Inhalational Anaesthetics

Structure-activity relationships of inhalational agents

Describe the uptake, distribution and elimination of inhalational anaesthetic agents and the factors which influence induction and recovery from inhalational anaesthesia including the:
- Concepts of partition coefficients, concentration effect and second gas effect
- Relationships between inhaled and alveolar concentration
- Significance of the distribution of cardiac output and tissue partition coefficients on uptake and distribution of volatile agents

Describe the concept and clinical application of MAC in relation to inhaled anaesthetic agents

Describe how the pharmacokinetics of drugs commonly used in anaesthesia in neonates and children differ from adults and the implications for anaesthesia

Properties of an ideal inhalational anaesthetic agent

Inhaled anaesthetics are chemicals with general anaesthetic properties that can be delivered by inhalation. They can be divided into:

  • Volatile anaesthetic agents
    Volatility refers to the tendency of a liquid to vaporise. Volatile agents include:
    • Sevoflurane
    • Isoflurane
    • Desflurane
    • Methoxyflurane
    • Enflurane
    • Halothane
    • Ether
  • Anaesthetic gases
    • Nitrous oxide
    • Xenon

Key Principles of Inhalational Agents

Key principles:

  • The clinical effect of an inhalational agent is dependent on its partial pressure within the CNS
  • At equilibrium, the partial pressure in the CNS (PB) equals the partial pressure in blood (Pa), and in the alveoli (PA)
    Reaching equilibrium is rarely achieved in practice as it takes many hours.
  • Rate of onset and offset of an inhalational agent are dependent on both physiological and pharmacological factors affecting the transfer of agent:
    • Into the alveoli
    • From the alveoli into blood
    • From blood into the CNS

Minimum Alveolar Concentration (MAC)

MAC is defined as the minimum alveolar concentration at steady state which prevents a movement response to a standard surgical stimulus (midline incision) in 50% of a population.

Note that this definition:

  • Does not reflect lack of awareness
    Reflects the action of an agent on spinal cord reflexes.
  • Consciousness is better estimated by MAC-awake
    End-tidal concentration of agent that prevents appropriate responses to a verbal command in 50% of a population.
    • Note that this technically measures awareness rather than memory.
    • MAC-awake is typically one-third of MAC for commonly-used agents
  • Is only valid at sea-level
    The clinical effect of an agent is dependent on its partial pressure not concentration.
    • At 1atm, these are almost the same
      1atm ≃ 100kPa; therefore 2% sevoflurane is ≃ 2kPa
    • As altitude increases, the actual partial pressure will fall for any given concentration i.e. 2% sevoflurane at 0.5atm is ≃ 1kPa of sevoflurane.

MAC is:

