General Anaesthetics

Classification

Inhalational: volatile liquids(halothane, isoflurane, sevoflurane, desflurane, enflurane) + gas(N2O). IV: barbiturate(thiopentone) · non-barbiturate(propofol, etomidate, ketamine) · adjuncts(midazolam, fentanyl).

Guedel’s Stages (historically via ether)

I — Analgesia: onset→loss of consciousness, pain blunted, consciousness preserved. II — Excitement/Delirium: LOC→regular breathing. DANGEROUS(delirium, irregular resp, retching, laryngospasm risk) — cortex depressed before deeper inhibitory structures → subcortical disinhibition. WHY IV induction preferred: bypasses this stage rapidly vs slow inhalational induction lingering here. III — Surgical anaesthesia: regular resp→resp paralysis, 4 planes. Surgery performed at lightest adequate plane. IV — Medullary paralysis: resp+vasomotor centre depression, circulatory collapse = OVERDOSE, not target.

Mechanism

NO single validated mechanism(genuine lack of consensus — false certainty = exam error). Best-supported: ↑GABA-A Cl- currents(most volatiles, propofol, barbiturates, benzodiazepines) + ↓NMDA glutamate receptors(ketamine’s DISTINCT dominant mechanism). Meyer-Overton correlation(potency∝lipid solubility) → old “unitary lipid theory” → SUPERSEDED by specific protein-target evidence(hydrophobic binding pockets on receptors, not membrane disruption itself).

MAC = alveolar conc where 50% don’t move to standardized incision. ADDITIVE across agents(N2O’s own MAC too high alone → reduces required MAC of co-administered volatile). ↓MAC: age↑, hypothermia, pregnancy, opioids/sedatives. ↑MAC: chronic alcohol use, hyperthermia.

Individual Agents — Inhalational

Halothane: potent but superseded — halothane hepatitis(rare, immune-mediated, reactive trifluoroacetyl metabolite-hapten, worse with repeat exposure) + myocardial catecholamine sensitization(arrhythmia risk +adrenaline). Isoflurane: pungent(NOT for induction), minimal cardiac sensitization vs halothane, widely used maintenance. Sevoflurane: pleasant/non-pungent → PREFERRED for inhalational induction esp. CHILDREN(IV access often impractical). Low blood-gas solubility→rapid on/off. Desflurane: LOWEST blood-gas solubility→fastest on/off, best depth control. Pungent(not for induction), needs special heated vaporizer(low boiling point). N2O: weak alone(high MAC, can’t achieve surgical anaesthesia alone at 1atm), good analgesic + MAC-sparing adjunct. Diffusion hypoxia = distinctive risk — low blood solubility→rapid outward diffusion at end of admin→dilutes alveolar O2/CO2 → give 100% O2 (not room air) for several min after stopping.

Individual Agents — IV

Thiopentone: ultra-short barbiturate, rapid onset(high lipid solubility, crosses BBB fast), rapid offset from REDISTRIBUTION(brain→muscle/fat), NOT metabolism — recovery = PK redistribution phenomenon(high-yield point). No analgesia. Propofol: rapid on/off(rapid metabolism+redistribution, “clean” non-cumulative even with infusion) → induction+maintenance. Antiemetic property(genuine advantage, ↓PONV). Pain on injection, more hypotension than thiopentone(myocardial depression+vasodilation). Propofol infusion syndrome(rare, fatal — metabolic acidosis, rhabdomyolysis, cardiac failure; prolonged high-dose infusion, esp critically ill). Etomidate: MOST cardiovascular stability of any IV induction agent → favoured in haemodynamically unstable patients. Adrenocortical suppression(inhibits 11β-hydroxylase, even single dose) → limits use, esp infusion. Ketamine: NMDA antagonist(distinct mechanism) → “dissociative anaesthesia”(trance-like, cataleptic, profound analgesia+amnesia, eyes may stay open, reflexes preserved — distinct from unconsciousness of other agents). UNIQUELY preserves airway reflexes+resp drive. Cardiovascular STIMULATION(↑HR/BP, sympathetic — OPPOSITE direction from every other agent) → useful in shock/trauma/haemodynamic instability. Emergence delirium(hallucinations/vivid dreams) = drawback, ↓by co-administering benzodiazepine.

Adjuncts

Neuromuscular blockers(full detail: Skeletal Muscle Relaxants) = surgical relaxation independent of anaesthetic depth. “Balanced anaesthesia” = lower dose of EACH component(hypnotic+analgesic+relaxant) rather than one agent driven deep for all three → ↓toxicity of any single component. Opioids(fentanyl) = intraoperative analgesia(most induction agents except ketamine have NO analgesic property — hypnosis ≠ analgesia, frequently tested distinction).

