Clinical Pharmacokinetics and Pharmacodynamics of Propofol

Marko M Sahinovic, Michel M R F Struys, Anthony R Absalom, Marko M Sahinovic, Michel M R F Struys, Anthony R Absalom

Abstract

Propofol is an intravenous hypnotic drug that is used for induction and maintenance of sedation and general anaesthesia. It exerts its effects through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABAA receptor, and has gained widespread use due to its favourable drug effect profile. The main adverse effects are disturbances in cardiopulmonary physiology. Due to its narrow therapeutic margin, propofol should only be administered by practitioners trained and experienced in providing general anaesthesia. Many pharmacokinetic (PK) and pharmacodynamic (PD) models for propofol exist. Some are used to inform drug dosing guidelines, and some are also implemented in so-called target-controlled infusion devices, to calculate the infusion rates required for user-defined target plasma or effect-site concentrations. Most of the models were designed for use in a specific and well-defined patient category. However, models applicable in a more general population have recently been developed and published. The most recent example is the general purpose propofol model developed by Eleveld and colleagues. Retrospective predictive performance evaluations show that this model performs as well as, or even better than, PK models developed for specific populations, such as adults, children or the obese; however, prospective evaluation of the model is still required. Propofol undergoes extensive PK and PD interactions with both other hypnotic drugs and opioids. PD interactions are the most clinically significant, and, with other hypnotics, tend to be additive, whereas interactions with opioids tend to be highly synergistic. Response surface modelling provides a tool to gain understanding and explore these complex interactions. Visual displays illustrating the effect of these interactions in real time can aid clinicians in optimal drug dosing while minimizing adverse effects. In this review, we provide an overview of the PK and PD of propofol in order to refresh readers' knowledge of its clinical applications, while discussing the main avenues of research where significant recent advances have been made.

Conflict of interest statement

Marko M. Sahinovic reports no conflicts of interest. Michel M.R.F. Struys reports his research group/department has received grants and funding from The Medicines Company (Parsippany, NJ, USA), Masimo (Irvine, CA, USA), Fresenius (Bad Homburg, Germany), Acacia Design (Maastricht, The Netherlands), and Medtronic (Dublin, Ireland), as well as honoraria from The Medicines Company (Parsippany, NJ, USA), Masimo (Irvine, CA, USA), Fresenius (Bad Homburg, Germany), Baxter (Deerfield, IL, USA), Medtronic (Dublin, Ireland), and Demed Medical (Temse, Belgium). A.R. Absalom is an editor of the British Journal of Anaesthesia. His research group/department has received grants and funding from The Medicines Company (Parsippany, NJ, USA), Medtronic (Dublin, Ireland), and BD (Franklin Lakes, NJ, USA). He has also received honoraria (paid to the institution) from The Medicines Company (Parsippany, NJ, USA), Janssen Pharmaceutica NV (Beerse, Belgium) and Ever Pharma (Salzburg, Austria).

Figures

Fig. 1
Fig. 1
Propofol metabolic pathway. CYP cytochrome P450, UDP uridine 5′-diphosphate
Fig. 2
Fig. 2
Overview of a three-compartment pharmacokinetic/pharmacodynamic model

References

    1. Glen JB, James R. 2,6-Diisopropylphenol as an anaesthetic agent. London: United States Patent and Trademark Office; 1977. pp. 1–10.
    1. Thompson KA, Goodale DB. The recent development of propofol (DIPRIVAN) Intensive Care Med. 2000;26(Suppl 4):S400–S404.
    1. Schüttler J, Schwilden H, editors. Modern anesthetics (handbook of experimental pharmacology) Heidelberg: Springer; 2008.
    1. Baker MT, Naguib M. Propofol: the challenges of formulation. Anesthesiology. 2005;103:860–876.
    1. Bryson HM, Fulton BR, Faulds D. Propofol. An update of its use in anaesthesia and conscious sedation. Drugs. 1995;50:513–559.
    1. Fulton B, Sorkin EM. Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation. Drugs. 1995;50:636–657.
    1. Trapani G, Altomare C, Liso G, Sanna E, Biggio G. Propofol in anesthesia. Mechanism of action, structure-activity relationships, and drug delivery. Curr Med Chem. 2000;7:249–271.
    1. Joo HS, Perks WJ. Sevoflurane versus propofol for anesthetic induction: a meta-analysis. Anesth Analg. 2000;91:213–219.
    1. Liu H, Ji F, Peng K, Applegate RL, Fleming N. Sedation after cardiac surgery: is one drug better than another? Anesth Analg. 2017;124:1061–1070.
    1. Kochhar GS, Gill A, Vargo JJ. On the horizon: the future of procedural sedation. Gastrointest Endosc Clin N Am. 2016;26:577–592.
    1. Marik PE. Propofol: therapeutic indications and side-effects. Curr Pharm Des. 2004;10:3639–3649.
    1. Package insert, Diprivan (Propofol) Injectable Emulsion. Lake Zurich, IL: Fresenius Kabi; 2014.
    1. Hart B. “Diprivan”: a change of formulation. Eur J Anaesthesiol. 2000;17:71–73.
    1. Pubchem. Propofol. 2017. Available at: .
    1. Fischer MJM, Leffler A, Niedermirtl F, Kistner K, Eberhardt M, Reeh PW, et al. The general anesthetic propofol excites nociceptors by activating TRPV1 and TRPA1 rather than GABAA receptors. J Biol Chem. 2010;285:34781–34792.
