UPTAKE AND DISTRIBUTION

OF INHALED ANAESTHETICS
MODERATOR: Dr VIMAL
PRESENTER : Dr JOYCE
PHARMACOKINETICS

Absorption from alveoli into pulmonary capillary

blood
Distribution in the body
Metabolism
Elimination
Partial Pressure
Partial pressure is the portion of total pressure
contributed by one component of a gas mixture.

Each component contributes pressure in direct

proportion to its molar fraction.

The total pressure of the mixture is the sum of the

partial pressures of constituent gases.
FATE OF INHALED ANAESTHETIC
Alveolar partial pressures = brain partial pressure at
steady state.

Priniciple objective - Achieve constant and optimal

brain partial pressures

PA is used as index of

a. Depth of Anaesthesia
b. Recovery from Anaesthesia
c. Anaesthetic equal potency
DETERMINANTS OF ALVEOLAR PARTIAL
PRESSURE

1.Transfer of Inhaled Anaesthetic from Anaesthetic

machine to Alveoli depends on
A. Inspired partial pressure
B. Alveolar ventilation
C. Characteristics of anaesthetic breathing system.
D. FRC
2.Transfer of inhaled Anaesthetic from alveoli to arterial
blood depends on
A. Blood gas partition coefficient
B. Cardiac output
C. Alveolar to venous partial pressure difference

3.Transfer of inhaled anaesthetic from arterial blood to

brain depends on
A. Brain blood partition coefficient
B. Cerebral blood flow
C. Arterial to venous partial pressure difference
Determinants of alveolar partial
pressure
INHALED PARTIAL PRESSURE

A high PI required for

Uptake of inhaled anaesthetics
Accelerating induction of anaesthesia
A high PI required during initial administration of
anaesthesia

High PI ↑es rate of rise in the PA and P Brain

Accelerate induction of anesthesia

With time, as uptake into blood decreases, PI should

be decreased to match the decreased anaesthetic
uptake
CONCENTRATION EFFECT
The impact of PI on rate of rise of the PA of inhaled
anaesthetic - “CONCENTRATION EFFECT”

The concentration effect states that higher the PI,

more rapidly PA approaches PI

 Concentration effects results from

1.Concentrating effect
2.Augmentation of tracheal inflow
SECOND GAS EFFECT
The ability of high volume uptake of first gas to
accelerate rate of increase of PA of concurrently
administered companion gas or second gas

For example
The initial large volume uptake of N2O accelerates the
uptake of oxygen or volatile anaesthetics
Halothane 2 Absorption 2 Movement 1 2
O2 18 of 50%N2O 18 of gas from 9 18
80 40 40 40
N2O 100
i.e 40 trachea to
60 110
Total molecules fill the void

Halothane 2/100=2% 2/60=3.4% 3/110=2.7%

80/100=80% 40/60=67% 80/110=72%

N2O

Concentrating effect Augmentation of

tracheal inflow
ALVEOLAR VENTILATION

Increased alveolar ventilation

↓
Increases anesthetic uptake
↓
Rapid increase in rate of rise of PA
↓
Rapid induction of anesthesia
Decreased alveolar ventilation
↓

Decreases anesthetic uptake

↓
Slows establishment of PA

↓
Slow induction of Anesthesia
Greater the alveolar ventilation to FRC ratio, more
rapid is the rate of increase of PA.

 In Neonates this ratio is 5:1 & in Adults 1.5:1

 Induction of Anaesthesia more rapid in neonates

than in adults
SPONTANEOUS VERUS MECHANICAL
VENTILATION
Inhaled anaesthetics influence their own uptake by
dose dependent depression effect on alveolar ventilation.

It is a negative feedback protective mechanism.

 Prevents excessive depth of anaesthesia, when high PI is

administered during spontaneous breathing.

This protective mechanism lost when mechanical

ventilation replaces spontaneous breathing.
Impact of solubility
Rate of ↑e of PA of poorly soluble agent > soluble
agent
↑ing alveolar ventilation ↑es rate of rise of PA of
poorly soluble agents.
Change from spontaneous to mechanical ventilation
↓
↑es alveolar ventilation
↓
↑e depth of anaesthesia produced by soluble agents
Anaesthetic Breathing System
Characteristics of breathing system which influence
rate of rise of PA are

A. Volume of breathing system.

B. Solubility of inhaled anaesthetics in rubber /plastic
components of breathing system.
C. Gas inflow from anaesthetia machine.
The volume of anaesthetic breathing system acts as a
buffer to slow achievement of the PA.

