Thiopental

Thiopental sodium (sodium 5-ethyl-5-(pentan-2-yl)-2-thioxopyrimidine-4,6(1H,5H)-dione; CAS 76-75-5; molecular formula C11H17N2NaO2S; molecular weight 264.32 free acid) is a thiobarbiturate intravenous anesthetic synthesized by Ernest Volwiler and Donalee Tabern at Abbott Laboratories in 1932 and introduced clinically by John Lundy at the Mayo Clinic in 1934 (Pentothal). The compound is the canonical ultrashort-acting barbiturate; substitution of sulfur for oxygen at the 2-position substantially increases lipid solubility relative to oxybarbiturates, enabling rapid blood-brain crossing and a sleep onset within one circulation time (approximately 30 seconds). Mechanism is positive allosteric modulation of GABA-A receptors at the barbiturate site, distinct from the benzodiazepine site, with prolongation of GABA chloride channel open time. At higher concentrations barbiturates can directly open GABA-A channels in the absence of GABA. Pharmacokinetics: thiopental redistribution from brain to muscle and fat is responsible for the brief clinical effect (approximately 10 minutes from a single induction dose), not metabolic clearance; hepatic metabolism is slow (half-life 8 to 12 hours) and accumulating doses produce prolonged emergence. Cardiovascular effects include dose-dependent myocardial depression and reduction in systemic vascular resistance with reflex tachycardia. Respiratory effects include apnea at induction doses. The cerebral effects (reduction in cerebral metabolic rate and cerebral blood flow with relatively preserved cerebral perfusion pressure) underlie the use of thiopental in raised intracranial pressure and the so-called barbiturate coma in refractory status epilepticus. Propofol displaced thiopental as the dominant induction agent in the 1990s. Thiopental was the historical first agent in the three-drug US lethal injection protocol; manufacturing supply was withdrawn from US execution use after 2010.