Sodium Thiopental

Mechanism

Mechanism of action

Thiopental selectively binds to a hydrophobic subunit of the GABA_A receptor, facilitating the coupling of the GABA neurotransmitter to its primary binding site and dramatically prolonging the duration of Cl^- channel opening. At high concentrations, thiopental acquires the ability to directly activate the chloride channel in the absence of GABA and inhibits voltage-gated sodium channels, decreasing excitatory neurotransmission and drastically reducing the cerebral metabolic rate of oxygen consumption (CMRO₂).

Under the effect of thiopental at high inducing doses, the electroencephalogram (EEG) progresses towards a pattern of rescue-suppression and, eventually, electrical silence, coupled with reducing cerebral blood flow (CBF) by reflex vasoconstriction and secondarily decreasing intracranial pressure (ICP).

Pharmacokinetics

Kinetic Redistribution Awakening Model

After the administration of an intravenous bolus of thiopental (3 - 5 mg/kg), the plasma and brain concentration reaches its maximum peak in less than 1 minute, inducing immediate hypnosis. However, patient awakening typically occurs within 5 to 10 minutes. This rapid cessation of effect is not due to hepatic metabolic clearance of the drug, but rather to passive and massive redistribution from the brain (V1) to skeletal muscle tissue (V2) and adipose tissue (V3), rapidly reducing the partial pressure of the drug in the cerebral capillary plasma.

Pharmacokinetics

• Metabolism: Hepatic through slow microsomal oxidation mediated by the cytochrome P450 system, mainly through the formation of inactive carboxylated metabolites.
• Clearance: Low (1.6 - 4.3 mL/kg/min). It has a prolonged terminal elimination half-life of 11.6 hours due to its progressive accumulation in peripheral fatty compartments in continuous infusions ("saturation kinetics").
• Protein Binding: High (≈ 80% - 85%, mainly to albumin). In states of severe hypoalbuminemia or uremia, the free active fraction rises critically, requiring lower induction doses.

Indicators and dose

Dosage and Clinical Adjustment

• Induction of General Anesthesia: 3 - 5 mg/kg slowly intravenously in adults.
• Cerebral Protection against Severe Intracranial Hypertension: Intermittent boluses of 1.5 - 3 mg/kg guided by continuous electroencephalographic monitoring (search for rescue-suppression pattern) or ICP.
• Adjustment in Elderly: Reduce the initial dose by 30% to 50% due to the reduction in cardiac output and central volume of distribution associated with physiological aging.

Security

Absolute Contraindications

Acute Intermittent and Variegate Porphyria

Barbiturates potently induce the synthesis of the enzyme that controls heme synthesis, δ-aminolevulinic acid synthase (ALA-sistase). In patients with pre-existing genetic deficiencies in the heme biosynthetic chain, thiopental administration may precipitate a severe neurovisceral crisis characterized by severe cramping abdominal pain, rapidly progressive flaccid peripheral motor neuropathy, psychosis, and seizures.