3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.2. Inhalational anaesthetic agents
 3.1.3.2.1. Pharmacokinetics of inhalational anaesthetics 

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.