General Anesthesia Drugs & Protocols

Anaesthetic pharmacology is usually presented as a list of agents with their properties, which conceals why the list exists at all.

General anaesthesia is four separate requirements, not one.

Unconsciousness, so the patient does not experience the operation. Analgesia, so nociceptive input does not reach consciousness or produce autonomic responses. Muscle relaxation, where the operation requires it. Suppression of autonomic reflexes, so tachycardia, hypertension and movement do not occur.

No single agent provides all four at a safe dose, which is the entire justification for balanced anaesthesia. A drug that produced all four alone would need to be given at a dose that suppressed the cardiovascular system as well.

A second principle explains recovery. Emergence from a single dose of an intravenous agent is caused by redistribution, not by metabolism. The drug leaves the brain for muscle and fat long before the liver has cleared any meaningful quantity, and that distinction explains why repeated doses accumulate.

A third principle governs selection. Each agent is chosen for what it does badly as much as for what it does well, since the adverse effect profile determines suitability for a particular patient far more often than potency does.

1. Intravenous Induction Agents

Propofol is the default agent, and its hypotension is its defining limitation, produced by vasodilatation and myocardial depression together, which is why it is given cautiously and in reduced dose in the hypovolaemic or elderly patient. Prolonged high-dose infusion, particularly in children and in critical illness, carries the separate risk of propofol infusion syndrome with metabolic acidosis, rhabdomyolysis and cardiac failure.

Ketamine is the exception that maintains blood pressure, because it produces sympathetic stimulation through central mechanisms. This makes it the induction agent of choice in the shocked or hypovolaemic patient, and useful in the acute asthmatic because it bronchodilates.

Its limitation is that the sympathetic effect depends on intact catecholamine reserves, so in a patient who is catecholamine-depleted from prolonged shock it can cause direct myocardial depression instead.

Etomidate's cardiovascular stability is real but comes at a price, since even a single dose suppresses adrenal steroid synthesis by inhibiting 11-beta-hydroxylase, which is why its use in septic patients became controversial.

Thiopentone extravasation causes tissue necrosis because the solution is strongly alkaline, and intra-arterial injection causes severe vasospasm and can threaten the limb.

2. Why Redistribution Matters

A single dose of propofol or thiopentone produces unconsciousness within one arm-brain circulation time and wears off within minutes.

That recovery is not due to elimination. These agents are highly lipid-soluble, so they reach the brain rapidly because the brain receives a large share of cardiac output. Concentration then falls as the drug redistributes into muscle and, more slowly, fat, and the brain concentration drops below the level that maintains unconsciousness.

The drug is still in the body. Metabolism follows over hours.

Two consequences follow directly. Repeated doses or an infusion saturate the peripheral compartments, so recovery becomes dependent on metabolism and is progressively prolonged. And context-sensitive half-time, meaning the time for concentration to halve after stopping an infusion, lengthens with infusion duration for most agents.

Propofol has a comparatively flat context-sensitive half-time, which is precisely why it is suitable for total intravenous anaesthesia while thiopentone is not.

3. Inhalational Agents

Potency is expressed as minimum alveolar concentration, the alveolar concentration at which 50 per cent of patients do not move in response to a standard surgical stimulus.

A lower minimum alveolar concentration means a more potent agent.

It is additive between agents, so nitrous oxide at 60 per cent contributes and allows the volatile agent to be reduced, which is the basis of its continued use.

It falls with age, hypothermia, pregnancy, opioids, sedatives and acute alcohol intoxication, and rises with chronic alcohol use, hyperthermia and sympathomimetics.

Nitrous oxide has two examinable properties. It diffuses into air-filled cavities faster than nitrogen leaves, so it is contraindicated in pneumothorax, bowel obstruction, middle ear surgery and after recent intraocular gas. And it inactivates methionine synthase by oxidising vitamin B12, so prolonged or repeated exposure causes megaloblastic anaemia and neuropathy.