    1. Klement W, Arndt JO. Pain on injection of propofol: effects of concentration and diluent. Br J Anaesth. 1991;67:281–284.
    1. Allford MA, Mensah JA. Discomfort on injection. Eur J Anaesthesiol. 2006;23:971–974.
    1. Picard P, Tramèr MR. Prevention of pain on injection with propofol: a quantitative systematic review. Anesth Analg. 2000;90:963–969.
    1. Hardman JG, Hopkins PM, Struys MMR, editors. Oxford textbook of anaesthesia. Oxford: Oxford University Press; 2017.
    1. Asserhøj LL, Mosbech H, Krøigaard M, Garvey LH. No evidence for contraindications to the use of propofol in adults allergic to egg, soy or peanut. Br J Anaesth. 2016;116:77–82.
    1. American Society for Anesthesiology; Committee for Standards and Practice Parameters. Standards for basic anesthetic monitoring. ASA Standard Guidelines; 2015. p. 1–4. Available at: .
    1. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–882.
    1. Jevtovic-Todorovic V, Absalom AR, Blomgren K, Brambrink A, Crosby G, Culley DJ, et al. Anaesthetic neurotoxicity and neuroplasticity: an expert group report and statement based on the BJA Salzburg Seminar. Br J Anaesth. 2013;111:143–151.
    1. Raoof AA, Augustijns PR, Verbeeck RK. In vivo assessment of intenstinal, hepatic, and pulmonary first pass metabolism of propofol in the rat. Pharm Res. 1996;13:891–895.
    1. Uchegbu I, Jones M-C, Corrente F, Godfrey L, Laghezza D, Carafa M, et al. The oral and intranasal delivery of propofol using chitosan amphiphile nanoparticles. Pharm Nanotechnol. 2014;2:65–74.
    1. Mazoit JX, Samii K. Binding of propofol to blood components: implications for pharmacokinetics and for pharmacodynamics. Br J Clin Pharmacol. 1999;47:35–42.
    1. Tarr L, Oppenheimer B, Sager R. The circulation time in various clinical conditions determined by the use of sodium dehydrochlorate. Am Heart J. 1933;8:766.
    1. Dawidowicz AL, Kalitynski R, Fijalkowska A. Free and bound propofol concentrations in human cerebrospinal fluid. Br J Clin Pharmacol. 2003;56:545–550.
    1. Engdahl O, Abrahams M, Björnsson A, et al. Cerebrospinal fluid concentrations of propofol during anaesthesia in humans. Br J Anaesth. 1998;81:957–959.
    1. Dailland P, Cockshott ID, Lirzin JD, Jacquinot P, Jorrot JC, Devery J, et al. Intravenous propofol during cesarean section: placental transfer, concentrations in breast milk, and neonatal effects. A preliminary study. Anesthesiology. 1989;71:827–834.
    1. Gin T, Yau G, Jong W, Tan P, Leung RKW, Chan K. Disposition of propofol at caesarina section and in the postpartum period. Br J Anaesth. 1991;67:49–53.
    1. Tumukunde J, Lomangisi DD, Davidson O, Kintu A, Joseph E, Kwizera A. Effects of propofol versus thiopental on Apgar scores in newborns and peri-operative outcomes of women undergoing emergency cesarean section: a randomized clinical trial. BMC Anesthesiol. 2015;15:63.
    1. Simons P. J., Cockshott I. D., Douglas E. J., Gordon E. A., Hopkins K., Rowland M. Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of14C-propofol. Xenobiotica. 1988;18(4):429–440.
    1. Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology. 1992;76:334–341.
    1. Hannivoort LN, Eleveld DJ, Proost JH, Reyntjens KMEM, Absalom AR, Vereecke HEM, et al. Development of an optimized pharmacokinetic model of dexmedetomidine using target-controlled infusion in healthy volunteers. Anesthesiology. 2015;123:357–367.
    1. Court MH, Duan SX, Hesse LM, Venkatakrishnan K, Greenblatt DJ. Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology. 2001;94:110–119.
    1. Shioya N, Ishibe Y, Shibata S, Makabe H, Kan S, Matsumoto N, et al. Green urine discoloration due to propofol infusion: a case report. Case Rep Emerg Med. 2011;2011:1–4.
    1. Mikstacki A, Skrzypczak-Zielinska M, Tamowicz B, Zakerska-Banaszak O, Szalata M, Slomski R. The impact of genetic factors on response to anaesthetics. Adv Med Sci. 2013;58:9–14.
    1. Takizawa D, Sato E, Hiraoka H, Tomioka A, Yamamoto K, Horiuchi R, et al. Changes in apparent systemic clearance of propofol during transplantation of living related donor liver. Br J Anaesth. 2005;95:643–647.
    1. Hiraoka H, Yamamoto K, Miyoshi S, Morita T, Nakamura K, Kadoi Y, et al. Kidneys contribute to the extrahepatic clearance of propofol in humans, but not lungs and brain. Br J Clin Pharmacol. 2005;60:176–182.
    1. Takizawa D, Hiraoka H, Goto F, Yamamoto K, Horiuchi R. Human kidneys play an important role in the elimination of propofol. Anesthesiology. 2005;102:327–330.
    1. Dawidowicz AL, Fornal E, Mardarowicz M, Fijalkowska A. The role of human lungs in the biotransformation of propofol. Anesthesiology. 2000;93:992–997.