 High gas inflow rates from anaesthetic machine

negate this buffer effect.

Solubility of inhaled anaesthetics in the components

of breathing system initially slows the rate of rise of
PA .
TRANSFER OF INHALED ANESTHETIC FROM
ALVEOLI TO ARTERIAL BLOOD
Blood gas partition coefficient
The solubility of inhaled anaesthetics in blood and
tissues denoted by partition coefficient.

The partition coefficient is a distribution ratio

describing how the inhaled anaesthetic distributes
itself between two phases of equilibrium.

It is the ratio of concentration of anaesthetics in two

phases at equilibrium
Blood gas coefficient of Isoflurane is 1.4 at 37 deg C

Each ml of blood holds 1.4 times Isoflurane as does

alveolar gas

Alveolar gas Blood

Equilibrium
10 molecules 14 molecules
of isoflurane of isoflurane
No net movement of
molecules
Blood gas partition coefficient=
Affinity of agent for blood
Affinity of agent for gas

The rate of increase of PA is inversely related to

solubility of anesthetic in blood.

Partition coefficients are temperature dependent.

The solubility of a gas in liquid decreases when

temperature of liquid increases
Based on blood : gas partition coefficient ,
Inhaled anesthetics categorized as:

1.SOLUBLE
2.INTERMEDIATELY SOLUBLE
3.POORLY SOLUBLE
Inhaled anesthetics with high blood solubility slows
rate of ↑e in PA, Pa and induction of anesthesia

Inhaled anesthetics with low blood solubility

↓
Rapid increase in PA and Pa

Rapid induction of anesthesia

The impact of high blood solubility in the rate of rise
of Pa is ↑ed by ↑ing the PI above that required for
maintenance of anesthesia- OVER PRESSURE
TECHNIQUE.

Over pressure technique speeds induction of

anesthesia
BG partition coefficient altered by individual
variations in
 HEMATOCRIT
 LIPID CONTENT
 PROTEIN CONTENT
 WATER
BG partition coefficient 20% less in blood with a
hematocrit of 21% compared with hematocrit of 43%.

↓ed solubility of volatile anesthetic in anemic blood

↓
↑ed rate of ↑e in PA
↓
more rapid induction of Anesthesia
Fat act as a large reservoir for inhalational agents

Ingestion fatty meal alters the composition of blood

↓
20% ↑e in the solubility of volatile Anesthetic in blood.

Postprandial lipidemia slows rate of induction

The solubility of inhaled anesthetics in blood varies
with age.

The solubility of halothane, enflurane,

methoxyflurane & isoflurane - 18% less in neonates &
elderly compared to young adults.

In contrast, the solubility sevoflurane is not different

in neonates and young adults
 Blood Gas Partition Coefficient
SOLUBLE
 Methoxyflurane 12
INTERMEDIATELY SOULBLE
 Halothane 2.5
 Enflurane 1.9
 Isoflurane 1.4
POORLY SOLUBLE
 N2O 0.47
 Desflurane 0.45
 Sevoflurane 0.65
 Xenon 0.1
Tissue Blood Partition Coefficient
Determines uptake of anesthetic into tissues and the
time necessary for equilibration of tissues with the Pa.

Time for equilibration estimated by calculating a time

constant for each tissue.
Time constant
Time constant=
Amount of I.A that can be dissolved in the tissue
Tissue blood flow.

For volatile anaesthetics, equilibrium between the Pa

& P Brain depends on the anesthetics blood solubility
and requires 5 to 15minutes
Fat has an enormous capacity to hold anesthetic
combined with low blood flow, prolongs the time for
equilibrium between arterial blood & fat.

Fasting before elective operation results in transport

of
fat to the liver Increase anesthetic uptake by liver
slows rate of increase in the PA slows induction of
anesthesia
Fat blood partition coefficient
Halothane - 51.1
Isoflurane -44.9
N2O -2.3
Sevoflurane-47.5
Desflurane - 27.2
Oil gas partition coefficient
OGP Coefficients gives anesthetic requirements

Estimated MAC = 150

OGP coefficient

 150 is Constant which is a average value of product of

OG solubility and MAC for several inhaled anesthetics
with widely divergent lipid solubilities.
Inhaled anaesthetic Oil gas partition coefficient
Halothane 224
Isoflurane 98
N2O 1.4
Sevoflurane 55
desflurane 18.7
Cardiac output
Increased cardiac output

