Propofol
Pharmacology
Propofol (2,6-diisopropylphenol) is a sedative-hypnotic agent in a class of alkyl phenol compounds. It is an oil at room temperature, highly lipid-soluble, and administered as an emulsion. It is also an antioxidant, anticonvulsant, and anti-inflammatory agent, reduces intracranial pressure, and has bronchodilator properties. The site of action of propofol is at the GABAA receptor, where it activates the chloride channel. There may also be some action at the glutamate and glycine receptor sites. Propofol is an antagonist at the N-methyl-d-aspartate (NMDA) receptor. It is also an inhibitor of cytochrome P-450 enzymes.
On infusion, its effects are seen within less than 3 minutes, and peak concentrations are reached in less than 20 minutes.
It is highly protein-bound, with a volume of distribution of 2–5 L/kg after a single infusion and 25–60 L/kg after a continuous infusion of longer than 7 days. Propofol has a high clearance rate estimated at 1.5–2.2 L/min. This clearance rate exceeds hepatic blood flow and suggests extrahepatic metabolism.
Propofol is metabolized rapidly in the liver by conjugation to glucuronide and sulfate intermediates that are water-soluble and inactive. This occurs predominantly via oxidation by cytochrome P-450 (CYP) enzymes 2B6 and 2C9. Cytochrome P-450 isoforms 2A6, 2C19, 2D6, 2E1, 3A4, and 1A2 are also involved in the metabolism of propofol to a lesser extent. There is minimal enterohepatic circulation, and less than 1% is excreted unchanged.
Indications
Propofol is most useful when the goal of anesthesia or sedation is rapid induction and recovery. It can be used for the induction and maintenance of anesthesia.
Propofol is useful in the intensive care unit for sedation of mechanically ventilated patients, especially patients with severe head injuries. It may also be beneficial for conscious sedation in certain settings.
Propofol has been used as an adjunct anesthetic agent in the management of refractory withdrawal syndromes associated with alcohol or other sedative-hypnotics (eg, GHB and barbiturates) and in the treatment of status epilepticus. (These are not FDA-approved indications.)
Contraindications
Hypersensitivity to propofol or any of its components. Contraindicated in patients with allergies to eggs, egg products, soybeans, and soy products. The labeling on the Europe-manufactured product (Fresenius Propoven 1%) includes peanut hypersensitivity as a contraindication owing to concerns regarding potential peanut oil and soybean oil cross-reactivity.
Formulations vary and may contain benzyl alcohol, sodium benzoate, disodium edetate, or sodium metabisulfite. Consult individual product labeling for specific excipient information.
Adverse effects
Pain at the injection site can occur (use larger veins or premedicate with lidocaine).
Anaphylaxis, hypotension, bradycardia, supraventricular tachydysrhythmias, conduction disturbances, cough, bronchospasm, rash, pruritus, and hyperlipidemia may occur.
Anesthetic doses require respiratory support. Avoid rapid bolus doses because of the higher risk for hypotension, bradycardia, apnea, and airway obstruction.
Anesthetic doses may be associated with myoclonus, posturing, and seizure-like movement phenomena (jerking, thrashing). Seizures have been noted when patients were weaned from propofol.
Propofol infusion syndrome, a condition of metabolic acidosis, hyperkalemia, lipemia, renal failure, rhabdomyolysis, hepatomegaly, and cardiovascular collapse, has been associated most often with prolonged high-dose infusions (>5 mg/kg/h for >48 h) in both pediatric and adult populations. Children may be more susceptible; risk factors may include hypoxia, sepsis, and cerebral injury. The syndrome has also been reported following large-dose, short-term infusions during surgical anesthesia.
Acute pancreatitis with single or prolonged use can occur. Hyperlipidemia can also occur after prolonged use.
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