurane causes dose dependent reductions in,
a. glomerular filtration rate
b. renal blood flow, and
c. urine production
NB: same at equivalent MAC halothane & are readily reversible
fluoride, F
-
, is a metabolite of enflurane
values up to 20 mol/l are frequently recorded
however these rarely exceed the renal threshold for toxicity ~ 40-50 mol/l
low plasma F
-
concentrations, ( 15 mol/l), have been associated with a reduction of the
maximal urine concentrating ability by up to 25% (W&W)
the use of enflurane is probably safe with patients with renal disease, providing the depth &
duration of anaesthesia are not prolonged
Liver and GIT
intestinal and hepatic blood flow are reduced in proportion to the perfusion pressure, however
delivery of oxygen is not compromised
nausea and vomiting occur in ~ 3-15% of patients
evidence of impaired hepatic function has been observed intraoperatively, however is readily
reversed on cessation of anaesthesia
hepatic necrosis has been reported with repeated administration of enflurane and those with
previous sensitivities should receive another agent
Biotransformation
80% is exhaled as unchanged gas
2-5% is metabolised in the liver, by oxidative not reductive metabolism
this low figure is due to,
i. the absence of bromine
ii. the presence of the ether bond
iii. the low oil:gas partition coefficient
NB: increased stability of the molecule & less available to the liver
biotransformation may be increased by hepatic enzyme induction, however is not associated with
an increase in renal toxicity, as occurs with methoxyflurane
the major metabolites are,
i. difluoromethoxy-difluoroacetic acid
ii. F
-
ion
NB: the ratio of free F
-
released by the biotransformation of methoxyflurane, enflurane
and isoflurane is 23:3:1 in rat microsomes
31
Advantages
b. low blood:gas partition coefficient
rapid induction of and recovery from anaesthesia
rapid changes in depth of anaesthesia
c. relatively non-irritant and bronchodilator
laryngospasm and bronchospasm uncommon
d. nonflammable & nonexplosive in combination with O
2
e. muscle relaxation is often adequate for surgery
f. incidence of arrhythmias is less than halothane
g. uterine relaxation sometimes desirable
Disadvantages
a. deep anaesthesia with enflurane
respiratory & circulatory depression
hypoxia/hypercapnia/hypotension
b. seizure activity may occur with high concentrations, or hypocarbia
c. uterine relaxation contraindicated at parturition
32
ISOFLURANE
Structure:
Chemical name: 2,2,2-trifluoro-1-chloroethyl-difluoromethyl ether
Introduced: 1981
MAC: 1.15%
0.5% (70%-N
2
O/O
2
)
Bld-Gas:
Oil-Gas:
Fat-Bld:
1.4
99
Circulation
produces a dose dependent reduction in BP, c.f. halothane & enflurane
however, in contrast, CO is well maintained, the decrease in BP being due to vasodilatation and
decreased TPR, especially in skin & muscle
direct myocardial depression has been demonstrated in vitro, however, this is not evident at
normal gas tensions in man
with spontaneous respiration, the ensuing hypercapnia and SNS stimulation result in increases in
the HR & CO
the cardiac and peripheral vascular effects are antagonised by -blockade, and are thought to
result in part from direct stimulation of -receptors
coronary blood flow is unaltered and myocardial MRO
2
is decreased in proportion to the
reduction in myocardial work
this would suggest a wider margin of cardiovascular safety, c.f. H & E
in theory, however, a subendocardial steal syndromemay result from dilation of coronary
arterioles diverting blood away from ischaemic regions in diseased hearts
these circumstances are believed to exist in only ~ 23% of severe IHD patients (Eger 1989)
NB: to date, ischaemia during isoflurane anaesthesia has only been associated with
significant degrees of hypotension, therefore this contraindication requires further
