General anesthetics

General Anaesthetics

Introduction to General Anaesthesia

• General anaesthesia: A state of controlled unconsciousness induced to allow painless surgical procedures.

• General anaesthetics: Drugs that induce reversible loss of consciousness.

The Four Stages of Anaesthesia

1. Stage 1: Analgesia

   • Pain relief is achieved.

2. Stage 2: Excitation

   • Characterized by excitation due to inhibition of inhibitory reticular neurons.

3. Stage 3: Surgical Anaesthesia

   • The desired state for performing surgery.

4. Stage 4: Medullary Paralysis

   • Includes respiratory arrest and vasomotor collapse.

• Note: These stages were originally based on inhaled ether and may not apply to modern rapid-acting general anaesthetics, combined medications, and premedication strategies used today.

Balanced Anaesthesia

• A strategy that combines multiple drugs to minimize toxicity and achieve specific anaesthetic goals:

  • Suppression of response to noxious stimuli

  • Analgesia: Opioids or local anaesthetics.

  • Unconsciousness: Achieved through a combination of intravenous and inhalation anaesthetics.

  • Specific paralysis (if required): Muscle relaxants.

• While it's possible to use a single general anaesthetic, they tend to be more toxic on their own.

Typical Regime of Balanced Anaesthesia

• Premedication to relieve anxiety:

  • Benzodiazepines

• Reduction of secretion and vagal reflexes:

  • Antimuscarinics

• Postoperative antiemesis:

  • Antiemetics

• Pain relief:

  • Opioids or NSAIDs

• Maintenance of anaesthesia:

  • Inhaled anaesthetics

• Induction of anaesthesia:

  • Intravenous anaesthetics

• Progress of surgery:

  • Reversal of skeletal muscle relaxants using cholinesterase inhibitors

Mechanism of Action of General Anaesthetics

• General characteristics: General anaesthetics are a diverse group of chemicals with no distinct structure-activity relationship.

• They exert multiple effects, with some being specific and others resulting from generalized CNS depression.

• The neurophysiology of consciousness is not fully understood, complicating efforts to definitively determine the mechanisms by which general anaesthetics work.

• Mechanisms likely involve effects on synaptic transmission within the central nervous system (CNS).

Proposed Mechanisms

Lipid Theory

• This theory suggests a strong correlation between lipid solubility and anaesthetic potency, positing that alterations in membrane lipid structure underlie the mechanism; however, this theory has been largely discredited.

Protein Theory

• Proposes that anaesthetics bind to the hydrophobic portions of ion channels, leading to:

  • Enhanced tonic inhibitory synaptic transmission.

  • Increased activity at ligand-gated Cl- channels, such as GABAA and glycine receptors (e.g., propofol and thiopentone).

  • Suppression of excitatory synaptic transmission by inhibiting nicotinic and NMDA (glutamate) receptors (e.g., ketamine, N2O).

  • Reduced neuronal excitability through increased opening of two-pore domain K+ channels (notably by volatile and gaseous anaesthetics, unlike intravenous types).

CNS Regions Involved in Various Effects of Anaesthesia

• Unconsciousness: Cortex, thalamus, brainstem

• Analgesia: Spinothalamic tract

• Amnesia: Amygdala, hippocampus

• Immobility: Spinal cord central pattern generators

Intravenous Anaesthetics

• Applications:

  • Induction of anaesthesia: Rapid onset (10-30 seconds) to swiftly reach stage 3 anaesthesia. More pleasant than gas induction because it reaches desired states faster.

  • Maintenance of anaesthesia: Usually performed using propofol, either through repeated bolus injections or continuous infusion.

Distribution of Intravenous Anaesthetics

• Onset: Loss of consciousness within a few minutes post-injection, primarily in the brain compartment.

Propofol

• Characteristics:

  • Rapid and pleasant induction and recovery.

  • Duration depends significantly on redistribution.

  • Suitable for maintaining anaesthesia; has very fast clearance, resulting in minimal hangover effects even at high doses.

  • Exhibits first-order kinetics in metabolism.

  • Possesses anti-emetic properties but carries serious risks including hypotension and apnea, inducing vasodilation more than thiopentone does.

Thiopentone (Thiopental)

• Nature: Ultra-short-acting barbiturate suitable for induction.

• Risks & Effects:

  • Rapid, pleasant induction with duration dependent on redistribution, unsuitable for repeated dosing owing to delayed recovery (due to accumulation in adipose tissue).

  • Serious risk of hypotension and apnea, featuring direct myocardial depression and reduced sympathetic output, with a narrow safety margin between anaesthetic and cardiovascular depression doses.

Ketamine

• Mechanism: NMDA antagonist providing analgesic effects.

