L10 Clinical Pharmacology General anaesthetics

Overview

This lecture covers General Anaesthesia as a pharmacological intervention: its goals and stages, the “balanced anaesthesia” strategy of combining agents (premedication, induction, maintenance, recovery), the pharmacology of the main IV agent (Propofol) and the principal inhalation agents (especially Sevoflurane), the pharmacokinetic principles that govern the speed and potency of inhaled agents (blood:gas and oil:gas partition coefficients, MAC), the cellular/molecular mechanism of action (GABA_A and NMDA receptor modulation), and the systemic/adverse effects of these agents, including malignant hyperthermia.

Principles and Goals of General Anaesthesia

General anaesthesia is defined (Urban & Bleckwenn, BJA 2002) as “a pharmacological intervention used to prevent the psychological and somatic adverse effects of surgical trauma and also to create convenient conditions for surgery”.

Four desirable components:

• Immobility
• Analgesia
• Unconsciousness
• “Not harming the patient”

Objectives that must be met: unconsciousness, muscular relaxation, and suppression of reflex responses to noxious surgical stimuli. No single drug achieves all of these goals.

Desirable vs adverse effects of GA (Urban et al., BJA 2002):

• Desirable: amnesia; suppression of responses to noxious stimuli (analgesia); unconsciousness/anxiolysis; myorelaxation/immobility.
• Adverse: cardiovascular instability; excitation/convulsions; emesis; shivering.

Stages of Anaesthesia

1. Stage I – Analgesia: analgesia (extent depends on agent), amnesia, euphoria.
2. Stage II – Excitement: excitement, delirium, combative behaviour.
3. Stage III – Surgical Anaesthesia: unconsciousness, regular respiration, decreasing eye movement. Surgery commences and is completed within this stage.
4. Stage IV – Medullary Depression: respiratory arrest, cardiac depression and arrest, no eye movement.

Rapid induction (Stages I–II) is managed with IV anaesthetics; maintenance (Stage III) with inhalation anaesthetics; withdrawal of anaesthesia for recovery moves the patient back toward Stage I/awake.

Conscious Sedation vs General Anaesthesia

• Conscious sedation: pharmacological CNS depression that maintains verbal communication and protective airway reflexes, e.g. during GI endoscopy. Agents: nitrous oxide (inhalation), propofol (IV), and/or oral agents.
• General anaesthesia is used where: surgery requires deep muscle relaxation for long periods; the surgical area cannot be adequately anaesthetised with local/regional anaesthesia; the procedure risks significant blood loss or affects breathing; or patient preference/an uncooperative patient influences the decision even for small procedures.

Balanced Anaesthesia: Drug Sequence and Adjuncts

Balanced anaesthesia achieves a sufficient operable depth of anaesthesia with desirable outcomes by combining multiple pharmacological agents, limiting the dose and toxicity of each individual drug. Depth of anaesthesia with a volatile anaesthetic may be titrated using a processed EEG.

Sequence of agents:

1. Pre-medication: benzodiazepines, e.g. midazolam.
2. Induction: propofol.
3. Maintenance: sevoflurane +/- N2O, + O2.
4. Recovery: anaesthetic withdrawal + O2.

GABA_A and NMDA receptors are specific targets for IV anaesthetics, with partial specificity also shown by inhaled halogenated anaesthetics.

Classification of general anaesthetics:

• Inhalation: Gas (nitrous oxide, N2O) or Volatile liquids (sevoflurane).
• Parenteral/Intravenous: Induction and maintenance agents (propofol).

GA does not provide effective pain relief, so additional analgesics (e.g. Temgesic) are needed intra- and post-operatively.

Pre-medication detail: midazolam is given IV as an anxiolytic/sedative; it is slow acting with little respiratory or CV depression. It is a GABA allosteric modulator, effective in reducing preoperative anxiety, and is not generally needed when IV induction anaesthesia is fast. Its metabolism via the CYP3A family (primarily CYP3A4 and CYP3A5) creates a large potential for drug interactions.

Induction agents: propofol, thiopental sodium, ketamine — these induce rapid unconsciousness. Other agents, e.g. analgesics, may be additionally used.

Maintenance agents: chosen according to length/type of surgery and the patient’s general health/disease status.

• Short procedures — e.g. propofol (IV).
• Long procedures — e.g. sevoflurane (inhalation).

