Propofol Injection: MedlinePlus Drug Information

The amnestic properties of propofol have been extensively described in the literature . Local inactivation of wakefulness-promoting areas, such as locus coeruleus and dorsal raphe, enhance anaesthesia, while local activation of various other wakefulness-promoting areas, including pontis oralis and centromedial thalamus, facilitate emergence from anaesthesia. In recent years, cognitive neuroscience has seen a resurgence of interest in this topic, with attempts to integrate anaesthesia and sleep research in order to address this deficiency. This even potentially enables them to predict the influence of the effect of changing haemodynamic parameters on drug disposition. This fact is also consistent with the observations of clinical practitioners. The volume of V2 declines with age, while V3 and metabolic clearance decline only when other medication are concurrently administered.

• Since a small number of case reports of anaphylactic and anaphylactoid reactions have been published, the Diprivan® package insert also advises against Diprivan® use in patients with allergies to eggs, egg products, soy beans or soy products .
• In order to mathematically delineate the interaction between different drugs, their combined effectiveness to reach a certain clinically relevant endpoint is assessed.
• You are encouraged to report negative side effects of prescription drugs to the FDA.
• Propofol undergoes extensive PK and PD interactions with both other hypnotic drugs and opioids.

These differences influence the range of patients to which the different models are applicable. Cortínez et al. have investigated the predictive performance of different PK models in obese patients and concluded that when models were implemented as published (i.e. using the TBW as a weight-scaling measure), the global performance of the Eleveld model was best compared with other models. Older propofol models, such 4rabet online as the Marsh and Schnider models, were developed from studies involving healthy adults with a limited range of weights. As indicated above, a benefit of the Schnider model over the Marsh model is that it adjusts the dose and infusion rate according to the patient’s age. Although numerous multicompartmental mammillary models exist, only two adult models are commonly used in clinical practice for target-controlled infusions (TCIs), namely the Marsh and Schnider models.

PD Interactions

A combination of inhaled anaesthetic preconditioning and propofol postconditioning appears to work synergistically in decreasing IRI . These cardioprotective effects are less profound than those caused by sevoflurane . Propofol cardioprotective effects in cardiac surgery is a focus of research. The negative inotropic effect is mediated through a concentration-dependent decrease in the uptake of Ca2+ into the sarcoplasmatic reticulum, which is simultaneously accompanied by an increase of myofilament sensitivity to Ca2+, partially counteracting the effect . Furthermore, propofol also inhibits the physiological baroreflex responses, thereby enhancing cardiovascular depression .

Sleep and anaesthesia studies have consistently demonstrated decreases in cortical activity and cerebral blood flow ; however, these changes are not homogeneous across the cortex and across different drugs. These nuclei are extensively affected by clinical concentrations of hypnotic drugs. Adaptations to the compartmental models using ‘administration lag time’ and presystemic compartments can improve the prediction accuracy , however only PBPK models use cardiac output and blood flow terms to more accurately describe the drug kinetics in greater detail. These difficulties have stimulated the development of unified PK models, which are derived from data collected in a diverse group of patients and clinical conditions, and are thus designed to provide accurate predictive performance well in a wide range of patients and clinical conditions. There are currently a number of propofol models specifically developed for obese patients, such as the Cortínez and van Kralingen models, or a general purpose model that is probably also suitable for use in the obese (the Eleveld allometric model) (see Table 1). Users attempting to use the Schnider model in severely obese patients must either change to a different model, enter a ‘false’ combination of parameters (i.e. a greater height or a lower weight in place of the TBW), or administer propofol by manually controlled infusion.

The most prominent effect is systemic blood pressure reduction accompanied by a decrease in cardiac output. On the other hand, the role of propofol as a potent treatment of status epilepticus has been well-established 127, 128. Propofol decreases cerebral blood flow, intracranial pressure, and cerebral metabolic rate, while maintaining dynamic and static autoregulation and vascular responsiveness to carbon dioxide . The antiemetic action of propofol is well known and has been extensively described 118, 119. This effect could be caused by an action of propofol at the spinal level. Explicit memory seems to be most affected, and in a dose-dependent manner.