Volatile agents are all trigger agents for malignant hyperthermia, and their environmental impact as greenhouse gases has become a genuine consideration in agent selection.

4. Neuromuscular Blocking Agents

Depolarising blockade is produced by suxamethonium, which binds the acetylcholine receptor and holds it open, causing initial fasciculation then flaccid paralysis. It is not reversed by neostigmine, which would prolong it.

Non-depolarising blockade is competitive antagonism at the receptor, produced by rocuronium, vecuronium, atracurium and cisatracurium, and it is reversible.

Atracurium and cisatracurium undergo Hofmann elimination, a spontaneous chemical degradation at body pH and temperature, which makes them the agents of choice in significant hepatic or renal failure.

Reversal is where recent practice has changed. Neostigmine inhibits acetylcholinesterase and increases acetylcholine at the junction, so it works only when some spontaneous recovery has occurred, and it requires an antimuscarinic such as glycopyrrolate to prevent bradycardia and secretions.

Sugammadex encapsulates rocuronium and vecuronium directly, removing them from the junction, so it reverses even profound blockade within minutes and does not depend on spontaneous recovery. It has no effect on atracurium or suxamethonium.

5. Opioids and Adjuncts

Opioids provide analgesia and blunt autonomic responses, and their choice is governed by duration.

Fentanyl has a rapid onset and intermediate duration and is the workhorse. Remifentanil is metabolised by plasma esterases with a context-sensitive half-time that stays constant regardless of infusion duration, which makes it uniquely predictable but means analgesia must be established before it is stopped. Morphine is longer acting, and its active metabolite accumulates in renal failure.

Multimodal analgesia is the governing principle, combining paracetamol, non-steroidal anti-inflammatory drugs where not contraindicated, local or regional techniques, and adjuncts such as ketamine, dexmedetomidine or magnesium, so that opioid requirement falls.

Dexmedetomidine is an alpha-2 agonist providing sedation and analgesia without significant respiratory depression, and it causes bradycardia and hypotension. The sedation it produces is described as arousable and resembles natural sleep, which is why it is favoured where the patient must cooperate, as in awake fibreoptic intubation.

6. Total Intravenous Anaesthesia

Anaesthesia maintained entirely by intravenous infusion, usually propofol with remifentanil, frequently using target-controlled infusion.

Its advantages are less postoperative nausea, no environmental emission, no trigger for malignant hyperthermia and better conditions for neurophysiological monitoring.

Its principal risk is awareness, because the safeguard of end-tidal agent monitoring does not exist. Depth of anaesthesia monitoring using processed electroencephalography is therefore used, and the intravenous line must be visible and secure, since a disconnection or tissued cannula delivers no anaesthetic at all while the paralysis continues.

7. Two Pharmacogenetic Conditions

Both are inherited, both present under anaesthesia, and both are examined.

Suxamethonium apnoea

Suxamethonium is normally hydrolysed within minutes by plasma cholinesterase, also called butyrylcholinesterase or pseudocholinesterase, which is why its action is so brief.

An inherited abnormality of that enzyme prolongs paralysis, from minutes to hours in the homozygous atypical form. The patient is paralysed but fully conscious once the induction agent wears off, which is the specific danger.

Management is supportive: continue ventilation and, critically, continue sedation until neuromuscular function returns, monitored by nerve stimulator. The family must be tested, since the trait is inherited and the diagnosis protects relatives.

Acquired reductions in enzyme activity occur in liver disease, pregnancy, malnutrition and with certain drugs, but these prolong the block by minutes rather than hours.

Porphyria

Thiopentone and other barbiturates induce delta-aminolevulinic acid synthase, the rate-limiting enzyme of haem synthesis, which drives production of porphyrin precursors and can precipitate an acute attack.

An acute porphyric crisis presents with severe abdominal pain, autonomic instability, hyponatraemia, neuropathy and psychiatric disturbance, and it can be fatal.

Propofol is considered safe, as are the volatile agents, most opioids and suxamethonium, which is why the practical exam point is simply to avoid barbiturates in a patient with known porphyria.

