Pharmacology of Inhalational Anaesthetics

Mode of Action

The molecular basis of inhalational anaesthesia is not fully understood. Historically, the Meyer-Overton hypothesis demonstrated that the potency (expressed as Minimum Alveolar Concentration, MAC) of an anaesthetic agent increased in direct proportion to its oil:gas partition coefficient. This led to the interpretation that the site of action was the lipid bilayer of nerve membranes, and when sufficient drug dissolved in this layer, anaesthesia occurred.

Recent research suggests that inhalational agents act on specific membrane proteins, altering ion flux or receptor function. Key protein targets include:

• GABAA Receptors: Potentiation occurs with halothane, isoflurane, and sevoflurane.
• Glycine Receptors: Often at the same CNS sites as the GABAA receptors and are of particular importance in lower brain centers and the spinal cord; potentiated by low concentrations of all volatile agents.
• Two-Pore-Domain Potassium Channels: Complex distribution within the CNS. Activated by volatile and gaseous anaesthetics; may modulate membrane excitability.
• Other targets may include NMDA receptors, HCN (Hyperpolarization-activated cyclic nucleotide–gated) channels, and some sodium channel subtypes.

Potency

The potency of an inhalational anaesthetic agent is measured by its MAC (Minimum Alveolar Concentration). MAC is defined as the minimum alveolar concentration at steady-state that prevents reaction to a standard surgical stimulus (skin incision) in 50% of subjects at 1 atmosphere. MAC is affected by various physiological and pharmacological factors and is additive when a mixture of agents is used together.

Pharmacokinetics

At steady-state, the partial pressure within the alveoli (PA) is in equilibrium with that in the arterial blood (Pa) and the brain (Pb). However, achieving steady-state may take hours, depending on the agent and physiological factors.

Ventilation

Increased alveolar ventilation results in a faster rise in PA and Pb, reducing the onset time of anaesthesia. A large Functional Residual Capacity (FRC) can dilute the inspired concentration, increasing onset time.

Inspired Concentration

Increasing the inspired concentration leads to a more rapid rise in PA, reducing onset time.

Cardiac Output

A low cardiac output reduces anaesthetic uptake but accelerates the rise in PA and onset of anaesthesia, especially with agents having a high blood:gas partition coefficient.

Blood:Gas Partition Coefficient

This coefficient defines the ratio of anaesthetic in blood and gas at equilibrium. Agents with a low blood:gas partition coefficient exert a high partial pressure in blood, leading to a faster onset and offset of action.

Metabolism

Halogen ions are released following metabolism by hepatic cytochrome P450 enzymes and can cause hepatic or renal damage. The stability of the carbon-halogen bond affects metabolism:

• C-F Bonds: Relatively stable; minimally metabolized.
• C-Cl, C-Br, C-I Bonds: Increasingly easier to metabolize; potential for toxicity.

Nitrous Oxide (N₂O)

N₂O has a high MAC and is widely used in combination with other inhaled anaesthetic agents or with O₂ as Entonox (50% nitrous oxide and 50% oxygen). It is produced by heating ammonium nitrate. It interferes with DNA synthesis even after brief exposure.

It is produced by heating ammonium nitrate to 250°C, following the reaction: NH₄NO₃ → N₂O + 2H₂O. N₂O is stored as a liquid in French blue cylinders at a pressure of 51 bar at 20°C, but the gauge does not accurately reflect the amount left until most of the liquid has evaporated into gas. The filling ratio, which represents the mass of N₂O in relation to the cylinder’s volume, is set at 0.75 in temperate regions and reduced to 0.67 in tropical regions to prevent cylinder explosions due to heat. The gas has a critical temperature of 36.5°C and a critical pressure of 72 bar.

Effects

• Respiratory: Small fall in tidal volume offset by increased respiratory rate.
• Cardiovascular: Mild myocardial depression offset by increased sympathetic activity (however, in patients with cardiac failure there may be a significant reduction in cardiac output).
• CNS: Increases cerebral blood flow (CBF).

Special Considerations:

• Concentration Effect: Rapid uptake increases alveolar concentration of remaining gases.
• Second Gas Effect: Enhances uptake of concurrently administered volatile agents.
• Diffusion Hypoxia: Rapid elimination can dilute alveolar oxygen; supplemental oxygen is recommended post-anesthesia.