investigation (R.G. Merin, Adv. Anesthesia 1989)
33
the HR is increased via reflex mechanisms but arrhythmias are uncommon
isoflurane does not affect ventricular conduction and does not increase the excitability of
ventricular myocardium
~ 3x the dosage of adrenaline may be employed for haemostasis
Respiration
produces a dose dependent depression of respiration, approximately equivalent to that caused by
halothane at 1 MAC P
aCO2
50 mmHg
however, the depression of the normal responses to hypoxia & hypercapnia are depressed to a
greater extent than halothane/enflurane
spontaneous respiration reduction of tidal volume but little change in respiratory rate
produces similar reductions of pulmonary compliance and FRC
this, with the inhibition of hypoxic pulmonary vasoconstriction decreased efficiency of gas
exchange seen with all three volatile agents
preanaesthetic concentrations of isoflurane airway reflex stimulation, with increased
secretions and/or coughing and laryngospasm
therefore, intravenous induction is a greater priority
at anaesthetic doses bronchodilatation as do the other agents
Nervous System
results in cerebral vasodilatation in addition to peripheral effects, thus,
a. CBF is increased, despite the decreased perfusion pressure
b. ICP is increased in proportion to CBF
c. CSF reabsorption is increased & CSF volume decreased
lessens the effects on ICP
d. cerebral vessels remain responsive to CO
2
ICP can be controlled by hyperventilation & hypocapnia
EEG shows progressive changes with depth of anaesthesia,
i. 1 MAC - slow waves with increasing voltage
ii. 1.5 MAC - burst suppression
iii. 2 MAC - electrical silence
unlike enflurane, isoflurane does not induce convulsive activity
34
Muscle
reduces the response of skeletal muscle to sustained nerve stimulation, and enhances the blockade
by depolarizing and non-depolarizing relaxants
this results from actions on the CNS and NMJ, as for enflurane
also, the increased blood flow due to peripheral vasodilatation enhances the delivery and removal
of these agents to the muscle
relaxation of uterine smooth muscle is the same as for halothane and enflurane
Kidney
isoflurane produces dose dependent reductions in,
c. urine production
NB: same at equivalent MAC as halothane & readily reversible
the quantity of F
-
ion released by degradation of isoflurane is small and there is no
contraindication to its use in renal disease
Liver and GIT
the incidence of nausea and vomiting is approximately the same as for other halogenated agents
there is minimal evidence of impaired hepatic function intraoperatively
hepatic failure has not been reported with isoflurane (??)
Biotransformation
only 0.2% of isoflurane is metabolised in the liver
this figure is ~ 1% of the amount for halothane (15-50%), and 10% of that for enflurane (2-5%),
and is due to,
i. the absence of bromine
ii. the presence of the ether bond
iii. the low oil:gas partition coefficient
iv. the F
3
C-C-O arrangement, increasing C-F bond strength
NB: increased stability of the molecule & less available to liver
the major metabolites are,
i. trifluoroacetic acid
ii. F
-
ion
however, the quantities produced are insufficient to cause cell damage
35
Advantages
b. low blood:gas partition coefficient
rapid induction of and recovery from anaesthesia
rapid changes in depth of anaesthesia
c. nonflammable & nonexplosive in combination with O
2
d. enhancement of muscle relaxation
e. incidence of arrhythmias is less than halothane
f. maintenance of CO and lack of myocardial depression
g. minimal biotransformation
h. ICP controllable via P
aCO2
Disadvantages
a. deep anaesthesia with isoflurane
respiratory & circulatory depression
b. more pungent odour and initial respiratory irritation
c. possible subendocardial steal syndrome with hypotension in IHD