    1. He YL, Ueyama H, Tashiro C, Mashimo T, Yoshiya I. Pulmonary disposition of propofol in surgical patients. Anesthesiology. 2000;93:986–991.
    1. Bodenham A, Culank LS, Park GR. Propofol infusion and green urine. Lancet. 1987;2:740.
    1. Takita A, Masui K, Kazama T. On-line monitoring of end-tidal propofol concentration in anesthetized patients. Anesthesiology. 2007;106:659–664.
    1. Grossherr M, Hengstenberg A, Meier T, Dibbelt L, Gerlach K, Gehring H. Discontinuous monitoring of propofol concentrations in expired alveolar gas and in arterial and venous plasma during artificial ventilation. Anesthesiology. 2006;104:786–790.
    1. Colin P, Eleveld DJ, van den Berg JP, Vereecke HEM, Struys MMRF, Schelling G, et al. Propofol breath monitoring as a potential tool to improve the prediction of intraoperative plasma concentrations. Clin Pharmacokinet. 2016;55:849–859.
    1. B. Braun. Exhaled propofol concentration monitor, Edmon. Available at: .
    1. Gepts E, Camu F, Cockshott ID, Douglas EJ. Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth Analg. 1987;66:1256–1263.
    1. Shafer A, Doze VA, Shafer SL, White PF. Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology. 1988;69:348–356.
    1. Kirkpatrick T, Cockshott ID, Douglas EJ, Nimmo WS. Pharmacokinetics of propofol (diprivan) in elderly patients. Br J Anaesth. 1988;60:146–150.
    1. Schüttler J, Ihmsen H. Population pharmacokinetics of propofol: a multicenter study. Anesthesiology. 2000;92:727–738.
    1. Wietasch JKG, Scholz M, Zinserling J, Kiefer N, Frenkel C, Knüfermann P, et al. The performance of a target-controlled infusion of propofol in combination with remifentanil: a clinical investigation with two propofol formulations. Anesth Analg. 2006;102:430–437.
    1. Struys MMRF, Sahinovic MM, Lichtenbelt BJ, Vereecke HEM, Absalom AR. Optimizing intravenous drug administration by applying pharmacokinetic/pharmacodynamic concepts. Br J Anaesth. 2011;107:38–47.
    1. Sahinovic MM. Intravenous drug dose optimization and drug effect monitoring in anaesthesia. Groningen: Rijksuniversiteit Groningen; 2017.
    1. Green B, Duffull SB. What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol. 2004;58:119–133.
    1. Eleveld DJ, Proost JH, Absalom AR, Struys MMRF. Obesity and allometric scaling of pharmacokinetics. Clin Pharmacokinet. 2011;50:751–753.
    1. Snell O. Die Abhängigkeit des Hirngewichtes von dem Körpergewicht und den geistigen Fähigkeiten. Arch Psychiatr Nervenkr. 1892;23:436–446.
    1. Huxley JS, Needham J, Lerner IM. Terminology of relative growth-rates. Nature. 1941;148:225.
    1. Wang C, Allegaert K, Peeters MYM, Tibboel D, Danhof M, Knibbe CAJ. The allometric exponent for scaling clearance varies with age: a study on seven propofol datasets ranging from preterm neonates to adults. Br J Clin Pharmacol. 2014;77:149–159.
    1. Eleveld DJ, Colin P, Absalom AR, Struys MMRF. Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation. Br J Anaesth. 2018;120(5):942–959.
    1. Eleveld DJ, Proost JH, Vereecke H, Absalom AR, Olofsen E, Vuyk J, et al. An allometric model of remifentanil pharmacokinetics and pharmacodynamics. Anesthesiology. 2017;126:1005–1018.
    1. West GB, et al. A general model for the origin of allometric scaling laws in biology. Science. 1997;276:122–126.
    1. Proost J. Pharmacokinetic-pharmacodynamic modelling of anesthetic drugs. In: Absalom AR, Mason KP, editors. Total intravenous anesthesia and target controlled infusions. Cham: Springer International Publishing; 2017.
    1. Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth. 1991;67:41–48.
    1. Schnider TW, Minto CF, Gambus PL, Andresen C, Goodale DB, Shafer SL, et al. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology. 1998;88:1170–1182.
    1. Absalom AR, Mani V, De Smet T, Struys MMRF. Pharmacokinetic models for propofol: defining and illuminating the devil in the detail. Br J Anaesth. 2009;103:26–37.
    1. De Baerdemaeker LEC, Mortier EP, Struys MMRF. Pharmacokinetics in obese patients. Contin Educ Anaesth Crit Care Pain. 2004;4:152–155.
    1. Cortínez LI, Anderson BJ, Penna A, Olivares L, Munoz HR, Holford NHG, et al. Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model. Br J Anaesth. 2010;105:448–456.
    1. van Kralingen S, Diepstraten J, Peeters MYM, Deneer VHM, van Ramshorst B, Wiezer RJ, et al. Population pharmacokinetics and pharmacodynamics of propofol in morbidly obese patients. Clin Pharmacokinet. 2011;50:739–750.
    1. Cortínez LI, De la Fuente N, Eleveld DJ, Oliveros A, Crovari F, Sepúlveda P, et al. Performance of propofol target-controlled infusion models in the obese: pharmacokinetic and pharmacodynamic analysis. Anesth Analg. 2014;119:302–310.
