One pKa, one enzyme
— and two drugs kept for what they alone can do.

• Tautomerism is why the vial works. Barbiturates dissolve only as the enol form, which alkali favours — and the same equilibrium run backwards in arterial blood is what precipitates crystals in a hand.
• Only about an eighth of a dose of thiopentone is available to act, and acidaemia and hypoalbuminaemia both increase that fraction.
• Thiopentone saturates its own metabolism. At high dose, handling moves from first-order towards zero-order, which is why it cannot be infused the way propofol can.
• Barbiturates induce δ-aminolaevulinic acid synthetase, which is why porphyria is an absolute contraindication rather than a caution.
• Etomidate is a far more potent inhibitor of steroid synthesis than it is a hypnotic, and the disparity in concentration is why a single dose suppresses the adrenal axis long after the patient has woken.

Barbituric acid is the condensation product of urea and malonic acid — a six-membered pyrimidine ring, formally 2,4,6-trioxohexahydropyrimidine. On its own it has no hypnotic activity at all. Three modifications turn it into a drug, and each one is a separate teaching point.

1. Substitution at C5 — replacing the hydrogens on carbon 5 with alkyl or aryl groups — is what confers hypnotic activity. Larger and more branched substituents give greater lipid solubility, faster onset and shorter duration.
2. The atom at C2 defines the two classes. Oxygen gives an oxybarbiturate — methohexitone, pentobarbitone. Sulphur gives a thiobarbiturate — thiopentone, which is simply the sulphur analogue of the oxybarbiturate pentobarbitone.
3. Keto–enol tautomerism at that same C2 position is what makes an intravenous preparation possible at all.

The two classes differ in more than one atom’s worth of behaviour. Thiobarbiturates are very lipid soluble, highly protein bound and completely metabolised in the liver. Oxybarbiturates are less lipid soluble, less protein bound, and some are excreted almost entirely unchanged in the urine. That is the whole reason thiopentone is an induction agent and phenobarbitone is not.

The vial contains the sodium salt as a pale yellow powder mixed with 6% by weight anhydrous sodium carbonate, and the space above it is filled with nitrogen rather than air. Both measures exist to hold the tautomeric equilibrium on the soluble side.

The carbonate hydrolyses on reconstitution, releasing hydroxide and giving a strongly alkaline solution at about pH 10.5, which favours the water-soluble enol form. Nitrogen replaces air for the complementary reason: air contains carbon dioxide, which would dissolve, form carbonic acid, lower the pH, and push the equilibrium back towards the insoluble keto form. The resulting 2.5% solution is stable for several days and is bacteriostatic by virtue of its own alkalinity — the opposite of propofol’s problem, and for the opposite reason.

Thiopentone is a weak acid with a pKa of 7.6. Plasma pH is 7.4. Those two numbers are close enough together that a small change in one produces a large change in how much drug is in a form that can cross a membrane — and that is unusual. Propofol, with a pKa of 11, is essentially entirely unionised at any pH the patient can generate.

Two filters sit between the dose and the brain, and they multiply:

1. 80% is bound to plasma protein, leaving 20% free. Only free drug can leave the circulation.
2. Of that free fraction, about 60% is unionised at pH 7.4, by the Henderson–Hasselbalch relation for a weak acid. Only unionised drug crosses a lipid membrane.

At pH 7.4 with a pKa of 7.6 that gives 1 ÷ (1 + 10^−0.2) = 0.61, or 60%. Multiplying the two filters: 20% × 60% = 12% of the administered dose is both free and unionised, and therefore immediately available to act. The remaining 88% is a reservoir in dynamic equilibrium with it.

One consequence runs the other way and is worth stating. Despite only an eighth of the dose being immediately available, thiopentone has a rapid onset — because that eighth is extremely lipid soluble, because the brain receives a large share of the cardiac output, and because the bound drug is in dynamic equilibrium and replenishes the free fraction as it is taken up.

A single dose of thiopentone behaves exactly as lesson 1 describes: emergence in five to ten minutes by redistribution to muscle, not by metabolism. The plasma concentration falls tri-exponentially — first to the well-perfused viscera, then to muscle and skin, and finally by hepatic elimination.