Maintenance adjuvants: anti-emetics (metoclopramide), analgesics (fentanyl). For procedures requiring good muscle relaxation, neuromuscular blocking agents are used:

• Non-depolarising nACh receptor blockers, e.g. rocuronium (a tubocurarine-like drug), reversible with the binding agent sugammadex.
• Depolarising inhibitor, e.g. succinylcholine.
  (Covered in more detail in the ELM2/MB ChB2 musculo-relaxants lecture.)

Intravenous Anaesthetics: Propofol

Propofol is delivered IV into a large vein by infusion pump or slow bolus, formulated in an egg and soyabean oil vehicle (10% soyabean oil, 2.25% glycerol, 1.2% egg phosphatide).

Effects: a dose-dependent brain depressant that inhibits sensation to pain and produces sedation. Most commonly used for anaesthetic induction, but can also be used for maintenance of anaesthesia, as an amnesic, and as an anticonvulsant.

Mechanism of action: GABA_A receptor allosteric modulator. Propofol enhances the effect of GABA (an inhibitory neurotransmitter) at the receptor, slowing Cl⁻ channel-closing time and thereby increasing CNS depression. It is also a Na⁺ channel blocker and possibly an excitatory NMDA receptor inhibitor.

Pharmacokinetics: fast onset (15–30 s) and fast recovery (5–15 min) even though its half-life is long, because it disperses quickly to other tissues. Rapid hepatic/extrahepatic metabolism means it can also be used to maintain anaesthesia by constant infusion. Metabolites are excreted renally.

Propofol ADRs (significant — narrow therapeutic margin):

• Cardiovascular and respiratory depression (particularly combined with a benzodiazepine)
• Low blood pressure due to systemic vasodilation
• Diminished cerebral blood flow and reduced cerebral metabolic oxygen consumption, with increased intracranial pressure
• Airway obstruction
• Apnoea
• Pain at the injection site, due to TRPA1 channel activation on sensory nerves (no antagonist available) — mitigated by administering lignocaine at the injection site first
• Obesity, and hepatic or renal injury, increase the risk of accumulation

Example induction protocol with propofol:

1. Pre-mix 1 mL 1% lignocaine with 20 mL 1% propofol.
2. Give 3–5 mL, flush, and wait 45–60 s.
3. Monitor the patient’s response until clinical signs show onset of anaesthesia; repeat if needed.
4. Be prepared to open the airway and ventilate.
5. Have vasopressor agents (noradrenaline, phenylephrine) ready to correct hypotension.
   • Noradrenaline: powerful α-adrenergic agonist with weak β-adrenergic agonist activity, which helps maintain cardiac output.
   • Phenylephrine: pure α-agonist, raises BP by increasing systemic vascular resistance, usually with a compensatory decrease in cardiac output.

Intraoperative hypotension is associated with risk of MI, AKI, etc.

Inhalation Anaesthetic Pharmacokinetics

Depth of anaesthesia is determined by the concentration (partial pressure) of anaesthetic in brain tissue. The forward movement of an inhalational agent is driven by a series of partial pressure gradients (agent moves from high pressure to low pressure): alveoli → blood → brain. These gradients depend on the solubility of the volatile anaesthetic in blood and body tissue.

Two main factors determine the pharmacokinetic properties of an inhalation anaesthetic:

1. Blood:gas partition coefficient (solubility in blood) — determines speed of induction/recovery.
2. Oil:gas partition coefficient (solubility in fat) — determines potency.

Blood:Gas Partition Coefficient

This is the ratio of the amount of anaesthetic dissolved in blood to the amount in the same volume of gas in contact with that blood; the blood compartment acts as a reservoir for the anaesthetic.

• High blood:gas coefficient → anaesthetic is highly soluble in blood, taking longer to saturate it → slower onset and slower recovery.
• Low blood:gas coefficient → faster onset and recovery.

Low blood-solubility agents (e.g. N2O, sevoflurane) diffuse into blood producing a low blood concentration, so blood saturation is achieved quickly, giving rapid equilibration between alveolar and arterial anaesthetic concentration → rapid induction requiring little anaesthetic, prompt changes, and a brief recovery period.

