Review
Propofol: A review of its non-anaesthetic effects

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Abstract

Propofol, a short-acting intravenous anaesthetic agent has gained wide acceptance since its introduction in the late 80s, not only in operating rooms but also in other departments, due to its several advantages. Apart from its multiple anaesthetic advantages, it has been reported recently that propofol exerts a number of non-anaesthetic effects. The drug stimulates constitutive nitric oxide (NO) production and inhibits inducible NO production. Propofol has also anxiolytic properties, which may be related to several neuromediator systems. Moreover, it has antioxidant, immunomodulatory, analgesic, antiemetic and neuroprotective effects. Furthermore, propofol inhibits both platelet aggregation and intracellular calcium increases in response to thrombin or ADP and it also exerts direct inhibitory effects on recombinant cardiac sarcolemmal KATP channels. All these beneficial properties may expand propofol's clinical use.

Introduction

Propofol (2, 6-disopropylphenol) is an intravenous short-acting anaesthetic agent that, since its introduction in the late 80s has gained wide acceptance for inducing and maintaining anaesthesia, as well as for sedation. The drug exerts many notable advantages such as minimal side effects, controllable anaesthetic state, quick onset and rapid emergence from general anaesthesia (Glen, 1980, Glen and Hunter, 1984).

Apart from its multiple anaesthetic advantages, propofol exerts a number of non-anaesthetic effects. Ιntravenous anaesthesia with propofol alone seems to be associated with a lower incidence of postoperative nausea and vomiting (Dandoy et al., 1990, Jost et al., 1997, McCollum et al., 1988). Furthermore, it has immunomodulatory activity (Hokey et al., 2005), and may, therefore have an ability to enhance cytotoxic T lymphocyte activity against several types of human tumors. Moreover, propofol acts as a modulator of gamma-aminobutyric acid (GABA A) receptors and experimental studies suggest that propofol's facilitation of these receptors might contribute to analgesia (Dong and Xu, 2002). At doses that do not produce sedation, propofol has anxiolytic effects (Kurt et al., 2003), is a potent antioxidant (Mathy-Hartert et al., 2000) and can lead to memory impairment, especially for memories that are encoded and retrieved by the episodic memory system (Veselis et al., 2008). In addition, in vivo and in vitro studies have revealed propofol's neuro-protective properties (Engelhard et al., 2004, Gelb et al., 2002;). Furthermore, propofol is a modulator of platelet aggregation, (Aoki et al., 1998, Hirakata et al., 1999) NO synthesis (Gonzalez-Correa et al., 2008) and may preserve the endogenous organ protective mechanisms against ischemic or hypoxic injury through its effects on KATP channels. These effects are summarized in Table 1, Table 2, Table 3.

In this review, the experimental and clinical data regarding the commonest non-anaesthetic effects of the intravenous anaesthetic propofol along with the underlying mechanisms are presented. Possible clinical implications are also discussed.

Section snippets

Propofol's antiemetic effects

Numerous studies have demonstrated that propofol possesses direct antiemetic effects. Its use for induction and maintenance of anaesthesia has been associated with a lower incidence of postoperative nausea and vomiting (Dandoy et al., 1990, Jost et al., 1997, McCollum et al., 1988). Borgeat and Stirnemann confirmed that propofol's antiemetic actions really exist (Borgeat and Stirnemann, 1998). Furthermore, they demonstrated that total propofol anaesthesia leads to less postoperative nausea and

Propofol and immunity

Several studies have reported the effects of propofol on cytokine production. In critically ill patients propofol increased serum levels of IL-1β, IL-6 and tumor necrosis factor-α. Additionally, propofol leads to a decrease in IL-2 levels, whereas those of IFN-γ increase as well as in vivo as in vitro (Helmy and Al-Attiyah, 2001, Salo et al., 1997). IFN-γ mediates the differentiation of helper T cells into Th1 lymphocytes, which activate cytotoxic T lymphocyte. Since cytotoxic T lymphocyte is

Propofol and analgesia

Propofol acts as a modulator of GABAA and glycine receptors, which also exist in the spinal cord and have a crucial role in pain transmission (Hales and Lambert, 1991, Millan, 1999, Xu, 1999) and propofol's effect on these receptors might contribute to analgesia (Dong and Xu, 2002). Propofol acts on these receptors, though on a different recognition site from the barbiturates and benzodiazepines, but unlike barbiturates, potentiates glycinergic transmission (Hales and Lambert, 1991) and may

Anxiolytic-like profile of propofol

The effects of propofol on anxiety have not been well investigated. Some experimental studies have demonstrated that propofol produces an anxiolytic effect in animal models (Hara et al., 1993, Matsuo et al., 1997). Kurt et al. reported in a study conducted in mice thatpropofol at 40 and 60 mg/kg can produce anxiolytic-like effects when administrated, both alone or with diazepam, caffeine, l-arginine or m-chlorophenylpiperazine (Kurt et al., 2003). None of the drugs in this study had an effect