8. The Anaesthetic Machine and Circuits

A small amount of equipment knowledge is examined directly and explains several safety features.

Safety features that exist because of past deaths

The pin index system on cylinders and the non-interchangeable screw thread on pipelines prevent a gas being connected to the wrong yoke, since delivering nitrous oxide from an oxygen supply was a historical cause of death.

The oxygen failure alarm sounds when oxygen supply pressure falls, and it is powered by the oxygen supply itself so it cannot fail silently.

The hypoxic guard links the nitrous oxide and oxygen flowmeters mechanically or electronically so that a mixture below about 25 per cent oxygen cannot be delivered.

The oxygen flush delivers high-flow oxygen bypassing the vaporiser, which is why it must never be used during controlled ventilation without care, since it can deliver a large volume rapidly and cause barotrauma while also diluting the anaesthetic.

Absorbers and circuits

Soda lime absorbs carbon dioxide, allowing low fresh gas flows and rebreathing of exhaled gas. Exhausted soda lime raises the capnograph baseline, which is how it is detected.

Low flow anaesthesia reduces cost, conserves heat and moisture and reduces environmental emission, but requires close monitoring of inspired oxygen since the delivered and inspired concentrations diverge at low flows.

Circuit disconnection remains the commonest critical incident, and capnography detects it faster than any other monitor.

9. Worked Examples

Example 1. A hypotensive trauma patient with a systolic pressure of 80 requires emergency intubation. Which induction agent, and why?

Ketamine, with the dose reduced.

Propofol would be the wrong choice because it causes hypotension through vasodilatation and direct myocardial depression, and that effect is exaggerated in a hypovolaemic patient whose blood pressure is being maintained by high sympathetic tone. Removing that tone produces cardiovascular collapse.

Ketamine differs because it produces central sympathetic stimulation, raising heart rate and systemic vascular resistance, so blood pressure is generally maintained or increased. It also provides analgesia, which is useful in trauma, and bronchodilates.

One caveat matters and is worth stating. The sympathetic effect depends on intact catecholamine reserves, so in a patient exhausted by prolonged shock ketamine's direct myocardial depressant effect can predominate and cause hypotension.

Etomidate is an alternative for cardiovascular stability but carries adrenal suppression even after a single dose, which made its use in septic patients contentious. Whichever agent is chosen, the dose is reduced substantially in shock.

Example 2. Why does a single dose of propofol wear off in minutes when its elimination half-life is hours?

Because recovery from a single dose is caused by redistribution rather than by elimination.

Propofol is highly lipid soluble, so after injection it reaches the brain within one arm-brain circulation time, since the brain is a vessel-rich organ receiving a large share of cardiac output. Unconsciousness follows almost immediately.

Concentration in the brain then falls as the drug moves down its concentration gradient into muscle and, more slowly, into fat, both of which are large reservoirs. Once the brain concentration falls below the threshold for unconsciousness, the patient wakes, and this happens within minutes.

The drug has not left the body. Hepatic metabolism proceeds over hours.

The clinical consequences follow directly. Repeated doses progressively saturate the peripheral compartments, so redistribution can no longer terminate the effect and recovery becomes dependent on metabolism, taking much longer. This is why the third dose lasts considerably longer than the first, and it is the basis of the context-sensitive half-time concept.

Example 3. A patient with severe renal and hepatic impairment requires neuromuscular blockade for a prolonged operation. Which agent and why?

Atracurium or cisatracurium.

Most neuromuscular blocking agents depend on the liver or the kidney for elimination, so in combined organ failure their duration becomes unpredictable and prolonged. Vecuronium is the clearest example, undergoing both hepatic metabolism and renal excretion, and its active metabolite accumulates.

Atracurium and cisatracurium are eliminated principally by Hofmann elimination, a spontaneous non-enzymatic chemical breakdown that occurs at normal body pH and temperature and requires neither organ. Their duration is therefore essentially unchanged in organ failure, which makes them the agents of choice in this situation and in the intensive care unit.

