Propofol

Pharmacology
1. Propofol (2,6-diisopropylphenol) is a sedative-hypnotic-anesthetic 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 proposed site of action of propofol is at the GABA(A) receptor, where it activates the chloride channel. There may also be some action at the glutamate and glycine receptor sites. Propofol is considered an antagonist at the N-methyl-D-aspartate (NMDA) receptor. It is also an inhibitor of cytochrome P-450 enzymes.
2. Intravenous injection of a therapeutic dose of propofol for sedation induces an initial response within 10 to 50 seconds.
3. It is highly protein bound (97-99%), with a volume of distribution of approximately 60 L/kg after a continuous 10-day infusion. Propofol has a high clearance rate estimated at 1.6-3.4 L/min in 70-kg adults. This clearance rate exceeds hepatic blood flow and suggests extrahepatic metabolism.
4. 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) enzyme 2B6. Cytochrome P-450 isoforms 2A6, 2C9, 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
1. Induction and maintenance of general anesthesia in adults and children aged 3 years and older. Can be used for maintenance in children aged 2 months and older.
2. Monitored sedation in adults during procedures.
3. Monitored sedation in intubated, mechanically ventilated adult patients.
4. Propofol has also 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
1. Hypersensitivity to propofol or any of its components. Contraindicated in patients with allergies to eggs, egg products, soybeans, and soy products (use an alternative anesthetic, or trial a small dose of propofol prior to giving the full dose). 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.
2. Formulations vary and may contain benzyl alcohol, sodium benzoate, disodium edetate, or sodium metabisulfite. Consult individual product labeling for specific excipient information.
Adverse effects
1. Pain and/or burning at the injection site can occur. Use larger veins or premedicate with lidocaine.
2. Anaphylaxis, apnea, hypotension, bradycardia, supraventricular tachydysrhythmias, conduction disturbances, cough, bronchospasm, rash, pruritus, and hyperlipidemia may occur.
3. Anesthetic doses require respiratory support. Avoid rapid bolus doses because of the higher risk for hypotension, bradycardia, apnea, and airway obstruction.
4. 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.
5. Propofol infusion syndrome is a serious and life-threatening condition characterized by severe metabolic acidosis, hyperkalemia, lipemia, renal failure, rhabdomyolysis, hepatomegaly, cardiac arrhythmias, and myocardial failure. Risk factors include patients with decreased oxygen delivery to tissues, serious neurological injury, sepsis, high dosages of vasoconstrictors, steroids, inotropes, and prolonged high-dose propofol infusions (>5 mg/kg/h for >48 hours). This syndrome has also been reported following large-dose, short-term infusion of propofol during surgical anesthesia.
6. Acute pancreatitis with single or prolonged use can occur. Hyperlipidemia can also occur after prolonged use.
7. Use with caution in patients who have a history of seizures. When propofol is administered to a patient with epilepsy, there is a risk for seizures during the recovery phase.
8. Propofol vials can still support the growth of microorganisms despite the addition of additives to inhibit their rate of growth. Strictly adhere to product labeling recommendations for handling and administering propofol.
9. Edetate disodium, an ingredient of the propofol emulsion and strong chelator of trace minerals, may lead to decreased zinc levels that can occur during prolonged therapy (>5 days) or in patients with a predisposition to zinc deficiency, such as those with burns, diarrhea, or sepsis. Zinc replacement may be needed.
10. There have been reports of the abuse of propofol, which have resulted in fatalities and other injuries.
11. Urine may be discolored green or dark green.
12. Use in pregnancy. FDA Category B. Fetal risk cannot be ruled out. Propofol crosses the placenta and may be associated with neonatal CNS and respiratory depression (Introduction).
Drug or laboratory interactions
1. An additive effect with other CNS depressants may result in lower propofol dose requirements if propofol is given concomitantly. Through its inhibition of cytochrome P-450 enzymes, propofol may increase levels of substrate drugs including midazolam, diazepam, and opiates such as sufentanil and alfentanil, causing respiratory depression, bradycardia, and hypotension.
2. Propofol levels may be increased by lidocaine, bupivacaine, and halothane, producing an increased hypnotic effect.
3. Concurrent use with succinylcholine may result in bradycardia.
Dosage and method of administration. Propofol currently is administered as an intravenous medication only, and the dose must be individualized and titrated (see Table III-14).

TABLE III-14. DOSING GUIDELINES FOR PROPOFOL

Indication	Doses^a,b,c,d (All Intravenous)
Indication	Initial Dose	Maintenance Dose (mg/kg/h)
Sedation
Patient undergoing procedural sedation	0.3-0.75 mg/kg over 3-5 min	1.5-3
Intubated patient in ICU	Start with 0.3 mg/kg/h; titrate in small increments every 5-10 min to effect.	0.3-3
Status epilepticus	1-2 mg/kg	1.2-12

^aDose rates vary and should be titrated to desired clinical effect.

^bSome institutions avoid use in children younger than 16 years and have put limits on maximum infusion rates and duration (eg, not to exceed 4 mg/kg/h for 24-48 hours, not to be used beyond 72 hours, or not more than 9 mg/kg/h for 2-4 hours) to prevent propofol infusion syndrome.

^cIn elderly, debilitated, or neurosurgical patients, use 80% of usual adult dose.

^dNote: some formulations (eg, Fresenius Propoven 2%) contain twice the concentration of propofol compared with the standard 1% formulation.

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Introduction