Transcript Pharmacokinetics of Inhaled Anesthetics

Pharmacokinetics of Inhaled
Anesthetics
Mehdi Sefidgar
January 2015
Walls of text incoming....
1st things 1st... Definitions
• Pharmacokinetics vs Pharmacodynamics?
– Absorption (Uptake)
– Distribution or Redistribution
– Metabolism (Biotransformation)
– Excretion (Elimination)
1st things 1st.... 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
1st things 1st.... 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
Vapour Pressure & Desflurane
• Vapour Pressure is why Desflurane is kept in
special containers
– Desflurane Boiling Temp of 23.5o C
– Desflurane Vapour Pressure at 20o 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)
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
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!
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!
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
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, CO2 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 FI (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 FA
(Fraction alveolar)
Uptake
• Rate of Uptake is determined by FA / FI
– The quicker alveolar fractional concentration
reaches inspired concentration the quicker the
onset of effect of the drug
– Recall FA 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
FI
• As anesthetic gases comes into the circuit, the FI will rise
based on 1st order kinetics (see formula)
• FFGO 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 1st 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 FI by either increasing the
fractional concentration we set or by increasing the fresh
gas flow (in order to decrease the time constant)
FI Example Calculation
• Lets say we want an FI 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% FI
• 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% FI in 1.5 minutes
– This is the most important factor when it comes to increasing spead of
rate of rise of FI
– 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
1st 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% FI in 4 minutes and then can lower our
dial to 6% afterwards
• What are other ways of decreasing the time constant??
Things that Slow down FI
• Obviously if we set lower concentrations or
FGF rates
• Other factors
– CO2 absorbent degredation of inhaled anesthetics
– Solubility of inhaled gas with plastic components
of circuit
– Both of these play minor roles
• So far we have been assuming that the pt is not
breathing and just looking at the circuit
equilibration of FI
• In reality, as the pt exhales, the gases from the
lungs further dilute the anesthetic gas in the
circuit and decrease FI
– 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
FA
• If we assume for the moment that there is no
uptake by the blood, then FA rises similarly to FI
– Meaning 1st 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 FA approaching FI
– We can either decrease the FRC or increase the
Minute ventilation to decrease our time constant
– Or we can try to increase our FI as a starting point
FA
• 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 FA / FI is the uptake by
the bloodstream
– This is governed by the solubility of the anesthetic agent
FA / FI
• The rate of uptake of any agent by the bloodstream is
governed by the FICK Equation
– VB = uptake by blood
– Delta is the blood:gas partitian coefficient (ie. Solubility in
blood)
– Q = Cardiac output
– PA = alveolar partial pressure of anesthetic
– PV = venous partial pressure of anesthetic
– PB = barometric pressure
Rate of rise of FA / FI
• 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 VB 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
So what factors affect the rate of rise
of FA / FI 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 FA:FI
• 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
• FI
– Higher FI results in higher FA
• PA – PV
– As alveolar partial pressure minus venous partial
pressure reaches 0, the rate of FA / FI increases
rapidly
FUN FACTS
• Increasing Minute ventilation
will have a bigger impact on
rate of rise of FA / FI for more
soluble anesthetics than it will
for less soluble anesthetics
– Less soluble anesthetic will still
have a faster rate of rise of FA /
FI
• Same thing for Cardiac Output
– Increased cardiac output will
slow down rate of rise of FA / FI
more so for more soluble
agents
FUN FACTS
• Doubling CO should
decrease FA/FI
• Doubling MV should
increase FA/FI
• But both at the same
time would cause a
slight increase in FA/FI
– Because Increasing
cardiac output would
also decrease PA – PV
which would slightly
increase FA/FI
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
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
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..)
Quiz
• What effect does V/Q mismatch have on rate
of rise of FA / FI ?
• What effect will a Left to Right Cardiac Shunt
have on rate of rise of FA / FI ?
• What about a Right to Left Cardiac Shunt?
Questions?