Toxicity: Prolonged exposure can inhibit methionine synthase, affecting DNA synthesis and leading to megaloblastic anemia.

Halothane

A halogenated hydrocarbon with a non-irritant, sweet odor, unstable when exposed to light. It is stored with 0.01% thymol to prevent decomposition.

• Effects:
  • Respiratory: Depresses minute ventilationd due to decreased tidal volume; blunts hypoxic and hypercapnic responses; bronchodilator (useful in asthmatic patients).
  • Cardiovascular: Causes bradycardia by due to increased vagal tone; myocardial depression; reduces systemic vascular resistance; sensitizes myocardium to catecholamines.
  • CNS: Increases cerebral blood flow significantly (more than any other volatile agent), raising intracranial pressure.
• Metabolism: Up to 25% metabolized by hepatic cytochrome p450, producing trifluoroacetic acid and halide ions.
• Toxicity: Risk of halothane hepatitis, with an incidence of 1 in 2,500 to 35,000; higher risk with repeated exposure.
  
  Halothane should be avoided if it has been given in the previous 3 months, if there is a past history of adverse reaction to halothane, or if there is pre-existing liver disease.

Isoflurane

A widely used agent for maintenance anesthesia; an isomer of enflurane.

• Effects:
  • Respiratory: Depresses ventilation (more than halothane), decreases VE (Minute Ventilation); increases PaCO₂; pungent odor may cause airway irritation.
  • Cardiovascular: Reduces systemic vascular resistance, leading to hypotension; may cause
    coronary steal
    in theory, but not clinically significant.
  • CNS: Increases cerebral blood flow minimally; reduces cerebral metabolic rate.
• Metabolism: Minimal metabolism; potential for carbon monoxide production when interacting with dry soda lime.

Enflurane

Less commonly used due to better alternatives.

• Effects:
  • Respiratory: Significant depression of ventilation.
  • Cardiovascular: Decreases cardiac output, contractility, and blood pressure with increased heart rate.
  • CNS: At high concentrations and hypocapnia, can produce EEG patterns indicative of seizure activity.
• Metabolism: About 2% metabolized; produces fluoride ions; potential nephrotoxicity at high fluoride levels.

Desflurane

Notable for rapid induction and recovery due to its low bloodpartition coefficient.

• Effects:
  • Respiratory: Depresses ventilation; pungent odor can cause airway irritation; not suitable for induction.
  • Cardiovascular: May cause tachycardia and hypertension at concentrations above 1 MAC.
• Metabolism: Very low metabolism (0.02%); requires a specialized vaporizer due to its high vapor pressure.

Sevoflurane

Preferred for inhalation induction, especially in pediatrics, due to its pleasant odor and rapid onset.

• Effects:
  • Respiratory: Predictable depression of ventilation, rise in PaCO2 and a fall in minute ventilation.
  • Cardiovascular: Reduces systemic vascular resistance leading fall in BP without significant effects on heart rate or contractility.
  • CNS: There is some evidence that children exhibit a higher incidence of post operative agitation and delirium compared with halothane.
• Metabolism: Undergoes more metabolism than other volatile agents (except halothane); produces inorganic fluoride ions.
• Toxicity: Can react with soda lime to produce Compound A; animal studies suggest nephrotoxicity at high levels, but not observed in humans at clinical concentrations.

Ether (Diethyl Ether)

An inexpensive agent still used in some regions lacking modern anesthetics.

• Effects:
  • Respiratory: Stimulates respiration; bronchodilator; may cause airway irritation.
  • Cardiovascular: Increases cardiac output and blood pressure due to sympathomimetic effects.
  • Other: Provides analgesia and good muscle relaxation.
• Adverse Effects:
  • High incidence of nausea and vomiting.
  • Flammable and explosive risks require careful handling; avoid ignition sources during use.

Xenon

An inert, odorless noble gas with anesthetic properties.

• Effects:
  • Rapid Induction and Emergence: Due to extremely low bloodpartition coefficient (0.14).
  • Analgesia: Provides significant analgesic effects.
  • Minimal Cardiovascular Impact: Stable hemodynamic profile.
• Limitations:
  • High cost of extraction and production limits widespread use.