INHALATIONAL AGENTS – UPTAKE AND DISTRIBUTION P C A Kam

Minimum alveolar concentration (MAC)

1. The minimum alveolar concentration at 1 atmosphere that produces immobility in

50% of patients or animals exposed to a noxious stimulus.
2. A measure of anesthetic potency.
3. Equally applicable to all inhaled anesthetics.
4. Measured at equilibrium, where the partial pressure at the site of action presumably
equals the partial pressure in the alveolus.
1. Anesthetic effect results from the partial pressure of the gas at the
site of drug effect, not the concentration.
2. Gases diffuse down their partial pressure gradients, regardless of the
total partial pressure of all gases present!
5. Factors not affecting MAC:
1. Eger claims that stimulus intensity (e.g. skin incision, tail clamp, 50
Hz current via needle electrodes) does not affect MAC. Subsequent
research and every day clinical experience suggests this may not be
true.
2. Small variability between individuals within a species (SD = + 10-20
percent).
3. Varies by about 50% between species.
4. No gender effect.
5. No time effect (e.g. MAC after 10 hours of anesthesia is the same as
MAC during the first hour.)
6. No effect from pH.
7. No effect from pCO2, (except when over 90 mm Hg) despite widely
held belief that elevated CO2 increases anesthetic requirement.
8. Elevations in blood pressure.
9. Mild drops in blood pressure.
10. Hypothyroidism
 11. Chronic alcoholism probably doesn't affect MAC.
12. Anemia (unless sufficiently severe to cause tissue hypoxia)
6. Factors affecting MAC:
1. Significant hypoxia (below 40 mm Hg) decreases MAC.
2. Hypothermia decreases MAC.
3. Hyperthermia increases MAC.
4. Hyperthyroidism slightly raises MAC (about 15%)
5. Increasing age decreases MAC:
Neonatal Halothane MAC: 1.1
70 y.o. MAC: 0.63
6. Circadian rhythms alter MAC + 10%
7. Opioids reduce MAC, but there is a ceiling effect beyond which
additional opioid does not lower MAC.
8. Diazepam reduces MAC.
9. Scopolamine slightly lowers MAC.
10. Other volatile agents reduce MAC:
MACs are additive:
50% N2O + .5MAC Halothane = 1 MAC of anesthetic
11. Drugs which reduce central catecholamines lower MAC:
Reserpine
Alpha methyl dopa (Aldomet)
chronic amphetamine use
clonidine
12. Drugs which raise central catecholamines raise MAC:
acute amphetamine intoxication
ephedrine
MAO inhibitors
13. Relaxants lower MAC slightly (but don't push your luck!)
14. Pregnancy decreases MAC
G. MACawake = minimum alveolar concentration at which patients still respond
to commands. Originally thought to be about 0.6 MAC. Subsequent work
suggests it is closer to 0.2 MAC, at least for isoflurane.
 H. MACei = minimum alveolar concentration to block movement to
endotracheal intubation. About 1.3 MAC.
I. MACbar = minimum alveolar concentration to block adrenergic
responsiveness. About 1.5 MAC.

Mechanisms of General Anesthesia

A. Wide variety of agents cause anesthesia:
Drug MAC
Halothane 0.77%
Isoflurane 1.11%
Enflurane 1.66%
Nitrous Oxide 110%
Nitrogen 30 ATM
Hydrogen 180 ATM
B. Interaction of anesthetics is through Van der Waals forces, not covalent bonding.
C. No structure-activity relationship for inhaled anesthetics.
D. Anesthetic potency correlates amazingly well with the anesthetic oil/gas partition
coefficient: MAC * oil/gas partition coefficient = 2.08 + 20%.
- Strongly suggests a lipid site of anesthetic effect.
E. Inhaled anesthetics appear to act at many sites in the CNS.
F. Very high pressure (e.g. 5-50 atmospheres) can reverse the effects of anesthetics
G Good evidence for protein Theories
Luciferase experiments suggest protein enzymes or receptors involved
Evidence that specific protein receptors are involved
GABAa (volatile agents) and NMDA (eg Xenon) receptors are involved

Uptake of Inhaled Anesthetics.