  • A measure of potency (i.e. the EC50 of the agent, where the outcome is movement)
    The MAC of an agent is inversely proportional to potency; i.e. more potent agents require smaller alveolar concentrations to produce anaesthesia.
    • This gives rise to the Meyer-Overton hypothesis, which suggests that anaesthesia requires a sufficient number of molecules to dissolve into the neuronal cell membrane.
      • If this was true, the product of the oil:gas partition coefficient and MAC would be constant, which is not the case.
  • Additive
    The MACs of different agents used simultaneously are additive.
  • Normally-distributed
    Not all patients will be unresponsive at 1 MAC.
    • The standard deviation is 0.1, so 95% of patients will not move in response to a stimulus at 1.2 MAC
  • Estimated clinically using end-tidal gas measurement
    MAC is not based on arterial partial pressure (Fa) of agent.
    • This is an important difference, because even at steady-state, Fa ≠ FA
    • This occurs due to:
      • V/Q mismatch
        Shunted alveoli will not absorb anaesthetic agent, and unperfused alveoli will contain agent that is not being absorbed.
        • This is worsened by the effects of anaesthesia
      • Volatile agents are heavy and have finite diffusability
    • However, the difference between Fa and FA for any agent is the same at steady state (and in absence of nitrous oxide)
      This means that, at steady-state, MAC will be proportional to, and an accurate measure of, Pa.
  • One of several related terms:
    • MAC awake
      Concentration required to prevent response to a verbal stimuli in absence of noxious stimuli.
      • Typically ~1/3rd of MAC for most agents (sevoflurane, isoflurane, desflurane)
      • Notably higher for nitrous oxide (MAC-awake ~2/3rds of MAC)
      • MAC-awake is typically less than MAC-asleep as:
        • Hysteresis between alveolar and effect site concentrations
          During induction, alveolar concentration is higher than effect site concentration, and so overestimates effect. During wash out, alveolar concentration is less than effect site concentration, and the reverse effect occurs.
        • "Neural inertia"
          Intrinsic resistance of nerve cells to a change in their state.
    • MAC-BAR
      Minimum alveolar concentration required to block adrenergic response, i.e. to prevent a rise in HR or BP following skin incision.
    • MAC95
      The MAC required to prevent a movement response to a standard surgical stimulus in 95% of the population.
    • MAC.hr-1
      The amount of time a patient is exposed to 1 MAC of an agent. Used to compare different agents.

Factors Affecting MAC

Decreases MAC Increases MAC
Age (~6%/10 years ↑) and neonates Youth
Hypothermia Hyperthermia
Hypocapnoea Hypercapnoea
Hyponatraemia Hypernatraemia
Hypothyroidism Hyperthyroidism
Acute alcohol and other CNS depressant intoxication Chronic ETOH and CNS depressant abuse
Chronic amphetamine intake Acute amphetamine intake
Hypovolaemia/Hypotension
Lithium
Hypoxia
Anaemia
Pregnancy
SNS activation and anxiety
Increased Patm

Note that addition of other agents (e.g. opioids) will affect different MAC subtypes (e.g. MAC50 vs MACBAR) differently.

Partition Coefficients

A partition coefficient describes the relative affinity of an agent for two phases, and is defined as the ratio of the concentration of agent in each phase, when both phases are of equal volume and the partial pressures are in equilibrium at STP.

  • The blood:gas partition coefficient describes the solubility of the agent in blood relative to air, when the two phases are of equal volume and in equilibrium at STP
    A low blood:gas partition coefficient indicates a rapid onset and offset. This is because:
    • Poorly soluble agents generate a high Pa, which creates a steep gradient between Pa and PB, giving a rapid onset of action
    • Conversely, soluble agents dissolve easily into pulmonary blood without substantially increasing Pa
      This causes leads to a slow onset due to:
      • A large fall in PA as the agent leaves the alveolus, decreasing the gradient for further diffusion
      • A small gradient between Pa and PB

  • The oil:gas partition coefficient describes the solubility of the agent in fat relative to air, when both phases are of equal volume and in equilibrium at STP
    A high oil:gas partition coefficient indicates a greater potency, and therefore a low MAC.

Pharmacokinetics of Inhalational Agents

Achieving the required PB requires maintaining PA at a high enough level. By increasing PA, the pressure gradient for diffusion into blood, and therefore CNS, is increased.

As discussed above, rate of onset of an inhalational agent is dependent on rate of uptake:

  • Into the alveoli
  • From the alveoli into blood
  • From blood into the CNS

Factors affecting alveolar concentration of agent:

