Anaesthetics

Core

Introduction

Anaesthesia is the controlled, reversible suppression of consciousness and sensation needed to allow surgery. The pharmacology is unusual: instead of treating a disease, anaesthetic drugs produce a deep but transient pharmacological state, with margins of safety much narrower than most therapeutic drugs. The pre-clinical curriculum focuses on the principles, the major drug classes, and a small number of memorable hazards.

The Components of General Anaesthesia

General anaesthesia is best understood as a combination of five effects, sometimes called the "triad of anaesthesia" plus modern additions:

• Analgesia: absence of pain.
• Amnesia / Hypnosis: loss of consciousness and recall.
• Immobility / muscle relaxation: allowing surgical access and intubation.
• Autonomic stability: suppression of the cardiovascular and respiratory responses to surgery.
• Antiemesis: modern anaesthetic practice routinely includes prophylactic antiemetics for post-operative nausea and vomiting (PONV).

No single drug provides all of these reliably, so modern anaesthesia is a "balanced" combination of agents, typically:

1. Premedication: benzodiazepine for anxiety, antiemetic if needed.
2. Induction: rapid IV agent (propofol most often).
3. Intra-operative analgesia: opioid (fentanyl, alfentanil, remifentanil).
4. Muscle relaxation: neuromuscular blocking drug for intubation and surgery.
5. Maintenance: volatile inhalational agent (sevoflurane, desflurane, isoflurane) and/or continued IV infusion ("TIVA; total intravenous anaesthesia").
6. Reversal of muscle relaxant; emergence; postoperative analgesia (paracetamol, NSAID, opioid as appropriate); antiemetic cover.

"Conscious sedation" is a step down from general anaesthesia: sufficient drug to allow procedures (e.g. dentistry, endoscopy) without full loss of consciousness, usually a single agent like a benzodiazepine plus a small opioid dose. The aim is to preserve airway reflexes and spontaneous ventilation, but sedation can deepen unintentionally, so airway monitoring and rescue capability are mandatory throughout.

Mechanism of Action

The brain's overall level of activity reflects the balance between excitation (mainly mediated by glutamate at NMDA receptors) and inhibition (mainly GABA at GABA_A receptors). Anaesthetics tip the balance towards inhibition.

The vast majority of general anaesthetics work by potentiating GABA_A receptors:

• Inhalational: sevoflurane, isoflurane, desflurane, halothane.
• Intravenous: propofol, thiopental (a barbiturate), etomidate.

The exceptions act on different targets:

• Ketamine: NMDA receptor antagonist.
• Nitrous oxide (N₂O): NMDA antagonist.
• Xenon: NMDA antagonist; expensive but cardioprotective and increasingly used in selected paediatric and cardiac cases.

The brain regions targeted include the reticular activating system (arousal), thalamus (sensory relay), hippocampus (memory), brainstem (respiratory and CV centres), and dorsal horn / motor neurons of the spinal cord (analgesia and muscle relaxation).

General Anaesthesia

Intravenous General Anaesthetics

The IV agents are used for rapid induction (and sometimes maintenance):

• Propofol: the standard induction agent. Rapid onset (~30 seconds), rapid recovery (redistribution), white-emulsion appearance ("milk of amnesia"). Causes vasodilation and dose-dependent hypotension, depresses respiration, and has antiemetic and amnestic effects. Pain on injection is common; lidocaine is often added. Rare but well-described propofol infusion syndrome (metabolic acidosis, rhabdomyolysis, cardiac failure) with high-dose, prolonged use, particularly in critically ill children.
• Thiopental: an ultra-short-acting barbiturate, formerly the standard induction agent before propofol. Still used for rapid sequence induction in obstetrics and where propofol is contraindicated. Risk of laryngospasm; contraindicated in porphyria.
• Etomidate: rapid induction with relative cardiovascular stability, useful in haemodynamically unstable patients. Causes adrenal suppression (single dose can suppress cortisol for up to 24 hours), so avoided in septic shock or as maintenance.
• Ketamine: an NMDA antagonist with several distinguishing features:
  • Provides analgesia and amnesia without significant respiratory depression.
  • Maintains airway reflexes and respiratory drive.
  • Causes tachycardia and hypertension (sympathomimetic), the opposite of most anaesthetics.
  • "Dissociative" anaesthesia: a state in which the patient appears awake but disconnected.
  • Causes emergence phenomena: vivid dreams, hallucinations, particularly in adults; reduced by co-administered benzodiazepine.
  • Particularly useful in haemodynamically unstable trauma patients, paediatric procedures, and pre-hospital settings.