Clinical Relevance

Two organizing ideas: (1) Guedel stages explain why IV(not inhalational) induction is standard — bypass dangerous Stage II rapidly vs pass through it slowly. (2) “General anaesthesia” = SEVERAL effects(unconsciousness, amnesia, analgesia, muscle relaxation, autonomic reflex suppression), each targeted by DIFFERENT drug classes in balanced anaesthesia, not from one agent — why ketamine’s profile(analgesia+dissociation without hypotension/resp depression) is a distinct situational choice, not an inferior default-avoid option.

Classification

1. Inhalational agents
   • Volatile liquids: halothane, isoflurane, sevoflurane, desflurane, enflurane
   • Gas: nitrous oxide
2. Intravenous agents
   • Barbiturate: thiopentone
   • Non-barbiturate: propofol, etomidate, ketamine, benzodiazepines (midazolam, as an adjunct), opioids (fentanyl, as an adjunct)

Stages of Anaesthesia (Guedel’s Classification)

Historically described with ether, whose slow onset made each stage clinically distinguishable — with modern fast-acting IV induction agents, a patient passes through these stages within seconds and they are rarely observed individually in practice, but the classification remains conceptually important and frequently examined:

• Stage I — Analgesia: from onset of anaesthetic administration to loss of consciousness; pain sensation is progressively blunted, consciousness preserved.
• Stage II — Excitement/Delirium: loss of consciousness to onset of regular breathing; paradoxically dangerous — delirium, irregular respiration, retching, and reflex-related risk (laryngospasm) are all more likely here because the cortex is depressed before deeper inhibitory structures are, disinhibiting subcortical activity. This is precisely why IV induction agents are preferred to inhalational induction — they carry the patient through Stage II so rapidly that its risks are essentially avoided, whereas a slow inhalational induction (as with ether) lingers in this dangerous stage.
• Stage III — Surgical Anaesthesia: regular respiration to respiratory paralysis, subdivided into four planes of progressively deeper anaesthesia (by eye movement, pupil size, and reflex loss) — surgery is performed within this stage, at the lightest plane that provides adequate suppression of reflex response.
• Stage IV — Medullary Paralysis: respiratory and vasomotor centre depression, circulatory collapse — anaesthetic overdose, not a therapeutic target; represents anaesthesia carried too deep.

Mechanism of Action

General anaesthetics do not have one single validated molecular mechanism the way local anaesthetics do — the field genuinely lacks full mechanistic consensus, and stating false certainty here is itself an examinable error. The best-supported framework: potentiation of inhibitory GABA-A receptor-mediated chloride currents (most volatile agents, propofol, barbiturates, benzodiazepines all enhance GABA-A activity, prolonging channel opening and increasing chloride influx, hyperpolarizing and inhibiting neurons) and, for some agents, inhibition of excitatory NMDA glutamate receptors (ketamine’s dominant, distinguishing mechanism — see below). The historical Meyer-Overton correlation (anaesthetic potency correlates strongly with lipid solubility across chemically diverse agents) supported an older “unitary lipid theory” of a non-specific membrane-disrupting mechanism, but this has been largely superseded by evidence for specific protein (receptor/channel) targets — the correlation is now understood as reflecting that anaesthetic-binding sites on these proteins happen to be hydrophobic pockets, not that lipid membrane disruption itself is the mechanism.

Minimum Alveolar Concentration (MAC) is the standard potency measure for inhalational agents — the alveolar concentration at which 50% of subjects fail to move in response to a standardized surgical incision. MAC values are additive across combined agents (a genuinely useful clinical/examined property, e.g. nitrous oxide’s own MAC is too high to achieve surgical anaesthesia alone at atmospheric pressure, but it usefully reduces the required MAC of a co-administered volatile agent) and are affected by patient factors: MAC is reduced by increasing age, hypothermia, pregnancy, and concurrent opioids/sedatives; increased by chronic alcohol use and hyperthermia.