d. uterine relaxation contraindicated at parturition
e. more expensive
36
METHOXYFLURANE
Structure:
Chemical name: 2,2-dichloro-1,1-difluoroethyl-methyl ether
Introduced: 1960
MAC: 0.16%
Bld-Gas:
Oil-Gas:
Fat-Bld:
12
970
Saturated Vapour Pressure: 3% 22.5 mmHg(20C)
Molecular Weight: 165 g
General Characteristics
MF is the most potent of the inhalational agents
because of its low vapour pressure and extreme solubility in rubber, as much as 30% of the agent
may be lost in the anaesthetic circuit
also, the high B:G coefficient further reduces the alveolar concentration early in induction
slow rise of F
A
/F
I
curve
thus, despite the low MAC, even with high inducing concentrations of 2-3%, induction may take
20-30 minutes
as for other agents, cardiovascular depression is the best guide to depth of anaesthesia
the extreme solubility of this agent in adipose tissue results in an extended, though pain free,
recovery period
due to renal toxicity and the availability of safer and effective agents, clinical use today is limited
37
Cardiovascular
decreases in HR, BP, baroreceptor responses, preganglionic SNS activity, are approximately the
same c.f. halothane at MAC equivalent doses
MF produces a dose-dependent depression of myocardial contractility, almost identical to
halothane and, as for halothane, alters TPR little
the reduction in BP being primarily the result of decreased cardiac contractility
the decrease in myocardial work is paralleled by a reduction in O
2
consumption and there is no
evidence of myocardial ischaemia
cardiovascular depressive effects are exaggerated by -antagonists as for the other agents
MF does interfere with impulse generation, conduction, and does sensitise the myocardium to
adrenergic agonists, though, to a slightly lesser degree than halothane
same precautions with adrenaline
Respiration
respiratory depression, hypercarbia, and inhibition of chemoreceptor responses are approximately
equal to those for halothane
as with other anaesthetic gases, pulmonary oxygen exchange is impaired and supplemental O
2
is
employed
as for halothane, MF causes bronchodilatation and does not stimulate the respiratory tract,
therefore premedication with atropine is not required
Nervous System
most CNS effects are similar to halothane,
a. CBF increased when perfusion pressure maintained
b. ICP follows changes in CBF
c. decreased cerebral O
2
consumption
d. early in hypotension CBF maintained then decreases as pressure continues to fall
Muscle
at deeper levels of anaesthesia, MF causes greater muscle relaxation than halothane, and the
enhancement of the effects of the competitive blockers is also greater
this is due to both a CNS effect and an effect at the postjunctional membrane of the NMJ
the later is not reversed by neostigmine
NB: in contrast to the other volatile agents, MF does not relax uterine muscle, thus
making it a useful agent for pain relief in the first stage of labour
38
Liver and GIT
impaired hepatic function is been observed intraoperatively, however is readily reversed on
cessation of anaesthesia
hepatic necrosis has been reported after administration of MF and probably relates to the
metabolic products
Renal System
MF causes dose dependent reductions in,
c. urine production
NB: same at equivalent MAC value for halothane & readily reversible
the major complication of MF anaesthesia is postoperative high output renal failure,
unresponsive to ADH
fluoride, F
-
ion, is a major metabolite of MF
patients receiving a dose equivalent to 2 MAC.hrs, frequently have plasma concentrations
above the renal threshold for toxicity (40-50 mol/l), with resultant direct distal tubular damage
polyuria, dehydration, hypernatraemia, azotaemia
in those who survive, recovery of renal function is usual, but may take up to 1 year
