Pharmacokinetics of inhalational anaesthetics

[Ref: SH4:p23]

Important phases

1. Absorption from alveoli into blood
2. Distribution in body
3. Metabolism
4. Elimination (principally via lung)

Age-related changes

In elderly:

• Vd is increased
  * Decreases in lean body mass
  * Increases in body fat
• Clearance is decreased
  * Decreased hepatic function
  * Decreased pulmonary gas exchange (secondary to lower metabolic rate)
• Tissue perfusion decreasd and regional blood flow altered
  * Decreased cardiac output

Delivery of anaesthetics to brain

• Brain is the target organ
• PA <===> Pa <===> Pbr

NB:

• PA = alveolar partial pressure
• Pa = arterial partial pressure
• Pbr = partial pressure at brain

Uptake of anaesthetic gas

"Severinghaus equation" [???]

• Uptake of anaesthetic gas
  = Solubility x Cardiac output x Alveolar-to-venous partial pressure difference / Barometric pressure
  * [RDM6:p132]
• In first minute, it can be simplied into:
  * Uptake = Solubility x CO x % of anaesthetic gas

Determinants of alveolar partial pressure

[Ref: SH4:p24]

• Alveolar partial pressure (PA) is determined by input minus loss.
• Input depends on
  * Inhaled partial pressure (PI)
  * Alveolar ventilation
  * Characteristics of delivery system
• Loss (uptake) depends on
  * Solubility in tissues
  * Cardiac output
  * Alveolar to venous partial pressure difference

Inhaled partial pressure (PI)

• High PI increases input of anaesthetics to offset uptake.

Concentration effect

• The higher the PI, the more rapidly PA approaches PI.
• Due to the concentrating effect and the ventilation effect

Concentrating effect

Uptake of all gases leads to:

• Smaller lung volume
  --> Concentration of inhaled anaesthetics increases
• Augmentation of tracheal inflow
  --> Increased alveolar ventilation

Second gas effect

• High-volume uptake of one gas (first gas) accelerates the rise in the PA of a concurrently administered gas (second gas)

Due to:

1. Increased tracheal inflow of all gases
2. Concentrating effect on the second gas as a result of high-volume uptake of the first gas

 

NB:

Uptake of gas can be compensated by

• Increased tracheal inflow
• Decreased expiration
• Reduction in lung volume

Alveolar ventilation (VA)

• Increased alveolar ventilation increases input of anaesthetics to offset uptake.

However,

• Hyperventilation
  --> Decreased PaCO2
  --> Cerebral blood flow decreases
  --> Decrease delivery of anaesthetics to brain

Thus,

• Hyperventilation may increase PA and Pa, but may slow down equilibration of Pbr with Pa.

Alveolar ventilation to FRC ratio

• In spontaneously breathing adult, ratio of alveolar ventilation to FRC = 1.5:1
• In spontaneously breathing neonate, ratio of alveolar ventilation to FRC = 5:1
  * Due to higher metabolic rate

Thus,

• Induction of anaesthesia is faster in neonates (spontaneously breathing)

Negative-feedback mechanism in spontaneous ventilation

Inhalational agents exert dose-dependent depressant effects on alveolar ventilation

Thus,

• When anaesthesia is deep, alveolar ventilation decreases
  --> Uptake of anaesthetics decreases
• When anaesthesia is light, alveolar ventilation increases
  --> Uptake of anaesthetics increases

Effect of solubility

The greater the solubility
--> The greater the impact of alveolar ventilation on rise of PA

i.e.,

• More soluble agents (e.g. halothane, isoflurane) is more influenced by changes in ventilation than less soluble agents (e.g. N2O)
• N2O uptake is rapid regardless of alveolar ventilation because uptake is limited (thus drop in PA due to uptake is limited).

Anaesthetic breathing system

Characteristics that influence PA:

• Volume of the breathing system
  * The higher the volume, the greater the buffer
• Fresh gas flow into the breathing system
  * The high gas flow negates the buffer effect
• Solubility of the inhaled agent in the rubber or plastic component of the breathing system

 

Solubility

Partition coefficient

• Solubility of inhaled anaesthetics is denoted by partition coefficient
• A partition coefficient is a distribution ratio describing how the inhaled anaesthetic distributes itself between two phases at equilibrium (i.e. where partial pressures in both phases are equal)

For example,

• Blood:gas partition coefficient of 2
  --> Concentration in blood is twice that in alveolar gas at equilibrium

Partition coefficient and temperature

Partition coefficient are temperature dependent

--> Solubility of a gas in a liquid is decreased when temperature rises

Blood:gas partition coefficient

Rate of rise in PA towards PI is inversely related to the solubility of the agent in blood

When solubility is low
--> Minimal amounts need to be dissolved to achieve equilibrium
--> Rapid induction
e.g. PA is >80% of PI in 10min for N2O, des, and sevo

NB:

• When haematocrit is low
  --> Blood:gas partition coeffient is decreased
  --> More rapid onset of anaesthetics
• Blood solubility for more soluble agents (halothane, enflurane, methoxyflurane, isoflurane) is about 18% less for neonates and elderly, when compared with young adults
• During bypass operations
  * Crystalloid prime and hypothermia
  --> Affects blood:gas partition coefficient by 2%

Tissue:gas partition coefficient

Fat takes a long time to equilibrate with PA because:
* High capacity to hold anaesthetics
* Low blood flow

