1. Pharmacokinetics of Inhaled Anesthetics Mehdi Sefidgar January 2015 Walls of text incoming....

2. 1 st things 1 st... Definitions Pharmacokinetics vs Pharmacodynamics? – Absorption (Uptake) – Distribution or Redistribution – Metabolism (Biotransformation) – Excretion (Elimination)

3. 1 st things 1 st.... Definitions Atmospheric pressure ~ 750-760mmHg – Force/unit-area exerted on a surface by the air above it Partial Pressure – Fractional force exerted by a specific gas in a mixture – DALTON’s LAW; Total pressure in a system = sum of all partial pressures of individual gases – What this actually means; When mixing gases, they each have the same partial pressure as they would have if they were each the only gas in the mixture Their partial pressures are additive. – Partial Pressure = total pressure x fractional volume of gas Ex for oxygen; Partial Pressure = 760 x 0.21 = 160mmHg – The reason you can use fractional volume is because of ideal gas law » Volume is proportional to mass

4. 1 st things 1 st.... Definitions Vapour Pressure – Pressure of gas when dealing with a gas/liquid phase system at equilibrium Tendency of the gas to want to escape liquid form – The pressure the gas phase is exerting on a closed container at a given temperature IDEAL GAS LAW: PV=nRT – Vapour Pressure is unrelated to volume of liquid phase. As long as there is even a little bit of liquid left the vapor pressure will remain constant. Boiling Point – The temperature at which Vapour Pressure > Atmospheric Pressure – The higher the intrinsic Vapour Pressure of a liquid the lower the boiling temperature will be

5. Vapour Pressure & Desflurane Vapour Pressure is why Desflurane is kept in special containers – Desflurane Boiling Temp of 23.5 o C – Desflurane Vapour Pressure at 20 o C is 669 mm Hg Recall atmospheric pressure is ~ 760 mm Hg – Recall Ideal Gas Law; PV=nRT V = nRT / P – By increasing the pressure of the system (ie. The bottle) we can prevent the volume of the gas phase from increasing (ie. boiling off)

6. Unique Features of Gases as Medications Nitrous, Xenon (true gases) Des/Sevo/Iso/Halo etc.. Technically vapour of volatile liquids – Only refers to state at certain temperatures We can group them together because as gases they all behave under the ideal gas law – PV=nRT Gases are non ionized with low molecular weights – Ie. Fast diffusion across blood/tissue, no need for active transport

7. Unique Features of Gases as Medications Gases interact with their environments based on partial pressures and NOT concentration – Meaning uptake and diffusion and effect of gases as medications is dependent on its partial pressure But Gases have to be transported to CSN via blood... In a liquid solution!

8. Gases in Solutions It gets a little tricky here; – Pressure of a gas (or partial pressure) can only be measured in the gas phase – While dissolved in a liquid or in solution, the amount of gas is measured as concentration – But recall we don’t care about the concentration but rather the partial pressure because gases will equilibrate and interact based on their partial pressure and NOT based on their concentrations So how do we figure out the partial pressure of a gas in solution?? – We have to imagine that a gas phase exists and is in equilibrium with the liquid phase HENRY’s LAW; concentration of a gas in solution is proportional to the partial pressure of the gas above the solution at equilibrium Solubility refers to the tendency of a gas to equilibrate with a solution – The higher the solubility the more gas (ie higher concentration) in solution for the SAME PARTIAL PRESSURE!

9. What does this mean for us? Gases will equilibrate based on their partial pressures & their solubility – So the partial pressure in the blood will equilibrate to the partial pressure in the alveoli The same thing happens at the blood/tissue membranes – Even though there is no gas phase at this level, there is still a partial pressure The bloodstream is like a closed desflurane container with limited total pressure preventing the gas phase from forming This equilibration process is very fast! – recall; non ionized, low molecular weight – For the sake of discussion we will assume its almost instantaneous Meaning This allows us to use the partial pressure in the alveoli as an estimate of the partial pressure in the CNS

10. Lets Put it All Together Turn on Vaporizer and Fresh Gas flow – Fresh gas mixes with a fixed fractional concentration of inhaled anesthetic (that we set) – This then mixes with the gas in the rest of the circuit Bag, CO 2 canister, circuit tubing Initially what we set as our desired concentration will be diluted until the system equilibrates – This will be determined by; Fresh gas flow rate Solubility of inhaled anesthetics with the plastic components The fractional concentration of anesthetic leaving the circuit and entering the patient is designated F I (Fraction inspired) This then mixes with gases in lungs and gets further diluted before reaching alveoli The fractional concentration of anesthetic gas in alveoli is designated F A (Fraction alveolar)

11. Uptake Rate of Uptake is determined by F A / F I – The quicker alveolar fractional concentration reaches inspired concentration the quicker the onset of effect of the drug – Recall F A is proportional to partial pressure (based on Ideal Gas Law) Partial pressure = 760 x fractional % Ie. Des @ 1 MAC = 760 x 0.06 (6%) So lets look at each component separately

12. FIFI As anesthetic gases comes into the circuit, the F I will rise based on 1 st order kinetics (see formula) F FGO is the fractional cocentration of our inhaled anesthetic T is time t is time constant – Time constant = volume (capacity) of circuit / fresh gas flow Ex; If our circuit is 8L and we set our FGF to 2L/min our time constant = 8/2 = 4 Principles of 1 st order kinetics mandate that – After 1 time constant 63% of maximum is achieved – After 3 time constants you reach 95% of maximum SO, we can increase the rate of F I by either increasing the fractional concentration we set or by increasing the fresh gas flow (in order to decrease the time constant)

13. F I Example Calculation Lets say we want an F I of 6% Example – We can set our vaporizer dial to 6% – If our time constant is 4 min (8L/2L per min) it will take 3 time constants (12 minutes) to reach 6% F I We can increase our fresh gas flow rate to decrease the time constant; lets say 16L/min (time constant of 0.5 min), – in this case we would reach 6% F I in 1.5 minutes – This is the most important factor when it comes to increasing spead of rate of rise of F I – But this is horribly inefficient and wastes lots of gas Alternatively we can increase our dial concentration – Keeping time constant at 4 min – We know that at 1 time constant we reach 63% of maximum (based on 1 st order kinetics), so if we want to reach 6% at 1 time constant we need to set our dial to 9.5 (6/0.63) – By doing this we will reach 6% F I in 4 minutes and then can lower our dial to 6% afterwards What are other ways of decreasing the time constant??