    1. Eleveld DJ, Proost JH, Cortínez LI, Absalom AR, Struys MMRF. A general purpose pharmacokinetic model for propofol. Anesth Analg. 2014;118:1221–1237.
    1. Absalom AR. “Paedfusor” pharmacokinetic data set. Br J Anaesth. 2005;95:110.
    1. Kataria BK, Ved SA, Nicodemus HF, Hoy GR, Lea D, Dubois MY, et al. The pharmacokinetics of propofol in children using three different data analysis approaches. Anesthesiology. 1994;80:104–122.
    1. Short TG, Aun CS, Tan P, Wong J, Tam YH, Oh TE. A prospective evaluation of pharmacokinetic model controlled infusion of propofol in paediatric patients. Br J Anaesth. 1994;72:302–306.
    1. Sepúlveda P, Cortínez LI, Sáez C, Penna A, Solari S, Guerra I, et al. Performance evaluation of paediatric propofol pharmacokinetic models in healthy young children. Br J Anaesth. 2011;107:593–600.
    1. Hara M, Masui K, Eleveld DJ, Struys MMRF, Uchida O. Predictive performance of eleven pharmacokinetic models for propofol infusion in children for long-duration anaesthesia. Br J Anaesth. 2017;118:415–423.
    1. Knibbe CAJ, Zuideveld KP, Aarts LPHJ, Kuks PFM, Danhof M. Allometric relationships between the pharmacokinetics of propofol in rats, children and adults. Br J Clin Pharmacol. 2005;59:705–711.
    1. Hoymork SC, Raeder J, Grimsmo B, Steen PA. Bispectral index, serum drug concentrations and emergence associated with individually adjusted target-controlled infusions of remifentanil and propofol for laparoscopic surgery. Br J Anaesth. 2003;91:773–780.
    1. Jones H, Rowland-Yeo K. Basic concepts in physiologically based pharmacokinetic modeling in drug discovery and development. CPT Pharmacomet Syst Pharmacol. 2013;2:e63.
    1. Masui K, Kira M, Kazama T, Hagihira S, Mortier EP, Struys MMRF. Early phase pharmacokinetics but not pharmacodynamics are influenced by propofol infusion rate. Anesthesiology. 2009;111:805–817.
    1. Upton RN, Ludbrook GL, Grant C, Martinez AM. Cardiac output is a determinant of the initial concentrations of propofol after short-infusion administration. Anesth Analg. 1999;89:545–552.
    1. Masui K, Upton RN, Doufas AG, Coetzee JF, Kazama T, Mortier EP, et al. The performance of compartmental and physiologically based recirculatory pharmacokinetic models for propofol. Anesth Analg. 2010;111:368–379.
    1. Upton RN, Ludbrook G. The performance of compartmental and physiologically based recirculatory pharmacokinetic models for propofol: a comparison using bolus, continuous, and target-controlled infusion data. Anesthesiology. 2005;103:344–352.
    1. Rudolph U, Antkowiak B. Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci. 2004;5:709–720.
    1. Sieghart W. Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev. 1995;47:181–234.
    1. Bormann J. The, “ABC” of GABA receptors. Trends Pharmacol Sci. 2000;21:16–19.
    1. Adapa RM. Consiousness and anesthesia. In: Absalom AR, Mason KP, editors. Total intravenous anesthesia and target controlled infusions. Cham: Springer International Publishing; 2017. pp. 63–78.
    1. Moruzzi G, Magoun HW. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol. 1949;1:455–473.
    1. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state switching. Neuron. 2010;68:1023–1042.
    1. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001;24:726–731.
    1. Leung LS, Luo T, Ma J, Herrick I. Brain areas that influence general anesthesia. Prog Neurobiol. 2014;122:24–44.
    1. Fiset P, Paus T, Daloze T, Plourde G, Meuret P, Bonhomme V, et al. Brain mechanisms of propofol-induced loss of consciousness in humans: a positron emission tomographic study. J Neurosci. 1999;19:5506–5513.
    1. Mashour GA, Alkire MT. Consciousness, anesthesia, and the thalamocortical system. Anesthesiology. 2013;118:13–15.
    1. Detsch O, Vahle-Hinz C, Kochs E, Siemers M, Bromm B. Isoflurane induces dose-dependent changes of thalamic somatosensory information transfer. Brain Res. 1999;829:77–89.
    1. Velly LJ, Rey MF, Bruder NJ, Gouvitsos FA, Witjas T, Regis JM, et al. Differential dynamic of action on cortical and subcortical structures of anesthetic agents during induction of anesthesia. Anesthesiology. 2007;107:202–212.
    1. Alkire MT, Haier RJ, Fallon JH. Toward a unified theory of narcosis: brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness. Conscious Cogn. 2000;9:370–386.
    1. Brown EN, Lydic R, Schiff ND. General anesthesia, sleep, and coma. N Engl J Med. 2010;363:2638–2650.
    1. Kaisti KK, Langsjo JW, Aalto S, Oikonen V, Sipila H, Teras M, et al. Effects of sevoflurane, propofol and adjunct nitrous oxide on regional cerebral blood flow, oxygen consumption, and blood volume in humans. Anesthesiology. 2003;99:603–613.
    1. Boly M, Perlbarg V, Marrelec G, Schabus M, Laureys S, Doyon J, et al. Hierarchical clustering of brain activity during human nonrapid eye movement sleep. Proc Natl Acad Sci USA. 2012;109:5856–5861.