Two points refine the answer. Hofmann elimination is slowed by hypothermia and acidosis, since both are physical determinants of the reaction rate. And cisatracurium is preferred over atracurium where histamine release matters, since atracurium can cause flushing, hypotension and bronchospasm, and laudanosine accumulation is less of a concern with cisatracurium.

Example 4. Why is nitrous oxide contraindicated in a patient with a pneumothorax?

Because it expands closed gas-filled spaces.

Nitrous oxide is approximately 34 times more soluble in blood than nitrogen. When it is delivered, it diffuses from blood into any air-filled cavity far faster than the nitrogen already in that cavity can diffuse out.

In a compliant space such as bowel, the volume increases. In a non-compliant space such as the middle ear or an eye containing intraocular gas, the pressure increases instead. In a pneumothorax the volume expands, and in a patient receiving positive pressure ventilation this can convert a simple pneumothorax into a tension pneumothorax.

The same reasoning applies to bowel obstruction, where distension worsens, to middle ear surgery, where a raised pressure can displace a tympanoplasty graft, and after intraocular gas injection, where expansion can raise intraocular pressure enough to threaten retinal perfusion for weeks after the procedure.

The separate hazard is worth recalling alongside: nitrous oxide irreversibly oxidises the cobalt in vitamin B12, inactivating methionine synthase, so prolonged or repeated exposure causes megaloblastic anaemia and subacute combined degeneration.

Example 5. A patient having total intravenous anaesthesia with neuromuscular blockade is at particular risk of awareness. Why, and what safeguards apply?

Because the routine safeguard used during inhalational anaesthesia does not exist, and the usual clinical signs are abolished.

During inhalational anaesthesia, end-tidal agent concentration is measured continuously, so any failure of delivery is immediately visible and the depth of anaesthesia can be inferred from a number related to minimum alveolar concentration. Total intravenous anaesthesia has no equivalent measurement of effect-site concentration, only an assumption based on the pump setting and a pharmacokinetic model.

That assumption fails in specific ways. A disconnected or tissued cannula delivers no drug at all while the pump continues to run and alarms nothing. A pump programming error, a wrong drug concentration or an occluded line produce the same result.

Neuromuscular blockade removes the safeguard of last resort, since a patient becoming aware cannot move, and heart rate and blood pressure are unreliable indicators, particularly when opioids or beta blockers are present.

The safeguards are therefore procedural and technological: the infusion line kept visible and checked, a dedicated cannula, processed electroencephalographic depth monitoring, and avoiding neuromuscular blockade where it is not needed.

Summary

General anaesthesia has four components, and no single agent supplies all four safely.

Emergence from a single intravenous dose is redistribution, not elimination.

Repeated doses saturate peripheral compartments and prolong recovery.

Propofol is the default agent and hypotension is its defining limitation.

Ketamine maintains blood pressure through central sympathetic stimulation.

Ketamine can depress the myocardium if catecholamine reserves are exhausted.

Etomidate is cardiovascularly stable but suppresses adrenal steroid synthesis.

Thiopentone is alkaline and causes tissue necrosis on extravasation.

Propofol has a flat context-sensitive half-time, suiting infusion.

Minimum alveolar concentration measures potency; lower means more potent.

It is additive between agents and falls with age, opioids and pregnancy.

Sevoflurane is non-irritant and suits inhalational induction in children.

Nitrous oxide expands air-filled spaces and inactivates methionine synthase.

All volatile agents trigger malignant hyperthermia.

Suxamethonium is depolarising and is not reversed by neostigmine.

Atracurium and cisatracurium undergo Hofmann elimination, independent of organ function.

Vecuronium accumulates in hepatic and renal failure.

Neostigmine requires some spontaneous recovery and an antimuscarinic.

Sugammadex encapsulates rocuronium and reverses profound blockade.

Total intravenous anaesthesia risks awareness, so depth monitoring and a visible line are used.