Thiopental

Introduction and Brief History

• Thiopental was developed in the 1930s and became widely used as an induction agent due to its rapid onset of sedation, short duration of action, and hypnosis.
• Even after its competitor, propofol, became available in the 1990s and largely replaced this agent, it was still widely utilized clinically in geriatric, neurologic, cardiovascular, and obstetric patients.
• As overall demand for this medication decreased, profits from manufacturing also diminished. At the same time, alternative uses of the drug included capital punishment, narcoanalysis in psychiatry, and as a truth serum which created a negative perception of thiopental. Ultimately, these factors led the main manufacturer, Hospira, to discontinue the production of thiopental in 2011.³
• Thiopental remains widely available in many low- and middle-income countries and is frequently used for anesthetic induction.

Trade Names

• Trade names include pentothal, penthiobarbital sodium, thiomebumal, thiopental Na, thiopental sodium, and thiopentone.⁴

Mechanism of Action and Pharmacokinetics

• The mechanism of action of thiopental is not fully elucidated, but the molecule binds to the gamma-aminobutyric acid (GABA)-A receptor, increasing the time at which the chloride ionopore is open. This increases the activity of GABA and exerts inhibitory effects on the central nervous system (CNS), primarily at the cerebral cortex and reticular formation.^5,6

Pharmacokinetics

• The rapid onset of action of thiopental is secondary to its rapid distribution into the effect site.
• The rapid awakening following an induction dose is secondary to rapid redistribution from the central to peripheral compartment.
• Thiopental is predominantly metabolized in the liver and eliminated via the kidneys.
• The elimination half-life of thiopental is 3-26 hours.
• Thiopental has a long context-sensitive half time. Repeated doses lead to prolonged anesthesia as the drug accumulates in the fatty tissues and acts as a reservoir.

Effects on Organ Systems¹

Central Nervous System

• Thiopental decreases cerebral metabolic oxygen requirement (CMRO2) and cerebral blood flow (CBF), thereby decreasing intracranial pressures. The decrease in CMRO₂ (up to 50% normal) is greater than the decrease in CBF.
• Thiopental is thought to possess “neuroprotective” properties and can be used for cerebral protection during incomplete brain ischemia (e.g., carotid endarterectomy, temporary occlusion of cerebral arteries, etc.). However, there is no benefit in the setting of global cerebral ischemia (e.g., cardiac arrest).
• Thiopental causes dose-dependent electroencephalogram (EEG) changes and “burst suppression” with larger doses. Thiopental has potent anticonvulsant activity.

Cardiovascular System

• Thiopental decreases cardiac output by decreasing systemic vascular resistance and venous return. It also causes direct myocardial suppression. Decreased doses should be used in the setting of hypovolemia.

Respiratory System

• Thiopental causes dose-dependent respiratory depression by depressing the medullary respiratory center and decreasing the ventilatory response to hypoxia and hypercarbia.
• Thiopental does not depress airway reflexes as much as propofol and events such as laryngospasm or bronchospasm can occur in lightly anesthetized patients.

Clinical Indications

• Thiopental has been used intravenously in clinical anesthesia for induction, reduction of intracranial pressure, and as an anticonvulsant based on its favorable pharmacologic profile.¹

Dose and Dosing Considerations

• Intravenous dosage⁴:
  • Adult induction dose: rapid induction (3-4 mg/kg) divided into 2 to 4 doses
  • Pediatric dose: induction, (neonate) 3-4 mg/kg; (1-6 months) 5-8 mg/kg IV; (1-15 y) 5-6 mg/kg
• Decreased doses should be used in patients with severe renal dysfunction and in the elderly.⁴
• Table 2 reviews key pharmacokinetics and pharmacodynamics of thiopental.

Adverse Effects/Toxicity

• Administration of thiopental can contribute to respiratory depression, laryngospasm, vasodilation, and decreases in blood pressure. Thiopental is a known vesicant that can cause tissue injury, pain, and necrosis with extravasation.⁴
• Thiopental administration in an unmonitored setting or at supratherapeutic doses can cause coma and death induced by respiratory depression and cardiovascular collapse.⁴

Contraindications

• Potential contraindications to the administration of thiopental include thiopental hypersensitivity, absence of suitable veins for intravenous administration given the high consequence of extravasation, and acute intermittent porphyria or variegate porphyria (South African)⁴ hypersensitivity to thiopental.

Controversy

• Hospira, the main manufacturer of thiopental in the United States, discontinued the production of the drug in 2011 as the result of ongoing criticism due to its use in capital punishment euthanasia in the United States.⁷
• The American Society of Anesthesiologists issued a statement in 2011 regarding the clinical void created when the drug was made unavailable.⁸ There were also many articles in the popular press regarding failed or painful executions that resulted from the shortage of thiopental in the years that followed its withdrawal from the market. See the links below in Other Resources section for more information on this topic.