Propofol protection during oxidative stress

Propofol's structure contains a phenolic hydroxyl group and thus resembles that of a-tocopherol (vitamin E), a natural antioxidant. As shown by both in vitro and in vivo studies, the antioxidant activity of propofol results partly from this phenolic chemical structure (Ansley et al., 1998). Propofol has been reported to inhibit lipid peroxidation in various experimental models to protect cells against oxidative stress and to increase the antioxidant capacity of plasma in humans (Hans et al.,

Propofol and amnesia

Propofol has been reported to cause dense amnesia, even for intense events (Nordstrom and Sandin, 1996). More vulnerable to propofol's action seem to be memories that are encoded and retrieved by the episodic memory system, whose pivotal component is the hippocampus (Deeprose et al., 2004, Tulving, 2001). Veselis et al. demonstrated that propofol at low doses (0.3, 1.2 or 2.5 μg/mL) had no effect on working memory, which is defined as a short term retention of information no longer available in

Propofol as neuroprotective agent

Propofol has proved to be an efficacious neuroprotective agent in several in vivo and in vitro models of cerebral ischemia (Engelhard et al., 2004, Gelb et al., 2002, Pittman et al., 1997). Although, initial studies with propofol and cerebral ischemia at first yielded contradictory results due to unconventional in vivo models of cerebral ischemia, like those of Kochs et al. (1992) and Tsai et al. (1994), the studies that followed were consistent with the neuroprotective effects of propofol (

Effects of propofol on platelet aggregation

Lysophosphatic acid (LPA) (Nietgen and Durieux, 1998), platelet-activating factor (PAF) (Imaizumi et al., 1995) and thromboxane A2 (TXA2) (Bulger and Maier, 2000) are proinflammatory lipid mediators that are secreted by activated platelets and induce their aggregation. Propofol has been reported to inhibit an LPA receptor response in a Xenopus oocyte model (Rossi et al., 1996). Moreover, it has been reported that propofol has inhibitory effects on platelet aggregation induced by adenosine

Effects of propofol on nitric oxide pathway

Nitric oxide (NO) synthesis requires the participation of nitric oxide synthase (NOS), present in two isoforms: constitutive (cNOS), which is calcium-dependent, and inducible (iNOS), expressed mainly by the presence of inflammatory mediators (Knowles and Moncada, 1994). Propofol has been reported to stimulate NO activities. Moreover, the direct participation of the enzyme NOS, is a fundamental point regarding NO synthesis. It can therefore be suggested that propofol modifies the activity of

Effects of propofol on cardiac sarcolemmal KATP

KATP channels exist in the plasma membranes of various tissues. In cardiac muscle cells, under normal physiologic conditions, KATP channels exist mainly in a closed, inactive form (Noma, 1983). In cardiomyocytes activation of sarcolemmal adenosine triphosphate-sensitive potassium (KATP) channels protects the heart against myocardial ischemia by shortening the duration of the cardiac action (Suzuki et al., 2001). It has been demonstrated that during myocardial ischemia the opening of KATP

Conclusion

In summary propofol is a short-acting intravenous anaesthetic agent that has several advantages, including rapid onset, swift emergence with few side effects and a favorably safety profile. It is obvious that the several nonanaesthetic effects that propofol exerts can substantially change the every day use of propofol and may expand its pharmacological and clinical use. However, more experience and data are needed with nonanaesthetic use of propofol and these characteristics should be further

References (123)

  • GlenJ.B. et al.

    Pharmacology of an emulsion formulation of ICI 35 868

    Br. J. Anaesth.

    (1984)
  • HandleyS.L.

    5-Hydroxytryptamine pathways in anxiety and its treatment

    Pharmacol. Ther.

    (1995)
  • IijimaT. et al.

    Neuroprotective effect of propofol on necrosis and apoptosis following oxygen–glucose deprivation—relationship between mitochondrial membrane potential and mode of death

    Brain Res.

    (2006)
  • IshiiH. et al.

    Effects of propofol on lactate accumulation and oedema formation in focal cerebral ischaemia in hyperglycaemic rats

    Br. J. Anaesth.

    (2002)
  • KarahalilB. et al.

    Diazepam and propofol used as anaesthetics during open-heart surgery do not cause chromosomal aberrations in peripheral blood lymphocytes

    Mutat. Res.

    (2005)
  • KudohA. et al.

    Plasma inflammatory cytokine response to surgical trauma in chronic depressed patients

    Cytokine

    (2001)
  • LambertD.G. et al.

    Muscarinic receptor subtypes: do they have a place in clinical anaesthesia?

    Br. J. Anaesth.

    (1995)
  • LascolaC. et al.

    Astroglial acid–base dynamics in hyperglycemic and normoglycemic global ischemia

    Neurosci. Biobehav. Rev.

    (1997)
  • MillanM.J.

    The induction of pain: an integrative review

    Prog. Neurobiol.

    (1999)
  • MinamiM. et al.

    Pharmacological aspects of anticancer drug-induced emesis with emphasis on serotonin release and vagal nerve activity

    Pharmacol. Ther.

    (2003)
  • NordstromO. et al.