Inhaled General Anaesthetics

Inhalational agents are delivered as a percentage in inspired gas, equilibrating between alveoli, blood and brain. The principal UK volatile agents are:

• Sevoflurane: pleasant smelling, suitable for gas induction (especially in children); rapid onset and offset.
• Isoflurane: long-established maintenance agent; cheap.
• Desflurane: the fastest emergence; pungent, so unsuitable for gas induction.
• Halothane: largely historical; classic association with halothane hepatitis, an idiosyncratic, potentially fatal hepatic reaction.
• Nitrous oxide: less potent (high MAC), used as a carrier gas with other agents to reduce their dose, and in dental and obstetric "gas and air" (Entonox is N₂O 50% / O₂ 50%).
• Xenon: cardioprotective, environmentally neutral; cost limits use.

Two pharmacokinetic concepts govern induction and recovery:

• Blood:gas partition coefficient: lower values mean less drug "stored" in blood, faster equilibration with brain, faster induction and recovery (e.g. desflurane, sevoflurane, nitrous oxide).
• Oil:gas partition coefficient: correlates with potency. The more lipid-soluble, the more potent.

Minimum Alveolar Concentration (MAC)

MAC is the standard measure of inhalational anaesthetic potency. Defined as the alveolar concentration (at 1 atmosphere) at which 50% of patients fail to move to a surgical incision. Lower MAC = more potent.

MAC values are additive across inhaled agents (so adding nitrous oxide reduces the MAC of the volatile agent). Several physiological factors modify MAC, worth knowing for exams:

Factors that increase MAC (need more agent): infancy, hyperthermia, chronic alcohol use, central stimulants.
Factors that decrease MAC (need less agent): old age, hypothermia, pregnancy, opioids, benzodiazepines, other anaesthetics, acute alcohol intoxication.

Local and Regional Anaesthesia

Local anaesthetics reversibly block voltage-gated sodium channels in nerve fibres, preventing action potential generation and propagation. The principles of action potentials are covered in Action Potentials.

Three properties of the drug determine its clinical profile:

• Lipid solubility → potency.
• pKa → speed of onset (lower pKa, more drug in the un-ionised form at tissue pH, faster diffusion across membranes).
• Protein binding → duration of action.

Local anaesthetics are use-dependent: they bind sodium channels preferentially when those channels are actively cycling between open and inactivated states. Pain (small unmyelinated C and thinly myelinated Aδ) fibres fire more frequently than other modalities, so they are blocked first. The order of loss is roughly: pain → temperature → touch → pressure → motor.

The two chemical classes:

• Amides (lidocaine, bupivacaine, ropivacaine, prilocaine): metabolised by hepatic CYP enzymes; longer-acting; the great majority of clinically used agents.
• Esters (procaine, tetracaine, benzocaine, cocaine): metabolised by plasma cholinesterases; shorter-acting; higher rates of allergic reactions.

Memory hook: amides have an "i" in their first syllable (lidocaine, bupivacaine, ropivacaine), esters do not (procaine, tetracaine).

Adrenaline is often added to local anaesthetic to vasoconstrict and slow systemic absorption, prolonging local action and reducing systemic toxicity. Avoid in end-organ tissue (fingers, toes, ears, nose, penis) because of ischaemic risk.

Local anaesthetic systemic toxicity (LAST) is the major hazard, particularly with bupivacaine: cardiac arrhythmia, seizures, eventual cardiac arrest. The antidote is intravenous lipid emulsion (Intralipid), which acts as a "lipid sink" sequestering the drug.

Regional anaesthesia uses a local anaesthetic deposited around a specific nerve or plexus to anaesthetise a body region while the patient remains awake:

• Spinal anaesthesia: injection into the cerebrospinal fluid; rapid, dense block of the lower body.
• Epidural anaesthesia: injection into the epidural space; slower onset, more controllable, used in labour and major surgery.
• Peripheral nerve blocks: brachial plexus block (interscalene, supraclavicular, axillary) for upper limb, femoral / sciatic / popliteal blocks for lower limb.

Neuromuscular Blocking Drugs

Neuromuscular blocking drugs (NMBDs) act at the post-synaptic nicotinic acetylcholine receptor at the neuromuscular junction (NMJ). Their division is fundamental:

• Depolarising NMBD: suxamethonium (succinylcholine):
  • Acts as an acetylcholine receptor agonist, causing persistent depolarisation with initial fasciculations followed by flaccid paralysis.
  • Onset 30-60 seconds, duration 5-10 minutes: the standard agent for rapid sequence induction.
  • Metabolised by plasma cholinesterase (also called pseudocholinesterase: the soluble blood enzyme that breaks down suxamethonium, distinct from acetylcholinesterase at the synapse). Inherited deficiency is rare and prolongs the drug's action for hours, sometimes days.
  • Side effects: hyperkalaemia (especially in burns, denervation, prolonged immobility: potentially fatal), bradycardia, raised intraocular pressure, raised intragastric pressure, malignant hyperthermia trigger.
• Non-depolarising NMBDs: rocuronium, atracurium, vecuronium, mivacurium:
  • Competitive antagonists at the nicotinic ACh receptor.
  • Onset slower (1-3 minutes), duration longer (typically 30-60 minutes).
  • Reversed by neostigmine (acetylcholinesterase inhibitor; given with glycopyrronium to prevent bradycardia) or, for rocuronium specifically, sugammadex (a chelating agent that "encapsulates" the drug).
  • Atracurium is unique in undergoing spontaneous Hofmann elimination at body temperature and pH; useful in renal and hepatic failure.

Malignant hyperthermia is a life-threatening genetic susceptibility (autosomal dominant, RYR1 mutations) triggered by suxamethonium and volatile inhalational anaesthetics. Presents with hyperthermia, rigidity, hypercapnia and rhabdomyolysis. The antidote is dantrolene, which inhibits RyR1-mediated calcium release from the sarcoplasmic reticulum in skeletal muscle, preventing the sustained contractile response.

Side Effects and Specific Hazards

Common adverse effects of general anaesthesia:

• Postoperative nausea and vomiting (PONV), particularly with volatile agents, opioids, and N₂O. Risk factors include female sex, non-smoking, history of motion sickness, and use of post-op opioids (the Apfel score). Prophylaxis with ondansetron and dexamethasone is standard.
• Cardiovascular instability: hypotension is the rule with most agents.
• Respiratory depression.
• Postoperative cognitive dysfunction (POCD) and delirium, particularly in older patients.
• Chest infection.
• Anaphylaxis: suxamethonium, rocuronium and the antibiotic prophylaxis are common triggers.
• Awareness under anaesthesia: rare but feared.

Summary

• General anaesthesia is the controlled combination of analgesia, hypnosis, immobility, autonomic stability, with antiemesis added in modern practice.
• Most agents potentiate GABA_A; ketamine, nitrous oxide and xenon are NMDA antagonists.
• IV induction agents: propofol (workhorse), thiopental, etomidate (CV-stable but adrenal-suppressing), ketamine (sympathomimetic, dissociative).
• Inhaled agents: sevoflurane, isoflurane, desflurane, halothane, nitrous oxide, xenon. Potency described by MAC.
• Local anaesthetics block voltage-gated sodium channels in a use-dependent manner. Amides are first-line; bupivacaine has the greatest cardiotoxicity. Intralipid is the antidote for systemic toxicity.
• Neuromuscular blockade: suxamethonium (depolarising, RSI, hyperkalaemia, malignant hyperthermia trigger) versus rocuronium / atracurium (non-depolarising, reversed by neostigmine or sugammadex).
• Malignant hyperthermia: triggered by suxamethonium and volatile agents in genetically susceptible patients; antidote is dantrolene.
• PONV prophylaxis (ondansetron + dexamethasone), respiratory depression, hypotension and emergence delirium are the common adverse effects.

Drug Summary Table

Reviewed by: Dr. Marcus Judge

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