A. Factors raising the alveolar concentration, assuming a constant inspired anesthetic
concentration, and no uptake by blood:
1. The inspired concentration.
 a. The rate of rise is directly proportional to the inspired concentration.
2. The alveolar ventilation
a. The larger the minute alveolar ventilation (Valveolar), the more rapid
the rise in alveolar concentration.
b. Inspired gas is diluted by the FRC, so the larger the FRC, as a
fraction of Valveolar, the slower the alveolar rise in anesthetic
concentration.
c. For ventilatory rates over 4 half breaths, the ventilatory rate does not
make any difference at the same Valveolar.
3. The time constant
The time required for flow through a container to equal the capacity of the
container (e.g. volume/flow)
Time Constant % washin/washout
1 63%
2 86%
3 95%
4 98%

The time constant for the lungs is FRC/Valveolar.

The time constant for the anesthesia circuit is circuit capacity/FGF.
4. The larger the FRC, the slower the washin of a new gas.
5. The rate of rise of the alveolar concentration is greatly slowed by anesthetic
uptake by the blood.

B. Factors determining uptake by blood.

1. Solubility in blood:
a. The blood/gas partition coefficient.
b. The relative capacity per unit volume of two solvents (e.g. gas and
blood) to hold the anesthetic gas.
c. The relative molar amount in equal volumes of blood and gas when
the partial pressures are equal.
 Gas Blood/Gas Brain/Blood
Nitrous Oxide 0.47 1.06
Isoflurane 1.41 2.60
Enflurane 1.78 1.45
Halothane 2.30 2.30
Diethyl Ether 12.1 1.03
Methoxyflurane 12.0 1.70

d. Other things equal, the more soluble the anesthetic, the more drug
will be taken up by the blood, and the slower the rise in alveolar
concentration.
2. Cardiac Output:
a. The flow of blood through the lungs determines the amount of blood
available to remove anesthetic gas.
b. The greater the cardiac output, the slower the rise in alveolar
concentration.
c. Mathematically, changes in cardiac output have exactly the same
influence on anesthetic uptake from the lungs as changes in
solubility, since both influence exactly the same process: the size of
the storage capacity of the blood for anesthetic agent over a given
time interval.
3. The mixed venous anesthetic concentration:
a. The higher the mixed venous concentration, the slower the anesthetic
uptake.
b. Initially 0.
c. At equilibrium, the venous partial pressure = arterial partial pressure
= alveolar partial pressure (e.g. uptake = 0).
d. The uptake from the lung, in liters of gas/minute:

blood solubility x cardiac output x ( Palveolar - Pvenous )

uptake from lung =
atmospheric pressure
 e. The rate of rise of the mixed venous concentration depends on the
tissue uptake of the anesthetic.
4. Tissue uptake of anesthetic:
a. The tissue uptake (including blood) equals the uptake from the lungs.
b. The same factors which govern uptake by the blood from the lungs
govern uptake by the tissues from the blood:
1. The tissue/blood partition coefficient (tissue solubility)
2. The tissue blood flow.
3. The tissue anesthetic concentration (analogous to the mixed
venous tissue concentration)
c. Tissue uptake, in liters of gas/minute =

tissue solubility x tissue blood flow x ( Parterial - Ptissue )