Biotransformation
as much as 50-70% of the absorbed dose is metabolised in the liver to,
i. F
-
ion
ii. oxalic acid
iii. difluoromethoxyacetic acid
iv. dichloroacetic acid
this high figure is due two factors,
i. despite the presence of the ether bond, the molecule is more susceptible to
metabolism (ethyl C
1
-F >> C
2
-F)
ii. the extreme oil:gas partition coefficient
NB: decreased stability of the molecule & more is available to liver
the peak serum F
-
concentrations are found 2-4 days postoperative
biotransformation may be increased by hepatic enzyme induction
39
Advantages
a. provides profound analgesia
b. nonflammable & nonexplosive in combination with O
2
c. enhancement of muscle relaxation
d. doesn't relax uterine smooth muscle analgesia in labour
Disadvantages
a. deep anaesthesia with MF
profound respiratory & circulatory depression
b. renal toxicity has effectively removed it from general use
c. slow induction, changes of depth, and emergence from anaesthesia
40
SEVOFLURANE
Structure:
Chemical name: 2,2,2-trifluoro-1-[trifluoromethyl]-
ethyl-fluoromethyl-ether
Introduced: Experimental
MAC: 1.71 0.07% (Katoh 1987)
Bld-Gas:
Oil-Gas:
Fat-Bld:
0.59
55
the clinically derived MAC is below that predicted by O:G partition coefficient 2.6%
volatile, nonflammable, halogenated ether which has the second lowest B:G solubility of the
volatile inhalational agents
it has a pleasant odour enabling very rapid induction & emergence
highly suitable for paediatric anaesthesia
biotransformation is similar to that for enflurane, with subnephrotoxic levels of F
-
being reached
no other signs of viscerotoxicity have been found in animal models
depresses the CVS but to a lesser degree than halothane and does not sensitise the myocardium
to catecholamines
no signs of increased CNS activity have yet been found
unstable in soda-lime, however, metabolites are apparently non-toxic
Miller states that it was withdrawn from clinical trials in 1980, possibly due to some reports of
renal toxicity
41
DESFLURANE
Structure:
Chemical name: 2,2,2-trifluoro-1-fluoroethyl-difluoromethyl ether
Introduced: Experimental
MAC: 6
Bld-Gas:
Oil-Gas:
Fat-Bld:
0.42
?
Critical Temperature: ?
the low solubility plus high vapour pressure:MAC ratio enable very rapid gaseous induction,
similar figure c.f. cyclopropane
desflurane is less pungent than isoflurane or enflurane, but more than sevoflurane or halothane
even so, the very rapid induction & emergence
highly suitable for paediatric anaesthesia
minimal metabolism and free F
-
production less than isoflurane
cost is likely to be the only negative factor preventing its widespread use
plus the requirement for pressurised delivery systems due to the low boiling point
one report of raised ICP unresponsive to hyperventilation, therefore may be contraindicated in
neuroanaesthesia
NB: Muzzi et al. Anaesthesiol. 1992
ICP with supratentorial tumours > isoflurane
42
Summary of Volatile Agent Effects
System Halothane Enflurane Isoflurane
Cardiovascular
heart rate
blood pressure
myocardial contractility
stroke volume
TPR
cardiac output
LVED pressure
coronary blood flow
coronary resistance
conduction (AV & LV)
myocardial excitability
--
-
--(-)
---
0(-)
-
++
--
+/-
---
+++
+/-
-
---
---
--
--
++
--
-/+
(-)
+
+/-
-
-
-
---
0(-)
0(+)
(-)
--(-)
(-)
0(+)
Central Nervous System
cerebral blood flow
vascular resistance
oxygen consumption
cerebrospinal fluid
formation
reabsorption
volume
intracranial pressure
excitability
++
--
--
+
+
0
++
0
++
--
--
+
-
++
+++
+++
+
(-)
-(-)
0
+
-
+/-
(+)
Respiratory
minute ventilation
tidal volume
respiratory rate
bronchial irritation
bronchial tone
-
--
+
+
-
---
-
-
++
-
-
--
+
+++
-
Reflexes
baroreceptor
chemoreceptor
central
peripheral
--
-
-
(-)
-(-)
--
-
--
--(-)
43
NITROUS OXIDE
Structure:
=
Chemical name: dinitrogen monoxide