    1. Ferrarelli F, Massimini M, Sarasso S, Casali A, Riedner BA, Angelini G, et al. Breakdown in cortical effective connectivity during midazolam-induced loss of consciousness. Proc Natl Acad Sci USA. 2010;107:2681–2686.
    1. Massimini M, Ferrarelli F, Huber R, Esser SK, Singh H, Tononi G. Breakdown of cortical effective connectivity during sleep. Science. 2005;309:2228–2232.
    1. Tononi G. An information integration theory of consciousness. BMC Neurosci. 2004;5:42.
    1. Nordström O, Sandin R. Recall during intermittent propofol anaesthesia. Br J Anaesth. 1996;76:699–701.
    1. Andrade J, Deeprose C. Unconscious memory formation during anaesthesia. Best Pract Res Clin Anaesthesiol. 2007;21:385–401.
    1. Veselis RA, Pryor KO, Reinsel RA, Mehta M, Pan H, Johnson R. Low-dose propofol-induced amnesia is not due to a failure of encoding: left inferior prefrontal cortex is still active. Anesthesiology. 2008;109:213–224.
    1. Kurt M, Bilge SS, Kukula O, Celik S, Kesim Y. Anxiolytic-like profile of propofol, a general anesthetic, in the plus-maze test in mice. Pol J Pharmacol. 2003;55:973–977.
    1. Smith I, Monk TG, White PF, Ding Y. Propofol infusion during regional anesthesia: sedative, amnestic, and anxiolytic properties. Anesth Analg. 1994;79:313–319.
    1. Ure RW, Dwyer SJ, Blogg CE, White AP. Patient-controlled anxiolysis with propofol. Br J Anaesth. 1991;67:857P–858P.
    1. Matsuo M, Ayuse T, Oi K, Kataoka Y. Propofol produces anticonflict action by inhibiting 5-HT release in rat dorsal hippocampus. NeuroReport. 1997;8:3087–3090.
    1. Volke V, Kõks S, Vasar E, Bourin M, Bradwejn J, Männistö PT. Inhibition of nitric oxide synthase causes anxiolytic-like behaviour in an elevated plus-maze. NeuroReport. 1995;6:1413–1416.
    1. Zacny JP, Coalson DW, Young CJ, Klafta JM, Lichtor JL, Rupani G, et al. Propofol at conscious sedation doses produces mild analgesia to cold pressor-induced pain in healthy volunteers. J Clin Anesth. 1996;8:469–474.
    1. Anker-Moller E, Spangsberg N, Arendt-Nielsen L, Schultz P, Krinstensen M, Bjerring P. Subhypnotic doses of thiopentone and propofol cause analgesia to experimentally induced acute pain. Br J Anaesth. 1991;66:185–188.
    1. Nadeson R, Goodchild CS. Antinociceptive properties of propofol: involvement of spinal cord gamma-aminobutyric acid(A) receptors. J Pharmacol Exp Ther. 1997;282:1181–1186.
    1. Jewett BA, Gibbs LM, Tarasiuk A, Kendig JJ. Propofol and barbiturate depression of spinal nociceptive neurotransmission. Anesthesiology. 1992;77:1148–1154.
    1. Nishiyama T, Matsukawa T, Hanaoka K. Intrathecal propofol has analgesic effects on inflammation-induced pain in rats. Can J Anaesth. 2004;51:899–904.
    1. Peng K, Liu H-Y, Wu S-R, Liu H, Zhang Z-C, Ji F-H. Does propofol anesthesia lead to less postoperative pain compared with inhalational anesthesia? A systematic review and meta-analysis. Anesth Analg. 2016;123:846–858.
    1. Borgeat A, Stirnemann HR. Antiemetische Wirkung von propofol. Anaesthesist. 1998;47:918–924.
    1. Sneyd JR, Carr A, Byrom WD, Bilski AJ. A meta-analysis of nausea and vomiting following maintenance of anaesthesia with propofol or inhalational agents. Eur J Anaesthesiol. 1998;15:433–445.
    1. Reddi KK. Nature and possible origin of human serum ribonuclease. Biochem Biophys Res Commun. 1975;67:110–118.
    1. CAVAZZUTI M., PORRO C.A., BARBIERI A., GALETTI A. BRAIN AND SPINAL CORD METABOLIC ACTIVITY DURING PROPOFOL ANAESTHESIA. British Journal of Anaesthesia. 1991;66(4):490–495.
    1. Strebel S, Lam AM, Matta B, Mayberg TS, Aaslid R, Newell DW. Dynamic and static cerebral autoregulation during isoflurane, desflurane, and propofol anesthesia. Anesthesiology. 1995;83:66–76.
    1. Fox J, Gelb AW, Enns J, Murkin JM, Farrar JK, Manninen PH. The responsiveness of cerebral blood flow to changes in arterial carbon dioxide is maintained during propofol-nitrous oxide anesthesia in humans. Anesthesiology. 1992;77:453–456.
    1. Kotani Y, Nakajima Y, Hasegawa T, Satoh M, Nagase H, Shimazawa M, et al. Propofol exerts greater neuroprotection with disodium edetate than without it. J Cereb Blood Flow Metab. 2008;28:354–366.
    1. Fan W, Zhu X, Wu L, Wu Z, Li D, Huang F, et al. Propofol: an anesthetic possessing neuroprotective effects. Eur Rev Med Pharmacol Sci. 2015;19:1520–1529.