  • Inspired concentration
    A high inspired concentration (Fi) will increase the rate of increase of alveolar concentration (FA). Inspired concentration is dependent on:
    • Delivered concentration in fresh gas
    • Fresh gas flow
      Increasing FGF (and the concentration of agent in the added gas) increases Fi.
    • Volume of the breathing system
      A lower circuit volume will increase the rate at which the patient reaches equilibrium with the circuit, and therefore increase Fi.
    • Circuit absorption
      Absorption of agent by the circuit will decrease Fi.
  • VA
    Increased alveolar ventilation increases Fi, as it replenishes agent that has been taken up into the vasculature.
    • Similarly, increased dead space will prolong induction, as anaesthetic gas will be delivered to non-perfused alveoli
  • FRC
    A large FRC will dilute the amount of agent inspired with each breath, and so reduce Fi.
    • This is measured with the VA/FRC ratio
      Increased ratio increases speed of onset.
      • Normal in adults: 1.5:1
      • Normal in neonates: 5:1
  • Second gas effect
    Use of N2O with another agent will increase the PA of that agent. This is because:
    • N2O is 20x as soluble in blood as either blood or nitrogen, and is administered in high concentrations, so it is rapidly absorbed from alveoli
    • If nitrous oxide is delivered at high concentrations, it's rapid absorption means that alveoli will shrink, causing:
      • An increase in the fractional concentration of all other gases
        This is known as the concentration effect, and increases the pressure gradient driving diffusion into blood, increasing speed of onset.
        • The concentration effect is the cause of the second gas effect
        • The concentration effect is more pronouced as FiN2O increases
        • The concentration effect is more profound in lung units with moderately low V/Q ratios, causing in a large increase in Fa
          This results in a larger value of Fa for any given FA, even at steady state.
      • Augmented ventilation as more inhalational agent is drawn in the alveoli from dead space gas
    • The second gas effect also causes diffusion hypoxia
      When inspired N2O is reduced, N2O will leave blood and enter the alveolus, displacing other gases in the alveolus.
      • This can cause a reduction in PAO2, and therefore hypoxaemia
      • Diffusion hypoxia is avoided by delivering 100% oxygen, which maintains an adequate PAO2 as N2O is removed

  • Note that N2O reaches a higher ratio faster than desflurane, despite its lower blood:gas partition coefficient, due to the concentration effect

Factors affecting drug uptake from the lungs:

  • Blood:gas partition coefficient
    Agents with a low blood:gas partition coefficient reach equilibrium more rapidly. The blood:gas coefficient is affected by:
    • Temperature
      Blood:gas partition coefficients decrease as temperature increases.
    • Haematocrit
      Variable effect, which depends on the particular agents affinity for red cells or plasma (and serum constituents, e.g. albumin).
      • An agent that is less soluble in red cells (e.g. isoflurane) will have a decreased blood-gas partition coefficient in anaemia.
    • Fat
      Blood:gas partition coefficient increases following fat ingestion.
  • Alveolar blood flow
    Increased alveolar blood flow increases uptake and delivery to tissues, including the CNS.
    • However, the increased uptake causes a reduction in PA
      Therefore, rate of onset is reduced when alveolar blood flow is high.
      • This effect is more pronounced with agents with a high blood:gas partition coefficient
      • Alveolar blood flow is a function of:
        • Cardiac output
        • Shunt
  • Alveolar-Venous partial pressure gradient
    The difference in partial pressure of agent in the alveolus and venous blood is due to the uptake of drug in tissues. Tissue uptake is dependent on:
    • Tissue blood flow
      As the CNS has a high blood flow, it will equilibrate more quickly.
    • Blood:tissue solubility coefficients
      • Muscle has similar affinity to blood, but equilibrates more slowly than the CNS due to lower blood flow
      • Fat has a much higher affinity for anaesthetic than muscle, but equilibrates very slowly due to the very low blood flow
        This is of greater importance in the obese, especially during prolonged anaesthesia, as they have a longer equilibration time and therefore prolonged emergence.

Wash-out of Inhalational Agents

Recovery is dependent on how quickly an inhalational agent can be eliminated from the effect site, and can be graphed by the FA/FA0 ratio over time:

Washout can be divided into:

  • Rapid washout
    Of agent in circuit and FRC.
    • The time constant for removal of agent from the circuit is a function of circuit volume and fresh gas flow, i.e.
  • Slow washout
    Of agent in patient.
    • The time constant for removal of agent from the patient is a function of FRC and minute ventilation, i.e.