Introduced: 1844
MAC: 105%
Bld-Gas:
Oil-Gas:
0.47
1.4
Critical Temperature: 36.5C
Boiling Point: -88C
Liquifying Pressure (36.5C): 74 bar ? 72 bar
Vapour Pressure (20C): 52 bar 39,000 mmHg
Normal Cylinder Pressure: 52 bar
N
2
O is a colourless gas, without appreciable odour or taste
first synthesised by Priestly in 1772
first used in anaesthetic practice by Cotton & Wells in 1844
marketed in steel cylinders as a liquid under pressure in equilibrium with the gas phase at normal
room temperature
the normal filling ratio = 0.65
heat is required to vaporise the liquid, latent heat of vaporisation
if this is rapid the cylinder becomes cold, lowering the vapour pressure of the cylinder
the gas is neither flammable, nor explosive, but will support combustion of flammable agents
Chemical Preparation
prepared commercially by heating ammonium nitratebetween 245-270 C
NH
4
NO
3
Heat N
2
O + 2H
2
O
contamination with the higher oxides of nitrogen, nitrogen dioxideor nitric oxide, may lead to,
a. laryngospasm
b. cyanosis due to methaemoglobinaemia
c. chemical pneumonitis and respiratory failure
44
Pharmacokinetics
nitrous oxide is a potent analgesic agent but a weak anaesthetic agent, producing surgical
anaesthesia predictably only under hyperbaric conditions
the rate of approach of alveolar to inspired concentration is rapid due to the low solubility in
blood
the rate of uptake, after inhalation of a 80%-N
2
O/20%-O
2
mixture,
a. at 1 min ~ 1000 ml/min
b. at 5 min ~ 500 ml/min
c. at 90 min ~ 100 ml/min
the time taken to reach 90% arterial saturation is about 20 min
this large uptake of gas, and rapid egress on emergence, results in,
a. the concentration effect
b. the second gas effect
c. diffusion hypoxia
although N
2
O has a "low" blood solubility c.f. other anaesthetic agents, it is considerably more
soluble than nitrogen (0.014) ~ 34 times
therefore, any closed, gas-filled cavity will expand during nitrous oxide anaesthesia as nitrogen is
exchanges for N
2
O, e.g.,
a. pneumothorax
b. occluded middle ear
c. pneumopericardium
d. closed loop intestinal obstruction
e. renal or lung cysts
f. pneumocranium
the main value of nitrous oxide in anaesthesia is as an adjuvant to the inhalational agents
with inhalation of 70%-N
2
O / 30%-O
2
, the MAC values are reduced ~ 35-45% as follows,
a. halothane 0.74% 0.29%
b. enflurane 1.68% 0.58%
c. isoflurane 1.15% 0.50%
NB: smaller doses of the volatile agents, with N
2
O, result in equal anaesthesia but less
cardio-respiratory depression
45
Central Nervous System
N
2
O depresses the CNS and produces analgesia
N
2
O increases cerebral blood flow and raises ICP
however these remain responsive to changes in the P
aCO2
and are less effected than with the
volatile agents
when used with barbiturate induction + droperidol/fentanyl + relaxant,
good anaesthesia and a moderate fall in ICP
Cardiovascular System
effects depend upon whether N
2
O is administered alone, with a volatile agent, or with narcotics,
a. N
2
O alone
small, direct myocardial depressant effect
CO, contractility & HR reduced
TPR increases, therefore no change in BP
small increase in circulating NA
b. N
2
O + volatile
circulating NA increases
CO, HR, TPR & BP all > volatile alone
SNS activation: Halothane > Isoflurane ~ Enflurane
increases the arrhythmogenic potential of all agents
less volatile agent required, therefore less cardiorespiratory depression
c. N
2
O + narcotic
generally causes only further circulatory depression
TPR may increase but this further reduces CO
with high dose fentanyl and poor LV function, myocardial depression may be
clinically significant
Respiratory System
effects on respiration are generally small
there is no change in the respiratory response to CO
2
there is a decrease in hypoxic drivewhen 50% N
2
O is inspired
