"The barbiturates are the old masters of induction — a single arm–brain circulation to sleep, terminated not by metabolism but by redistribution. Thiopentone still owns two niches: crash induction and the protected brain. But its alkaline solution is unforgiving, and in porphyria it is lethal."
Tanya's notes, triangulated with Miller's Anesthesia; Morgan & Mikhail's Clinical Anesthesiology; Stoelting's Pharmacology.A sulphur-substituted barbituric-acid derivative
Barbiturates are derivatives of barbituric acid (malonic acid + urea; 2,4,6-trioxohexahydropyrimidine). They divide into two classes by the substituent at position 2:
| Class | Position-2 group | Examples |
|---|---|---|
| Oxybarbiturates | Oxygen | Methohexital, phenobarbital |
| Thiobarbiturates | Sulphur | Thiopentone (thiopental) |
Structure–activity relationships
| Substitution | Effect on activity |
|---|---|
| Position-5 aryl/alkyl group | Hypnotic / sedative potency |
| Phenyl group | Anticonvulsant activity |
| Sulphur / methyl group | Rapid onset of action (methyl >>> sulphur) |
Redistribution ends the sleep; the liver ends the drug
Onset & offset
High lipid solubility → crosses the blood–brain barrier and accumulates rapidly in the CNS (onset 10–30 s). Consciousness returns by redistribution to muscle/fat within 5–10 min, not by metabolism.
Metabolism
Hepatic — oxidation, desulphuration, ring cleavage and N-dealkylation → water-soluble metabolites (renal) or biliary conjugates. Enzyme inducers ↑ barbiturate metabolism.
Kinetics: low doses follow first-order (constant fraction) kinetics; high doses shift to zero-order (constant amount). Half-lives: thiopentone ~12 h, methohexital ~4 h. Volume of distribution is increased in pregnancy. Alkalinising the urine increases barbiturate excretion.
GABA-A potentiation and the protected brain
Barbiturates bind GABA-A, enhancing and mimicking GABA (↑ chloride conductance → hyperpolarisation) and raising the threshold of excitability of the post-synaptic neuron; at higher concentrations they directly open the chloride channel (GABA-mimetic → barbiturate anaesthesia). They also inhibit excitatory transmission (glutamate, acetylcholine).
Cerebral protection (dose-related)
↓ CMRO₂ (↓ neuronal-signalling ATP consumption, not basal metabolism) → cerebral vasoconstriction → ↓ CBF and ↓ ICP, while MAP falls proportionally so CPP is preserved. Basis for burst-suppression neuroprotection.
Central respiratory depression
- Central respiratory depression — onset ~1–1.5 min after administration, lasting ~15 min.
- ↓ Ventilatory response to a rising CO₂.
- Patients with chronic lung disease are more susceptible to respiratory depression.
- Laryngospasm/bronchospasm can occur, especially at light planes — caution in reactive airways.
Falls in output, a reflex rise in rate
Cardiac output falls
Via negative inotropy (↓ Ca²⁺ influx), ↓ ventricular filling (venodilation) and ↓ sympathetic outflow.
Heart rate rises
Baroreceptor-reflex tachycardia in response to the fall in BP → ↑ myocardial O₂ consumption.
Prolongs the QT interval and flattens T waves; to be avoided in patients with ventricular arrhythmias. The reflex tachycardia and raised MVO₂ make it less ideal in coronary disease than a rate-neutral agent.
The barbiturate's hazards
- At low doses, an anti-analgesic (hyperalgesic) effect.
- Garlic/onion taste; allergic reactions; local tissue irritation; urticarial rash.
- Excitatory phenomena (myoclonus, hiccups) — more with methohexital > thiopentone.
The alkaline solution causes intense vasospasm, crystallisation, thrombosis and distal ischaemia/gangrene. Do not remove the cannula; management: dilute (saline), brachial plexus / stellate block for vasodilation, and heparin ± papaverine to limit thrombosis.
Induction, ECT and cerebral protection
| Agent | Induction dose | Onset | Maintenance |
|---|---|---|---|
| Thiopentone | 3–4 mg/kg IV | 10–30 s | 50–100 mg every 10–12 min |
| Methohexital | 1–2 mg/kg IV | 10–30 s | 20–40 mg every 4–7 min |
- Induction & maintenance of anaesthesia.
- Methohexital for ECT (short seizures, rapid recovery); premedication methohexital ~25 mg/kg per rectum (paediatric).
- Cerebral protection (burst suppression).
- Outpatient anaesthesia — rapid onset & emergence. Not an analgesic.
When to reach for a different agent
- Porphyria — absolute (induces ALA synthase → acute crisis).
- Reactive airways / status asthmaticus — relative (laryngospasm/bronchospasm risk).
- Fixed-output cardiac lesions / severe hypovolaemia — myocardial depression and reflex tachycardia poorly tolerated.
- Mixing with Ringer's lactate or acidic drugs in the same line (precipitation).
High-yield one-liners
Q: Why does the patient wake after one dose of thiopentone?
Redistribution from brain to muscle/fat (5–10 min), not metabolism.
Q: Absolute contraindication?
Porphyria (stimulates ALA synthase).
Q: How does it protect the brain and keep CPP?
↓ CMRO₂ → cerebral vasoconstriction → ↓ CBF & ↓ ICP; MAP falls too, so CPP is preserved.
Q: Management of intra-arterial injection?
Leave cannula, dilute, regional block (brachial plexus/stellate), heparin ± papaverine.
Q: Which barbiturate is used for ECT and why?
Methohexital — short-acting oxybarbiturate, lowers the seizure threshold least / gives good seizures with rapid recovery.
References
- Dr. Tanya. Induction Agents — handwritten viva notes (primary source for this node).
- Gropper MA, Cohen NH, Eriksson LI, et al. (eds). Miller's Anesthesia. 9th ed. Elsevier; 2020.
- Butterworth JF, Mackey DC, Wasnick JD. Morgan & Mikhail's Clinical Anesthesiology. 7th ed. McGraw-Hill; 2022.
- Flood P, Rathmell JP, Urman RD. Stoelting's Pharmacology & Physiology in Anesthetic Practice. 6th ed. Wolters Kluwer; 2022.