Oil:gas partition coefficient

Oil:gas partition parallel anaesthetic requirements
--> MAC can be estimated by 150 divided by the oil:gas partition coefficient

Nitrous oxide and closed air space

• Blood:gas partition coefficient of N2O = 0.46
• Blood:gas partition coefficient of N2 = 0.014

Thus,

N2O is 34 times more soluble
--> N2O can leave blood to enter an air-filled cavity 34 times more rapidly than nitrogen can enter blood to leave the cavity
--> Pressure / volume of an air-filled cavity increases

 

The magnitude of the increase depends on

• Partial pressure of N2O
• Blood flow to the cavity
• Duration of N2O administration

Implication

• Middle ear pressure may increase if eustachian tube patency is compromised by inflammation or oedema
  --> May be partly responsible for N&V caused by N2O
• Rapid increase in the volume of pneumothorax
• Also increase volume of bowel gas, but slowly
  --> Probably not clinically significant in the absence of bowel obstruction
• Intraocular gas bubbles are used for internal retinal tamponade
  --> May persist for 10 weeks post-op
  * During this time, N2O will result in rapid increase in the volume of intraocular gas

Cardiac output

• Increased cardiac output
  --> Increased uptake
  --> Decreases PA
  --> Onset of anaesthesia is delayed

NB:

• Increased cardiac output hastens equilibration between Pa and Pbr (and partial pressure at tissues)
• BUT, PA is reduced. Thus Pa is lower than otherwise.

Cardiac output and effect of solubility

• Changes in cardiac output have more impact on more soluble anaesthetics

Thus,

• Rise in PA of N2O would be rapid regardless of cardiac output (or alveolar ventilation)

Positive-feedback mechanism in spontaneous ventilation

• Inhaled anaesthetics which exert dose-dependent cardiac depressant effect can have a positive-feedback effect
• When anaesthesia is too deep
  --> Cardiac output decreases
  --> PA increases
  --> Further deepens anaesthesia

NB:

• Unlike negative-feedback in alveolar ventilation

Effect of right-to-left shunt

• When there is a right-to-left shunt
  --> Pa would be lower than PA
  * Especially when solubility is poor
• When solubility is low
  --> Uptake is minimal
  --> Dilution effect is greater

Alveolar-to-venous partial pressure difference

A-v difference reflects tissue uptake of the inhaled anaesthetics.

Affected by:

• Tissue solubility
• Tissue blood flow
• Arterial-to-tissue partial pressure difference

 

NB:

• Anxiety delays onset because of
  * Increased sympathetic stimulation
  * Decreased % of CO going to brain
  * Hypocapnia decreases cerebral blood flow
• Hypovolaemia hasten onset because of
  * Increased % of CO going to brain
• In lung disease (V/Q mismatch and/or shunt)
  * Onset is delayed --> More so if AA is less soluble

 

Recovery from anaesthesia

[Ref: SH4:p31]

Difference between induction and recovery

Concentration effect

• Induction can be accelerated by concentration effect
• Recovery cannot be (one cannot administer negative concentration)

Tissue concentrations

• At induction, tissue concentrations are all equal and all zero
• At recovery, tissue concentrations all differ, depending on the solubility and duration

Fat and muscles

• At the end of anaesthesia, fat and muscles might not have equilibrated
  --> Partial pressure that these tissues may still be lower than Pa
  --> AA continues to be transfered from blood into fat and muscles
  --> Initially accelerates the decline in PA

Duration of anaesthetics

• The longer the duration
  --> More AA is absorbed in high capacity tissues such as fat and muscles
  --> Time to recovery is longer
• This effect is more pronouced in more soluble AAs
• Oil:gas solubility is relevant here, not blood:gas solubility

Correlation with blood:gas partition coefficient

• During induction, rate of rise in PA correlates with the blood:gas partition coefficient.
• During recovery, correlation is not as strong.
• Increase in PA during induction is not influenced by metabolism
  * Not even for highly metabolised AA such as halothane and methoxyflurane
• Decline in PA can be due to:
  * Continued uptake of AA by fat and muscles
  * Metabolism
• Examples of effects of metabolism
  * PA of halothane decreases faster than isoflurane and enflurane
  * PA of methoxyflurane decrease faster than enflurane (even though methoxyflurane is about 6 times more soluble)
  --> Both due to greater metabolism of halothane and methoxyflurane

Context-sensitive half-time

• Elimination of AA depends on
  * length of administration
  * Blood-gas solubility of the AA
• Time needed for a 50% decrease in PA of enflurane, isoflurane, desflurane, and sevoflurane is <5min.
  * Primarily a function of alveolar ventilation
  * Does not increase significantly with duration
• Time needed for a 80% decrease in PA of desflurane and sevoflurane is < 8min
  * Does not increase significantly with duration

However,

• Time needed for a 80% decrease in PA of enflurane and isoflurane increases significantly with duration.

 

Thus,

• The major difference in the rate at which desflurane, sevoflurane, isoflurane, and enflurane are eliminated occur in the final 20% of the elimination process

Diffusion hypoxia

• Diffusion hypoxia occurs when inhalation of N2O is discontinued suddenly
  --> High volume of N2O enters alveoli from blood

Two effect:

1. Dilution of O2
   --> PAO2 decreases
2. Dilution of CO2
   --> PACO2 decreases
   --> Decrease hypercapnic drive
   --> Decreased ventilation
   --> Exacerbates the diffusion hypoxia

• This movement of N2O is the greatest in the first 1 to 5 minutes.