14. Things that Slow down F I Obviously if we set lower concentrations or FGF rates Other factors – CO 2 absorbent degredation of inhaled anesthetics – Solubility of inhaled gas with plastic components of circuit – Both of these play minor roles

15. So far we have been assuming that the pt is not breathing and just looking at the circuit equilibration of F I In reality, as the pt exhales, the gases from the lungs further dilute the anesthetic gas in the circuit and decrease F I – This holds true for any fresh gas flow < 4L/min – At FGF > 4L/min you get little mixing of exhaled breaths and the gases in the circuit, excess gas is shunted off via pop off valve

16. FAFA If we assume for the moment that there is no uptake by the blood, then F A rises similarly to F I – Meaning 1 st order kinetics – Except for the time constant the capacity will now be the FRC and our “flow rate” will be the Minute ventilation So the same principles apply when we want to speed up the rate of F A approaching F I – We can either decrease the FRC or increase the Minute ventilation to decrease our time constant – Or we can try to increase our F I as a starting point

17. FAFA Things get more complicated when you actually take into account blood flow – Now some of the anesthetic gas in the alveoli is going to be taken up by the blood – How much is determined by the solubility and blood flow – Remember its the partial pressure we care about and since the partial pressure in the alveoli is pretty much equal to the partial pressure in the CNS we want to try to increase our alveolar partial pressure Agents with higher solubilities will dissolve easier into the blood but this will result in more being taken up and less remaining in the alveoli Meaning a LOWER partial pressure remaining in the alveoli So even though a higher solubility means higher concentration in the blood, it ends up meaning a LOWER partial pressure! Think about Solubility as increasing our capacity in the time constant equation, increasing our capacity will slow down our rate of rise and therefore our desired effect The most important factor in the rate of rise of F A / F I is the uptake by the bloodstream – This is governed by the solubility of the anesthetic agent

18. F A / F I The rate of uptake of any agent by the bloodstream is governed by the FICK Equation – V B = uptake by blood – Delta is the blood:gas partitian coefficient (ie. Solubility in blood) – Q = Cardiac output – P A = alveolar partial pressure of anesthetic – P V = venous partial pressure of anesthetic – P B = barometric pressure

19. Rate of rise of F A / F I So we can use all the previous equations including the FICK equation to determine what factors will speed up an inhalational induction or slow it down Based on the FICK equation; Anything that increases V B will slow us down as more anesthetic gets taken up by the blood resulting in lower partial pressure in the alveoli and therefore in the CNS

20. So what factors affect the rate of rise of F A / F I in a normal patient Solubility – Lower solubility means less anesthetic gas taken away from the alveoli resulting in higher partial pressure and an increase in F A :F I Cardiac output – Lower cardiac output will take less of our anesthetic gas away to other tissues (fat, muscles, etc.) and leave more to build up partial pressure in the alveoli (and also CNS) Minute ventilation – Higher minute ventilation will decrease our time constant and speed up equilibration F I – Higher F I results in higher F A P A – P V – As alveolar partial pressure minus venous partial pressure reaches 0, the rate of F A / F I increases rapidly

21. FUN FACTS Increasing Minute ventilation will have a bigger impact on rate of rise of F A / F I for more soluble anesthetics than it will for less soluble anesthetics – Less soluble anesthetic will still have a faster rate of rise of F A / F I Same thing for Cardiac Output – Increased cardiac output will slow down rate of rise of F A / F I more so for more soluble agents

22. Doubling CO should decrease F A /F I Doubling MV should increase F A /F I But both at the same time would cause a slight increase in F A /F I – Because Increasing cardiac output would also decrease P A – P V which would slightly increase F A /F I FUN FACTS

23. Distribution After uptake (and even during) anesthetic gases are being distributed to various tissues – Generally broken down into 3 categories Vessel rich group (highest blood flow) – ~ 75ml/min/100g of tissue – Brain, heart, kidneys, liver, digestive tract, glandular tissue Muslces – ~ 3ml/min/100g of tissue Fat (lowest blood flow) – ~ 1-2ml/min/100g of tissue At each of these tissues there are separate solubilities and partition coefficients Pts will continue to take up anesthetics until all compartments are equilibrated, however this takes time – Mainly due to low blood flow to the muscle and fat groups

24. Metabolism of Anesthetics Most enzymes that metabolize anesthetic gases are saturated at doses much less than that required for MAC Metabolism does NOT play a significant role in affecting either the rate of induction or emergence

25. Elimination Insignificant losses via skin and abdominal viscera – More so with open abdominal surgeries but still small Fat tissue around muscles can steal anesthetics by diffusion – This can account for ~ 1/3 of uptake in long cases During recovery fat tissue can still be absorbing anesthetics – This redistribution accounts for the early recovery – Regardless of time of infusion (you never fully saturate fat stores, takes weeks..)

26. Quiz What effect does V/Q mismatch have on rate of rise of F A / F I ? What effect will a Left to Right Cardiac Shunt have on rate of rise of F A / F I ? What about a Right to Left Cardiac Shunt?

27. Questions?