Increased pulmonary blood flow

Increased anaesthetic uptake

Decrease in alveolar concentration

Delayed induction
Low cardiac output increased alveolar concentration
 anaesthetic overdose

Changes in cardiac output affects soluble agents more

than insoluble agents

Volatile anaesthetics that depress cardiac output exert

a positive feedback response
 Volatile anaesthetic

↓ed cardiac output due to myocardial depression

Alveolar concentration rises

Increase in depth of anaesthesia

More myocardial depression

POSITIVE FEEDBACK LOOP

Effect of shunts
Dilutional effect of right to left shunt decreases partial
pressure of anesthetic in arterial blood

Rate of induction slowed down in right to left shunts

A left to right shunt has opposite effects

Alveolar to venous partial pressure
difference
Flow of anesthetic gas from alveoli to pulmonary
artery is driven by the partial pressure gradient
between alveolar gas (P alv) and mixed venous blood
Distribution of anaesthetic into tissues
Blood exiting the pulmonary capillaries enters the
pulmonary vein and the left heart

Inhaled anesthetics are then distributed via arterial

blood to various body tissues
Rate of increase of anesthetic partial pressure within
each tissue is determined by

 Tissue-specific arterial blood flow,

 Effective volume(product of anatomic volume and
tissue/blood partition coefficient
 Anesthetic partial pressure gradient between arterial
blood and the tissue
Vessel rich tissues
Includes heart , brain, lungs, spinal cord, liver and kidney
Compose approximately 10 % of adult human body mass
Receives 70 % of cardiac output under normal resting
conditions
Because of small mass and high blood flow -equilibrate
rapidly with the Pa.
 After 5-15 minutes approximately 75% of returning venous
blood have same partial pressure as PA.
 Uptake of volatile anesthetic decreased after 5-15 minutes.
After highly perfused tissues skeletal muscle is the
next compartment to equilibrate with inhaled
anaesthetic.

 Muscle composes 40% of body mass and receives 10-

15% of cardiac output at rest

Third tissue group is fat, composes 25% of body mass

and receives 10 % of cardiac output
Large effective volume and low blood flow slow
equilibration of anesthetics between blood and fat.

Uptake from the lungs continues even after several hours

of continuous administration of inhaled anaesthetics.
Vessel poor group
Include skin, cortical bone and connective tissue
Compose approximately 15% of adult body and
receives <5% of cardiac output
Recovery from anaesthesia
Depicted by rate of decrease in the P Brain.
Factors influencing recovery
 1.Concentration of inhaled anaesthetics.
 2.Solubility of inhaled anaesthetics.
 3.Duration of administration.
 4.Type of tissue.
 a) Vessel rich group tissues
 b) Vessel poor group tissues.
 5.Absorption in to components of breathing system.
 6.Fresh gas flow.
Context sensitive recovery from anaesthesia
After short period of inhalation and uptake anaethetic
clearance from the blood occurs by exhalation and
distribution  rapid decrease in P alv to low value after
discontinuing anaesthetic delivery.

After prolonged inhalation and uptake anaesthetic

partial pressures in muscle and other tissues
increase closer to blood reducing distributive clearance
Clearance from central compartment slowed by
reverse flow of anaesthetic from high capacity tissues.

So in prolonged inhalational anaesthesia fall in Palv

less due to slow clearance phase  slower recovery
from anaesthesia.
Diffusion hypoxia or fink effect
Occurs when inhalation of N2O is discontinued
abruptly at the end of surgery when patient is
spontaneously breathing in atmospheric air

Inspired mixture changes from N2O + O2 to N2 +O2

↓
N2O starts diffusing out of blood into alveoli while N2
diffuses into blood
↓
Due to difference in solubility of two gases N2O diffuses
out more rapidly
↓
 Dilute the PAO2
↓
PaO2 decreases
↓
also dilution of PACO2 by N2O
↓
Decreases the stimulus to breath
↓
Exaggerates decrease in PaO2
Out pouring of N2O into alveoli greatest during first 1-
5 minutes after N2O discontinuation

To prevent this fill the lungs with O2 at the end of

anaesthesia to ensure that arterial hypoxia will not
occur
References
Stoelting’s textbook of Pharmacology and Physiology
in Anesthetic practice.. 5 th edition.
Miller’s Anesthesia, 8 th edition
Comparative Pharmacology for Anaesthetist
THANK YOU