tissue uptake =
atmospheric pressure

d. The rate of rise in tissue anesthetic concentration is proportional to

tissue blood flow.
e. The rate of rise in tissue anesthetic concentration is inversely
proportional to the tissue capacity.
1. The tissue capacity is: tissue volume x tissue solubility 3
f. Just as discussed for the lungs, the tissues have a time constant:
solubilityxvolume
1. time constant = 4
flow
2. Each ml of grey matter gets about 1 ml of blood/minute, so
the time constants for the brain equal the solubilities of the
anesthetics (in minutes):
Gas 1 TC 2 TC 3 TC
Nitrous Oxide 1.06 2.12 3.18
Isoflurane 2.60 5.20 7.80
Enflurane 1.45 2.90 4.35
Halothane 2.30 4.60 6.90
3. By contrast, resting muscle has a blood flow of 3 ml/min /
100 ml tissue (in minutes):
 Gas bl/m 1 TC 2 TC 3 TC
Nitrous Oxide 1.15 38 77 115
Isoflurane 4.0 133 267 400
Enflurane 1.7 57 113 170
Halothane 3.5 117 233 350
4. The blood flow to fat is similar to the blood flow to resting
muscle. However, anesthetics are very soluble in fat, which
results in very long time constants (in hours):
Gas bl/f 1 TC 2 TC 3 TC
Nitrous Oxide 2.3 1.3 2.6 3.9
Isoflurane 45.0 25 50 75
Enflurane 36.2 20 40 60
Halothane 60 33 67 100
Thus, eventually fat governs the uptake of all anesthetics,
until equilibrium is reached (at several days)
g. The contribution of each tissue to the mixed venous partial pressure
concentration is the tissue anesthetic partial pressure * the flow to
that tissue.
h. The body can be roughly divided into 4 tissue groups, vessel rich
group (brain, heart, lungs, kidney, splanchnic bed, glands), the
muscle group, the fat group, and the vessel poor group (bones,
cartilage, ligaments):
Group % MASS %CO TC Nitrous TC Halothane
VRG 10 75 1.3 3.3
MG 50 18 30 106
FG 20 5.5 100 2720
VPG 20 1.5 160 390

C. Unifying the above concepts:

 1. Wash in of gas to the FRC occurs very fast (within 1 minute), so we will
ignore it.
2. The alveolar/inspired partial pressure ratio approaches 1 with time.
F alveolar U Lung
3. = 1- 5
F inspired F inspired x V alveolar
Where ULung = uptake from lung Note that F inspired x V alveolar 6 is the rate of
drug delivery to the lungs, while ULung is the rate of drug leaving the lung.

The concentration and second gas effects:

A. The concentration effect (applies to the effects of nitrous oxide on the uptake of
nitrous oxide):
1. The higher the inspired concentration, the more rapid the rise in alveolar
concentration. Explanations:
a. The concentrating effect: As gas is taken up by the blood, the
remaining gas is present in a smaller volume, which diminishes the
change in partial pressure that might otherwise be expected.
b. The ventilation effect: As gas is taken up, more gas is brought in to
the lungs to replace the lost volume, which both increases Valveolar and
lowers the influence of uptake on reducing Falveolar
2. Examples:
Example 1: We instantaneously fill a 4 liter box (the lungs) with 50%
nitrous oxide. The concentrating effect tells us that if half of
the nitrous oxide is taken up (1 liter), we will have 1 liter of
nitrous in a 3 liter box, for a concentration of 33%, not 25%
as might be expected. If we consider the ventilation effect:
the 1 liter of nitrous taken up will be replaced with another
liter of 50% nitrous (the inspired gas), which will add another
.5 liters of nitrous to the box. This results in 1.5 liters of
nitrous in a 4 liter box, for a final concentration of .38%.
Example 2: We start with a 4 liter box the lungs filled with 100% nitrous
oxide (don't try this), connected to gas supply that is also
 100% nitrous oxide. No matter how much nitrous is taken
up, the concentration cannot fall below 100%.
3. The concentration effect is only significant for gases present in high
concentrations (e.g. nitrous). It is negligible for the potent agents.
B. The second gas effect (applies to the effects of nitrous oxide on the uptake of a
another gas):
1. Analogous to the concentration effect, but relates instead to a the use of a
potent agent concurrently with a second gas present in large quantity, usually
nitrous oxide.
2. The higher the inspired concentration of the second gas (nitrous), the more
rapid the rise in alveolar concentration. Explanations:
a. The concentrating effect: As the second gas (nitrous) is taken up in
significant volumes, all remaining gases (including the potent agent,
which is the "first" gas) are concentrated in the remaining volume.
b. The ventilation effect: As the second gas is taken up in significant
volumes, additional fresh gas in brought into the lungs. This
increases Valveolar, which increases the rate of rise of anesthetic
concentration.
3. Example:
We instantaneously fill a 4 liter box with 50% nitrous oxide and 400 cc (1%)
isoflurane. The concentration effect tell us that if half of the nitrous oxide is
taken up, the concentration of isoflurane will increase from 1% to 1.33%
(400 cc / 3 liters). The ventilation effect tells us that another liter of fresh
gas, containing 500 mls of nitrous, and 100 mls of isoflurane will be brought
into the lungs, resulting in a concentration of 1.25%. Although the
ventilation effect has lowered the concentration of isoflurane slightly, it has
increased Valveolar, which will more than offset the change.

