Barbiturate · Antiepileptic · Alcohol withdrawal

Phenobarbital

Reviewed by Alex G, BSN, RN, CEN, CCRN, CMC, NREMT-P · From the Reference tab of the app

Indications

Status epilepticus, second line when fosphenytoin, valproate or levetiracetam is unavailable (AES 2016)
Neonatal seizures, still first line (Sezaby label)
Alcohol withdrawal, as a loading-dose alternative or for benzodiazepine-resistant cases (off-label)
Benzodiazepine or barbiturate withdrawal (off-label)
Long-term epilepsy treatment, orally

Mechanism of action

Phenobarbital is a positive allosteric modulator of the GABA-A receptor. Barbiturates bind transmembrane pockets at the α–β and γ–β subunit interfaces, separate from the benzodiazepine site and from the β–α pockets used by etomidate. Binding lengthens each channel opening rather than making openings more frequent, and at higher concentrations phenobarbital opens the channel without GABA, so there is no ceiling effect. It also blocks AMPA and kainate glutamate receptors and reduces calcium-dependent transmitter release.

Pharmacology

CNS: anticonvulsant at levels below those that cause hypnosis; sedation to coma at higher levels; no analgesia
Respiratory: dose-related depression and apnea, especially with fast IV doses or after benzodiazepines
Cardiovascular: vasodilation and myocardial depression cause hypotension with rapid or large IV doses
Hepatic: induces CYP3A4, CYP2B6, CYP2C enzymes and UGTs, lowering levels of many drugs; induces ALA synthase, which can trigger acute porphyria

Pharmacokinetics

Onset	IV about 5 min; peak effect at 15 min or later (label)
Duration	Long: a loading dose keeps therapeutic levels for days
Half-life	Adults 53–118 h (mean 79 h); children 60–180 h (label); about 1 week in neonates (Sezaby label)
Distribution	Vd about 0.5–0.7 L/kg; the least lipid-soluble barbiturate; crosses the placenta
Protein binding	20–45% (label)
Metabolism	Liver: mainly CYP2C9, with CYP2C19 and CYP2E1, to inactive p-hydroxyphenobarbital, then conjugation
Elimination	25–50% unchanged in urine; alkaline urine and high flow increase it (label)
Steady state	About 2–3 weeks without a load, which is why it is loaded
Dialysis	Dialyzable; EXTRIP 2014 recommends hemodialysis in severe poisoning, alongside multiple-dose charcoal

Chemistry

5-ethyl-5-phenylbarbituric acid: a barbiturate, whose pyrimidinetrione ring comes from urea and malonic acid; the two groups on carbon 5 give CNS activity, and the phenyl adds anticonvulsant selectivity
An oxybarbiturate (oxygen at carbon 2, where thiopental has sulfur), so less lipid-soluble and slower than induction barbiturates
Weak acid, pKa 7.3: about half ionized at pH 7.4, so alkalinizing the urine traps the ion and speeds excretion
The sodium salt injection (65 or 130 mg/mL in 67.8% propylene glycol and 10% alcohol, pH 9.2–10.2) is strongly alkaline: it injures tissue and precipitates with acidic drugs
Most US injection is marketed without FDA approval; Sezaby (2022), a preservative-free powder, is approved only for neonatal seizures

Adverse effects and cautions

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Pentobarbital

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Sources

Label: Phenobarbital sodium injection (Hikma, 2024)
FDA label: Sezaby (2022)
PubChem: phenobarbital
Chiara 2013 (GABA-A sites)

For education and exam preparation only. Follow your institution’s protocols. Typical adult values for study. Follow your local protocols and medical direction.