What makes thiopentone different from propofol is what happens after that.

Two further modifiers: the volume of distribution is slightly larger in women and larger again in pregnancy, prolonging the elimination half-life in both. Clearance is not altered even in advanced cirrhosis — which is initially surprising until you remember the low extraction ratio: a capacity-limited drug has considerable hepatic reserve before clearance falls.

This is the cleanest example in the module of a physicochemical property producing a catastrophe, and it can be reasoned out from section 02 rather than memorised.

1. A 2.5% solution of thiopentone at pH 10.5 enters arterial blood at pH 7.4.
2. The sudden fall in pH swings the tautomeric equilibrium away from the soluble enol form and towards the insoluble keto form.
3. Thiopentone precipitates as crystals in the arterial blood.
4. Those crystals lodge in small distal vessels, producing intense pain and distal ischaemia, with arterial spasm and thrombosis compounding it.

Two contrasts complete the picture. Intravenous injection does not precipitate, because the drug is continually diluted by more venous blood arriving from the periphery — the arterial problem is that the drug is being carried towards progressively smaller vessels rather than away into a larger one. Perivascular extravasation is a third and separate problem: painful, and capable of causing serious tissue necrosis if a large dose extravasates.

And, for the direct comparison: propofol given intra-arterially causes no appreciable harm, although the onset of anaesthesia is delayed. It has a neutral pH and no tautomeric equilibrium to disturb.

The acute porphyrias are disorders of haem synthesis in which a partial block at one step causes the accumulation of porphyrin precursors — δ-aminolaevulinic acid and porphobilinogen — which are neurotoxic and produce the acute crisis of abdominal pain, autonomic instability, neuropsychiatric disturbance and peripheral neuropathy.

Barbiturates are not the only agents involved, and the rest of the list is worth knowing because two of them are in this module. Drugs that may precipitate an acute porphyric crisis include the other barbiturates, etomidate, halothane, cocaine, lidocaine and prilocaine — though bupivacaine is safe, clonidine, metoclopramide, hyoscine, diclofenac and ranitidine.

Propofol is safe in porphyria, and it is the induction agent of choice for these patients. Ketamine is generally regarded as safe as well.

The imidazole nucleus does the same job it does in midazolam: it makes the molecule water soluble at acidic pH and lipid soluble at physiological pH, which is exactly what an intravenous drug needs. With a pKa of 4.2, etomidate is about 99% unionised at pH 7.4 and crosses into the brain within a minute.

Etomidate is unique among the injected and inhaled anaesthetics in being given as a single isomer. The anaesthetic effect resides in the R(+) isomer. How much more potent it is than S(−) depends on the source and on what is being measured: Stoelting gives about fivefold for anaesthetic potency, while Peck reports a thirty-fold difference in activity at the GABA-A receptor and describes the S(−) form as clinically inactive. The direction is not in dispute and the argument built on it is the important part — a difference this large between two molecules with identical atoms and identical lipid solubility is strong evidence that these drugs act at a shaped protein site.

The solvent is the other half of the presentation. The original formulation in 35% propylene glycol causes pain on injection in up to a quarter of patients, and venous irritation. The lipid emulsion formulation has virtually abolished both — while leaving the incidence of myoclonus unchanged, which is a useful natural experiment: it establishes that the myoclonus is a central drug effect and not a response to the solvent.

Kinetics are straightforward and favourable. Initial distribution half-life 2.7 minutes, redistribution half-life 29 minutes, elimination half-life 2.9 to 5.3 hours, clearance 18 to 25 mL/kg/min with a hepatic extraction ratio of about 0.5. About 75% is bound to albumin, and — as with thiopentone — a fall in albumin produces a marked increase in the free active fraction. Metabolism is by ester hydrolysis to an inactive carboxylic acid and ethanol, carried out by hepatic microsomal enzymes and plasma esterases; less than 3% appears unchanged in the urine. Etomidate may also inhibit plasma cholinesterase, which places it alongside the other drugs that enzyme handles.