    1. Sneyd JR. Excitatory events associated with propofol anaesthesia: a review. J R Soc Med. 1992;85:288–291.
    1. Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology. 1998;89:980–1002.
    1. Samra SK, Sneyd JR, Ross DA, Henry TR. Effects of propofol sedation on seizures and intracranially recorded epileptiform activity in patients with partial epilepsy. Anesthesiology. 1995;82:843–851.
    1. Hug CC, McLeskey CH, Nahrwold ML, Roizen MF, Stanley TH, Thisted RA, et al. Hemodynamic effects of propofol: data from over 25,000 patients. Anesth Analg. 1993;77:S21–S29.
    1. Ebert TJ. Sympathetic and hemodynamic effects of moderate and deep sedation with propofol in humans. Anesthesiology. 2005;103:20–24.
    1. Sprung J, Ogletree-Hughes ML, McConnell BK, Zakhary DR, Smolsky SM, Moravec CS. The effects of propofol on the contractility of failing and nonfailing human heart muscles. Anesth Analg. 2001;93:550–559.
    1. Kazama T, Ikeda K, Morita K, Kikura M, Doi M, Ikeda T, et al. Comparison of the effect-site k(eO)s of propofol for blood pressure and EEG bispectral index in elderly and younger patients. Anesthesiology. 1999;90:1517–1527.
    1. Xia Z, Godin DV, Ansley DM. Application of high-dose propofol during ischemia improves postischemic function of rat hearts: effects on tissue antioxidant capacity. Can J Physiol Pharmacol. 2004;82:919–926.
    1. Li F, Yuan Y. Meta-analysis of the cardioprotective effect of sevoflurane versus propofol during cardiac surgery. BMC Anesthesiol. 2015;15:128.
    1. Huang Zhiyong, Zhong Xingwu, Irwin Michael G., Ji Shangyi, Wong Gordon T., Liu Yanan, Xia Zhong-yuan, Finegan Barry A., Xia Zhengyuan. Synergy of isoflurane preconditioning and propofol postconditioning reduces myocardial reperfusion injury in patients. Clinical Science. 2011;121(2):57–69.
    1. Nieuwenhuijs D, Sarton E, Teppema L, Dahan A. Propofol for monitored anesthesia care: implications on hypoxic control of cardiorespiratory responses. Anesthesiology. 2000;92:46–54.
    1. Nieuwenhuijs D, Sarton E, Teppema LJ, Kruyt E, Olievier I, van Kleef J, et al. Respiratory sites of action of propofol: absence of depression of peripheral chemoreflex loop by low-dose propofol. Anesthesiology. 2001;95:889–895.
    1. Jonsson MM, Lindahl SGE, Eriksson LI. Effect of propofol on carotid body chemosensitivity and cholinergic chemotransduction. Anesthesiology. 2005;102:110–116.
    1. Yamakage M, Kamada Y, Toriyabe M, Honma Y, Namiki A. Changes in respiratory pattern and arterial blood gases during sedation with propofol or midazolam in spinal anesthesia. J Clin Anesth. 1999;11:375–379.
    1. McKeating K, Bali IM, Dundee JW. The effects of thiopentone and propofol on upper airway integrity. Anaesthesia. 1988;43:638–640.
    1. Kabara S, Hirota K, Hashiba E, Yoshioka H, Kudo T, Sato T, et al. Comparison of relaxant effects of propofol on methacholine-induced bronchoconstriction in dogs with and without vagotomy. Br J Anaesth. 2001;86:249–253.
    1. Nakayama M, Murray PA. Ketamine preserves and propofol potentiates hypoxic pulmonary vasoconstriction compared with the conscious state in chronically instrumented dogs. Anesthesiology. 1999;91:760–771.
    1. Meierhenrich R, Gauss A, Mühling B, Bracht H, Radermacher P, Georgieff M, et al. The effect of propofol and desflurane anaesthesia on human hepatic blood flow: a pilot study. Anaesthesia. 2010;65:1085–1093.
    1. Latte D. Demeure, Bernard J.-M., Blanloeil Y., Peltier P., Francois T., Chatal J.-F. Induction of anaesthesia by propofol and hepatic blood flow in the rabbit. Clinical Physiology. 1995;15(5):515–522.
    1. Zhu Tao, Pang Qiying, McCluskey Stuart A., Luo Chaozhi. Effect of propofol on hepatic blood flow and oxygen balance in rabbits. Canadian Journal of Anesthesia/Journal canadien d'anesthésie. 2008;55(6):364–370.
    1. Wouters Patrick F., Van de Velde Marc A., Marcus Marco A. E., Deruyter Hendrik A., Van Aken Hugo. Hemodynamic Changes During Induction of Anesthesia with Eltanolone and Propofol in Dogs. Anesthesia & Analgesia. 1995;81(1):125–131.
    1. Palanca BJ, Mashour GA, Avidan MS. Processed electroencephalogram in depth of anesthesia monitoring. Curr Opin Anaesthesiol. 2009;22:553–559.
    1. Bruhn J, Myles PS, Sneyd R, Struys MMRF. Depth of anaesthesia monitoring: what’s available, what’s validated and what’s next? Br J Anaesth. 2006;97:85–94.
    1. Sahinovic MM, Eleveld DJ, Miyabe-Nishiwaki T, Struys MMRF, Absalom AR. Pharmacokinetics and pharmacodynamics of propofol: changes in patients with frontal brain tumours. Br J Anaesth. 2017;118:901–909.