Interactions with Hypnotic Drugs

Concomitant infusion with drugs competing for the same plasma binding sites, or use in patients with low plasma proteins, could potentially result in high unbound plasma propofol fraction, causing more profound effects and adverse effects. This dose should be adjusted (reduced) when propofol is administered to less-fit patients undergoing general anaesthesia, such as those fulfilling the ASA physical status categories ASA 3 or 4, or when propofol is used to induce and maintain sedation in critically ill patients in the ICU. It is well-described that propofol undergoes chemical interactions with a number of frequently used drugs, and should thus not be administered through the same intravenous line with these particular drugs. Several PD studies have been performed, with most of them using a sigmoidal Emax model to characterize the relationship between blood concentration, the concentration in a hypothetical effect site, and the resultant clinical drug effect. There are a number of patient studies describing the analgesic effects of subhypnotic doses of propofol 112, 113. Propofol interacts with numerous other drugs, including chloral hydrate, diazepam, fentanyl, and morphine; such interactions can increase the anesthetic and sedative effects of propofol, producing potentially dangerous effects, such as cardiorespiratory depression and slowing of heart rate.

The drug interactions listed above are not all of the possible interactions or adverse effects. An EEG study on patients undergoing general anesthesia with propofol found that it causes a prominent reduction in the brain’s information integration capacity. There is considerable variability in a patient’s response to propofol, at times showing profound sedation with small doses. The most well-known PK/PD models for propofol have already been discussed earlier in this article. Administration of intravenous hypnotic drugs brings some unique challenges compared with volatile anaesthetics.

This resurgence has revealed several brain areas that play a crucial role in generation of consciousness, and which are extensively influenced by hypnotic drugs. Lastly, they reported a higher metabolic clearance in women (of all ages) compared with men, which might explain clinical observations of a more rapid emergence from propofol anaesthesia in women compared with men . This finding confirms an impression widely shared by practicing anaesthetists that the maintenance infusion rates required for adequate anaesthesia are reduced in older individuals, especially when comedication is administered. In the updated version of the model, the authors used PK data derived from 30 previously published studies containing data collected from children of all ages, adults, obese adults, and elderly individuals. In 2005, Knibbe and colleagues published an interspecies PK model for propofol, which was a two-compartment model applicable in rats, children and adults.

Propofol is also used for monitored anesthesia care (MAC), also known as procedural sedation or conscious sedation, and to sedate mechanically ventilated ICU patients. This potentially lethal metabolic derangement has been reported in critically ill patients after a prolonged infusion of high-dose propofol, sometimes in combination with catecholamines and/or corticosteroids. One of the reasons propofol is thought to be more effective (although it has a longer half-life than lorazepam) is that studies have found that benzodiazepines like midazolam and lorazepam tend to accumulate in critically ill patients, prolonging sedation. Its interaction with propofol has been extensively studied in regard to multiple clinical endpoints, and it showed a supra-additive interaction with propofol in regard to hypnotic and analgesic endpoints. This is more pronounced for analgesic drug effects (e.g. loss of response to noxious stimuli) than for hypnotic clinical endpoints, such as loss of responsiveness to verbal commands . As with midazolam, a clear interaction model has yet to be developed and a well-designed interaction study needs to be performed, preferably using accurate PK models such as the Eleveld model for propofol and the Hannivoort model for dexmedetomidine .

Most propofol formulations cause pain on injection, which is thought to be due to direct and indirect irritation of venous adventitia by free aqueous propofol through an interaction with TRPV1 and TRPA1 receptors 15, 16. Other adverse effects are cardiovascular (bradycardia, hypotension) and metabolic (hyperlipidaemia secondary to infusion of lipid formulation) . The adverse effects of propofol are well-documented, with the most common being pain on injection. Rapid and smooth induction with nearly no excitation phenomena, relatively short context-sensitive time, rapid terminal half-life time and low incidence of postoperative nausea and vomiting (PONV) make it a very versatile hypnotic drug. Propofol (2,6-diisopropylphenol) is a potent intravenous hypnotic drug that was developed by Imperial Chemical Industries Limited (London, UK), patented by John (Iain) Glen and Roger James in 1977 , and commercially launched in 1986 in Europe and 1989 in the US . 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.