Barbiturate · Antiepileptic · Alcohol withdrawal
Phenobarbital
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
In the one-pagers
- Mental Health: Meds and CommunicationAlcohol withdrawal: risk, dosing strategy and resistance: Phenobarbital: Weight-based load or add-on; self-tapering: Resistance or benzodiazepine contraindication
- Toxidromes and AntidotesDecontamination, enhanced elimination and ECMO: Multiple-dose charcoal: only for life-threatening carbamazepine, dapsone, phenobarbital, quinine or theophylline (AACT/EAPCCT 1999); needs a protected airway and a working gut.
- Pediatric Assessment and EmergenciesEvidence and controversies: NEOLEV2 2020: Phenobarbital 80% vs levetiracetam 28%: Phenobarbital first in neonates
- Sedation, Pain and Delirium ScalesAlcohol withdrawal in the ICU: Phenobarbital acts at a separate GABA-A site, also blocks glutamate (AMPA), and with a half-life of about 53–118 hours (mean 79, label) tapers itself. It is given as a weight-based load (often 10–15 mg/kg IV, ideal body weight) or as an add-on. In an ED trial (Rosenson 2013, n = 102), one 10 mg/kg dose added to benzodiazepines cut ICU admission from 25% to 8%. Watch
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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 the order, the label and your institution's protocols.