Speaker: Dr Bhagirath.S.N

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

Pioneers in the field of pharmacokinetics of Pioneers in the field of pharmacokinetics of inhalational anestheticsinhalational anesthetics

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 KetyProfessor 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.EgerProfessor Emeritus of Anesthesia & Perioperative

care, University of California, San Francisco

Understanding Basic Understanding Basic concepts…………….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.

Understanding Basic Understanding Basic concepts…………….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.

Understanding Basic Understanding Basic concepts…………….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.

Concept of FConcept of FA, A, FFII and F and FAA / F / FII ratio ratio

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.

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.

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

Factors affecting Uptake

Describes the tendency of a gas to equilibrate with a solution, hence determining its concentration in solution.

1. Solubility2. Alveolar Blood flow3. 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.

Partition Coefficients of Volatile 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.

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)

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.

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.

VentilationVentilationEssentially 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

ConcentrationConcentrationIncreased 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 FI increases FA

Increasing FI increases rate of rise of FA / FI

“Concentration Effect”

Concentration Effect consists of two Phenomena: •Concentrating effect

•Augmented Inflow effect

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.

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)

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

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, normalAnesthetic content is maintained.

For poorly soluble agents: anesthetic deficient blood mixes with Normal Anesthetic containing blood

Mixing leads to dilutionReduction of arterial anesthetic partial pressure

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

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 N2O will result in a drastic decrease in Saturation levels which ought to be recognized early and addressed to prevent critical situation.

RecoveryRecovery 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

RecoveryIf 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

ReferencesReferences

Miller’s Anesthesia 7th EditionP 540-555

Clinical Anesthesia by BarashP 413-424

Pharmacology & Physiology in Anesthetic Practice by Robert.K.StoeltingP 23-33

A Practice of Anesthesia by Wylie and Churchill DavidsonP