Changes in Ventilation and Circulation

A. Changes in Ventilation
1. Increasing ventilation increases the rate of rise of alveolar concentration.
2. The change is greatest for more soluble anesthetics:
 a. Nitrous rises quite fast, regardless of Valveolar.
b. Changing Valveolar will notably increase the rate of rise of halothane,
but it will be less than a proportional change (i.e. a 50% increase will
result in less than a 50% acceleration of induction).
c. With ether, which is highly soluble, the change is proportional (i.e. a
50% increase will accelerate induction by 50%).
3. Anesthetics depress Valveolar, which slows the rate of rise of the alveolar
concentration. However, the concentration only stops rising towards the
inspired concentration when the patient stops breathing entirely.
a. This depression is sets an upper limit on the alveolar concentration
which can be obtained in a spontaneously breathing patient. For
halothane, patients stop breathing entirely when the concentration in
the brain reaches 2.5%.
b. There is a delay caused by the time required for transport of the
anesthetic from the lungs to the brain, and so in the first few minutes,
patients may breath spontaneously with alveolar concentrations
higher than 2.5%.
4. Hyperventilation reduces cerebral blood flow.
The effect on induction time is function of solubility:
a. For nitrous oxide, the reduction in cerebral blood flow more then
compensates for the increased rate of rise of the alveolar
concentration with hyperventilation, so induction time is actually
slower in the hyperventilating patient (remember hyperventilation
didn't help that much in the first place).
b. For halothane, the reduction in cerebral blood flow almost exactly
balances the effect of the increased rate of rise of alveolar
concentration.
c. For ether, the increased rate of rise of alveolar concentration more
than compensates for the reduction in cerebral blood flow, so
induction is faster.
 B. Changes in Cardiac Output
1. Increasing cardiac output lowers the alveolar anesthetic concentration, and
slows the rate of rise of alveolar anesthetic concentration.
2. The change is greatest for more soluble anesthetics (as was the influence of
changes in ventilation)
a. Nitrous rises quite fast, regardless of cardiac output.
b. The potent agents are highly affected by cardiac output, with
halothane the most affected, isoflurane the least.
3. If the cardiac output is lowered, the effect depends on the distribution of
cardiac output.
a. If the cerebral circulation is less, then induction will be slower, even
though the alveolar concentration will rise more quickly.
b. If the cardiac output is reduced, but cerebral circulation is maintained
(the usual situation), then the cardiac alveolar concentration will rise
more rapidly, and this rapid rise will be quickly reflected in the brain
anesthetic concentration.
c. Thus, patients in hypovolemic shock will have very rapid rises in
cerebral anesthetic concentration.
d. Patients in septic shock may have fairly slow rises in cerebral
anesthetic concentration.
4. Anesthetics may reduce cardiac output, which will lower the rate of rise of
anesthetic concentration.
Effect of V/Q abnormalities
A. Ventilating unperfused alveoli (dead space)
Increases arterial - end tidal anesthetic partial pressure difference (as it also does for
the carbon dioxide), but, assuming that the perfused alveoli are normally ventilated
(e.g. that the patient is eucapnic), then the rate of rise of the alveolar concentration,
and the rate of anesthetic induction, is unchanged.
B. Perfusing unventilated alveoli (shunting)
Delays the increase in arterial partial pressure, particularly for the poorly soluble
anesthetics (e.g. nitrous oxide). The reason is that for a poorly soluble agent, the
increased ventilation of the ventilated alveoli (assuming the patient is eucapnic) only
 delivers slightly more anesthetic to the lungs, and not enough to compensate for the
unventilated alveoli. However, for a very soluble gas (e.g. the potent agents, but also
for carbon dioxide, in the opposite direction, since the patient is eucapnic!) the
increased ventilation of the ventilated alveoli is adequate to compensate for the lack
of gas transport in the shunted blood. As mentioned, that is how the patient remains
eucapnic in the first place.
C. Left-right arteriovenous or intracardiac systemic shunts
No effect on anesthetic uptake or the rate of rise in alveolar pressure. The
shunted blood has equilibrated with the current alveolar pressure, and is
superfluous to both tissue perfusion (since it is shunting) and to the alveoli
(since it has equilibrated and thus neither adds nor removes anesthetic from
the lungs).
However: a left to right systemic shunt will antagonize the effects of a
intrapulmonary (e.g. right to left) shunt that were discussed above. This is
easily visualized by imagining that the blood which shunted through the lung
without exchanging gas is rerouted back to the lung, by the systemic left to
right shunt, for another try at gas exchange!