High blood-solubility agents (e.g. halothane) dissolve completely into blood, requiring larger amounts and longer recovery periods → longer anaesthetic duration with slower changes in response to the inhaled drug concentration.

Example arterial blood values (alveolar concentration set to 1): nitrous oxide 0.47; sevoflurane 0.6; halothane 2.3.

Potency and MAC

Lipid-soluble substances depress the CNS and act as anaesthetics — the more lipid-soluble an agent, the more potent it is (high oil:gas partition coefficient ∝ high anaesthetic activity). The oil:gas partition coefficient (a measure of fat solubility) determines potency (and also affects kinetics), but correlates with potency without explaining the mechanism of action.

$\text{MAC (Minimum Alveolar Concentration)}={\text{ED}}_{50}$

MAC is a measure of anaesthetic potency: the concentration of gas in the lungs needed to eliminate reflex movements to a surgical incision in 50% of patients. MAC is generally low for the most potent gaseous anaesthetics. Some gases act in synergy — equivalent anaesthesia can be maintained by simultaneous administration of two gases at doses well below their individual MACs, and well below the simple addition of their individual MACs.

The Overton-Meyer correlation (1900) shows a close correlation, in man, between anaesthetic potency (MAC) and oil:gas partition coefficient (log-log relationship). In order of increasing oil:gas partition coefficient/potency: N2O, Xenon, Desflurane, Sevoflurane, Enflurane, Isoflurane, Halothane (most potent).

Characteristics of inhalation anaesthetics:

Drug	Blood:gas	Oil:gas	MAC %	Induction/recovery	Notes
Nitrous oxide (N2O)	0.47	1.4	105	Fast	Good analgesic effect but low potency; must be combined with other anaesthetic agents
Sevoflurane	0.6	53	2	Fast	Used for day-case surgery because of fast onset and recovery
Isoflurane	1.4	91	1.2	Medium	Pungent odour; not used for induction
Halothane	2.3	220	0.75	Medium	Not used nowadays due to potential accumulation of hepatotoxic metabolites and arrhythmias

Sevoflurane – Volatile Anaesthetic of Choice

Sevoflurane is a fluorinated methyl isopropyl ether with an absence of pungency, facilitating rapid mask induction.

• Lower blood solubility than halothane → low blood solubility allows reliable, fast induction and rapid equilibration; it also expedites “wash-out” and therefore recovery (eliminated through exhalation).
• Good lipid solubility → potent inhaled anaesthetic (the GA is held longer at the site of action on CNS lipid membrane/receptors).
• Produces dose-dependent CNS, cardiovascular, and respiratory depressant effects.

Sevoflurane appears to induce the least cerebral vasodilation of the modern agents, which likely makes it the volatile agent of choice for neurosurgical patients with elevated intracranial pressure.

Key points: speed of induction/recovery is determined by anaesthetic solubility in blood (blood:gas partition coefficient) — low blood:gas coefficients produce rapid induction and recovery (e.g. nitrous oxide, sevoflurane), high coefficients show slow induction and recovery (e.g. halothane). Potency is determined by solubility in fat (lipid solubility) — drugs with high lipid solubility have a low MAC, i.e. a lower % of volatile anaesthetic is needed (sevoflurane MAC is 2).

Mechanism of Action of General Anaesthetics

The mechanism of action of GAs is unclear: there is no single receptor explanation, as GA drugs may be physically very different but have similar effects. Evidence:

1. Anaesthetic potency correlates with lipid solubility, suggesting GAs need to cross cell membranes (mainly composed of lipid).
2. Gases have differing chemical structures: nitrous oxide (N2O), sevoflurane (CH2F—O—CH(CF3)2), xenon gas (70%).

Protein theory of General Anaesthetic action: proposes that gaseous anaesthetics produce their effects by binding to specific receptor and channel proteins within the cell membrane.

Cellular-Level Effects

General anaesthetics affect synaptic transmission, NOT axonal conduction, by:

• Reducing/enhancing inhibitory neurotransmitter release, causing CNS depression (enhancing GABA/glycine transmission).
• Blocking receptors involved in excitation, e.g. nitrous oxide as an NMDA receptor antagonist.
• Blocking ACh (nicotinic) receptors and/or 5-HT3 receptors.

Halogenated anaesthetics can raise adrenaline levels, causing ventricular arrhythmias.