Factors affecting volatile washout:

  • Brain-Blood and Tissue-Blood
    • Tissue:Blood coefficient of agent
    • Duration and depth of anaesthesia
      Important for highly soluble agents used in long cases.
  • Blood-Alveolus
    • Blood:gas coefficient of agent
      Highly soluble agents will have an increased amount of drug dissolved in tissue, so a large resevoir of drug exists that will have to be removed.
    • Alveolar Cardiac output
      Decreased cardiac output increases elimination.
      • Shunt
        Decreases elimination.
  • Alveolus-Air
    • MVA/FRC
      Increased alveolar ventilation increases elimination.
  • Other factors
    • Metabolism of agent
      Agents undergoing metabolism are eliminated more rapidly.
    • Absorption of agent into circuit
    • Percutaneous loss
      Loss of agent by diffusion from tissues into external environment.

Alteration to Pharmacokinetics

Increased rate of induction in children due to:

  • Increased VA/FRC ratio
    Increases PA.
  • Lower albumin and cholesterol
    Reduced blood-gas solubility coefficients for some agents.

Increased rate of induction in elderly due to:

  • Lower MAC requirement
  • Lower albumin
    Reduces blood-gas solubility coefficients for some agents.
  • Lower cardiac output
    Pa and therefore PB is established more rapidly.

Altered rate of induction in pregnancy due to:

  • Increased VA/FRC ratio
    • Increased minute ventilation
      This is of greater importance in spontaneous ventilation, as this is controlled by the anaesthetist during controlled ventilation.
    • Decreased FRC
      Increases PA, increasing PB and speed of onset.
  • Lower albumin
    Reduces blood-gas solubility coefficients for some agents.
  • Increased CO
    Reduces rate of rise of PA, reducing PB and therefore speed of onset.
  • Reduced MAC requirement
    Progesterone has some sedative properties.

Alteration to Pharmacokinetics with Special Methods of Administration

In target-controlled anaesthesia, FGF and agent FI are controlled by the machine to reach the target FA rapidly at low concentrations. This causes:

  • An initial over-pressure of FI, in order to fill the FRC and reach the desired FA
  • A more rapid induction, as the target Fa is reached more rapidly

In liquid injection, anaesthetic agent is injected into the breathing system. This causes:

  • A very large degree of overpressure
    In this circumstance, the rate of rise of end-expired agent concentration is identical for different agents.
    • i.e. Onset is independent of the blood:gas coefficient

Mechanism of Action of Inhaled Anaesthetic Agents

Mechanisms of action can be divided into:

  • Macroscopic
    At the level of the brain and spinal cord.
    • In the spine by:
      • Decreasing transmission of noxious afferent signals at the thalamus
      • Inhibition of spinal efferents, decreasing motor responses
    • In the brain by:
      • Global depression of CBF and glucose metabolism
  • Microscopic
    Synapses and axons by:
    • Inhibiting pre-synaptic excitatory activity:
      • ACh
      • 5-HT
      • Glutamine
    • Augmenting post-synaptic inhibitory activity:
      • GABAA
  • Molecular
    Anaesthetic agents may alter the function of molecules within the CNS. These include:
    • Alteration of α-subunits of the GABAA receptor
      This prolongs the time it spends open once activated, prolonging the inhibitory Cl- current and increasing the degree of hyperpolarisation.
    • Enhance the activity of two-pore K+ channels
      Increases the resting membrane potential of both pre-synaptic and post-synaptic CNS neurons.