Nitrous Oxide transfer to closed gas spaces

A. Key concept: every gas equilibrates to its partial pressure, regardless of the partial
pressures of other gases present.
B. Compliant walls (e.g. bowel)
1. Assumption: The nitrous is highly soluble, and diffuses readily, when
compared to the other gases in the bowel (although nitrous is insoluble
compared to the potent agents, it is 30 times more soluble than nitrogen).
2. Nitrous will diffuse across the bowel wall, while the other gases don't move,
until the partial pressure of nitrous within the bowel = the arterial partial
pressure = alveolar partial pressure.
3. In other words, if the inspired concentration of nitrous is 66%, then 2 liters of
nitrous will be added to each liter of bowel gas, making an intrabowel
concentration of 66%, and the bowel 3 times larger.
 4. The formula for the theoretical limit of bowel distention is Vnew = Vold * 1/(1-
FiN20).
5. A simple way of remembering is: set the O2 flow to 1 liter/minute, and the
adjust the nitrous flow to the desired inspiratory percentage. The theoretical
limit is the total fresh gas flow (e.g. if the O2 is 1 l/min, and the nitrous is 2
l/min, then the maximum bowel extension is three fold).
6. The actual expansion is substantially less, owing to simultaneous, albeit
slower, diffusion of nitrogen and other gases, in the opposite direction, and
metabolic uptake of any oxygen present.
7. Nitrous oxide takes 2.5 hours to double the size of the bowel.
8. Nitrous oxide can double the size of a pneumothorax in 10 minutes!
C. Non-Compliant walls (e.g. inner ear)
1. The volume, by definition, doesn't change.
2. Since nitrous will, at equilibrium, have the same pressure on both sides of
any membrane, the theoretical limit on the pressure is the original pressure
(atmospheric), plus the partial pressure of nitrogen. If the patient is
breathing 70% nitrous oxide, then the maximum pressure is 1.7 atmospheres.