Synaptic transmission (ordered): action potential in the presynaptic neuron → Ca²⁺ entry → neurotransmitter release (GABA, glycine) into the synaptic cleft → binding opens postsynaptic Cl⁻ channels. Presynaptically, anaesthetics depress the amount of transmitter released. Postsynaptically, inhibitory synaptic transmission is augmented by anaesthetics, preventing the neuron from being depolarised.

GABA_A receptor modulation (ordered):

1. GABA binds to the receptor, opening the chloride (Cl⁻) ion channel, leading to hyperpolarisation.
2. Anaesthetic binding enhances GABA binding, increasing postsynaptic Cl⁻ entry.
3. Increased Cl⁻ entry increases hyperpolarisation (more negative charge within the cytosol) of the neuron, reducing neural excitability (susceptibility to depolarisation).

Receptor target profile (Rudolph & Antkowiak, Nat Rev Neurosci 2004): ligand-gated and voltage-gated ion channels are relevant targets for inhaled anaesthetics at clinically relevant concentrations.

• Isoflurane and sevoflurane: potentiate the inhibitory GABA_A and glycine receptors, and inhibit most other channels tested (nACh muscle, nACh neuronal, 5-HT3, AMPA, Na⁺, Ca²⁺), with the exception of background K⁺ channels, which they potentiate.
• Nitrous oxide and xenon: nil effect at GABA_A, glycine, nACh (muscle), 5-HT3, AMPA, Na⁺, Ca²⁺, and background K⁺ channels, but inhibit nACh (neuronal) and NMDA receptors.

Allosteric potentiation of the GABA_A receptor produces CNS depression; inhibition of the NMDA receptor aids this depressive action.

Dose-dependent behavioural endpoints: as the MAC fraction administered increases, effects appear in this order — amnesia (lowest MAC fraction, roughly 0.1–0.25) → unconsciousness (roughly 0.25–0.5) → analgesia and immobility (highest, roughly 0.75–1.25, overlapping). These map to CNS regions: unconsciousness (cortex, thalamus, brainstem); amnesia (amygdala, hippocampus); analgesia (spinothalamic tract); immobility (spinal cord central pattern generators). Cardiovascular responses occur at higher doses than these behavioural endpoints.

Systemic and Adverse Effects

Main systemic effect of GAs: cardiovascular depression. Supra-anaesthetic doses can depress all parameters.

• Effects on blood pressure increase with depth of anaesthesia: sevoflurane has little effect on vasoactivity; halothane increases BP; N2O decreases BP.
• GAs generally induce respiratory depression (except N2O and ketamine): O2 exchange becomes less efficient and pCO2 increases.
• Cardiac dysrhythmias are less common with sevoflurane.

Malignant hyperthermia

An inherited, life-threatening clinical syndrome of skeletal muscle hypermetabolism. Triggered in susceptible individuals primarily by inhalational anaesthetic agents and the muscle relaxant succinylcholine. Linked to a ryanodine receptor mutation in skeletal muscle. Diagnosis relies on the caffeine–halothane contracture test, measuring contraction forces of freshly biopsied muscle tissue exposed to caffeine or halothane (FC and FH respectively), performed at clinical testing centres if a familial/genetic link is suspected. Patients with above-threshold FC or FH are diagnosed as MH-susceptible.