Incomplete Theories of the Mechanism of Action of General Anaesthetic Agents

Meyer-Overton Hypothesis:

  • Potency of anaesthetics relates to their lipid solubility
  • Anaesthetic molecules dissolve into CNS membranes, disrupting their effect
  • Flaws:
    • Not all lipid soluble drugs have general anaesthetic affects
    • Other factors disrupt cell membranes without causing anaesthesia

Volume Expansion, Pressure Reversal (Mullin's Critical Volume Hypothesis):

  • CNS cell membranes expand with general anaesthetic agents
    This distorts channels responsible for maintaining membrane potential and generating action potentials.
  • Increased ambient pressure reverses general anaesthesia
  • Flaws:
    • Does not account for stero-selectivity of drug-receptor interactions
      I.e. receptors select for one steroisomer over others.

Structure-Activity Relationships of Inhaled Anaesthetics

  • Chemical structures of different volatile anaesthetics are covered in the pharmacopeia.

Different chemical and physical properties alter the effect of inhalational agents:

  • Physical
    • Molecular weight
      A decrease in molecular weight decreases boiling point and therefore increases SVP.
  • Chemical
    • H+ content
      Greater hydrogen content:
      • Increases flammability
      • Increases potency
    • F- content
      Greater fluoride content:
      • Decreases flammability
      • Decreases oxidative metabolism
        This decreases toxicity.
      • Decreases potency
    • Cl- content
      Increased chloride increases potency.
    • -CHF2 (Di-fluor-methyl group)
      • Produces CO in the presence of dry soda lime

The Ideal Inhaled Anaesthetic Agent

From the properties discussed above, we can construct the following ideal agent:

  • Physicochemical
    • Liquid at room temperature
    • High SVP
    • Low specific heat capacity
    • Long shelf-life
    • Light stable
    • Heat stable
    • Does not react with the components in the breathing circuit
      • Rubber
      • Metal
      • Plastic
      • Soda lime
    • Not flammable/explosive
    • Smells nice
    • Preservative free
    • Environmentally friendly
    • Cheap
  • Pharmacokinetic
    • High oil:gas partition coefficient
      Low MAC.
    • Low blood:gas partition coefficient
      Rapid onset and offset.
    • Not metabolised
    • Non-toxic
  • Pharmacodynamic
    • Does not cause laryngospasm or airway hyperreactivity
    • No effect on HDx parameters
    • Analgesic
    • Hypnotic
    • Amnestic
    • Anti-epileptic
    • No increase in ICP
    • Skeletal muscle relaxation
    • Anti-emetic
    • No tocolytic effects
    • Not teratogenic or otherwise toxic
  • No drug interactions

References

  1. Khan KS, Hayes I, Buggy DJ. Pharmacology of anaesthetic agents II: inhalation anaesthetic agents. Continuing Education in Anaesthesia Critical Care & Pain, Volume 14, Issue 3, 1 June 2014, Pages 106–111.
  2. Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
  3. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
  4. Leslie RA, Johnson EK, Goodwin APL. Dr Podcast Scripts for the Primary FRCA. Cambridge University Press. 2011.
  5. Miller RD, Eriksson LI, Fleisher LA, Weiner-Kronish JP, Cohen NH, Young WL. Miller's Anaesthesia. 8th Ed (Revised). Elsevier Health Sciences.
  6. Zhou JX, Liu J. The effect of temperature on solubility of volatile anesthetics in human tissues. Anesth Analg. 2001 Jul;93(1):234-8.
  7. Hendrickx J, Peyton P, Carette R, De Wolf A. Inhaled anaesthetics and nitrous oxide: Complexities overlooked: things may not be what they seem. Eur J Anaesthesiol. 2016 Sep;33(9):611-9.
  8. Aranake A, Mashour GA, Avidan MS. Minimum alveolar concentration: ongoing relevance and clinical utility. Anaesthesia. 2013 May;68(5):512-22. doi: 10.1111/anae.12168.
  9. Lerman J, Gregory GA, Willis MM, Eger EI 2nd. Age and solubility of volatile anesthetics in blood. Anesthesiology. 1984 Aug;61(2):139-43.
Last updated 2017-10-08

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