Propofol

Mechanism

Pharmacodynamic Mechanism of Hypnosis and Antiemesis

Propofol exerts its hypnotic action through positive allosteric modulation of the GABA_A receptor, increasing chloride conductance mediated by β₂ and β₃ subunits. Additionally, it has notable intrinsic antiemetic properties (unlike most inducers), explained by the reduction of serotonin and dopamine levels in the brain area postrema, and the selective inhibition of 5-HT₃ receptors at the level of the chemoreceptor trigger zone.

Pharmacokinetics

Pharmacokinetics

• Commercial Presentation: 1% or 2% lipid emulsion containing soybean oil, glycerol and egg lecithin (medium with high susceptibility to bacterial growth, requires strict aseptic technique).
• Distribution: Very high apparent volume of distribution (2 - 10 L/kg). It distributes and rinses extremely quickly.
• Metabolism: Extensive hepatic and intrahepatic through conjugation with glucuronides and sulfates mediated by CYP2B6 and CYP2C9 isoenzymes. Significant extrahepatic metabolism is described in the lungs (≈ 30%).
• Context-Sensitive Half-Life (CSHT): Following prolonged continuous infusion (up to 8 hours), the context-sensitive half-life remains below 40 minutes, preventing the substantial clinical accumulation seen with thiopental.

Indicators and dose

Dosage and Clinical Adjustment

• Induction of General Anesthesia (Healthy Adult): 1.5 - 2.5 mg/kg slow intravenous route.
• Maintenance of Anesthesia (TIVA): 4 - 12 mg/kg/hour (100 - 300 µg/kg/min) or guided by target controlled infusion systems (TCI - Marsh or Schnider models).
• Conscious Sedation: 1.5 - 4.5 mg/kg/hour (25 - 75 µg/kg/min).

Security

Adverse Effects and Critical Toxicity

• Arterial Hypotension: Decreases systemic venous and arterial tone in a dose-dependent manner by inhibition of central sympathetic outflow and direct vasorelaxation by nitric oxide, markedly attenuating the baroreflex of reflex tachycardia.
• Respiratory Depression: Produces transient apnea in 25% - 35% of patients after standard induction doses.

Propofol Infusion Syndrome (PRIS)

Prolonged administration of propofol at doses higher than 4 - 5 mg/kg/hour for more than 48 hours can trigger Propofol Infusion Syndrome (PRIS). This clinical picture is associated with the inhibition of the transport of long-chain fatty acids into the mitochondria due to interference with carnitine palmitoyltransferase I and the uncoupling of the oxidative phosphorylation chain at the level of complexes I and II. Critical clinical manifestations: refractory severe lactic acidosis, massive rhabdomyolysis, hyperkalemia, steatotic hepatomegaly, acute renal failure and progressive cardiac arrhythmias (severe bradycardia with ST segment elevation of the right lead progressing to asystole).