Self-test

1. Define general anaesthesia according to Urban & Bleckwenn (2002).
2. List the four desirable components of general anaesthesia.
3. Explain why “balanced anaesthesia” is used instead of a single anaesthetic agent.
4. Describe the four stages of anaesthesia in order, and state which class of anaesthetic (IV vs inhalation) manages induction versus maintenance.
5. Distinguish conscious sedation from general anaesthesia, including an example use case and the agents used for conscious sedation.
6. List the four sequential stages of drug administration in balanced anaesthesia (premedication through recovery) with an example drug or agent for each.
7. Why is midazolam useful as a premedication, and what makes its metabolism prone to drug interactions?
8. Describe the mechanism of action of propofol at the GABA_A receptor, and name its two other proposed molecular actions.
9. Explain why propofol has a fast recovery time despite having a long half-life.
10. List propofol’s significant adverse effects.
11. A patient given propofol reports pain at the injection site. What is the underlying mechanism, and how is it clinically mitigated?
12. In the standard propofol induction protocol, why are vasopressors such as noradrenaline or phenylephrine kept ready, and how do their mechanisms of action differ?
13. Distinguish what the blood:gas partition coefficient determines from what the oil:gas partition coefficient determines for an inhalation anaesthetic.
14. Explain why an anaesthetic with a low blood:gas partition coefficient (e.g. sevoflurane) has a faster onset and recovery than one with a high coefficient (e.g. halothane).
15. Define Minimum Alveolar Concentration (MAC) and state what it represents statistically.
16. What relationship does the Overton-Meyer correlation demonstrate?
17. Explain why sevoflurane is favoured for neurosurgical patients with raised intracranial pressure.
18. Describe the “protein theory” of general anaesthetic mechanism of action, and the two lines of evidence noted for a lipid-related mechanism.
19. Describe the steps of GABA_A receptor modulation by inhaled anaesthetics, from GABA binding through to reduced neural excitability.
20. Distinguish the receptor effects of isoflurane/sevoflurane from those of nitrous oxide/xenon on GABA_A, glycine, and NMDA receptors.
21. List the main systemic cardiovascular and respiratory effects of general anaesthetics, noting which agents are exceptions to the respiratory depression effect.
22. Describe malignant hyperthermia: its cause, its main triggers, and how it is diagnosed.
23. Two inhaled agents are compared: Drug A (blood:gas 0.47, oil:gas 1.4) and Drug C (blood:gas 2.3, oil:gas 220). Which will have the faster onset/recovery, and which is more potent? Explain your reasoning using the partition coefficients.
24. Explain why “a measure of the speed of anaesthetic induction” is not part of the definition of MAC, using the distinction between the two partition coefficients.
25. A patient receiving propofol induction develops significant hypotension. Explain the mechanism linking propofol to this effect, and describe how this differs mechanistically from the way halothane and N2O each affect blood pressure.

