Pharmacokinetics of Inhalational Anaesthetics

1. Speaker: Dr Bhagirath.S.N

2. Presentation outlinePresentation outline
 History of pharmacokinetics of inhalational anesthetics
 Basic concepts of pharmacokinetics
 Inspiratory concentration ( FI )
 Alveolar concentration ( FA )
 Factors affecting alveolar uptake
 Solubility
 Alveolar blood flow
 Partial pressure difference between alveolar gas and venous blood.
 Factors affecting tissue uptake
 Tissue solubility
 Tissue blood flow
 Partial pressure difference between arterial blood and tissue.
 Anaesthetic uptake curve
 Ventilation
 Concentration Effect
 Concentrating Effect
 Augmented Inflow Effect
 Factors affecting arterial concentration ( Fa )
 Factors affecting elimination

3. Pioneers in the field of pharmacokinetics of inhalationalPioneers in the field of pharmacokinetics of inhalational
anestheticsanesthetics
Kety was among the first to explore the pharmacokinetics of
Inhalational anesthetics in his article “The physiological and physical
factors governing the uptake of anesthetic gases by the body” in 1950
edition of Anesthesiology. Best remembered for discovering methods
to document blood flow patterns in brain and work on Schizophrenia.
Late Seymour Kety
Professor Emeritus of Neuroscience,
Mclean Hospital, Massachusetts
Edmond Eger keenly followed up on Kety’s foundations
and nearly two decades later in 1974 published his
findings under the title “Anesthetic uptake and action”
He is best remembered for development of
Desflurane, which he defends vehemently till today…!
Edmond.I.Eger
Professor Emeritus of Anesthesia & Perioperative care,
University of California, San Francisco

4. Understanding Basic concepts…………….Understanding Basic concepts…………….1 of 31 of 3
Partial pressure of a gas in a mixture of gases is the pressure it would
have if it alone occupied the entire volume. This pressure is
proportional to its fractional mass in the mixture of gases.
Solubility
Partial pressures assume importance because gases equilibrate
based on partial pressures, not concentrations.
Partial Pressure in
gaseous phase
Partial pressure in
Solution
Since pressure of a gas can only be measured in gaseous phase, while
in solution we measure concentration as an indicator of amount of gas.
Partial pressure of a gas in solution, therefore refers to the pressure of
the gas in the gas phase (if it were present) in equilibrium with the
liquid.
Why speak in
terms of partial
pressure ?
Describes the tendency of a gas to equilibrate with a solution, hence
determining its concentration in solution.
For any gas in equilibrium with a liquid, a certain volume of the gas
dissolves in a given volume of the liquid.-Henry’s Law
Need to know
partial pressure &
solubility
As it helps us to estimate the concentration of a particular gas in a
mixture of gases in solution and ultimately aids in estimating it’s
clinical effect.

5. Understanding Basic concepts…………….Understanding Basic concepts…………….2 of 32 of 3
The implications of these properties are that anesthetic gases administered via the
lungs diffuse into blood until the partial pressures in alveoli and blood are equal.
transfer of anesthetic from blood to target tissues also proceeds
toward equalizing partial pressures
because gases equilibrate throughout a system based on partial pressures
monitoring the alveolar concentration of inhaled anaesthetic provides an index of their
effects in the brain
PALVEOLI=PBLOOD=PCNS
To put it in another way, faster rise in alveolar concentrations of a given anesthetic
herald a faster induction
.

6. Understanding Basic concepts…………….Understanding Basic concepts…………….3 of 33 of 3
A partition coefficient describes the relative affinity of an anesthetic for
two phases at equilibrium
Partition
Co-efficient
The blood-gas partition coefficient (λ, or “blood solubility”) describes the
partitioning of an anesthetic between blood and gas
For example, Isoflurane has a blood-gas partition coefficient of 1.4,
which means that at equilibrium, the concentration of Isoflurane in blood
is 1.4 times its concentration in the gas (alveolar) phase.
“Equilibrium” means that no difference in partial pressure
The partition coefficient indicates the relative capacity of the two phases
to hold an anesthetic.
To summarise, if a given anesthetic achieves a partial pressure ‘P’ with a
concentration of 1 in a particular phase (gaseous phase), then to achieve
the same partial pressure ‘P’ in a different phase (say liquid phase) it
needs 1.4 times the concentration of the same anesthetic.
Clinical
Implication
A larger blood-gas partition co-efficient produces greater uptake and slower
induction.

7. Concept of FConcept of FA,A, FFII and Fand FAA / F/ FII ratioratio
The fractional concentration of anesthetic leaving the circuit is designated as FI
(fraction inspired).
The fractional concentration of anesthetic present in the alveoli after
undergoing dilution in the dead space of the airways (trachea, bronchi) is
referred to as FA (fraction alveolar).
FI
FA
FA /
FI
If FA = FI, then it implies that, very little anesthetic is being taken up from the
alveoli and whatever anesthetic is inspired is accumulating in the alveoli.
But in reality, pulmonary circulation does take up anesthetic from the alveoli
and therefore FA always lags behind FI i.e. FA / FI ratio is < 1.0
Greater the uptake, slower the rate of rise of alveolar concentration and
lower the FA / FI ratio i.e. longer it takes for induction to achieve.