    Recall during intermittent propofol anaesthesia

    Br. J. Anaesth.

    (1996)
  • SalemM.L.

    Systemic treatment with n−6 polyunsaturated fatty acids attenuates EL4 thymoma growth and metastasis through enhancing specific and non-specific anti-tumor cytolytic activities and production of TH1 cytokines

    Int. Immunopharmacol.

    (2005)
  • AcquavivaR. et al.

    Propofol attenuates peroxynitrite-mediated DNA damage and apoptosis in cultured astrocytes: an alternative protective mechanism

    Anesthesiology

    (2004)
  • AdembriC. et al.

    Neuroprotective effects of propofol in models of cerebral ischemia: inhibition of mitochondrial swelling as a possible mechanism

    Anesthesiology

    (2006)
  • AlkireM.T. et al.

    Lesions of the basolateral amygdala complex block propofol-induced amnesia for inhibitory avoidance learning in rats

    Anesthesiology

    (2001)
  • AnsleyD.M. et al.

    Propofol enhances red cell antioxidant capacity in swine and humans

    Can. J. Anaesth.

    (1998)
  • AokiH. et al.

    In vivo and in vitro studies of the inhibitory effect of propofol on human platelet aggregation

    Anesthesiology

    (1998)
  • AppaduB.L. et al.

    Does propofol interact with D2 dopamine receptors?

    Anaesth. Analg.

    (1994)
  • BagdyG. et al.

    Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635

    Int. J. Neuropsychopharmacol.

    (2001)
  • BarannM. et al.

    Inhibition by anaesthetics of 14C-guanidinium flux through the voltage-gated sodium channel and the cation channel of the 5-HT3 receptor of N1E-115 neuroblastoma cells

    Naunyn-Schmiedeberg's Arch. Pharmacol.

    (1993)
  • BarannM. et al.

    Molecular actions of propofol on human 5-HT3A receptors: enhancement as well as inhibition by closely related phenol derivatives

    Anesth. Analg.

    (2008)
  • BevenseeM.O. et al.

    Intracellular pH regulation in cultured astrocytes from rat hippocampus. I. Role Of HCO3

    J. Gen. Physiol.

    (1997)
  • BorgeatA.

    Subhypnotic doses of propofol do not possess antidopaminergic properties

    Anaesth. Analg.

    (1997)
  • BorgeatA. et al.

    [Antiemetic effect of propofol]

    Anaesthesist

    (1998)
  • BorgeatA. et al.

    Propofol and spontaneous movements: an EEG study

    Anesthesiology

    (1991)
  • BorgeatA. et al.

    The nonhypnotic therapeutic applications of propofol

    Anesthesiology

    (1994)
  • BulgerE.M. et al.

    Lipid mediators in the pathophysiology of critical illness

    Crit. Care Med.

    (2000)
  • ChangH.R. et al.

    Expression of disialogangliosides GD2 and GD3 on human soft tissue sarcomas

    Cancer

    (1992)
  • CockshottI.D.

    Propofol (‘Diprivan’) pharmacokinetics and metabolism—an overview

    Postgrad. Med. J.

    (1985)
  • CostallB. et al.

    5-HT3 receptors

    Curr. Drug Targets CNS Neurol. Disord.

    (2004)
  • CromheeckeS. et al.

    Cardioprotective properties of sevoflurane in patients undergoing aortic valve replacement with cardiopulmonary bypass

    Anaesth. Analg.

    (2006)
  • D'EspositoM. et al.

    Prefrontal cortical contributions to working memory: evidence from event-related fMRI studies. Experimental brain research

    Exp. Hirnforschung

    (2000)
  • DandoyM. et al.

    [Anaesthesia using propofol during surgery of strabismus in children. A comparison of two different protocols of induction and maintenance]

    Cah. Anesthésiol.

    (1990)
  • DaskalopoulosR. et al.

    Propofol protection of sodium-hydrogen exchange activity sustains glutamate uptake during oxidative stress

    Anesth. Analg.

    (2001)
  • De La CruzJ.P. et al.

    Antiplatelet effect of the anaesthetic drug propofol: influence of red blood cells and leucocytes

    Br. J. Pharmacol.

    (1999)
  • DeloguG. et al.

    Plasma levels of IL-10 and nitric oxide under two different anaesthesia regimens

    Eur. J. Anaesthesiol.

    (2005)
  • DongX.P. et al.

    The actions of propofol on gamma-aminobutyric acid-A and glycine receptors in acutely dissociated spinal dorsal horn neurons of the rat

    Anaesth. Analg.

    (2002)
  • EngelhardK. et al.

    Influence of propofol on neuronal damage and apoptotic factors after incomplete cerebral ischemia and reperfusion in rats: a long-term observation

    Anesthesiology

    (2004)
  • ErgunR. et al.

    Neuroprotective effects of propofol following global cerebral ischemia in rats

    Neurosurg. Rev.

    (2002)
  • FeinerJ.R. et al.

    Mild hypothermia, but not propofol, is neuroprotective in organotypic hippocampal cultures

    Anaesth. Analg.

    (2005)

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