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Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
Pharmacokinetics of Inhalational Anaesthetics
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Pharmacokinetics of Inhalational Anaesthetics

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Pharmacokinetics of Inhalational Anaesthetics

Pharmacokinetics of Inhalational Anaesthetics

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  • 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

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