Individual Agent Highlights

Inhalational

• Halothane: potent, but now largely superseded due to two specific, high-yield liabilities — halothane hepatitis (rare but severe immune-mediated hepatic necrosis from a reactive trifluoroacetyl metabolite forming a hapten with liver proteins, more common with repeated exposure) and marked sensitization of the myocardium to catecholamines (risk of arrhythmia with concurrent adrenaline use).
• Isoflurane: pungent (limits use for inhalational induction, since the smell can provoke breath-holding/laryngospasm in an awake patient), minimal cardiac sensitization compared with halothane, still widely used for maintenance.
• Sevoflurane: pleasant-smelling and non-pungent, making it the preferred agent for inhalational induction, particularly in children (where IV access before induction is often impractical); low blood-gas solubility gives rapid onset/offset.
• Desflurane: the lowest blood-gas solubility of the volatile agents, giving the fastest onset/offset and best control over anaesthetic depth intraoperatively, but pungent (also unsuitable for induction) and requires a special heated vaporizer given its low boiling point.
• Nitrous oxide: weak anaesthetic alone (high MAC, cannot reliably achieve surgical anaesthesia by itself at 1 atmosphere) but a good analgesic and useful MAC-sparing adjunct; diffusion hypoxia is its distinctive, examined risk — at the end of administration, nitrous oxide’s low blood solubility causes it to diffuse out of blood into alveoli rapidly, diluting alveolar oxygen and CO2, which is why 100% oxygen (not room air) is given for several minutes after discontinuing nitrous oxide.

Intravenous

• Thiopentone: ultra-short-acting barbiturate, rapid onset (crosses the blood-brain barrier quickly given high lipid solubility) with an equally rapid offset from redistribution (away from the brain into muscle/fat), not metabolism — recovery from a single dose is a pharmacokinetic redistribution phenomenon, not elimination, a frequently tested point. No analgesic property (a general property of most IV induction agents besides ketamine).
• Propofol: rapid onset and offset (rapid metabolism as well as redistribution, giving a “clean,” non-cumulative recovery profile even with repeated dosing or infusion — favouring it for both induction and maintenance/sedation), antiemetic property (a genuine advantage reducing postoperative nausea and vomiting), but causes pain on IV injection and more pronounced hypotension than thiopentone (myocardial depression plus vasodilation). Propofol infusion syndrome (rare but potentially fatal — metabolic acidosis, rhabdomyolysis, cardiac failure, associated with prolonged high-dose infusion, particularly in critically ill patients) is a specific, high-yield toxicity.
• Etomidate: notable for the most cardiovascular stability of any IV induction agent (minimal effect on blood pressure/heart rate), making it favoured in haemodynamically unstable patients, but causes adrenocortical suppression (inhibits 11β-hydroxylase, even after a single induction dose) — a specific, examined liability limiting its use, particularly by infusion.
• Ketamine: NMDA receptor antagonist, a genuinely distinct mechanism from the GABA-potentiating agents above — produces “dissociative anaesthesia” (a trance-like, cataleptic state with profound analgesia and amnesia, but with eyes sometimes open and reflexes preserved, distinct from the unconsciousness produced by other agents). Uniquely preserves airway reflexes and respiratory drive and causes cardiovascular stimulation (increased heart rate and blood pressure, from sympathetic stimulation, rather than depression) — the opposite haemodynamic direction from every other agent on this list, making it useful in shock/trauma/haemodynamically unstable patients where other agents’ hypotensive effect would be dangerous. Emergence delirium (hallucinations, vivid dreams on recovery) is its distinctive drawback, reduced by co-administering a benzodiazepine.

Adjuncts

Neuromuscular blockers (covered fully under Skeletal Muscle Relaxants) provide surgical muscle relaxation independent of anaesthetic depth — modern “balanced anaesthesia” deliberately uses lower doses of each individual component (hypnotic, analgesic, muscle relaxant) rather than relying on a single agent driven deep enough to achieve all three effects alone, reducing the toxicity of any one component. Opioids (fentanyl and derivatives) provide intraoperative analgesia, since most induction/maintenance agents (ketamine being the exception) have little or no analgesic property of their own — a frequently tested distinction between hypnosis/unconsciousness and analgesia as separate anaesthetic goals.

Clinical Relevance

Two organizing ideas run through this whole topic: first, the historical Guedel stages explain why IV induction, not inhalational induction, is now standard — bypassing the dangerous excitement stage rapidly rather than passing through it slowly; second, “general anaesthesia” is not one effect but several (unconsciousness, amnesia, analgesia, muscle relaxation, and suppression of autonomic reflex response), each targeted by different drug classes in modern balanced anaesthesia rather than assumed to come from a single agent — which is exactly why ketamine’s profile (analgesia and dissociation without the hypotension/respiratory depression of other agents) is worth understanding as a distinct, situational choice rather than an inferior alternative to be avoided by default.

• Guedel’s four stages of anaesthesia plotted against depth/time, marking why IV induction bypasses the dangerous Stage II.
• Thiopentone’s redistribution-driven recovery (blood/brain vs muscle/fat compartment concentration over time) vs a genuine elimination curve.
• Ketamine’s NMDA-antagonist mechanism contrasted with the GABA-A-potentiating mechanism shared by the other induction agents.

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