8. Factors affecting Inspiratory Concentration (FI)
The patient does not necessarily receive the same concentration set on the vaporizer as
there are numerous intervening factors which vary the concentration.
FGF Rate : Higher the rate of FGF, closer the inspired gas concentration will be to
fresh gas concentration.
Breathing Circuit
Volume:
Smaller the volume, closer the inspired gas concentration will be to
the fresh gas concentration.
Circuit Absorption: lower the circuit absorption, closer the inspired gas concentration will be
to the fresh gas concentration.

9. Factors affecting Alveolar Concentration (FA)
FA depends on uptake of anaesthetic by pulmonary circulation. If this uptake is poor, then
FA increases rapidly towards FI i.e. FA / FI =1.0
If on the other hand, pulmonary circulation readily takes up the anaesthetic agent, then FA
takes a longer time to equal FI
FA is nothing but the partial pressure of the anaesthetic. Since there is always a tendency to
equilibrate partial pressures of a given anaesthetic in alveoli, blood and brain; slower the
rise in partial pressure in alveoli (due to rapid uptake), more delayed will be the onset of
clinical action in brain.
Greater the uptake of anaesthetic agent, greater the difference between inspired and
alveolar concentrations and slower the rate of induction.
Fick’s equation:
VB = ∂b/g x Q x PA-PV / PB VB = Blood uptake
∂b/g = blood / gas partition
co-efficient.
Q = Cardiac output
PA = Alveolar partial pressure
Pv = Mixed venous partial pressure
PB = Barometric Pressure

10. Factors affecting Uptake
Describes the tendency of a gas to equilibrate with a solution, hence
determining its concentration in solution.
1. Solubility
2. Alveolar Blood flow
3. Partial pressure difference between alveolar gas & venous blood.
Solubility
Partition
Co-efficient
A partition coefficient describes the relative affinity of an anesthetic for
two phases at equilibrium
Relative solubility of an anaesthetic in air, blood and tissues are
expressed as partition co-efficients.
The ratio of concentrations of anaesthetic gas in two phases at
equilibrium is represented as partition co-efficient.
i.e. if a given anesthetic achieves a partial pressure ‘P’ with a
concentration of 1 in a particular phase (gaseous phase), then to achieve
the same partial pressure ‘P’ in a different phase (say liquid phase) it
needs 1.4 times the concentration of the same anesthetic.

11. Partition Coefficients ofVolatile Anesthetics at 37°c
Greater the co-efficient, more the solubility
More the solubility, greater the uptake
Greater uptake means longer time required for FA to approach FI
More the time required for FA to approach FI,
longer it takes for induction to be achieved.

12. Alveolar Blood FlowAlveolar Blood Flow
In absence of shunting (pulmonary), cardiac output equals alveolar blood flow. i.e. uptake
of anesthetic increases or decreases with rise or fall in cardiac output.
If cardiac output increases, uptake increases, FA takes longer to approach FI, Induction is
delayed. Less soluble an anesthetic, less relevant cardiac output becomes.
In low output states, there is less Cardiac output to take up anesthetic
So FA rapidly approaches FI
Predisposes patient to over dosage
Over dosage leads to cardiac depression
Decrease in Cardiac output
Lower output state Lesser Uptake
Vicious cycle:
(Positive Feedback
Mechanism)

13. Partial pressure difference between alveolar gas and venous blood
This difference relies entirely on tissue uptake
As tissues take up from blood, the partial pressure of the anesthetic in blood decreases
relative to alveoli, thus setting up a gradient between the alveoli and blood encouraging
greater uptake.
Factors which determine Tissue uptake
Tissue solubility (tissue/blood partition co-efficient)
Tissue blood flow
Partial pressure difference between arterial blood and tissue.
Vessel poor group
includes additional
compartment: tendons,
ligaments, cartilage,
teeth and hair.

14. Highly perfused vessel rich group
-Brain, Heart, Liver, Kidney, Endocrine organs
-Limitation of this group-moderate solubility, smaller volume
-Owing to high perfusion, these tissues take up first and get saturated.
Muscle Group
-Skin, muscle-not well perfused-so slower uptake
-But due to larger volumes-greater capacity-sustained uptake for hours
Fat Group
-Almost equal to muscle group
-Tremendous solubility of anesthetic leads to a total capacity that would take days to fill.
Vessel Poor Group
-Bones, ligaments, teeth, hair and cartilage.
-Minimal perfusion-insignificant uptake.
Initial steep rise
as perfusion rich
organs are still
taking up. Once
they reach their
capacity, uptake
is slower. Hence
curve is more
flatter.