    1. Schnider TW, Minto CF, Shafer SL, Gambus PL, Andresen C, Goodale DB, et al. The influence of age on propofol pharmacodynamics. Anesthesiology. 1999;90:1502–1516.
    1. Billard V, Gambus PL, Chamoun N, Stanski DR, Shafer SL. A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect. Clin Pharmacol Ther. 1997;61:45–58.
    1. Seo JH, Goo EK, Song IA, Park SH, Park HP, Jeon YT, et al. Influence of a modified propofol equilibration rate constant (k(e0)) on the effect-site concentration at loss and recovery of consciousness with the Marsh model. Anaesthesia. 2013;68:1232–1238.
    1. Sahinovic MM, Absalom AR, Struys MMRF. Administration and monitoring of intravenous anesthetics. Curr Opin Anaesthesiol. 2010;23:734–740.
    1. van den Berg JP, Vereecke HEM, Proost JH, Eleveld DJ, Wietasch JKG, Absalom AR, et al. Pharmacokinetic and pharmacodynamic interactions in anaesthesia. A review of current knowledge and how it can be used to optimize anaesthetic drug administration. Br J Anaesth. 2017;118:44–57.
    1. Michaels MR, Stauffer GL, Haas DP. Propofol compatibility with other intravenous drug products: two new methods of evaluating IV emulsion compatibility. Ann Pharmacother. 1996;30:228–232.
    1. Schmidt S, Gonzalez D, Derendorf H. Significance of protein binding in pharmacokinetics and pharmacodynamics. J Pharm Sci. 2010;99:1107–1122.
    1. Wilson ES, McKinlay S, Crawford JM, Robb HM. The influence of esmolol on the dose of propofol required for induction of anaesthesia. Anaesthesia. 2004;59:122–126.
    1. Vuyk J. Pharmacokinetic and pharmacodynamic interactions between opioids and propofol. J Clin Anesth. 1997;9:23S–26S.
    1. Perry S, Whelan E, Shay S, Wood A, Wppd M. Effect if I.V. anesthesia with propofol on drug distribution and metabolism in the dog. Br J Anaesth. 1991;66:66–72.
    1. Friedericy HJ, Bovill JG. The role of the cytochrome P450 system in drug interactions in anaesthesia. Baillieres Clin Anaesthesiol. 1998;12:213–228.
    1. Vuyk J, Mertens MJ, Olofsen E, Burm AG, Bovill JG. Propofol anesthesia and rational opioid selection: determination of optimal EC50-EC95 propofol-opioid concentrations that assure adequate anesthesia and a rapid return of consciousness. Anesthesiology. 1997;87:1549–1562.
    1. Le Guellec C, Lacarelle B, Villard PH, Point H, Catalin J, Durand A. Glucuronidation of propofol in microsomal fractions from various tissues and species including humans: effect of different drugs. Anesth Analg. 1995;81:855–861.
    1. Berenbaum MC. What is synergy? Pharmacol Rev. 1989;41:93–141.
    1. Minto CF, Schnider TW, Short TG, Gregg KM, Gentilini A, Shafer SL. Response surface model for anesthetic drug interactions. Anesthesiology. 2000;92:1603–1616.
    1. Short TG, Plummer JL, Chui PT. Hypnotic and anaesthetic interactions between midazolam, propofol and alfentanil. Br J Anaesth. 1992;69:162–167.
    1. Short TG, Chui PT. Propofol and midazolam act synergistically in combination. Br J Anaesth. 1991;67:539–545.
    1. Fidler M, Kern SE. Flexible interaction model for complex interactions of multiple anesthetics. Anesthesiology. 2006;105:286–296.
    1. Vinik HR, Bradley EL, Kissin I. Triple anesthetic combination: propofol-midazolam-alfentanil. Anesth Analg. 1994;78:354–358.
    1. Wilder-Smith OH, Ravussin P, Decosterd L, Despland P, Bissonnette B. Midazolam premedication reduces propofol dose requirements for multiple anesthetic endpoints. Can J Anaesth. 2001;48:439–445.
    1. McClune S, McKay AC, Wright PM, Patterson CC, Clarke RS. Synergistic interaction between midazolam and propofol. Br J Anaesth. 1992;69:240–245.
    1. Lichtenbelt BJ, Olofsen E, Dahan A, van Kleef JW, Struys MMRF, Vuyk J. Propofol reduces the distribution and clearance of midazolam. Anesth Analg. 2010;110:1597–1606.
    1. Dutta S, Karol MD, Cohen T, Jones RM, Mant T. Effect of dexmedetomidine on propofol requirements in healthy subjects. J Pharm Sci. 2001;90:172–181.
    1. Peden CJ, Cloote AH, Stratford N, Prys-Roberts C. The effect of intravenous dexmedetomidine premedication on the dose requirement of propofol to induce loss of consciousness in patients receiving alfentanil. Anaesthesia. 2001;56:408–413.
    1. Jang Y-E, Kim Y-C, Yoon H-K, Jeon Y-T, Hwang J-W, Kim E, et al. A randomized controlled trial of the effect of preoperative dexmedetomidine on the half maximal effective concentration of propofol for successful i-gel insertion without muscle relaxants. J Anesth. 2015;29:338–345.