Recovery from an inhalational anesthetic

A. Overall, it is the reverse process of the anesthetic induction:
1. The rate of fall in alveolar concentration determines anesthetic recovery.
2. Increased solubility slows recovery
3. Increased cardiac output slows recovery
4. Increasing ventilation may help the recovery from potent agents, but with
hyperventilation, the increased rate of fall in alveolar concentration is nearly
balanced by the reduced cerebral blood flow.
5. Hyperventilation probably delays recovery from nitrous oxide, because there
is little improvement in pulmonary wash-out, while wash-out from the brain
is delayed from the reduced cerebral blood flow.
6. There is no concentration effect on emergence, as there was on induction,
because the gas in high concentrations (nitrous oxide) is not being drawn
from an infinite reservoir, as it was on induction.
 B. Diffusion Hypoxia
1. Related to the large outpouring of nitrous oxide diluting the inspired oxygen
at the conclusion of a case.
2. Only a risk for the first 3-5 minutes after terminating the nitrous oxide.
3. Easily managed (and now almost never seen) with supplemental oxygen for
a few minutes following termination of the nitrous.
C. The low partial pressure of anesthetics in most peripheral tissues (especially fat)
means that during the initial recovery from anesthesia, anesthetic is continuing to
pass into these tissues, rather than being released from these tissues. Thus, recovery
is enhanced by redistribution of the inhalational anesthetic into fat and muscle, just
like it is for most intravenous anesthetics.

How vaporizers work

A. Vaporizers transfer a fraction of the gas from the fresh gas flow through the
vaporizer. This diverted gas passes over the anesthetic liquid, and becomes 100%
saturated with the anesthetic vapor. It is then added back to the fresh gas flow.
B. In type specific vaporizers, which are nearly universal now, the fraction of the fresh
gas flow diverted through the vaporizer is automatically adjusted for changes in
temperature.
C. In copper kettles, you manually adjust the oxygen flow into the vaporizer. The
entire flow passes through the vaporizer, and is fully saturated with anesthetic vapor
on leaving the copper kettle. This flow is then added to the fresh gas flow set
elsewhere on the machine. If your fresh gas flow is 0, then the patient will get very
high concentrations of anesthetic! (32% halothane, 32% isoflurane, 23% enflurane).
D. The % flow from a copper kettle equals the partial pressure of the anesthetic / 760
x(times 100%).
E. The vapor flow from a copper kettle equals:

PP
Vapor outflow = xGas inflow
760 - PP

where PP is the partial pressure. The % vapor inspired is approximately:

 vapor outflow
% anesthetic = x100%
fresh gas flow

The exactly correct solution, which nobody uses, requires adding the gas inflow to
the copper kettle to the denominator. Since this is usually less than 200 cc, while the
fresh gas flow is several liters, leaving it out simplifies the equation without
sacrificing much accuracy.
F. Useful Constants for Vaporizer questions:
PP ml vapor
Drug PP PP% 9 Mol Wt. Density 10
760 - PP ml liquid
Halothane 241 32% 1/2 197.4 1.86 227
Isoflurane 240 32% 1/2 184.5 1.50 196
Enflurane 175 23% 1/3 184.5 1.52 198
Sevoflurane 157 21% 1/4 200.1 1.52 183
Desflurane 669 88% n/a 168.0 1.47 211

The mls vapor/mls liquid calculation is as follows:

Density × 22.4 × 1000 ( 273 + 21)
= ×
Molecular Weight 273

G. When using a copper kettle, the "magic" fresh gas flow rate is 5 liters for halothane
and isoflurane and 3 liters for enflurane. At these flow rates, the copper kettle inflow
rate is approximately 100 times the % inspired vapor. For example, 100 ml flow
into a copper kettle yields 50 mls of vapor, which is 1% if the fresh gas flow is 5
liters.

Closed-Circuit Anesthesia
.
1. Very efficient use of gases, reduces environmental hazards.
2 Need to denitrogenate by administration of 100% O2 prior to starting.
3. Give baseline oxygen (200-300 l/min)
4. Add nitrous oxide and potent agent as necessary to achieve desired anesthetic state.
5 Gas necessary in first minute:
 U1 = blood solubility x cardiac output x desired percent

Note that this is the same as equation 3d on page 6, adjusted for Pvenous = 0.
6. Uptake at subsequent times (t) is:

U1
Ut =
t

7. Assuming a cardiac output of 5000 l/min, and a target concentration of 1 MAC, the
following table shows the solutions for halothane, enflurane, isoflurane and nitrous
oxide for concentrations of 1.11%, 0.77%, 1.66%, and 70%, respectively: