Anaesthetics

1. Introduction
2. The Components of General Anaesthesia
3. Mechanism of Action
4. General Anaesthesia
   • Intravenous General Anaesthetics
   • Inhaled General Anaesthetics
   • Minimum Alveolar Concentration (MAC)
5. Local and Regional Anaesthesia
6. Neuromuscular Blocking Drugs
7. Side Effects and Specific Hazards
8. Summary
9. Drug Summary Table
10. Quiz

• General anaesthesia is a combination of analgesia (no pain), amnesia (no memory of events), hypnosis (unconsciousness) and immobility (muscle relaxation). Autonomic stability (damping the heart rate, blood pressure and breathing responses to surgery) is also maintained. No single drug achieves all of these reliably; modern practice uses several drugs together.
• Most general anaesthetics work by potentiating (strengthening) the action of gamma-aminobutyric acid (GABA), the brain's main inhibitory neurotransmitter, at GABA_A receptors. The exceptions are ketamine, nitrous oxide and xenon, which work primarily by blocking N-methyl-D-aspartate (NMDA) receptors. These respond to glutamate, the main excitatory neurotransmitter.
• Local anaesthetics (lidocaine, bupivacaine, ropivacaine) reversibly block voltage-gated sodium channels (channels that open when the nerve membrane depolarises) in nerves, preventing action potential propagation. They are use-dependent: they bind preferentially to sodium channels that are opening and closing often, as happens in nerve fibres that fire frequently. Pain fibres (nociceptors, the nerve endings that sense pain) tend to be blocked first. Frequent firing is one proposed reason, but the mechanism is still debated.
• Neuromuscular blocking drugs (muscle relaxants) are split into depolarising (suxamethonium) and non-depolarising (rocuronium, atracurium) agents. Suxamethonium is the traditional drug for rapid sequence induction (RSI), a fast technique for starting anaesthesia and securing the airway when the stomach may not be empty. Rocuronium is an alternative for RSI, and non-depolarising drugs are used for sustained paralysis.

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 several effects. The core components are analgesia, amnesia, hypnosis and immobility. Anaesthetists also aim for autonomic stability, and modern practice adds antiemesis:

• Analgesia: absence of pain.
• Amnesia / Hypnosis: amnesia is loss of memory of events, and hypnosis is loss of consciousness.
• Immobility / muscle relaxation: allowing surgical access and intubation (passing a breathing tube into the trachea, or windpipe).
• Autonomic stability: suppression of the cardiovascular and respiratory responses to surgery.
• Antiemesis: prevention of nausea and vomiting. Modern anaesthetic practice gives antiemetics (drugs that prevent nausea and vomiting) in advance to patients at risk of 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: a benzodiazepine (a sedative drug such as midazolam) for anxiety, and an antiemetic if needed.
2. Induction: rapid IV agent (propofol most often).
3. Intra-operative analgesia: opioid (a strong painkiller related to morphine: fentanyl, alfentanil, remifentanil).
4. Muscle relaxation: neuromuscular blocking drug for intubation and surgery.
5. Maintenance: volatile inhalational agent (a liquid that evaporates into a gas the patient breathes: sevoflurane, desflurane, isoflurane) and/or continued IV infusion (total intravenous anaesthesia, TIVA).
6. Reversal of the muscle relaxant; emergence (waking up from anaesthesia); postoperative analgesia (paracetamol, a non-steroidal anti-inflammatory drug (NSAID) or an opioid, as appropriate); antiemetic cover.

"Conscious sedation" (also called moderate sedation: UK guidance from the Academy of Medical Royal Colleges now grades sedation as minimal, moderate or deep) is a step down from general anaesthesia: sufficient drug to allow procedures (e.g. dentistry, endoscopy) without full loss of consciousness, so the patient can still respond to speech. A single drug, usually a benzodiazepine such as midazolam, is preferred because it is easier to titrate (adjust to effect) and safer than combining drugs. An opioid is added only when the procedure is painful, because benzodiazepines have no analgesic effect. The aim is to preserve the airway reflexes (such as coughing and swallowing, which protect the airway) and spontaneous breathing. 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 and inhibition. Excitation is mainly mediated by glutamate, the main excitatory neurotransmitter, at N-methyl-D-aspartate (NMDA) receptors. Inhibition is mainly mediated by gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter, at GABA_A receptors. Anaesthetics tip the balance towards inhibition.

The vast majority of general anaesthetics work by potentiating GABA_A receptors (strengthening the inhibitory effect of GABA):

• 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. It gives rapid recovery and cardiovascular stability, and has shown organ-protective effects in experimental studies, but definitive benefits for patient outcomes remain unproven. Its use is limited by its high cost and the lack of standardised delivery systems.

The brain regions targeted include the reticular activating system (a brainstem network that keeps us awake), thalamus (sensory relay), hippocampus (a temporal lobe structure that forms memories) and brainstem (respiratory and cardiovascular centres). In the spinal cord, anaesthetics act on the dorsal horn (where pain fibres enter the cord) and on motor neurons. Acting at both sites contributes to 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 (the drug redistributes from the brain to other tissues such as muscle and fat), 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, an excess of acid in the blood; rhabdomyolysis; cardiac failure) with high-dose, prolonged use, particularly in critically ill children. Rhabdomyolysis is breakdown of muscle tissue. The syndrome can be fatal, so propofol is contraindicated in children under 16 years who are receiving intensive care.
• Thiopental: an ultra-short-acting barbiturate, formerly the standard induction agent before propofol. Still used for rapid sequence induction (RSI, a fast technique for securing the airway, explained below) in obstetric general anaesthesia and where propofol is contraindicated. In the UK it is available only from special-order manufacturers. Risk of laryngospasm (sudden spasm of the vocal cords that blocks the airway); contraindicated in porphyria (a group of rare inherited disorders in which some drugs can trigger acute attacks).
• Etomidate: rapid induction with relative cardiovascular stability, useful in haemodynamically unstable patients (those with an unstable blood pressure and circulation). Causes adrenal suppression (a single dose can suppress adrenal steroid production, including cortisol, for up to 72 hours, although the clinical importance of this is uncertain). It is used with caution in patients with underlying adrenal insufficiency (the adrenal glands not making enough steroid hormone), for example in sepsis (life-threatening organ dysfunction caused by infection). It is not used for maintenance of anaesthesia, because the suppression is greater with continuous administration.
• Ketamine: an NMDA antagonist with several distinguishing features:
  • Provides analgesia and amnesia, usually without significant respiratory depression (apnoea, a pause in breathing, is a rare side-effect).
  • Usually maintains airway reflexes (such as coughing and swallowing) and respiratory drive, but laryngospasm can occur, so the airway still needs watching.
  • Causes tachycardia (a fast heart rate) and hypertension (sympathomimetic: it mimics the effects of the sympathetic nervous system), the opposite of most anaesthetics.
  • "Dissociative" anaesthesia: a state in which the patient appears awake but disconnected.
  • Causes emergence phenomena (unpleasant experiences while waking up): vivid dreams and hallucinations, particularly in adults; reduced by a 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 (irritant to the upper airway), so unsuitable for gas induction. It is a very potent greenhouse gas, with a global warming potential (a measure of how strongly a gas warms the climate) about 2,500 times that of carbon dioxide. For this reason, NHS England has decommissioned it from routine use. From 1 April 2024, its use is limited to a few specified clinical exceptions, for example selected long cranial neurosurgical procedures.
• Halothane: largely historical; classic association with halothane hepatitis, an idiosyncratic (unpredictable, not dose-related), potentially fatal hepatic (liver) reaction.
• Nitrous oxide: less potent (high MAC), used as a carrier gas with other agents to reduce their dose. It is also used in dental and obstetric "gas and air" (Entonox is N₂O 50% / O₂ 50%). Nitrous oxide is a greenhouse gas too, and the NHS is working to reduce nitrous oxide waste.
• Xenon: rapid recovery, cardiovascular stability and a small environmental carbon dioxide footprint, but benefits for patient outcomes remain unproven; its high cost limits use.

Two pharmacokinetic concepts (how a drug moves into, around and out of the body) govern induction and recovery:

• Blood:gas partition coefficient (how soluble the agent is in blood compared with gas). Lower values mean less drug "stored" in blood, so the brain equilibrates faster. This gives faster induction and recovery (e.g. desflurane, sevoflurane, nitrous oxide).
• Oil:gas partition coefficient: correlates with potency. The more lipid-soluble the agent is, the more potent it is.

Minimum Alveolar Concentration (MAC)

MAC (minimum alveolar concentration) is the standard measure of inhalational anaesthetic potency. It is 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 with nitrous oxide on board, less volatile agent is needed to reach 1 MAC). Several patient and drug factors modify MAC, so anaesthetists adjust the dose to the patient (worth knowing for exams):

Factors that increase MAC (need more agent): infancy, hyperthermia, chronic alcohol use, central stimulants (drugs that stimulate the brain, such as amphetamines).
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 (the pH at which half of the drug is ionised) → speed of onset. A lower pKa means more of the drug is in the un-ionised (uncharged) form at tissue pH, so it diffuses across membranes faster.
• 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 fibres tend to be blocked first. These are the small unmyelinated C fibres (slow, dull pain) and the thinly myelinated Aδ fibres (fast, sharp pain). One proposed reason is that they fire more frequently than fibres carrying other sensations, but the exact mechanism of this differential block is still debated. The order of loss is roughly: pain → temperature → touch → pressure → motor.

The two chemical classes:

• Amides (lidocaine, bupivacaine, ropivacaine, prilocaine): metabolised by cytochrome P450 (CYP) enzymes in the liver; duration of action varies by drug (for example, bupivacaine lasts longer than lidocaine); the great majority of clinically used agents.
• Esters (procaine, tetracaine, benzocaine, cocaine): metabolised by plasma cholinesterases (enzymes in the blood that break down esters); duration varies, from short-acting procaine to long-acting tetracaine; higher rates of allergic reactions.

Memory hook: amides have two "i"s in their names (lidocaine, bupivacaine, ropivacaine, prilocaine), esters have only one (procaine, tetracaine, benzocaine).

Adrenaline is often added to local anaesthetic to vasoconstrict (narrow the blood vessels) and slow systemic absorption, prolonging local action and reducing systemic toxicity. Use adrenaline with caution in the fingers, toes and other appendages (ears, nose, penis) because of the risk of ischaemic necrosis (tissue death from lack of blood supply). It is sometimes used there in selected cases, for example in wide-awake hand surgery.

Local anaesthetic systemic toxicity (LAST) is the major hazard, particularly with bupivacaine. It occurs when too much local anaesthetic reaches the bloodstream. It often starts with nervous system symptoms (tingling around the mouth, a metallic taste, agitation), followed by seizures. Cardiac arrhythmia (an abnormal heart rhythm) and cardiac arrest can follow, and cardiovascular toxicity can sometimes occur without warning symptoms. Treatment starts by stopping the local anaesthetic, assessing the circulation and following cardiopulmonary resuscitation (CPR) procedures. If the patient does not respond rapidly, intravenous lipid emulsion (Intralipid) is given alongside CPR. It is thought to act as a "lipid sink", soaking up the drug so that less of it reaches the heart and brain.

Regional anaesthesia uses a local anaesthetic deposited around a specific nerve or plexus (a network of nerves), or into the spinal or epidural space, to anaesthetise a body region. The patient can remain awake, or can be given sedation (a relaxed state without loss of consciousness):

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

Preview the Anaesthetics quiz