• Application: Used for induction of anaesthesia in trauma patients due to its lack of hypotensive effects; preserves respiration, may elevate BP & HR.

• Effects: Induces a state termed 'dissociative anaesthesia' where patients experience analgesia and amnesia while being conscious and having muscle tone, useful in primitive conditions.

• Risks: Hallucinations and dysphoria may occur upon slow recovery; also recognized as a drug of abuse.

Etomidate

• Characteristics: Similar to thiopental but metabolized faster; less risk of cardiovascular depression.

• Effects: May cause involuntary movements during induction as well as a high incidence of nausea, and carries a possible risk of adrenocortical suppression. Recognized as a drug of abuse, termed 'space oil.'

Summary of Intravenous Anaesthetics Effects and Comments

Inhalation Anaesthetics

Applications

• Maintenance of Anaesthesia: Depth controlled by adjusting partial pressure of inhalation anaesthetics. Less suitable for induction due to longer onset and potentially unpleasant feelings associated with facemasks.

Potency: Minimum Alveolar Concentration (MAC)

• Definition: The concentration of an inhaled anaesthetic (vol/vol or in mmHg) in the end-tidal gas that prevents response to a standardized painful stimulus in 50% of patients.

• Important notions:

  • The smaller the MAC, the more potent the anaesthetic.

  • 1 MAC of one gas provides equal anaesthesia to 1 MAC of another without synergistic or antagonistic effects; thus, MAC values are additive.

Potency Implications

• MAC is inversely proportional to anaesthetic lipophilicity based on the Meyer-Overton correlation (lipophilicity denoted by oil:gas partition coefficient). Since inhalational anaesthetics primarily serve to maintain unconsciousness, MAC is less relevant for potency comparison among them.

Pharmacokinetics Overview

• The pharmacokinetics of inhalation anaesthetics depend on the rate of drug entering/leaving the lungs via inspired gas, influencing the kinetic behavior during anaesthesia induction and recovery.

Delivery from Lungs to Brain

• Transfer of Drug from Lung to Blood involves:

  • Drug solubility and inhaled concentration

  • Alveolar ventilation rates

• Transfer from Blood to Brain relies on:

  • Pulmonary blood flow/cardiac output

Solubility and Blood-Gas Partition Coefficient

• Definition: The ratio of anaesthetic concentration in blood to that in the gas phase when equilibrium is reached.

• Notable principles:

  • High blood solubility indicates slow induction (e.g., halothane, B:G = 2.3).

  • Low blood solubility indicates rapid induction (e.g., nitrous oxide, B:G = 0.47).

Factors Influencing Induction Time

1. Anaesthetic Concentration in Inspired Air: Higher concentrations lead to faster induction of anaesthesia.

2. Pulmonary Ventilation: Increasing minute ventilation elevates alveolar anaesthetic tension, raising arterial blood tension, especially pronounced in drugs with high blood-gas coefficients.

3. Cardiac Output (Pulmonary Blood Flow): Higher cardiac output can slow induction due to increased volume of blood available for gas dissolution, potentially diminishing the rate of increase in arterial gas tension.

Metabolism and Elimination

• Metabolism: Relevant for safety related to halogenated anaesthetics such as halothane and methoxyflurane, although not crucial for action duration.

• Elimination: Primarily through the lungs, following the reverse processes of induction, with recovery duration linked to the mass of anaesthetic in body tissues, especially adipose tissue.

General Pharmacological Actions of Inhalational Anaesthetics

• Respiration: General depression of respiration and CO2 response.

• Cardiovascular System: Generalized reduction in arterial pressure and peripheral vascular resistance, least with isoflurane.

• Kidney: Depression of renal blood flow and urine output.

• Muscle: Can cause muscle relaxation at high concentrations.

Toxicity and Side Effects

• Includes:

  • Depression of respiratory and cardiovascular drive.

  • Malignant hyperthermia (associated specifically with halogenated agents like halothane and enflurane).

  • Management includes discontinuation of triggering agents, rapid cooling, and administration of dantrolene to block calcium release from the sarcoplasmic reticulum.

  • Increased risks of hepatotoxicity and nephrotoxicity after prolonged exposure.

Nitrous Oxide (N2O)

• Characteristics: Weak anaesthetic, insufficient alone for general anaesthesia.

• Use: Often combined with other agents (50-70% in O2) to maintain general anaesthesia, effectively reducing MAC value of volatile agents.

• Applications: Common in dentistry and obstetrics due to rapid induction and recovery, minimal cardiovascular/respiratory impact, and not metabolized.

Inhalation Anaesthetics: Specific Agents

Isoflurane

• Widely used inhalational agent noted for its vasodilatory effects and potential to hypotension.