Because redistribution terminates a single dose, hepatic dysfunction does not appreciably alter recovery from one. In cirrhosis the volume of distribution doubles while clearance is normal, so the elimination half-life doubles — but the initial distribution half-life and therefore the clinical effect of a single dose are essentially unchanged.

Of the commonly used intravenous anaesthetics, etomidate produces the least cardiovascular disturbance. Peripheral vascular resistance may fall slightly — less than with any other induction agent — while myocardial oxygen supply, contractility and blood pressure remain largely unchanged. Hypersensitivity reactions are less common than with the other agents, and histamine release is rare.

A separate and striking finding is that in a haemorrhagic shock model, etomidate’s pharmacokinetics and pharmacodynamics were not altered — in contrast to the marked changes seen with other intravenous anaesthetics in the same model. That is a strong argument in exactly the patient who most needs it.

The other adverse effects are the reason etomidate is not simply the default in every sick patient. Myoclonus occurs with a highly variable incidence — from essentially none to 70% across series — and is a central effect independent of the solvent, reduced but not abolished by opioid or benzodiazepine premedication. It can be mistaken for a seizure, and in a patient with a full stomach the muscle activity is itself a hazard. Pain on injection affects up to a quarter of patients with the propylene glycol formulation. Nausea and vomiting are more frequent than with any other induction agent. And etomidate may precipitate a porphyric crisis, which is easily forgotten because it is not a barbiturate.

Etomidate produces a dose-dependent, reversible inhibition of 11β-hydroxylase, a cytochrome P450–dependent enzyme, and to a lesser extent of 17α-hydroxylase. The imidazole nitrogen binding the haem iron of a cytochrome P450 enzyme is the same chemistry that makes the azole antifungals enzyme inhibitors; it is a property of the ring, not an idiosyncrasy of this molecule.

What makes it clinically important is where 11β-hydroxylase sits. It catalyses the final step of both the glucocorticoid and the mineralocorticoid arms — 11-deoxycortisol to cortisol, and 11-deoxycorticosterone to corticosterone and thence aldosterone. A single enzyme inhibition therefore reduces cortisol and aldosterone together, and causes the immediate precursor, 11-deoxycorticosterone, to accumulate behind the block.

The single-dose mortality question, presented fairly

This is a genuinely unresolved question, and the honest account of it has four parts rather than a conclusion.

1. The original signal was about infusions, not single doses. In 1983 Ledingham and Watt reported retrospective data showing increased mortality among intensive care patients receiving long-term etomidate infusion compared with those receiving benzodiazepines, and postulated adrenal suppression as the cause. Subsequent work confirmed the suppression. Infusion for sedation was abandoned, and nobody disputes that decision.
2. Whether a single induction dose does the same is a different question. A Cochrane review in 2015 of single-dose etomidate against other induction agents for tracheal intubation in critically ill patients found no conclusive evidence that etomidate increases mortality.
3. Retrospective analyses point the other way. In the CORTICUS study of 500 patients with septic shock, 20% of whom received etomidate, retrospective analysis found significantly higher 28-day mortality in those who had received it, and no benefit from steroid supplementation. Retrospective subgroup analysis of a trial designed to answer a different question is weak evidence, and it is not nothing.
4. The remaining studies are inconclusive. Miller’s own conclusion is that the impact of a single dose of etomidate in critically ill patients remains unclear.

Both drugs are read most usefully against lesson 1’s ideal-agent list, because each is a different pattern of compliance and failure against the same specification — and because each fails in a way that is survivable in the right patient.

The last row is worth pausing on, because it is the module’s neatest example of two drugs being unsuitable for the same thing for entirely unrelated reasons. Etomidate actually has a shorter context-sensitive half-time than propofol, and on kinetics alone would be an excellent infusion agent. What rules it out is an endocrine effect that has nothing to do with its kinetics. Thiopentone is ruled out by its kinetics alone. The same clinical conclusion, reached down two completely different routes — and being able to say which route applies to which drug is the difference between knowing the fact and understanding it.