there is no change in bronchomotor tone
46
Interaction with Vitamin B
12
B
12
is a bound coenzyme of methionine synthase, having a tetrapyrrole ring and a central cobalt
atom
N
2
O oxidizes the cobalt from Co
+
to Co
++
, which can no longer function as a methyl carrier
oxidation is irreversibleand new enzyme has to be synthesised effects last up to 3 days
NB: blockade of this reaction appears to be the sole metabolic action of N
2
O, with a
subsequent reduction of the two products,
i. tetrahydrofolate
ii. methionine
methionineis a dietary constituent, however daily requirements are ~ 2 times the average intake
in addition to its role in protein synthesis, methionine acts as a precursor to
S-adenosylmethionine(SAM), which is a direct methyl donator in a number of important
reactions,
a. noradrenaline adrenaline
b. synthesis of arachidonic acid
c. myelination of nerves
? decreased SAM subacute combined degeneration of the cord
d. SAM active formate, + THF 10-formyl-THF
the product 10-formyl-THF is a precursor to 5,10-methylene-THF which is essential for the
production of the essential DNA base deoxythymidine
after administration of N
2
O the first detectable changes are a reduction in methionine synthase
activity, followed soon after by an interference with DNA synthesis
the later is manifest by an abnormal deoxyuridine suppression test
47
following very prolonged administration, ( 4 days), agranulocytosis is an almost universal result
NB: "interference with thymidine synthesis is to be expected in man after 12 hrs of
exposure to N
2
O, but may appear within 2h or even less" Nunn (BJA 1987)
subsequent recommendations (Nunn),
a. N
2
O > 24h absolute contraindication
b. N
2
O ~ 24h reasonable for healthy patient
bone marrow will be megaloblastic
abnormal dU-suppression test
c. N
2
O 2h hepatic methionine synthasewill be depressed
effects on DNA synthesis unpredictable
d. N
2
O 0.5h no measurable effect
cumulative if interval < 3 days
replacement R
X
with methioninereduced the occurrence of neurological sequelae in
experimental monkeys
administration providing SAM for methyl transfer
this should theoretically also apply to man
replacement R
X
with folinic acid, (5-formyl-THF), cannot restore methionine levels, or its
products (SAM), but it can restore deoxythymidine synthesis
there is irrefutable evidence that N
2
O is a mild teratogen and this is undoubtedly due to its effects
on DNA synthesis
therefore, the use of N
2
O in pregnancy during the period of organogenesis is inadvisable
if necessary, cover with folinic acid may offer some protection
NB: the possibility of N
2
O abuse should be considered in any person with access to the
gas who presents with symptoms & signs resembling subacute combined
degeneration of the cord - especially dentists!!
Other Organ Systems
skeletal muscle does not relax in the presence of 80% N
2
O, and muscle blood flow is unaltered
unlike the halogenated GA's, N
2
O is most unlikely to contribute to malignant hyperpyrexia
the liver, kidneys, and GIT show no marked effects in response to N
2
O, and there is no evidence
of toxicity
N & V occur in ~ 15% of patients postoperative
48
Biotransformation
rapidly and predominantly eliminated unchanged through the lungs
significant biotransformation is unable to be assessed
Advantages
a. nonflammable & nonexplosive
b. non-irritant
c. potent analgesic
d. very rapid onset, changes in depth and recovery
e. little or no toxicity during normal applications
Disadvantages
a. weak anaesthetic agent
b. no augmentation of muscle relaxation
c. diffusion hypoxia on recovery
d. expansion of closed internal air-spaces
e. depressed methionine synthase activity
megaloblastic marrow changes
demyelination of the cord in long term abusers
49
DIETHYL ETHER
Structure:
Chemical name: di-ethyl ether
