Propofol

General Information

Propofol (2,6-diisopropylphenol) is a versatile, short-acting intravenous sedative /hypnotic agent used as an anesthetic and for sedation of patients in ICU. It is marketed as Diprivan by AstraZeneca. It is formulated as an emulsion in 10% soybean oil, 2.25% glycerol, 1.2 % egg phosphatide, and disodium edentate (EDTA).

Chemical Structure: C12H18O

 Molecular weight: 178.28.

Dosage:

Dose required to induce anesthesia is 2.0 – 2.5 mg/kg intravenously. Anesthesia can be maintained with either a continuous infusion (6.0 – 12.0 mg/kg/h) or with intermittent bolus injections (20 – 50mg).  As propofol is  only slightly soluble in water it is formulated in a white, oil in water emulsion.

Pharmacokinetics:

3 compartment linear model:  plasma, rapidly equilibrating tissues & slowly equilibrating tissues. Following an IV bolus, there is rapid equilibration of propofol levels between plasma and highly perfused tissues of the brain, followed by redistribution to inactive tissue depots such as fat and muscle. The range in half life values depends on the study conditions (bolus or infusion).

  • The initial distribution half life: 2-8 minutes
  • Slow distribution half life: 30 -70 minutes
  • Terminal elimination half life: 4 – 24 hours.
  • Central volume of distribution: 20 – 40 L
  • Volume of distribution at steady state: 150 – 700 L 

See PMID 3500657. Gepts E, Camu F, Cockshott ID, Douglas EJ. Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth Analg 66: 1256 – 1263, 1987.

See PMID 10719952. Schutter J, Ihmsen H. Population pharmacokinetics of propofol: a multicenter study. Anesthesiology 92: 727 – 738, 2000.

Clearance

Propofil is rapidly and extensively metabolized mainly in the liver (60%) and to a lesser extent the kidneys (30%).  It is eliminated by hepatic conjugation to inactive glucuronide metabolites which are excreted by the kidney. Approximately 50 -70% is excreted as propofol glucuronide. The remainder is hydroxylated by cytochrome  P450.

Clearance Rates:

  • 23 – 50 ml/kg/min (1.6 – 3.4 L/min for a 70kg adult) AstraZeneca: DiprivanR (propofol) injectable emulsion for IV administration prescribing information. Wilmington, DE 2001
  • 2.39 +/- 0.34 L/min (PMID: 2354095)  Lange H, Stephan H, Rieke H, Kellerman M, Sonntag H, Bircher J. Hepatic and extrahepatic disposition of propofol in patients undergoing coronary bypass surgery. Br J Anaesth. 64: 563 – 570, 1990.
  • 2.09 +/- 0.65 L/min (PMID 3261954) Shafer A, Doze VA, Shafer SL, White PF. Pharmacokinectics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology 69: 348 – 356, 1988.
  • 1.7 +/- 0.3 L/Min (PMID 3500657 – see full ref above))

PMID 16042671. Hiraoka H, Yamamoto K, Miyoshi S, Morita T, Nakamura K, Kadoi Y, Kunimoto F, Horiuchi R. Kidneys contribute to the extrahepatic clearance of propofol in humans, but not lungs and brain. Br J Clin Pharmacol 60: 176 – 182, 2005.

PMID 12067002. Favetta P, Degoute C-S, Perdrix J-P, Dufresne C, Boulieu R, Guitton J. Propofol metabolites in man following propofol induction and maintenance. Br J Anaesth 88: 653 – 658, 2002.

PMID: 9771309. Guitton J, Buronfosse T, Desage M, Flinois JP, Perdrix JP, Brazier JL, Beaune P. Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth 80: 788 – 795, 1998.

Pharmacological Effects:

The Cardiovascular System

Propofol causes a decrease in arterial pressure resulting from a decreased sympathetic tone with a reduction in vascular resistance.  Reflex responses to hypotension are also inhibited. Loss of vascular tone as a result of a reduced Ca2+ influx may also contribute to hypotension.

PMID: 15983452. Ebert TJ. Sympathetic and hemodynamic effects of moderate and deep sedation with propofol in humans. Anesthesiology 103: 20 – 24, 2005.

The Brain

Propofol reduces cerebral blood flow, cerebral metabolic rate & intracranial pressure dose dependently.

Propofol also protects the brain against ischemic injury. The neuro-protective effect has been attributed to its antioxidant property, the potentiation of GABAA – mediated inhibition of synaptic transmission and its inhibition of glutamate release.

PMID: 2363528.  Van Hemelrijck J, Fitch W, Mattheussen M, Van Aken H, Plets C, Lauwers T. Effect of propofol on cerebral circulation and autoregulation in the baboon. Anesth Analg 71: 49 – 54, 1990.

PMID: 3259086.  Herregods L, Verbeke J, Rolly G, Colardyn F. Effect of propofol on elevated intracranial pressure. Preliminary results. Anaesthesia 43 Suppl: 107 -109, 1988.

PMID: 11954772. Ergun R, Akdemir G, Sen S, Tasci A, Ergungor F. Neuroprotective effects of propofol following global ischemia in rats. Neurosurg Rev 25: 95 – 98, 2002.

PMID: 15875133. Kawaguchi M, Furuya H, Patel PM. Neuroprotective effects of anesthetic agents. J Anesth 19: 150 -160, 2005.

PMID: 10027021. Ito H, Watanabe Y, Isshiki A, Uchino H. Neuroprotective properties of propofol and midazolam, but not pentobarbital, on neuronal damage induced by forebrain ischemia, based on GABAA receptors. Acta Anaesthesiol scand 43: 153 – 162, 1999.

Effects on Central Nervous System Receptors

Propofol both activates and enhances the actions of GABA at GABAA receptors. These receptors are ligand-gated ion channels coupled to an integral chloride channel. Receptor activation rapidly increases chloride ion conductance and hyperpolarization of the post synaptic membrane. The effect of propofol on GABAA receptor function is concentration dependent, with low concentrations (1 -100uM) potentiating GABA-activated currents and moderate concentrations directly activating channel opening.

Respiratory Effects

At doses providing deep sedation or general anesthesia, propofol decreases resting ventilation and increases resting end-tidal CO2.

Propofol affects central chemoreceptor sensitivity and therefore has an effect on the control of ventilation. It reduces the ventilator y response to hypercapnia and hypoxia. Plasma propofol concentrations of 0.5 and 1.3 ug/ml decreased the slope of the ventilatory response to hypercapnia by 20% and 40% respectively.

PMID: 11605929. Nieuwenhuijs D, Sarton E, Teppema LJ, Kruyt E, Olievier I, van Kleef J, Dahan A. Respiratory sites of action of propofol: absence of depression of peripheral chemoreflex loop by low-dose propofol. Anesthesiology 95: 889 – 895, 2001.

Reviews

PMID: 18482023 Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neurosci Ther 14: 95 – 106, 2008.

PMID: 18175094. Vanlersberghe C, Camu F. Propofol. Handbook Exp Pharmacol 182: 227 – 252, 2008. 

PMID: 8536552. Fulton B, Sorkin EM. Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation. Drugs 50: 636 – 657, 1995.

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