15. VentilationVentilation
Essentially amounts to replacing the anaesthetic in the alveoli that has been taken up by
pulmonary blood flow.
Greater the Uptake
More needs to be replaced
Ventilation has to be increased
Increasing ventilation rapidly makes more sense for soluble anaesthetics as their uptake is
faster. (is of little consequence if anesthetic is less soluble)
Highly soluble anesthetic (Halothane)
Faster uptake
Depresses ventilation
So slower replacement for an anesthetic that is being taken up faster
Negative Feedback
Mechanism

16. ConcentrationConcentration
Increased uptake tends to decrease FA. To counter this, Inspired concentration can be
increased. (“Over pressurisation”: analogous to Intravenous bolus)
Two consequences of this are:-
 Increasing FIincreases FA
 Increasing FIincreases rate of rise of FA / FI “Concentration Effect”
Concentration Effect consists of two Phenomena:
•Concentrating effect
•Augmented Inflow effect

17. CONCENTRATING EFFECTCONCENTRATING EFFECT
Uptake of 50 % anesthetic from the alveoli causes a shrinking of alveolar volume
Relative to the reduced volume, the remaining 50 % of the anesthetic concentration
constitutes no longer 50% but instead amounts to a concentration higher than that.
i.e. relative to the reduced volume, the anesthetic is concentrated following uptake.
If in addition to this new anesthetic floods the alveoli (thanks to ventilation), there will be
a several fold increase in alveolar concentration.

18. AUGMENTED INFLOW EFFECTAUGMENTED INFLOW EFFECT
If 50 % of an anesthetic is taken up by the pulmonary circulation, an inspired
concentration of 20 % (20 parts of anesthetic per 100 parts of gas) will result in an
alveolar concentration of 11 % (10 parts of anesthetic remaining in a total volume of 90
parts of gas)
The 10 parts of absorbed gas must be replaced by an equal volume of 20 %
mixture to prevent alveolar collapse.
i.e. relative to the reduced volume, the anesthetic is concentrated following uptake.
Thus the alveolar concentration becomes 12 % (10 + 2 parts of anesthetic in a total of
100 parts of gas)

19. SECOND GAS EFFECTSECOND GAS EFFECT
In contrast after absorption of 50 % of the anesthetic in the 80 % gas mixture, 40 parts
of 80 % gas must be inspired.
This further increases the alveolar concentration from 67 % to 72 % (40 +32 parts
of anesthetic in a volume of 100 parts of gas)
Concentration effect of N2O is more significant than with other volatile anesthetics owing
to greater concentration in which N2O can be used.
Effectively a high concentration of N2O will not only augment its uptake but also any
other gas with it-- Second gas effect

20. Factors affecting Arterial Concentration (Fa)
Ventilation Perfusion mismatch
General assumption: Partial Pressure alveoli = Partial pressure arterial circulation
Reality: Partial Pressure alveoli > Partial pressure arterial circulation
Probable reasons: Venous admixture
Alveolar dead space
Non-uniform alveolar gas distribution
For highly soluble agents: initially increased Partial Pressure in alveoli
But, after mixing with unventilated blood, normal
Anesthetic content is maintained.
For poorly soluble agents: anesthetic deficient blood mixes with
Normal
Anesthetic containing blood
Mixing leads to dilution
Reduction of arterial anesthetic partial pressure

21. Factors affecting Elimination
Recovery from any anesthesia depends on lowering the brain anesthetic concentration.
This elimination can happen secondary to
• Biotransformation (more with soluble agents)
• Transcutaneous loss (minimal)
• Exhalation (Most important)
Factors which tend to speed induction tend to speed recovery
• Elimination of rebreathing
• High FGF
• Low anesthetic circuit volume
• Low absorption from circuit
• Decreased solubility
• High cerebral blood flow
• Increased ventilation

22. Diffusion Hypoxia
N2O elimination is so rapid that it mixes with and dilutes alveolar oxygen and
carbon-di-oxide. This leads to hypoxia.
Prevention
Even after discontinuing N2O administration, administration of 100 % Oxygen for 5 –
10 minutes will prevent diffusion hypoxia by counter-acting the dilution.
Clinical Significance
Failure to administer 100 % Oxygen before discontinuing N2
O will result in a drastic
decrease in Saturation levels which ought to be recognized early and addressed to
prevent critical situation.

23. Recovery
Recovery in general is faster than induction because apart from those compartments
(brain) that take up anesthetic agent quickly, there are other compartments (eg: Fat)
which take up anesthetics slowly and therefore over a prolonged duration.
Implication of this is that long after administration of Inhalational agent has been
stopped, these compartments (fat) are still in the process of saturating themselves by
taking up anesthetic from blood.
This results in drop in arterial partial pressure of anesthetic
To equilibrate partial pressures blood tends to take up more
anesthetic from the alveoli
Decrease in partial pressure of anesthetic in alveoli
So with increased uptake, progressive decrease in alveolar
partial pressure ensues
Hastens
Recovery

24. Recovery
If it is prolonged anaesthesia (>4 hours), there is enough time to saturate all
compartments and consequently the rate of decline in alveolar partial pressures is less
i.e. recovery takes a longer time.
Conclusion: Recovery depends on duration of anaesthesia

25. ReferencesReferences
Miller’s Anesthesia 7th
Edition
P 540-555
Clinical Anesthesia by Barash
P 413-424

26. Pharmacology & Physiology in
Anesthetic Practice by
Robert.K.Stoelting
P 23-33
A Practice of Anesthesia by Wylie
and Churchill Davidson
P