Barbiturate Pharmacology and Clinical Use

Introduction to Barbiturates

Barbiturates are derivatives of barbituric acid and include both long-acting agents, such as phenobarbital, and short-acting agents, including pentobarbital, secobarbital, amobarbital, butalbital, and thiopental, with varying elimination half-lives and durations of action 1, 2

Phenobarbital, a long-acting barbiturate, has an elimination half-life of 80-120 hours and a duration of action of 6-12 hours, with a molecular weight of 232 Da and a pKa of 7.2, and approximately 20-25% is excreted unchanged in urine 1
Pentobarbital, a short-acting barbiturate, has an elimination half-life of 15-48 hours and a duration of action of 3-4 hours, with a molecular weight of 226 Da and a pKa of 7.9, and less than 5% is excreted unchanged in urine 1
Short-acting barbiturates are more protein-bound and lipid-soluble than long-acting counterparts, with a more rapid onset, higher pKa, shorter duration of action, and are metabolized nearly exclusively in the liver 1
Long-acting barbiturates accumulate less extensively in tissue, are less lipid-soluble, and are excreted as active drugs by the kidneys more readily 1

The American Academy of Sleep Medicine and other guideline societies should be consulted for the use of barbiturates as anticonvulsants or anesthetics, as they have varying degrees of recommendation for different seizure types and anesthesia purposes 1
Barbiturates are potent inducers of the hepatic CYP450 enzyme system, increasing metabolic clearance of other medications that are CYP substrates, and have additive depressant effects on the CNS and respiratory system when combined with other CNS depressants 1, 3
Butalbital-acetaminophen-caffeine is classified as a Schedule III controlled substance due to its barbiturate content, and is primarily metabolized in the liver through the cytochrome P450 system, which it can also induce 3

Secobarbital and amobarbital are intermediate-acting barbiturates that are no longer licensed for use in the United States, United Kingdom, and most developed countries, and can only be prescribed to patients already taking them for intractable insomnia 2
Butalbital is an intermediate-acting barbiturate that is no longer licensed as a standalone agent but remains available in combination products 2
The FDA and other regulatory agencies describe the formulation and concentration of pentobarbital sodium, such as 50 mg/mL in a vehicle of propylene glycol, alcohol, and water for injection 2