Introduced: 1846
MAC: 1.92
Bld-Gas:
Fat-Bld:
12
49
Flammable Range 2-36.5% Air
2-82% O
2

General Properties
first prepared by V. Cordus in 1540 by condensation with sulphuric acid
used for tooth extraction by W.E. Clarke in 1842
? first used by Crawford Long of Georgia
first public demonstration by W. Morton in 1846 in Boston
highly volatile and poor stability, therefore avoid light, heat, air
compatible with soda lime circuit
excellent analgesic stages/planes of anaesthesia (Guedel - see over)
stimulates respiration, therefore less danger of hypoxia
stimulates respiratory secretions, therefore need atropine
increases SNS activity but low arrhythmic potential
causes uterine relaxation
may cause hyperglycaemia
postoperative vomiting a major problem
chemical preparation by condensation of ethyl alcohol,
2 C
2
H
5
-OH C
2
H
5
-O-C
2
H
5
+ H
2
O
50
Stages of Anaesthesia - Guedel
Stage Of Analgesia
from the beginning of induction to the loss of consciousness
Stage Of Delerium
from the loss of consciousness to the beginning of surgical anaesthesia
excitement involuntary movement may be minimal or marked
breathing is irregular
skeletal muscle tone increases
increases in BP & HR may be marked
* the duration of this stage should be minimised
Stage Of Surgical Anaesthesia
from the beginning of surgical anaesthesia to the cessation of respiration
divided into four planes according to the depth of anaesthesia
differentiation is by assessment of
i. respiration
ii. eyeball movements
iii. pupillary size
iv. reflex responses
Stage Of Medullary Depression
from the weakened respiration of Plane 4, Stage 3 to circulatory failure
51
CHLOROFORM
Structure:
Chemical name: trichloromethane
Introduced: 1847
MAC: 0.72%
Boiling Point: 61 C
General Properties
anaesthetic action discovered by P. Flourens in France 1847
first employed by Simpson, in Scotland 1847
nonflammable
compatible with soda lime circuit
may contain impurities phosgene, chlorine, carbon tetrachloride
stabilised by 0.6 - 1% ethyl alcohol
light anaesthesia in the presence of adrenaline VF
increases SNS activity
depresses hepatic function and in large doses is hepatotoxic
may also be nephrotoxic
Manufacture
acetone with chlorine and lime; or, hydrogenation of carbon tetrachloride
in the presence of iron
52
CYCLOPROPANE
Structure:
Chemical name: cyclopropane
Introduced: 1844
MAC: 9.2%
Critical Temperature: 124.7C
Boiling Point -32.9C
Saturated Vapour Pressure: 6.3 bar ~ 90 psi (20C)
Normal Cylinder Pressure: ? bar
Flammable Range 2.4- 10.3% Air
? - 60% O
2
General Properties
first prepared by Freud, in Germany in 1881
first used for anaesthesia by R.M. Waters, in U.S.A.
must use in closed circuit to minimize cost and reduce danger of explosion
incompatible for use with nitrous oxide, as supports combustion
very rapid induction
SNS stimulant "cyclopropane shock"
respiratory depressant
arrhythmogenic, therefore must avoid adrenaline
good muscle relaxant
Manufacture
found as a natural gas
produced from dihalide propane,
CH
2
Cl-CH
2
-CH
2
Cl + Zn
++
cyclic -CH
2
-CH
2
-CH
2
- + ZnCl
2
53
TRICHLORETHYLENE
Structure:
Chemical name: trichlorethylene
Introduced: 1934
MAC: 0.17
Bld-Gas:
Oil-Gas:
9.15
?
Saturated Vapour Pressure: 8.5% 64.5 mmHg(20C)
General Properties
first manufactured by Fischer in Germany in 1864
first used clinically by Jackson in U.S.A. in 1934
nonflammable
unstable in soda lime circuit dichloracetylene
this causes cranial nerve palsies, esp. V & VII
stabilised with thymol 0.01%
potent analgesic
increases vagal tone but BP stable
arrhythmogenic, therefore problems with adrenaline
tendency to cause tachypnoea
approximately 25% metabolised
causes significant nausea and vomiting
Manufacture
from acetylene and chlorine CHCl=CCl
2
54

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