    1. Hammer GB, Sam WJ, Chen MI, Golianu B, Drover DR. Determination of the pharmacodynamic interaction of propofol and dexmedetomidine during esophagogastroduodenoscopy in children. Paediatr Anaesth. 2009;19:138–144.
    1. Ngwenyama NE, Anderson J, Hoernschemeyer DG, Tobias JD. Effects of dexmedetomidine on propofol and remifentanil infusion rates during total intravenous anesthesia for spine surgery in adolescents. Paediatr Anaesth. 2008;18:1190–1195.
    1. Ohtani N, Kida K, Shoji K, Yasui Y, Masaki E. Recovery profiles from dexmedetomidine as a general anesthetic adjuvant in patients undergoing lower abdominal surgery. Anesth Analg. 2008;107:1871–1874.
    1. Coppens MJ, Versichelen LFM, Mortier EP. Struys MMRF. Do we need inhaled anaesthetics to blunt arousal, haemodynamic responses to intubation after i.v. induction with propofol, remifentanil, rocuronium? Br J Anaesth. 2006;97:835–841.
    1. Diz JC, Del Río R, Lamas A, Mendoza M, Durán M, Ferreira LM. Analysis of pharmacodynamic interaction of sevoflurane and propofol on Bispectral Index during general anaesthesia using a response surface model. Br J Anaesth. 2010;104:733–739.
    1. Harris RS, Lazar O, Johansen JW, Sebel PS. Interaction of propofol and sevoflurane on loss of consciousness and movement to skin incision during general anesthesia. Anesthesiology. 2006;104:1170–1175.
    1. Schumacher PM, Dossche J, Mortier EP, Luginbuehl M, Bouillon TW, Struys MMRF. Response surface modeling of the interaction between propofol and sevoflurane. Anesthesiology. 2009;111:790–804.
    1. Sebel LE, Richardson JE, Singh SP, Bell SV, Jenkins A. Additive effects of sevoflurane and propofol on gamma-aminobutyric acid receptor function. Anesthesiology. 2006;104:1176–1183.
    1. Kazama T, Ikeda K, Morita K. Reduction by fentanyl of the Cp50 values of propofol and hemodynamic responses to various noxious stimuli. Anesthesiology. 1997;87:213–227.
    1. Smith Chris, McEwan Angus I., Jhaveri Rajiv, Wilkinson Michael, Goodman David, Smith L. Richard, Canada Andrew T., Glass Peter S. A. The Interaction of Fentanyl on the Cp50 of Propofol for Loss of Consciousness and Skin Incision. Anesthesiology. 1994;81(4):820–828.
    1. Schraag S, Mohl U, Bothner U, Georgieff M. Interaction modeling of propofol and sufentanil on loss of consciousness. J Clin Anesth. 1999;11:391–396.
    1. Hentgen E, Houfani M, Billard V, Capron F, Ropars J-M, Travagli JP. Propofol-sufentanil anesthesia for thyroid surgery: optimal concentrations for hemodynamic and electroencephalogram stability, and recovery features. Anesth Analg. 2002;95:597–605.
    1. Bouillon TW, Bruhn J, Radulescu L, Andresen C, Shafer TJ, Cohane C, et al. Pharmacodynamic interaction between propofol and remifentanil regarding hypnosis, tolerance of laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:1353–1372.
    1. Kern SE, Xie G, White JL, Egan TD. A response surface analysis of propofol-remifentanil pharmacodynamic interaction in volunteers. Anesthesiology. 2004;100:1373–1381.
    1. Kuizenga MH, Vereecke HEM, Struys MMRF. Model-based drug administration. Curr Opin Anaesthesiol. 2016;29:475–481.
    1. Saint-Maurice C, Cockshott ID, Douglas EJ, Ricjard MO, Harmey JL. Pharmacokinetics of propofol in young children after a single dose. Br J Anaesth. 1989;63:667–670.
    1. White M, Kenny GNC. Intravenous propofol anaesthesia using a computerised infusion system. Anaesthesia. 1990;45:204–209.
    1. Cox EH, Knibbe CAJ, Koster VS, Langemeijer MWE, Tukker EE, Lange R, et al. Influence of different fat emulsion-based intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol. Pharm Res. 1998;15:442–448.
    1. Knibbe CAJ, Melenhorst-de Jong G, Mestrom M, Rademaker CMA, Reijnvaan AFA, Zuideveld KP, et al. Pharmacokinetics and effects of propofol 6% for short-term sedation in paediatric patients following cardiac surgery. Br J Clin Pharmacol. 2002;54:415–422.
    1. Knibbe CA, Aarts LP, Kuks PF, Voortman HJ, Lie-A-Huen L, Bras LJ, et al. Pharmacokinetics and pharmacodynamics of propofol 6% SAZN versus propofol 1% SAZN and Diprivan-10 for short-term sedation following coronary artery bypass surgery. Eur J Clin Pharmacol. 2000;56:89–95.
    1. Knibbe CAJ, Zuideveld KP, DeJongh J, Kuks PFM, Aarts LPHJ, Danhof M. Population pharmacokinetic and pharmacodynamic modeling of propofol for long-term sedation in critically ill patients: a comparison between propofol 6% and propofol 1% Clin Pharmacol Ther. 2002;72:670–684.
    1. Servin F, Farinotti R, Haberer JP, Desmonts JM. Propofol infusion for maintenance of anesthesia in morbidly obese patients receiving nitrous oxide. A clinical and pharmacokinetic study. Anesthesiology. 1993;78:657–665.

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