Answers

Reveal answers

1. GA is “a pharmacological intervention used to prevent the psychological and somatic adverse effects of surgical trauma and also to create convenient conditions for surgery.”
2. Immobility, analgesia, unconsciousness, and “not harming the patient.”
3. No single drug can achieve all the desired goals of anaesthesia, so balanced anaesthesia combines multiple agents to achieve a sufficient depth of anaesthesia while limiting the dose and toxicity of each individual drug.
4. Stage I (Analgesia: analgesia, amnesia, euphoria) → Stage II (Excitement: excitement, delirium, combative behaviour) → Stage III (Surgical Anaesthesia: unconsciousness, regular respiration, decreasing eye movement — surgery occurs here) → Stage IV (Medullary Depression: respiratory arrest, cardiac depression/arrest, no eye movement). Rapid induction (Stages I–II) is managed with IV anaesthetics; maintenance (Stage III) with inhalation anaesthetics; recovery is withdrawal of anaesthesia.
5. Conscious sedation pharmacologically depresses the CNS while maintaining verbal communication and protective airway reflexes (e.g. GI endoscopy; agents include nitrous oxide, propofol, oral agents). General anaesthesia is used when deep, prolonged muscle relaxation is required, local/regional anaesthesia is inadequate, significant blood loss/breathing effects are likely, or due to patient preference/uncooperative patients.
6. Pre-medication (benzodiazepine, e.g. midazolam) → Induction (propofol) → Maintenance (sevoflurane +/- N2O, + O2) → Recovery (anaesthetic withdrawal + O2).
7. Midazolam is a GABA allosteric modulator that reduces preoperative anxiety, given IV, slow-acting with little respiratory/CV depression. It is metabolised by the CYP3A family (mainly CYP3A4 and CYP3A5), which poses a large number of potential drug interactions.
8. Propofol is a GABA_A receptor allosteric modulator, enhancing GABA’s effect and slowing Cl⁻ channel-closing time. It is also a Na⁺ channel blocker and possibly an excitatory NMDA receptor inhibitor.
9. Although propofol’s half-life is long, it disperses (redistributes) quickly to other tissues, giving fast recovery (5–15 min) despite the long T½.
10. CV and respiratory depression (especially with a benzodiazepine); low BP from systemic vasodilation; diminished cerebral blood flow with reduced cerebral metabolic O2 consumption and increased intracranial pressure; airway obstruction; apnoea; pain at injection site; increased accumulation risk in obesity or hepatic/renal injury.
11. Pain at the injection site is due to TRPA1 channel activation on sensory nerves (no antagonist available); it is mitigated by administering lignocaine at the injection site before propofol.
12. Propofol can cause significant hypotension via systemic vasodilation, so vasopressors are kept ready. Noradrenaline is a powerful α-agonist with weak β-agonist activity that helps maintain cardiac output; phenylephrine is a pure α-agonist that raises BP by increasing systemic vascular resistance, usually with a compensatory decrease in cardiac output.
13. The blood:gas partition coefficient (blood solubility) determines the speed of induction and recovery. The oil:gas partition coefficient (fat solubility) determines potency.
14. A low blood:gas coefficient means the anaesthetic is less soluble in blood, so blood saturates quickly, giving rapid equilibration between alveolar and arterial concentration — rapid induction requiring little anaesthetic and a brief recovery. A high coefficient (e.g. halothane) means the anaesthetic dissolves more completely into blood, requiring larger amounts and longer to reach equilibrium, hence slower onset and recovery.
15. MAC (Minimum Alveolar Concentration) is a measure of anaesthetic potency, equivalent to the ED50: the concentration of gas in the lungs needed to eliminate reflex movements to a surgical incision in 50% of patients.
16. It shows a close correlation, in man, between anaesthetic potency (MAC) and the oil:gas partition coefficient — the more lipid-soluble an agent, the more potent (lower MAC) it is.
17. Sevoflurane appears to induce the least cerebral vasodilation of the modern agents, which likely makes it the volatile agent of choice for neurosurgical patients with elevated intracranial pressure.
18. The protein theory proposes that gaseous anaesthetics act by binding to specific receptor and channel proteins in the cell membrane. Supporting evidence: (1) anaesthetic potency correlates with lipid solubility, suggesting GAs must cross the lipid-based cell membrane; (2) despite this correlation, the gases have very differing chemical structures (e.g. N2O vs sevoflurane vs xenon), suggesting a specific protein interaction rather than a purely non-specific lipid effect.
19. GABA binds the receptor, opening the Cl⁻ channel and causing hyperpolarisation → anaesthetic binding enhances GABA binding, increasing postsynaptic Cl⁻ entry → the increased Cl⁻ entry increases hyperpolarisation (more negative intracellular charge), reducing neural excitability/susceptibility to depolarisation.
20. Isoflurane and sevoflurane potentiate the inhibitory GABA_A and glycine receptors and inhibit most other channels (nACh muscle/neuronal, 5-HT3, AMPA, Na⁺, Ca²⁺), while potentiating background K⁺ channels. Nitrous oxide and xenon have nil effect at GABA_A, glycine, nACh (muscle), 5-HT3, AMPA, Na⁺, Ca²⁺, and background K⁺ channels, but inhibit nACh (neuronal) and NMDA receptors.
21. Cardiovascular: generally depressant, worsening with depth of anaesthesia (sevoflurane little effect on vasoactivity, halothane increases BP, N2O decreases BP), and dysrhythmias (less common with sevoflurane). Respiratory: generally depressant (less efficient O2 exchange, raised pCO2) — except N2O and ketamine, which are exceptions.
22. Malignant hyperthermia is an inherited, life-threatening syndrome of skeletal muscle hypermetabolism, triggered primarily by inhalational anaesthetics and succinylcholine, linked to a ryanodine receptor mutation in skeletal muscle. It is diagnosed via the caffeine–halothane contracture test on freshly biopsied muscle tissue, measuring contraction forces (FC and FH); above-threshold values indicate MH susceptibility.
23. Drug A has the lower blood:gas coefficient (0.47 vs 2.3), so it will have the faster onset/recovery. Drug C has the higher oil:gas coefficient (220 vs 1.4), so it is the more potent agent.
24. MAC is a measure of potency (ED50 for eliminating reflex response to incision), correlating with the oil:gas (fat solubility) coefficient — not with speed, which is instead governed by the blood:gas partition coefficient.
25. Propofol causes hypotension through systemic vasodilation (a GABA_A-mediated CNS/vascular depressant effect). This differs from halothane, which increases BP, and from N2O, which decreases BP — the note does not elaborate on the specific mechanism behind halothane’s or N2O’s blood pressure effects [slide does not elaborate].