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 vapourise. 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 (P_B) equals the partial pressure in blood (P_a), and in the alveoli (P_A)
  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 (1cm forearm incision) in 50% of a population.

Note that this definition:

• Does not reflect lack of awareness
• Does reflect the action of an agent on spinal cord reflexes
  This is why 1 MAC is adequate for the majority of patients, as awareness and recall are suppressed at lower MAC values than are required for immobility.
• 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 (F_a) of agent.
  • This is an important difference, because even at steady-state, F_a ≠ F_A
  • 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 diffusibility
  • However, the difference between F_a and F_A 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, P_a.
• One of several related terms:
  • MAC awake
    Concentration required to prevent response to a verbal stimuli in absence of noxious stimuli.
    • Typically ~1/3^rd of MAC for most agents (sevoflurane, isoflurane, desflurane)
    • Notably higher for nitrous oxide (MAC-awake ~2/3^rds 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

Note that addition of other agents (e.g. opioids) will affect different MAC subtypes (e.g. MAC₅₀ vs MAC_BAR) 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 P_a, which creates a steep gradient between P_a and P_B, giving a rapid onset of action
  • Conversely, soluble agents dissolve easily into pulmonary blood without substantially increasing P_a
    This causes leads to a slow onset due to:
    • A large fall in P_A as the agent leaves the alveolus, decreasing the gradient for further diffusion
    • A small gradient between P_a and P_B
      
      
• 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 P_B requires maintaining P_A at a high enough level. By increasing P_A, 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 (F_i) will increase the rate of increase of alveolar concentration (F_A). 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 F_i.
  • 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 F_i.
  • Circuit absorption
    Absorption of agent by the circuit will decrease F_i.
• V_A
  Increased alveolar ventilation increases F_i, 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 F_i.
  • This is measured with the V_A/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 P_A 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 pronounced as FiN₂O increases
      • The concentration effect is more profound in lung units with moderately low V/Q ratios, causing in a large increase in F_a
        This results in a larger value of F_a for any given F_A, 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 $F_A \over F_I$ 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 P_A
    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 F_A/F_A0 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.
    $\tau = {CV \over FGF}$
• 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.
    $\tau = {FRC \over MV}$

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 reservoir of drug exists that will have to be removed.
  • Alveolar Cardiac output
    Decreased cardiac output increases elimination.
    • Shunt
      Decreases elimination.
• Alveolus-Air
  • MV_A/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 V_A/FRC ratio
  Increases P_A.
• 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
  P_a and therefore P_B is established more rapidly.

Altered rate of induction in pregnancy due to:

• Increased V_A/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 P_A, increasing P_B and speed of onset.
• Lower albumin
  Reduces blood-gas solubility coefficients for some agents.
• Increased CO
  Reduces rate of rise of P_A, reducing P_B 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 F_I are controlled by the machine to reach the target F_A rapidly at low concentrations. This causes:

• An initial over-pressure of F_I, in order to fill the FRC and reach the desired F_A
• A more rapid induction, as the target F_a 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:
    • GABA_A
• Molecular
  Anaesthetic agents may alter the function of molecules within the CNS. These include:
  • Alteration of α-subunits of the GABA_A 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 stereoisomer 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

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