General Principles: Pharmacokinetics continued

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Pharmacokinetics: Propofol (Diprivan)

  • 5Overview: propofol (Diprivan): This anesthetic, first of a new class of intravenous anesthetic agents - the alkylphenols,  is currently the most popular induction agent and is used in over 50 countries.  In addition, propofol (Diprivan) may even be used for continuous IV infusion for anesthesia maintenance while still allowing for rapid recovery. At a certain point, perhaps when surgeries last more than two hours, propofol (Diprivan) use may not be cost-effective. Cardiovascular effects are relatively minor, slightly depressants in nature, with similar relatively minor effects on ventilation (even in doses used for continuous infusion).  The reduction  in BP following propofol (Diprivan) may be slightly greater than that observed with thiopental (Pentothal).

    • Propofol (Diprivan) appears to act by enhancing the GABA neurotransmitter system.

    • Because of propofol (Diprivan)'s lipid solubility, the drug must be administered as the emulsion consisting of soybean oil, glycerol, and purified egg phosphatide. [soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL); and disodium edetate (0.005%); with sodium hydroxide to adjust pH. The DIPRIVAN emulsion is isotonic and has a pH of 7-8.5.] Because propofol (Diprivan) solutions are emulsions, is not surprising that it appears "milky" white as a result of light scattering.

    • Recently, the FDA has issued a warning (April, 2001) concerning the off-label use of propofol (Diprivan) has a sedative in the pediatric ICU setting: 

      • "The FDA has determined that there may be important safety concerns when propofol, marketed by AstraZeneca as DIPRIVAN (propofol) Injectable Emulsion, is used for sedation in the Intensive Care Unit (ICU) in pediatric patients. Healthcare professionals are reminded that propofol is not approved in the U.S. for sedation in pediatric ICU patients" This conclusion was based on analysis described below:

    • Propofol (Diprivan) dosage schemes as suggested by the manufacturer (http://www.diprivan.com/productInfo/productInfo.html)

  • Propofol (Diprivan) structure: Propofol (Diprivan) is a phenol derivative (2,6-Diisopropylphenol)

phenol

 

propofol (Diprivan)

 

phenol

propofol (2,6-Diisopropylphenol)

  • 5Pharmacokinetics of propofol (Diprivan):

    • Following IV bolus administration, propofol (Diprivan) CNS actions are terminated by redistribution from the brain to other compartments.  This process occurs with a redistribution halftime in the 2-8 minute range. The plasma elimination halftime is about 1-3 hours in its accounted for by significant and rapid metabolism and hepatic and extrahepatic sites.

    • A "context-sensitive" halftime of about 40 minutes has been described as applicable after many hours of continues infusion. [Recall that by definition a "context-sensitive" halftime refers to the time it takes for the plasma concentration to fall by half after cessation of continuous infusion]

    • For IV bolus administration, propofol (Diprivan)  pharmacokinetic is reasonably described by a two-compartment model.

    • Propofol (Diprivan) metabolites are inactive glucuronide and sulfate derivatives.

    • Propofol (Diprivan) volume of distribution is about 20-40 L. 

    • For propofol (Diprivan), in a manner similar to other rapid-onset induction agents, anesthesia occurs in a "one arm-brain circulation"; anesthesia by this bolus IV method lasts about 5-10 minutes using a dose of 2-2.5 mg/kg, followed by rapid recovery.  Propofol (Diprivan), used for sedation & amnesia, may be infused at a rate of 2 mg/kg/h.  Note the warning above concerning the warning against the off-label propofol (Diprivan) use in the pediatric ICU setting.

  • 5,6Propofol (Diprivan) pharmacology-- a summary of organ system and other effects:

    • CNS: Propofol (Diprivan) reduces cerebral metabolic rate as measured in terms of oxygen consumption.  Cerebral blood flow and intracranial pressure  (ICP) are reduced following propofol (Diprivan) as well.  Alterations in PaCO2 will additionally change ICP even after propofol (Diprivan) use.

      • Thiopental (Pentothal) and propofol (Diprivan) induce changes in the EEG.  For propofol (Diprivan), these changes appear complex since anticonvulsive properties may be present in some circumstances, whereas post-anesthesia seizures have also been noted.

    • Pulmonary: Following IV administration, propofol (Diprivan) often induces apnea (frequency = 25%-30%).  The characteristics associated with apnea will be dependent on dose, rate of drug administration and importantly, the presence of other drugs.  Apnea may last  > thirty seconds and may be further prolonged by agents that themselves are respiratory depressants, such as opioids.The apneic state is typically preceded by a decrease tidal volume and tachypnea (rapid breathing).

      • Propofol (Diprivan) infusion is associated with not only a reduction in tidal volume and respiratory rate, but also reduced ventilatory responses to CO2 levels and hypoxia.

      • Ventilatory depressant effects caused by these drugs are counteracted by painful surgical stimulation.

      • Propofol (Diprivan) (to a lesser degree than halothane (Fluothane) an inhalational agent) causes some bronchodilation which in patients with asthma may induce increased intraoperative wheezing.

    • Some other  considerations regarding propofol (Diprivan) administration:

      1. Propofol (Diprivan) does not induce malignant hyperpyrexia or affect cortisol synthesis which is suppressed by etomidate (Amidate)

      2. Anaphylactic reactions have been noted with propofol (Diprivan), perhaps relating to the presence of sulfite, a preservative,found in some generic formulations, to the isopropyl phenol structure itself, or to the solvent (emulsion)

      3. The emulsion used propofol (Diprivan) is particularly conducive to bacterial growth. To minimize postoperative complications, aseptic techniques should be used in opening and ampules containing propofol (Diprivan) with contents withdrawn immediately into the sterile syringe.  The syringe should be used only on a single patient.

      4. Propofol (Diprivan) administration tends to decrease the likelihood of postoperative nausea and vomiting and can even be used, in reduced doses (10-15 mg IV), to manage nausea vomiting in the post anesthesia care unit (PACU).

      5. Propofol (Diprivan) injection may be painful but the pain may be reduced by adding a local anesthetic.

1Katzung, B. G. Basic Principles-Introduction , in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 1-33

2Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B The Dynamics of Drug Absorption, Distribution and Elimination. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 3-27

3Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 50-61.

4Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

5Dolin, S. J. "Drugs and pharmacology" in Total Intravenous Anesthesia, pp. 13-35 (Nicholas L. Padfield, ed), Butterworth Heinemann, Oxford, 2000

6Stoelting, R. K. and Miller, R.D. Intravenous Anesthetics, in Basics of Anesthesia, 4th edition, pp. 58-69, Churchill-Livingstone, 2000.

 

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